Colony stimulating factor-1 producing endothelial cells and mesenchymal stromal cells maintain monocytes within a perivascular bone marrow niche.

Macrophage colony stimulating factor-1 (CSF-1) plays a critical role in maintaining myeloid lineage cells. However, congenital global deficiency of CSF-1 (Csf1op/op) causes severe musculoskeletal defects that may indirectly affect hematopoiesis. Indeed, we show here that osteolineage-derived Csf1 prevented developmental abnormalities but had no effect on monopoiesis in adulthood. However, ubiquitous deletion of Csf1 conditionally in adulthood decreased monocyte survival, differentiation, and migration, independent of its effects on bone development. Bone histology revealed that monocytes reside near sinusoidal endothelial cells (ECs) and leptin receptor (Lepr)-expressing perivascular mesenchymal stromal cells (MSCs). Targeted deletion of Csf1 from sinusoidal ECs selectively reduced Ly6C- monocytes, whereas combined depletion of Csf1 from ECs and MSCs further decreased Ly6Chi cells. Moreover, EC-derived CSF-1 facilitated recovery of Ly6C- monocytes and protected mice from weight loss following induction of polymicrobial sepsis. Thus, monocytes are supported by distinct cellular sources of CSF-1 within a perivascular BM niche.

Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth.

Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1(+) precursors and postnatally from bone marrow-derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche.

ARISE I Consensus Review on the Management of Intracranial Aneurysms.

BACKGROUND: Intracranial aneurysms (IAs) remain a challenging neurological diagnosis associated with significant morbidity and mortality. There is a plethora of microsurgical and endovascular techniques for the treatment of both ruptured and unruptured aneurysms. There is no definitive consensus as to the best treatment option for this cerebrovascular pathology. The Aneurysm, Arteriovenous Malformation, and Chronic Subdural Hematoma Roundtable Discussion With Industry and Stroke Experts discussed best practices and the most promising approaches to improve the management of brain aneurysms. METHODS: A group of experts from academia, industry, and federal regulators convened to discuss updated clinical trials, scientific research on preclinical system models, management options, screening and monitoring, and promising novel device technologies, aiming to improve the outcomes of patients with IA. RESULTS: Aneurysm, Arteriovenous Malformation, and Chronic Subdural Hematoma Roundtable Discussion With Industry and Stroke Experts suggested the incorporation of artificial intelligence to capture sequential aneurysm growth, identify predictors of rupture, and predict the risk of rupture to guide treatment options. The consensus strongly recommended nationwide systemic data collection of unruptured IA radiographic images for the analysis and development of machine learning algorithms for rupture risk. The consensus supported centers of excellence for preclinical multicenter trials in areas such as genetics, cellular composition, and radiogenomics. Optical coherence tomography and magnetic resonance imaging contrast-enhanced 3T vessel wall imaging are promising technologies; however, more data are needed to define their role in IA management. Ruptured aneurysms are best managed at large volume centers, which should include comprehensive patient management with expertise in microsurgery, endovascular surgery, neurology, and neurocritical care. CONCLUSIONS: Clinical and preclinical studies and scientific research on IA should engage high-volume centers and be conducted in multicenter collaborative efforts. The future of IA diagnosis and monitoring could be enhanced by the incorporation of artificial intelligence and national radiographic and biologic registries. A collaborative effort between academic centers, government regulators, and the device industry is paramount for the adequate management of IA and the advancement of the field.

Intrarenal pressure with hand-pump or pressurized-bag irrigation: randomized clinical trial at retrograde intrarenal surgery.

