A microRNA or messenger RNA point of departure estimates an apical endpoint point of departure in a rat developmental toxicity model.

Traditional developmental toxicity testing practice examines fetal apical endpoints to identify a point of departure (POD) for risk assessment. A potential new testing paradigm involves deriving a POD from a comprehensive analysis of molecular-level change. Here, the rat ketoconazole endocrine-mediated developmental toxicity model was used to test the hypothesis that maternal epigenomic (miRNA) and transcriptomic (mRNA) PODs are similar to fetal apical endpoint PODs. Sprague-Dawley rats were exposed from gestation day (GD) 6-21 to 0, 0.063, 0.2, 0.63, 2, 6.3, 20, or 40 mg/kg/day ketoconazole. Dam systemic, liver, and placenta PODs, along with GD 21 fetal resorption, body weight, and skeletal apical PODs were derived using BMDS software. GD 21 dam liver and placenta miRNA and mRNA PODs were obtained using three methods: a novel individual molecule POD accumulation method, a first mode method, and a gene set method. Dam apical POD values ranged from 2.0 to 38.6 mg/kg/day; the lowest value was for placenta histopathology. Fetal apical POD values were 10.9-20.3 mg/kg/day; the lowest value was for fetal resorption. Dam liver miRNA and mRNA POD values were 0.34-0.69 mg/kg/day, and placenta miRNA and mRNA POD values were 2.53-6.83 mg/kg/day. Epigenomic and transcriptomic POD values were similar across liver and placenta. Deriving a molecular POD from dam liver or placenta was protective of a fetal apical POD. These data support the conclusion that a molecular POD can be used to estimate, or be protective of, a developmental toxicity apical POD.

A rat subchronic study transcriptional point of departure estimates a carcinogenicity study apical point of departure.

Considerations of human relevance and animal use are driving research to identify new approaches to inform risk assessment of chemicals and replace guideline-based rodent carcinogenicity tests. Here, the hypothesis was tested across four agrochemicals that 1) a rat 90-day transcriptome-based BEPOD is protective of a rat carcinogenicity study and 2) a subchronic liver or kidney BEPOD would approximate a cancer bioassay apical POD derived from other organs and a rat subchronic BEPOD would approximate a mouse cancer bioassay apical POD. Using RNA sequencing and BMDExpress software, liver and/or kidney BEPOD values were generated in male rats exposed for 90 days to either Triclopyr Acid, Pronamide, Sulfoxaflor, or Fenpicoxamid. BEPOD values were compared to benchmark dose-derived apical POD values generated from rat 90-day and rodent carcinogenicity studies. Across all four agrochemicals, findings showed that a rat 90-day study BEPOD approximated the most sensitive apical POD (within 10-fold) generated from the 90-day rat study and long-term rodent carcinogenicity studies. This study supports the conclusion that a subchronic transcriptome-based BEPOD could be utilized to estimate an apical POD within a risk-based approach of chronic toxicity and carcinogenicity agrochemical assessment, abrogating the need for time- and resource-intensive rodent carcinogenicity studies and minimizing animal testing.

Efficacy of beveled tip aspiration catheter in mechanical thrombectomy for acute ischemic stroke.

BACKGROUND: Direct aspiration thrombectomy techniques use large bore aspiration catheters for mechanical thrombectomy. Several aspiration catheters are now available. We report a bench top exploration of a novel beveled tip catheter and our experience in treating large vessel occlusions (LVOs) using next-generation aspiration catheters. METHODS: A retrospective analysis from a prospectively maintained database comparing the bevel shaped tip aspiration catheter versus non-beveled tip catheters was performed. Patient demographics, periprocedural metrics, and discharge and 90-day modified Rankin Scale (mRS) scores were collected. Patients were divided into two groups based on which aspiration catheter was used. RESULTS: Our data showed no significant difference in age, gender, IV tissue plasminogen activator administration, admission NIH Stroke Scale score, baseline mRS, or LVO location between the beveled tip and flat tip groups. With the beveled tip, Thrombolysis in Cerebral Infarction (TICI) 2C or better recanalization was more frequent overall (93.2% vs 74.2%, p=0.017), stent retriever usage was lower (9.1% vs 29%, p=0.024), and patients had lower mRS on discharge (median 3 vs 4, p<0.001) and at 90 days (median 2 vs 4, p=0.008). CONCLUSION: Patients who underwent mechanical thrombectomy with the beveled tip catheter had a higher proportion of TICI 2C or better and had a significantly lower mRS score on discharge and at 90 days.

