Transient Receptor Potential Melastatin 7 (TRPM7) Ion Channel Inhibitors: Preliminary SAR and Conformational Studies of Xenicane Diterpenoids from the Hawaiian Soft Coral Sarcothelia edmondsoni.

Waixenicin A, a xenicane diterpene from the octocoral Sarcothelia edmondsoni, is a selective, potent inhibitor of the TRPM7 ion channel. To study the structure-activity relationship (SAR) of waixenicin A, we isolated and assayed related diterpenes from S. edmondsoni. In addition to known waixenicins A (1) and B (2), we purified six xenicane diterpenes, 7S,8S-epoxywaixenicins A (3) and B (4), 12-deacetylwaixenicin A (5), waixenicin E (6), waixenicin F (7), and 20-acetoxyxeniafaraunol B (8). We elucidated the structures of 3-8 by NMR and MS analyses. Compounds 1, 2, 3, 4, and 6 inhibited TRPM7 activity in a cell-based assay, while 5, 7, and 8 were inactive. A preliminary SAR emerged showing that alterations to the nine-membered ring of 1 did not reduce activity, while the 12-acetoxy group, in combination with the dihydropyran, appears to be necessary for TRPM7 inhibition. The bioactive compounds are proposed to be latent electrophiles by formation of a conjugated oxocarbenium ion intermediate. Whole-cell patch-clamp experiments demonstrated that waixenicin A inhibition is irreversible, consistent with a covalent inhibitor, and showed nanomolar potency for waixenicin B (2). Conformational analysis (DFT) of 1, 3, 7, and 8 revealed insights into the conformation of waixenicin A and congeners and provided information regarding the stabilization of the proposed pharmacophore.

Performance of Automated RAPID Intracranial Hemorrhage Detection in Real-World Practice: A Single-Institution Experience.

BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) is a common finding in patients presenting to the emergency department with acute neurological symptoms. Noncontrast head computed tomography (NCCT) is the primary modality for assessment and detection of ICH in the acute setting. RAPID ICH software aims to automatically detect ICH on NCCT and was previously shown to have high accuracy when applied to a curated test data set. Here, we measured the test performance characteristics of RAPID ICH software in detecting ICH on NCCT performed in patients undergoing emergency stroke evaluation at a tertiary academic comprehensive stroke center. MATERIALS AND METHODS: This retrospective study assessed consecutive patients over a 6-month period who presented with acute neurological symptoms suspicious for stroke and underwent NCCT with RAPID ICH postprocessing. RAPID ICH detection was compared with the interpretation of a reference standard comprising a board-certified or board-eligible neuroradiologist, or in cases of discrepancy, adjudicated by a consensus panel of 3 neuroradiologists. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RAPID ICH for ICH detection were determined. RESULTS: Three hundred seven NCCT scans were included in the study. RAPID ICH correctly identified 34 of 37 cases with ICH and 228 of 270 without ICH. RAPID ICH had a sensitivity of 91.9% (78.1%-98.3%), specificity of 84.4% (79.6%-88.6%), NPV of 98.7% (96.3%-99.6%), PPV of 44.7% (37.6%-52.1%), and overall accuracy of 85.3% (80.9%-89.1%). CONCLUSIONS: In a real-world scenario, RAPID ICH software demonstrated high NPV but low PPV for the presence of ICH when evaluating possible stroke patients.

Can Tumor Location on Pre-treatment MRI Predict Likelihood of Pseudo-Progression vs. Tumor Recurrence in Glioblastoma?-A Feasibility Study.

A significant challenge in Glioblastoma (GBM) management is identifying pseudo-progression (PsP), a benign radiation-induced effect, from tumor recurrence, on routine imaging following conventional treatment. Previous studies have linked tumor lobar presence and laterality to GBM outcomes, suggesting that disease etiology and progression in GBM may be impacted by tumor location. Hence, in this feasibility study, we seek to investigate the following question: Can tumor location on treatment-naïve MRI provide early cues regarding likelihood of a patient developing pseudo-progression vs. tumor recurrence? In this study, 74 pre-treatment Glioblastoma MRI scans with PsP (33) and tumor recurrence (41) were analyzed. First, enhancing lesion on Gd-T1w MRI and peri-lesional hyperintensities on T2w/FLAIR were segmented by experts and then registered to a brain atlas. Using patients from the two phenotypes, we construct two atlases by quantifying frequency of occurrence of enhancing lesion and peri-lesion hyperintensities, by averaging voxel intensities across the population. Analysis of differential involvement was then performed to compute voxel-wise significant differences (p-value < 0.05) across the atlases. Statistically significant clusters were finally mapped to a structural atlas to provide anatomic localization of their location. Our results demonstrate that patients with tumor recurrence showed prominence of their initial tumor in the parietal lobe, while patients with PsP showed a multi-focal distribution of the initial tumor in the frontal and temporal lobes, insula, and putamen. These preliminary results suggest that lateralization of pre-treatment lesions toward certain anatomical areas of the brain may allow to provide early cues regarding assessing likelihood of occurrence of pseudo-progression from tumor recurrence on MRI scans.