BACKGROUND: The aim was to ascertain the impact of irrigation technique on human intrarenal pressure during retrograde intrarenal surgery. METHODS: A parallel randomized trial recruited patients across three hospital sites. Patients undergoing retrograde intrarenal surgery for renal stone treatment with an 11/13-Fr ureteral access sheath were allocated randomly to 100 mmHg pressurized-bag (PB) or manual hand-pump (HP) irrigation. The primary outcome was mean procedural intrarenal pressure. Secondary outcomes included maximum intrarenal pressure, variance, visualization, HP force of usage, procedure duration, stone clearance, and clinical outcomes. Live intrarenal pressure monitoring was performed using a COMETTMII pressure guidewire, deployed cystoscopically to the renal pelvis. The operating team was blinded to the intrarenal pressure. RESULTS: Thirty-eight patients were randomized between July and November 2023 (trial closure). The final analysis included 34 patients (PB 16; HP 18). Compared with PB irrigation, HP irrigation resulted in significantly higher mean intrarenal pressure (mean(s.d.) 62.29(27.45) versus 38.16(16.84) mmHg; 95% c.i. for difference in means (MD) 7.97 to 40.29 mmHg; P = 0.005) and maximum intrarenal pressure (192.71(106.23) versus 68.04(24.16) mmHg; 95% c.i. for MD 70.76 to 178.59 mmHg; P < 0.001), along with greater variance in intrarenal pressure (log transformed) (6.23(1.59) versus 4.60(1.30); 95% c.i. for MD 0.62 to 2.66; P = 0.001). Surgeon satisfaction with procedural vision reported on a scale of 10 was higher with PB compared with HP irrigation (mean(s.d.) 8.75(0.58) versus 6.28(1.27); 95% c.i. for MD 1.79 to 3.16; P < 0.001). Subjective HP usage force did not correlate significantly with transmitted intrarenal pressure (Pearson R = -0.15, P = 0.57). One patient (HP arm) developed urosepsis. CONCLUSION: Manual HP irrigation resulted in higher and more fluctuant intrarenal pressure trace (with inferior visual clarity) than 100-mmHg PB irrigation. REGISTRATION NUMBER: osf.io/jmg2h (https://osf.io/).

A qualitative co-design-based approach to identify sources of workplace-related distress and develop well-being strategies for cardiovascular nurses, allied health professionals, and physicians.

OBJECTIVE: Clinician distress is a multidimensional condition that includes burnout, decreased meaning in work, severe fatigue, poor work-life integration, reduced quality of life, and suicidal ideation. It has negative impacts on patients, providers, and healthcare systems. In this three-phase qualitative investigation, we identified workplace-related factors that drive clinician distress and co-designed actionable interventions with inter-professional cardiovascular clinicians to decrease their distress and improve well-being within a Canadian quaternary hospital network. METHODS: Between October 2021 and May 2022, we invited nurses, allied health professionals, and physicians to participate in a three-phase qualitative investigation. Phases 1 and 2 included individual interviews and focus groups to identify workplace-related factors contributing to distress. Phase 3 involved co-design workshops that engaged inter-professional clinicians to develop interventions addressing drivers of distress identified. Qualitative information was analyzed using descriptive thematic analysis. RESULTS: Fifty-one clinicians (24 nurses, 10 allied health professionals, and 17 physicians) participated. Insights from Phases 1 and 2 identified five key thematic drivers of distress: inadequate support within inter-professional teams, decreased joy in work, unsustainable workloads, limited opportunities for learning and professional growth, and a lack of transparent leadership communication. Phase 3 co-design workshops yielded four actionable interventions to mitigate clinician distress in the workplace: re-designing daily safety huddles, formalizing a nursing coaching and mentorship program, creating a value-added program e-newsletter, and implementing an employee experience platform. CONCLUSION: This study increases our understanding on workplace-related factors that contribute to clinician distress, as shared by inter-professional clinicians specializing in cardiovascular care. Healthcare organizations can develop effective interventions to mitigate clinician distress by actively engaging healthcare workers in identifying workplace drivers of distress and collaboratively designing tailored, practical interventions that directly address these challenges.

Comparing the outcomes of open, laparoscopic and robot-assisted partial nephrectomy: a network meta-analysis.