Tantra and Modern Neurosciences: Is there any Correlation?

BACKGROUND AND AIMS: Many studies have conclusively proven that meditative techniques derived from the Indian systems of philosophy, meditation and ritual classified as "Tantra" can bring about sustained changes in the structure and function of the nervous system of practitioners. The aim of this study is to provide neuroscientists a framework through which to interpret Tantra, and thereby provide a foundation upon which future interdisciplinary study can be built. METHODS: We juxtapose Tantric concepts such as the subtle body, nadis and mantras with relevant neuroscientific findings. Our premise is that through sustained internalization of attention, Tantric practitioners were able to identify and document subtle changes in their field of awareness, which usually do not cross the threshold to come into our perception. RESULTS: The descriptions left by Tantric philosophers are often detailed and empirical, but they are about subjective phenomena, rather than external objects. They also focus on individual experiences, rather than the group-level analyses favored by modern medical science. CONCLUSION: Systematic exploration of Tantric texts can be of tremendous value in expanding our understanding of human beings' experiential reality, by enabling us to build bridges between first-person and third-person approaches to the nervous system. This may open up new avenues for cognitive enhancement and treating neurological diseases.

Dissemination of Information on Neutropenic Diet by Top US Cancer Centers: In-line with the Evidence?

Aim: The neutropenic diet is commonly prescribed to cancer patients with neutropenia with the goal of reducing infections. However, multiple randomized trials have proved no benefit with neutropenic diets compared to less restricted diets with regards to reducing infectious risk. We aimed to ascertain if top cancer centers recommended for or against the use of neutropenic diets on their official websites. Methods: We reviewed the websites of the top 20 hospitals in the 2017 US News Best Hospitals for Cancer©, and ascertained recommendations for neutropenic diet (for, against, equivocal, or not addressed). Results: Seven websites (35%) made recommendations for, four (20%) against, and nine (45%) did not address the neutropenic diet. Only five (25%) backed any of their recommendations with evidence (four against, one for), including two (10%) links to abstracts (both against), whereas seven mentioned the FDA safe food handling guidelines (non-exclusive). Type of recommendation made (for or against) did not depend on US News rank (top vs bottom 10; p = 1.00.). Conclusion: The neutropenic diet continues to be recommended on many (35%) websites of top US cancer centers, despite strong evidence against its use. The website content of major US cancer centers should be updated to better guide patients regarding neutropenic diets.

Galectin-3 and incident cognitive impairment in REGARDS, a cohort of blacks and whites.

INTRODUCTION: The relationship between serum galectin-3 and incident cognitive impairment was analyzed in the Reasons for Geographic and Racial Differences in Stroke study. METHODS: Baseline galectin-3 was measured in 455 cases of incident cognitive impairment and 546 controls. Galectin-3 was divided into quartiles based on the weighted distribution in the control group, and the first quartile was the referent. RESULTS: There was an increasing odds of cognitive impairment across quartiles of galectin-3 (odds ratios, 1.00 [0.68-1.46], 1.45 [1.01-2.10], and 1.58 [1.10-2.27] relative to the quartile 1; P trend = .003) in an unadjusted model, which persisted after adjusting for age, sex, and race (P = .004). Adjustment for cardiovascular risk factors greatly attenuated this association (odds ratios, 0.97 [0.60-1.57], 1.52 [0.94-2.46], and 1.27 [0.76-2.12]; P = .15). The association differed by diabetes status (P interaction, .007). Among nondiabetics (293 cases, 411 controls), those with galectin-3 in the fourth compared with first quartile had an odds ratio of 1.6 (0.95-2.99; P trend, .02). In diabetics, the odds ratio was 0.23 (0.04-1.33). DISCUSSION: Serum galectin-3 was associated with increased risk of incident cognitive impairment in a large cohort study of blacks and whites but only in nondiabetics.

Admission Systolic Blood Pressure Predicts the Number of Blood Pressure Medications at Discharge in Patients With Primary Intracerebral Hemorrhage.

