Chronic sulfasalazine treatment in mice induces system xc- - independent adverse effects

Despite ample evidence for the therapeutic potential of inhibition of the cystine/glutamate antiporter system x(c) (−) in neurological disorders and in cancer, none of the proposed inhibitors is selective. In this context, a lot of research has been performed using the EMA- and FDA-approved drug sulfasalazine (SAS). Even though this molecule is already on the market for decades as an anti-inflammatory drug, serious side effects due to its use have been reported. Whereas for the treatment of the main indications, SAS needs to be cleaved in the intestine into the anti-inflammatory compound mesalazine, it needs to reach the systemic circulation in its intact form to allow inhibition of system x(c) (−). The higher plasma levels of intact SAS (or its metabolites) might induce adverse effects, independent of its action on system x(c) (−). Some of these effects have however been attributed to system x(c) (−) inhibition, calling into question the safety of targeting system x(c) (−). In this study we chronically treated system x(c) (−) - deficient mice and their wildtype littermates with two different doses of SAS (160 mg/kg twice daily or 320 mg/kg once daily, i.p.) and studied some of the adverse effects that were previously reported. SAS had a negative impact on the survival rate, the body weight, the thermoregulation and/or stress reaction of mice of both genotypes, and thus independent of its inhibitory action on system x(c) (−). While SAS decreased the total distance travelled in the open-field test the first time the mice encountered the test, it did not influence this parameter on the long-term and it did not induce other behavioral changes such as anxiety- or depressive-like behavior. Finally, no major histological abnormalities were observed in the spinal cord. To conclude, we were unable to identify any undesirable system x(c) (−)-dependent effect of chronic administration of SAS

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Lateral Atlantoaxial Osteoarthritis: A Narrative Literature Review.

Lateral atlantoaxial osteoarthritis (AAOA), or C1-C2 lateral mass arthritis (LMA), is an unfamiliar degenerative cervical disease with a clinical presentation that markedly differs from subaxial spondylosis. The prevalence of LMA in the nonsurgical outpatient setting is 4%. Risk factors include age and occupation. The typical patient is between 50 and 90 years old, presents with upper cervical or occipital pain, has limited rotation, and has pain provocation during passive rotation to the affected side. Pain stems from degeneration of the lateral C1-C2 articulation and may be referred or radicular, through the greater occipital nerve. Although there is no consensus on diagnostic work-up, the disease is classically seen on the open-mouth odontoid radiograph. Computerized tomography, magnetic resonance imaging, bone scan, and diagnostic injections are also useful. Initial treatment is conservative, and upwards of two-thirds of LMA patients obtain lasting relief with noninvasive measures and injections. In patients with severe, recalcitrant pain, limited C1-C2 fusion offers satisfactory and reliable relief. The goals of this review article are to provide a synthesis of the literature on LMA, to offer a treatment approach to LMA, and to identify problems with the current state of knowledge on LMA

Relationship between initial opioid prescription size and likelihood of refill after spine surgery

BACKGROUND CONTEXT: Best practices in opioid prescribing after elective surgery have been developed for most surgical subspecialties, including spine. However, some percentage of patients will become chronic users. PURPOSE: This study aimed to determine the relationship between the size of initial opioid prescription after surgery for degenerative spinal disease and the likelihood of refills. STUDY DESIGN/SETTING: Retrospective case-control study. PATIENT SAMPLE: Opioid-naïve patients aged 18 to 64 undergoing elective spinal procedures (anterior cervical discectomy and fusion, posterior cervical fusion, lumbar decompression, and lumbar fusion) from 2010 to 2015 filling an initial perioperative prescription using insurance claims from Truven Health MarketScan (n=25,329). OUTCOME MEASURES: Functional measure: health-care utilization. Primary outcome was occurrence of an opioid refill within 30 postoperative days. METHODS: We used logistic regression to examine the probability of an additional refill by initial opioid prescription strength, adjusting for patient factors. RESULTS: About 26.3% of opioid-naïve patients obtained refills of their opioid prescriptions within 30 days of surgery. The likelihood of obtaining a refill was unchanged with the size of the initial perioperative prescription across procedure categories. Patient factors associated with increased likelihood of refills included age 30 to 39 years (odds ratio [OR] 1.137, p=.007, 95% confidence interval [CI] 1.072-1.249), female gender (OR 1.137, p\u3c.001, 95% CI 1.072-1.207), anxiety disorder (OR 1.141, p=.017, 95% CI 1.024-1.272), mood disorder (OR 1.109 p=.049, 95% CI 1.000-1.229), and history of alcohol/substance abuse (OR 1.445 p=.006, 95% CI 1.110-1.880). CONCLUSIONS: For opioid-naïve patients, surgeons can prescribe lower amounts of opioids after elective surgery for degenerative spinal disease without concern of increased need for refills

Sellar Atypical Teratoid/Rhabdoid Tumor Presenting with Subarachnoid and Intraventricular Hemorrhage

BACKGROUND: Atypical teratoid/rhabdoid tumors (ATRT) are uncommon malignancies of the central nervous system and are often difficult to distinguish radiographically and pathologically from other common tumors. We present the first case of sellar ATRT presenting with subarachnoid hemorrhage (SAH) and intraventricular hemorrhage (IVH). CASE DESCRIPTION: A 62-year-old woman, who had presented with symptoms of headache, diabetes insipidus, hypothyroidism, and seizures, was found to have a sellar tumor with hemorrhagic transformation. Surgical resection was performed. The pathological examination findings were consistent with ATRT. Despite early surgical intervention, she later died before starting craniospinal radiotherapy and chemotherapy. CONCLUSION: To the best of our knowledge, although known to present with intratumoral hemorrhage, to date, no cases of sellar ATRT have presented with SAH or IVH have been reported. Considering our finding that ATRT can present with SAH and IVH, establishing the correct diagnosis using radiographic imaging, gender, pathological findings, and molecular markers is paramount for speedy treatment and management