OBJECTIVE: To perform a systematic review and network meta-analysis (NMA) to determine the advantages and disadvantages of open (OPN), laparoscopic (LPN), and robot-assisted partial nephrectomy (RAPN) with particular attention to intraoperative, immediate postoperative, as well as longer-term functional and oncological outcomes. METHODS: A systematic review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-NMA guidelines. Binary data were compared using odds ratios (ORs). Mean differences (MDs) were used for continuous variables. ORs and MDs were extracted from the articles to compare the efficacy of the various surgical approaches. Statistical validity is guaranteed when the 95% credible interval does not include 1. RESULTS: In total, there were 31 studies included in the NMA with a combined 7869 patients. Of these, 33.7% (2651/7869) underwent OPN, 20.8% (1636/7869) LPN, and 45.5% (3582/7689) RAPN. There was no difference for either LPN or RAPN as compared to OPN in ischaemia time, intraoperative complications, positive surgical margins, operative time or trifecta rate. The estimated blood loss (EBL), postoperative complications and length of stay were all significantly reduced in RAPN when compared with OPN. The outcomes of RAPN and LPN were largely similar except the significantly reduced EBL in RAPN. CONCLUSION: This systematic review and NMA suggests that RAPN is the preferable operative approach for patients undergoing surgery for lower-staged RCC.

In vivo ureteroscopic intrarenal pressures and clinical outcomes: a multi-institutional analysis of 120 consecutive patients.

OBJECTIVES: To evaluate the pressure range generated in the human renal collecting system during ureteroscopy (URS), in a large patient sample, and to investigate a relationship between intrarenal pressure (IRP) and outcome. PATIENTS AND METHODS: A prospective multi-institutional study was conducted, with ethics board approval; February 2022-March 2023. Recruitment was of 120 consecutive consenting adult patients undergoing semi-rigid URS and/or flexible ureterorenoscopy (FURS) for urolithiasis or diagnostic purposes. Retrograde, fluoroscopy-guided insertion of a 0.036-cm (0.014″) pressure guidewire (COMET™ II, Boston Scientific, Marlborough, MA, USA) to the renal pelvis was performed. Baseline and continuous ureteroscopic IRP was recorded, alongside relevant operative variables. A 30-day follow-up was completed. Descriptive statistics were applied to IRP traces, with mean (sd) and maximum values and variance reported. Relationships between IRP and technical variables, and IRP and clinical outcome were interrogated using the chi-square test and independent samples t-test. RESULTS: A total of 430 pressure traces were analysed from 120 patient episodes. The mean (sd) baseline IRP was 16.45 (5.99) mmHg and the intraoperative IRP varied by technique. The mean (sd) IRP during semi-rigid URS with gravity irrigation was 34.93 (11.66) mmHg. FURS resulted in variable IRP values: from a mean (sd) of 26.78 (5.84) mmHg (gravity irrigation; 12/14-F ureteric access sheath [UAS]) to 87.27 (66.85) mmHg (200 mmHg pressurised-bag irrigation; 11/13-F UAS). The highest single pressure peak was 334.2 mmHg, during retrograde pyelography. Six patients (5%) developed postoperative urosepsis; these patients had significantly higher IRPs during FURS (mean [sd] 81.7 [49.52] mmHg) than controls (38.53 [22.6] mmHg; P < 0.001). CONCLUSIONS: A dynamic IRP profile is observed during human in vivo URS, with IRP frequently exceeding expected thresholds. A relationship appears to exist between elevated IRP and postoperative urosepsis.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Detection and discrimination of achromatic contrast: A ganglion cell perspective.

The magnocellular (MC) pathway in the primate has much higher achromatic contrast sensitivity than the parvocellular (PC) pathway, and is implicated in luminance contrast detection. But MC pathway responses tend to saturate at lower achromatic contrast than do PC pathway responses. It has been proposed that the PC pathway plays a major role in discriminating suprathreshold achromatic contrast, because the MC pathway is in saturation. This has been termed the pulsed-pedestal protocol. To test this hypothesis, responses of MC and PC pathway ganglion cells have been examined under suprathreshold conditions with stimulus configurations similar to those in psychophysical tests. For MC cells, response saturation was much less for flashed or moving edges than for sinusoidal modulation, and MC cell thresholds predicted for these stimuli were similar to psychophysical discrimination (and detection) data. Results suggest the protocol is not effective in segregating MC and PC function.