BACKGROUND: Control of systolic blood pressure (SBP) after primary intracerebral hemorrhage improves outcomes. Factors determining the number of blood pressure medications (BPM) required for goal SBP<160 mm Hg at discharge are unknown. We hypothesized that higher admission-SBPs require a greater number of BPM for goal discharge-SBP<160 mm Hg, and investigated factors influencing this goal. MATERIALS AND METHODS: We conducted a retrospective review of 288 patients who presented with primary intracerebral hemorrhage. Admission-SBP was obtained. Primary outcome was the number of BPM at discharge. Comparison was made between patients presenting with and without a history of hypertension, and patients discharged on <3 and ≥3 BPM. RESULTS: Patients with hypertension history had a higher median admission-SBP compared with those without (180 vs. 157 mm Hg, P=0.0001). In total, 133 of 288 (46.2%) patients were discharged on <3 BPM; 155/288 (53.8%) were discharged on ≥3 BPM. Hypertension history (P<0.0001) and admission-SBP (P<0.0001) predicted the number of BPM at discharge. In patients without hypertension history, every 10 mm Hg increase in SBP resulted in an absolute increase of 0.5 BPM at discharge (P=0.0011), whereas in those with hypertension, the absolute increase was 1.3 BPM (P=0.0012). In comparison with patients discharged on <3 BPM, patients discharged on ≥3 BPM were more likely to have a higher median admission-SBP, be younger in age, belong to the African-American race, have a history of diabetes, have higher median admission-National Institutes of Health Stroke Scale and modified Rankin Scale of 4 to 5 at discharge. CONCLUSIONS: An understanding of the factors influencing BPM at discharge may help clinicians better optimize blood pressure control both before and after discharge.

Comparison of Outcomes of Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Chronic Kidney Disease.

There are few data comparing outcomes of transcatheter aortic valve implantation (TAVI) with surgical aortic valve replacement (SAVR) in patients with chronic kidney disease. In this retrospective cohort study using the National Inpatient Sample 2011 to 2014, we included a total of 2,820 TAVI and 4,054 SAVR procedures, representative of 14,039 TAVI and 19,835 SAVR procedures nationally. Co-primary outcomes were in-hospital mortality, acute kidney injury (AKI), dialysis-requiring AKI, and postoperative stroke. In multivariate analysis, TAVI was associated with a lower in-hospital mortality (odds ratio [OR] 0.47, 95% confidence interval [CI] 0.32 to 0.69, p < 0.001), rates of AKI (OR 0.18, 95% CI 0.14 to 0.22, p < 0.001), dialysis-requiring AKI (OR 0.30, 95% CI 0.20 to 0.44, p < 0.001), and postoperative stroke (OR 0.27, 95% CI 0.13 to 0.53, p < 0.001) compared with SAVR. In 1001 propensity-matched pairs of TAVI and SAVR procedures, TAVI was associated with lower in-hospital mortality (OR 0.67, 95% CI 0.45 to 0.99, p = 0.047) rates of AKI (OR 0.39, 95% CI 0.32 to 0.46, p < 0.001), dialysis-requiring AKI (OR 0.53, 95% CI 0.35 to 0.81, p < 0.001), postoperative stroke (OR 0.46, 95% CI 0.20 to 0.98, p = 0.045), significantly shorter length of stay (OR 0.35, 95% CI 0.29 to 0.42, p < 0.001), and nonsignificant difference in cost (OR 1.05, 95% CI 0.88 to 1.26, p = 0.57) compared with SAVR. In conclusion, TAVI may be a preferable approach to SAVR in patients with severe aortic stenosis in the setting of chronic kidney disease.

Neurological effects of proprotein convertase subtilisin/kexin type 9 inhibitors: direct comparisons.