Organic carbon budget for the eastern boundary of the North Atlantic subtropical gyre: major role of DOC in mesopelagic respiration.

Transports of suspended particulate (POCsusp) and dissolved (DOC) organic carbon are inferred from a box-model covering the eastern boundary of the North Atlantic subtropical gyre. Corresponding net respiration rates (R) are obtained from a net organic carbon budget that is based on the transport estimates, and includes both vertical and lateral fluxes. The overall R in the mesopelagic layer (100-1500 m) is 1.6 ± 0.4 mmol C m-2 d-1. DOC accounts for up to 53% of R as a result of drawdown of organic carbon within Eastern North Atlantic Central Water (ENACW) that is entrained into sinking Mediterranean Overflow Water (MOW) that leads to formation of Mediterranean water (MW) at intermediate depths (~900 m). DOC represents 90% of the respired non-sinking organic carbon. When converted into oxygen units, the computed net respiration rate represents less than half the oxygen utilization rates (OUR) reported for the mesopelagic waters of the subtropical North Atlantic. Mesoscale processes in the area, not quantified with our approach, could account in part for the OUR differences observed between our carbon budget and other published studies from the North Atlantic, although seasonal or interannual variability could also be responsible for the difference in the estimates.

Air-blocking ablation of osteoid osteoma; a technical note.

Osteoid osteoma accounts for approximately 10-12% of all benign bone tumors. Surgery was the treatment of choice for osteoid osteomas until percutaneous radiofrequency ablation (RFA) was introduced in 1992. Although RFA is generally considered curative in the treatment of osteoid osteoma, disease recurrence after ablation has been reported. We report a case in which RFA was delayed by the presence air surrounding the ablation probe. In this case, ablation could only be performed after the probe was removed and saline was injected through the introducer needle to displace the air. Air is reported to decrease radiofrequency energy transmission; a simple measure like injecting saline through an introducer could prevent such a complication. We also suggest that partial air in the ablation bed surrounding the ablation probe could decrease the energy transmission and may be one of the causes of early recurrences. Saline injection could be helpful in providing a more reliable environment for ablation.

Implementation of the 2013 Psychoactive Substances Act and mental health harms from synthetic cannabinoids.

AIMS: Use of synthetic cannabinoids is associated with a range of mental health harms. The 2013 Psychoactive Substances Act (PSA) was intended to limit retail availability of synthetic cannabinoids which had acceptable safety profiles. We evaluated numbers and clinical characteristics of patients presenting with mental health harms associated with use of synthetic cannabinoids for three months before and after implementation of the PSA on 18July 2013. METHODS: Retrospective audit of case notes of patients presenting to an emergency psychiatric service (EPS) in Dunedin. RESULTS: In the three months post-PSA, there was a 42% reduction in EPS contacts and 52% reduction in patient presentations, compared with the three months pre-PSA. Patient demographics (predominantly young males with prior contact with mental health services), presenting symptoms (mood and psychotic symptoms and suicidality), and management and disposition were identical in both periods. CONCLUSIONS: The decrease in mental health harms, as measured by frequency of EPS contacts, appeared to be due to reduced retail availability of synthetic cannabinoids rather that reduced toxicity of available products.

Carbon dynamics within cyclonic eddies: insights from a biomarker study.

It is generally assumed that episodic nutrient pulses by cyclonic eddies into surface waters support a significant fraction of the primary production in subtropical low-nutrient environments in the northern hemisphere. However, contradictory results related to the influence of eddies on particulate organic carbon (POC) export have been reported. As a step toward understanding the complex mechanisms that control export of material within eddies, we present here results from a sediment trap mooring deployed within the path of cyclonic eddies generated near the Canary Islands over a 1.5-year period. We find that, during summer and autumn (when surface stratification is stronger, eddies are more intense, and a relative enrichment in CaCO3 forming organisms occurs), POC export to the deep ocean was 2-4 times higher than observed for the rest of the year. On the contrary, during winter and spring (when mixing is strongest and the seasonal phytoplankton bloom occurs), no significant enhancement of POC export associated with eddies was observed. Our biomarker results suggest that a large fraction of the material exported from surface waters during the late-winter bloom is either recycled in the mesopelagic zone or bypassed by migrant zooplankton to the deep scattering layer, where it would disaggregate to smaller particles or be excreted as dissolved organic carbon. Cyclonic eddies, however, would enhance carbon export below 1000 m depth during the summer stratification period, when eddies are more intense and frequent, highlighting the important role of eddies and their different biological communities on the regional carbon cycle.