A quantitative description of macaque ganglion cell responses to natural scenes: the interplay of time and space.

KEY POINTS: Responses to natural scenes are the business of the retina. We find primate ganglion cell responses to such scenes consistent with those to simpler stimuli. A biophysical model confirmed this and predicted ganglion cell responses with close to retinal reliability. Primate ganglion cell responses to natural scenes were driven by temporal variations in colour and luminance over the receptive field centre caused by eye movements, and little influenced by interaction of centre and surround with structure in the scene. We discuss implications in the context of efficient coding of the visual environment. Much information in a higher spatiotemporal frequency band is concentrated in the magnocellular pathway. ABSTRACT: Responses of visual neurons to natural scenes provide a link between classical descriptions of receptive field structure and visual perception of the natural environment. A natural scene video with a movement pattern resembling that of primate eye movements was used to evoke responses from macaque ganglion cells. Cell responses were well described through known properties of cell receptive fields. Different analyses converge to show that responses primarily derive from the temporal pattern of stimulation derived from eye movements, rather than spatial receptive field structure beyond centre size and position. This was confirmed using a model that predicted ganglion cell responses close to retinal reliability, with only a small contribution of the surround relative to the centre. We also found that the spatiotemporal spectrum of the stimulus is modified in ganglion cell responses, and this can reduce redundancy in the retinal signal. This is more pronounced in the magnocellular pathway, which is much better suited to transmit the detailed structure of natural scenes than the parvocellular pathway. Whitening is less important for chromatic channels. Taken together, this shows how a complex interplay across space, time and spectral content sculpts ganglion cell responses.

Multiplexed and High-Throughput Label-Free Detection of RNA/Spike Protein/IgG/IgM Biomarkers of SARS-CoV-2 Infection Utilizing Nanoplasmonic Biosensors.

To tackle the COVID-19 outbreak, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an unmet need for highly accurate diagnostic tests at all stages of infection with rapid results and high specificity. Here, we present a label-free nanoplasmonic biosensor-based, multiplex screening test for COVID-19 that can quantitatively detect 10 different biomarkers (6 viral nucleic acid genes, 2 spike protein subunits, and 2 antibodies) with a limit of detection in the aM range, all within one biosensor platform. Our newly developed nanoplasmonic biosensors demonstrate high specificity, which is of the upmost importance to avoid false responses. As a proof of concept, we show that our detection approach has the potential to quantify both IgG and IgM antibodies directly from COVID-19-positive patient plasma samples in a single instrument run, demonstrating the high-throughput capability of our detection approach. Most importantly, our assay provides receiving operating characteristics, areas under the curve of 0.997 and 0.999 for IgG and IgM, respectively. The calculated p-value determined through the Mann-Whitney nonparametric test is <0.0001 for both antibodies when the test of COVID-19-positive patients (n = 80) is compared with that of healthy individuals (n = 72). Additionally, the screening test provides a calculated sensitivity (true positive rate) of 100% (80/80), a specificity (true negative rate) >96% (77/80), a positive predictive value of 98% at 5% prevalence, and a negative predictive value of 100% at 5% prevalence. We believe that our very sensitive, multiplex, high-throughput testing approach has potential applications in COVID-19 diagnostics, particularly in determining virus progression and infection severity for clinicians for an appropriate treatment, and will also prove to be a very effective diagnostic test when applied to diseases beyond the COVID-19 pandemic.

Photoswitchable Machine-Engineered Plasmonic Nanosystem with High Optical Response for Ultrasensitive Detection of microRNAs and Proteins Adaptively.