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably alter the lipid profile. We sought to examine the rates of ischaemic stroke and neurocognitive deficits in patients treated with and without PCSK9 inhibitors. Methods and results: Randomized controlled trials (RCTs) reporting rates of ischaemic stroke and neurocognitive deficits in patients using PCSK9 inhibitors were identified. Standard meta-analysis techniques were used to compare these outcomes among patients treated with and without PCSK9 inhibitors and the two US Food and Drug Administration-approved PCSK9 inhibitors, evolocumab and alirocumab. The results were presented in terms of risk ratio (RR) with 95% confidence intervals (CIs). Sixteen RCTs with 39 104 patients were included. Evolocumab was used in six RCTs with 33 450 patients, whereas alirocumab was used in 10 RCTs with 5654 patients. We observed a significantly lower risk of ischaemic stroke among those treated with PCSK9 inhibitors (RR 0.77, 95% CI 0.64-0.93) when compared with those without. We did not observe any difference in the risk of neurocognitive deficits between the aforementioned groups (RR 1.11, 95% CI 0.93-1.32). The lower stroke risk in the PCSK9 inhibitors group was driven by evolocumab studies. We observed no difference in the risk of neurocognitive deficits among evolocumab and alirocumab when compared with no PCSK9 inhibitors group. Conclusion: Treatment with PCSK9 inhibitors significantly lowers the risk of ischaemic stroke, without any increased risk of neurocognitive deficits. PCSK9 inhibitors are neuroprotective due to the decrease in ischaemic-mediated neurovascular events and should be considered cognitively innocuous medications.

Intra-arterial vasodilators for vasospasm following aneurysmal subarachnoid hemorrhage: a meta-analysis.

OBJECTIVE: The efficacy of intra-arterial vasodilators (IADs) for the treatment of vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) remains debatable. The objective of this meta-analysis was to pool estimates of angiographic and neurological response, clinical outcome, and mortality following treatment of vasospasm with IADs. METHODS: We searched PubMed, Embase, Scopus, Clinicaltrials.gov, Cochrane database, and CINAHL in December 2015 and August 2016. Studies reporting angiographic and neurological response, clinical outcome, and mortality following IAD treatment of vasospasm in 10 or more adults with aSAH were included. All established IADs were allowed. Two authors independently selected studies and abstracted the data. Mean weighted probabilities (MWP) were calculated using random effects model. RESULTS: Inclusion criteria were met by 55 studies (n=1571). MWP for immediate angiographic response to IAD treatment was 89% (95% CI 83% to 94%), post-IAD neurological improvement 57% (95% CI 49% to 65%), good outcome 66% (95% CI 60% to 71%), and mortality was 9% (95% CI 7% to 12%). After adjusting for publication bias, MWP for mortality was 5% (95% CI 4% to 7%). When transcranial Doppler (TCD) was used along with clinical deterioration for patient selection, rates of neurological response (64%) and good outcome (72%) were better. IADs were not superior to controls (balloon angioplasty or medical management). CONCLUSION: IAD treatment leads to a robust angiographic response and fair (but lower) rates of neurological response and good clinical outcome. Mortality was lower than the average reported in the literature. Rates of neurological response and good outcome were better when TCD was used for patient selection. Carefully designed studies are needed to compare IADs against medical management and balloon angioplasty.

The Brainstem in Emotion: A Review.

Emotions depend upon the integrated activity of neural networks that modulate arousal, autonomic function, motor control, and somatosensation. Brainstem nodes play critical roles in each of these networks, but prior studies of the neuroanatomic basis of emotion, particularly in the human neuropsychological literature, have mostly focused on the contributions of cortical rather than subcortical structures. Given the size and complexity of brainstem circuits, elucidating their structural and functional properties involves technical challenges. However, recent advances in neuroimaging have begun to accelerate research into the brainstem's role in emotion. In this review, we provide a conceptual framework for neuroscience, psychology and behavioral science researchers to study brainstem involvement in human emotions. The "emotional brainstem" is comprised of three major networks - Ascending, Descending and Modulatory. The Ascending network is composed chiefly of the spinothalamic tracts and their projections to brainstem nuclei, which transmit sensory information from the body to rostral structures. The Descending motor network is subdivided into medial projections from the reticular formation that modulate the gain of inputs impacting emotional salience, and lateral projections from the periaqueductal gray, hypothalamus and amygdala that activate characteristic emotional behaviors. Finally, the brainstem is home to a group of modulatory neurotransmitter pathways, such as those arising from the raphe nuclei (serotonergic), ventral tegmental area (dopaminergic) and locus coeruleus (noradrenergic), which form a Modulatory network that coordinates interactions between the Ascending and Descending networks. Integration of signaling within these three networks occurs at all levels of the brainstem, with progressively more complex forms of integration occurring in the hypothalamus and thalamus. These intermediary structures, in turn, provide input for the most complex integrations, which occur in the frontal, insular, cingulate and other regions of the cerebral cortex. Phylogenetically older brainstem networks inform the functioning of evolutionarily newer rostral regions, which in turn regulate and modulate the older structures. Via these bidirectional interactions, the human brainstem contributes to the evaluation of sensory information and triggers fixed-action pattern responses that together constitute the finely differentiated spectrum of possible emotions.