The Effect of Physical Therapy on Time to Discharge After Lumbar Interbody Fusion

BACKGROUND CONTEXT: With a lesser degree of tissue destruction and lower postoperative opiate burden, patients undergoing minimally-invasive spine surgery are primed to benefit from early mobilization, which can further enhance recovery and hasten rehabilitation after surgery. PURPOSE: To determine the role of physical therapy on earlier postoperative discharge after minimally-invasive transforaminal lumbar interbody fusion (TLIF). STUDY DESIGN/SETTING: Cohort study. PATIENT SAMPLE: All patients undergoing one- and two-level minimally-invasive TLIF for degenerative lumbar diseases were operated on by the senior author from January 1, 2016 until August 31, 2018. Demographic data, comorbidities, preoperative patient-reported outcomes (PROs), intraoperative parameters, and postoperative measures were abstracted from a prospectively maintained database, ie, Michigan Spine Surgery Improvement Collaborative (MSSIC). Data on ambulation were collected from the physical therapy notes. OUTCOME MEASURES: The primary outcome measure is postoperative length of acute care stay. Length of stay was divided into (1) discharge on postoperative day 1 (POD 1 cohort), (2) discharge on postoperative day 2 (POD 2 cohort), and (3) discharge on ≥3 postoperative days (POD ≥3 cohorts) to maintain three equal-time cohorts. METHODS: An ordinal logistic regression model was fitted to the data to estimate the effect of discharge on postoperative day 1 vs postoperative day 2 vs postoperative ≥ day 3. Anesthesiology (ASA) classification was used as a surrogate marker of comorbidity burden. RESULTS: Of the 90 patients, the day of first ambulation with physical therapy increased from a mean of 14.4 ± 9.6 hours after surgery in the POD 1 cohort, 19.2 ± 7.2 hours in the POD 2 cohort, to 24.0 ± 12.0 hours in the POD ≥3 cohort (p=0.009). Furthermore, mean distance ambulated upon first interaction with physical therapy decreased from 162.8 ± 127.5 feet in the POD 1 group, 111.2 ± 83.6 feet in the POD 2 group, to 58.7 ± 59.3 feet in the POD ≥3 group (p\u3c0.001). The three cohorts did not differ in baseline (preoperative) PROs: Oswestry Disability Index, EQ-5D, Numeric Rating Scale–Back Pain, and Numeric Rating Scale–Leg Pain. Following a multivariable ordinal logistical regression controlling for disposition to rehab over home (ORadj=6.07, p=0.029), the odds of longer length of stay decreased by 35% for every 50-feet ambulated (p=0.014). Preoperative Oswestry Disability Index failed to predict day of discharge (ORadj=1.01, p=0.146). CONCLUSIONS: Time to first ambulation with a therapist independently increases the odds of earlier discharge. Regardless of preoperative patient-reported outcomes, ambulation remains a stronger predictor of discharge. FDA DEVICE/DRUG STATUS: This abstract does not discuss or include any applicable devices or drugs

Systematic constellations of neurons are activated in lateral amygdala following Pavlovian fear conditioning

How memory is organized within neural networks is a fundamental question in neuroscience. We used Pavlovian fear conditioning to study the discrete organization patterns of neurons activated in an associative memory paradigm. In Pavlovian fear conditioning a neutral stimulus, such as an auditory tone, is temporally paired with an aversive unconditioned stimulus (US), such as a foot shock..

Validation of a System xc– Functional Assay in Cultured Astrocytes and Nervous Tissue Samples

Disruption of the glutamatergic homeostasis is commonly observed in neurological diseases and has been frequently correlated with the altered expression and/or function of astrocytic high-affinity glutamate transporters. There is, however, a growing interest for the role of the cystine-glutamate exchanger system xc– in controlling glutamate transmission. This exchanger is predominantly expressed in glial cells, especially in microglia and astrocytes, and its dysregulation has been documented in diverse neurological conditions. While most studies have focused on measuring the expression of its specific subunit xCT by RT-qPCR or by Western blotting, the activity of this exchanger in tissue samples remains poorly examined. Indeed, the reported use of sulfur- and carbon-radiolabeled cystine in uptake assays shows several drawbacks related to its short radioactive half-life and its relatively high cost. We here report on the elaborate validation of a method using tritiated glutamate as a substrate for the reversed transport mediated by system xc–. The uptake assay was validated in primary cultured astrocytes, in transfected cells as well as in crude synaptosomes obtained from fresh nervous tissue samples. Working in buffers containing defined concentrations of Na+, allowed us to differentiate the glutamate uptake supported by system xc– or by high-affinity glutamate transporters, as confirmed by using selective pharmacological inhibitors. The specificity was further demonstrated in primary astrocyte cultures from transgenic mice lacking xCT or in cell lines where xCT expression was genetically induced or reduced. As such, this assay appears to be a robust and cost-efficient solution to investigate the activity of this exchanger in physiological and pathological conditions. It also provides a reliable tool for the screening and characterization of new system xc– inhibitors which have been frequently cited as valuable drugs for nervous disorders and cancer