Modulating optoelectronic properties of inorganic nanostructures tethered with light-responsive molecular switches by their conformational change in the solid state is fundamentally important for advanced nanoscale-device fabrication, specifically in biosensing applications. Herein, we present an entirely new solid-state design approach employing the light-induced reversible conformational change of spiropyran (SP)-merocyanine (MC) covalently attached to gold triangular nanoprisms (Au TNPs) via alkylthiolate self-assembled monolayers to produce a large localized surface plasmon resonance response (∼24 nm). This shift is consistent with the increase in thickness of the local dielectric shell-surrounded TNPs and perhaps short-range dipole-dipole (permanent and induced) interactions between TNPs and the zwitterionic MC form. Water contact angle measurement and Raman spectroscopy characterization unequivocally prove the formation of a stable TNP-MC structural motif. Utilizing this form, we fabricated the first adaptable nanoplasmonic biosensor, which uses an identical structural motif for ultrasensitive, highly specific, and programmable detection of microRNAs and proteins at attomolar concentrations in standard human plasma and urine samples, and at femtomolar concentrations from bladder cancer patient plasma (n = 10) and urine (n = 10), respectively. Most importantly, the TNP-MC structural motif displays a strong binding affinity with receptor molecules (i.e., single-stranded DNA and antibody) producing a highly stable biosensor. Taken together, the TNP-MC structural motif represents a multifunctional super biosensor with the potential to expand clinical diagnostics through simplifying biosensor design and providing highly accurate disease diagnosis.

Mycobacterium tuberculosis releases an antacid that remodels phagosomes.

Mycobacterium tuberculosis (Mtb) is the world's most deadly pathogen. Unlike less virulent mycobacteria, Mtb produces 1-tuberculosinyladenosine (1-TbAd), an unusual terpene nucleoside of unknown function. In the present study 1-TbAd has been shown to be a naturally evolved phagolysosome disruptor. 1-TbAd is highly prevalent among patient-derived Mtb strains, where it is among the most abundant lipids produced. Synthesis of TbAd analogs and their testing in cells demonstrate that their biological action is dependent on lipid linkage to the 1-position of adenosine, which creates a strong conjugate base. Furthermore, C20 lipid moieties confer passage through membranes. 1-TbAd selectively accumulates in acidic compartments, where it neutralizes the pH and swells lysosomes, obliterating their multilamellar structure. During macrophage infection, a 1-TbAd biosynthesis gene (Rv3378c) confers marked phagosomal swelling and intraphagosomal inclusions, demonstrating an essential role in regulating the Mtb cellular microenvironment. Although macrophages kill intracellular bacteria through phagosome acidification, Mtb coats itself abundantly with antacid.

Reversible Tuning of the Plasmoelectric Effect in Noble Metal Nanostructures Through Manipulation of Organic Ligand Energy Levels.

Ligand-controlled tuning of localized surface plasmon resonance (LSPR) properties of noble metal nanostructures is fundamentally important for various optoelectronic applications such as photocatalysis, photovoltaics, and sensing. Here we demonstrate that the free carrier concentration of gold triangular nanoprisms (Au TNPs) can be tuned up to 12% upon functionalization of their surface with different para-substituted thiophenolate (X-Ph-S-) ligands. We achieve this unprecedentedly large optical response (plasmoelectric effect) in TNPs through the selective manipulation of electronic processes at the Au-thiolate interface. Interestingly, thiophenolates with electron withdrawing (donating) groups (X) produce λLSPR blue (red) shifts with broadening (narrowing) of localized surface plasmon resonance peak (λLSPR) line widths. Surprisingly, these experimental results are opposite to a straightforward application of the Drude model. Utilizing density functional theory calculations, we develop here a frontier molecular orbital approach of Au-thiophenolate interactions in the solid-state to delineate the observed spectral response. Importantly, all the spectroscopic properties are fully reversible by exchanging thiophenolates containing electron withdrawing groups with thiophenolates having electron donating groups, and vice versa. On the basis of the experimental data and calculations, we propose that the delocalization of electrons wave function controls the free carrier concentration of Au and thus the LSPR properties rather than simple electronic properties (inductive and/or resonance effects) of thiophenolates. This is further supported by the experimentally determined work functions, which are tunable over 1.9 eV in the X-Ph-S-passivated Au TNPs. We believe that our unexpected finding has great potential to guide in developing unique noble metal nanostructure-organic ligand hybrid nanoconjugates, which could allow us to bypass the complications associated with off-resonance LSPR activation of noble metal-doped semiconductor nanocrystals for various surface plasmon-driven applications.