Clival Chordoma: Case Report and Review of Recent Developments in Surgical and Adjuvant Treatments.

Chordomas are rare tumors that can develop anywhere along the craniospinal axis. These tumors present challenges with respect to diagnosis and treatment due to a high rate of recurrence, even after multiple surgeries, and the propensity to involve any region within the craniospinal axis. New developments in radiation therapy have improved recurrence-free survival in patients with chordomas. Different regimens of chemotherapy and molecularly-targeted therapies, as adjuvants to surgery, have been described in individual case reports and case series. The purpose of this paper is to describe a case of clival chordoma and review recent developments in diagnostic and therapeutic options. A 77-year-old female was referred because of diplopia and progressively worsening headaches. Head imaging revealed a large expansile and erosive mass in the skull base. The patient underwent a successful endoscopic endonasal trans-sphenoidal resection of the mass, with biopsy confirming the diagnosis of chordoma. Postoperatively, the patient experienced an improvement in neurological symptoms. Chordomas can present a diagnostic challenge due to the rare occurrence and a tendency to involve any region within the craniospinal axis.

Perfusion MRI Can Impact Treatment Decision in Ictal-Interictal Continuum.

Lateralized periodic discharges (LPDs) are commonly seen on EEG in critically ill patients. They are often associated with seizures, but some patients may have them without seizures. Therefore, they are considered to lie in the ictal-interictal continuum. When ictal, they require multiple antiepileptic drugs to treat effectively, which can expose the patient to iatrogenic complications. Therefore, optimal management is controversial. We present here two cases where perfusion-weighted MRI was useful in distinguishing ictal from interictal LPDs. In the first patient, hyperperfusion in the area showing LPDs was considered an indication that the LPDs were ictal, and aggressive treatment led to clinical improvement. The second patient had no asymmetry on perfusion-weighted MRI, and therefore, we did not escalate antiepileptic therapy, and the LPDs resolved spontaneously over the next few days. Perfusion-weighted MRI offers several advantages over other techniques, such as single-photon emission computerized tomography that have been used for this purpose before. It does not expose the patient to radiation, and newer techniques like arterial spin labeling can even obviate the need for intravenous contrast. Larger scale studies using perfusion-weighted MRI will be of great value to clinical practice.

Paraneoplastic cerebellar degeneration with anti-Yo antibodies - a review.

The ataxic syndrome associated with Anti-Yo antibody, or Purkinje cell cytoplasmic antibody type 1 (PCA1), is the most common variant of paraneoplastic cerebellar degeneration (PCD). The typical presentation involves the subacute development of pancerebellar deficits with a clinical plateau within 6 months. The vast majority of cases have been reported in women with pelvic or breast tumors. Magnetic resonance imaging of the brain is often normal in the early stages, with cerebellar atrophy seen later. The underlying mechanism is believed to be an immunological reaction to cerebellar degeneration-related protein 2 (CDR2), a protein usually found in the cerebellum that is ectopically produced by tumor cells. Although both B- and T-cell abnormalities are seen, there is debate about the relative importance of the autoantibodies and cytotoxic T lymphocytes in the neuronal loss. Cerebrospinal fluid abnormalities, primarily elevated protein, lymphocytic pleocytosis, and oligoclonal bands, are common in the early stages. The low prevalence of this condition has not allowed for large-scale randomized controlled trials. Immunotherapies, such as steroids, intravenous immune globulins, and plasma exchange, have been extensively used in managing this condition, with limited success. Although some reports indicate benefit from antitumor therapies like surgery and chemotherapy, this has not been consistently observed. The prognosis for anti-Yo PCD is almost uniformly poor, with most patients left bedridden. Further studies are required to clarify the pathophysiology and provide evidence-based treatment options.