[Ethical considerations in ENT during the COVID-19 pandemic: Qualitative analysis of open-ended questions]. / Questionnements éthiques en ORL pendant la pandémie COVID-19 : étude qualitative de témoignages.

INTRODUCTION: The current new SARS-CoV-2 pandemic has had a profound impact on medical practice. The objective was to analyse the ethical questions raised by the French ENT community during the first wave of COVID-19 infections. METHODS: Four open-ended questions concerning ethical considerations in ENT were sent out in April 2020: (i) difficulties to care for COVID-19 positive patients; (ii) impact of the health crisis on COVID-19 negative patients; (iii) communication within the healthcare teams and with hospital staff; and (iv) management of information by the press, or national ENT societies. A thematic analysis was carried out and crossed with the epidemiological data of each respondent. RESULTS: Thirty-one responses from 13 different French Departments, including 21 from public institutions and 10 from private practice, median age of 45 and 17 men for 14 women, were analysed. The main ethical considerations concerned the management by ENTs of COVID-19 positive patients, the modification of practices in consultation and in the operating room, the fear of loss of chance for COVID-19 negative patients, the appropriate use of teleconsultations and teleworking and the consequences of fake-news for the population. CONCLUSION: In preparation of possible future pandemic outbreaks, key ethical aspects are to adapt patient management to local resources and infection prevalence, and circulate clear institutional guidelines.

Ultrathin Plasmonic Tungsten Oxide Quantum Wells with Controllable Free Carrier Densities.

Localized surface plasmon resonances (LSPR) of nanostructures can be tuned by controlling their morphology, local dielectric environment, and free carrier concentration. We report the colloidal synthesis of an ∼3 tungsten-oxygen (W-O) layer thick (∼1 nm), two-dimensional (2D) WO3-x nanoplatelets (NPLs) (x ≈ 0.55-1.03), which display tunable near-infrared LSPR properties and additionally high free electron density (Ne) that arises predominantly from the large shape factor of 2D NPLs. Importantly, the W to O composition ratios inferred from their LSPR measurements show much higher percentage of oxygen vacancies than those determined by X-ray diffraction analysis, suggesting that the aspect ratio of ultrathin WO3-x NPLs is the key to producing an unprecedentedly large Ne, although synthesis temperature is also an independent factor. We find that NPL formation is kinetically controlled, whereas thermodynamic parameter manipulation leads to Ne values as high as 4.13 × 1022 cm-3, which is close to that of plasmonic noble metals, and thus our oxide-based nanostructures can be considered as quasi-metallic. The unique structural properties of 2D nanomaterials along with the high Ne of WO3-x NPLs provide an attractive alternative to plasmonic noble metal nanostructures for various plasmon-driven energy conversions and design of photochromic nanodevices.

Synthesis and Biological Evaluation of the Southern Hemisphere of Spirastrellolide A and Analogues.

The synthesis and biological evaluation of truncated spirastrellolide A analogues comprised of the southern hemisphere against protein phosphatase 2A are described. A convergent synthesis was designed featuring two gold-catalyzed cyclization reactions, specifically, a dehydrative cyclization of monoallylic diols for the synthesis of the tetrahydropyran (A-ring) and a regioselective spiroketalization for the efficient generation of the [6,6]-spiroketal (B, C-ring system). The synthesis of the southern hemisphere of spirastrellolide A was achieved involving the longest linear sequence of 19 steps. A total of eight spirastrellolide A analogues were synthesized, and preliminary PP2A enzyme assay inhibition studies were performed for the first time on analogues of the southern hemisphere. Several analogues showed inhibition, which is a positive indication and perhaps suggests that the unsaturated spiroketal fragment might be crucial to induce PP2A inhibition.

Angiotensin II mediates the axonal trafficking of tyrosine hydroxylase and dopamine ß-hydroxylase mRNAs and enhances norepinephrine synthesis in primary sympathetic neurons.

In the sympatho-adrenal system, angiotensin II (Ang II) acts as a key neuromodulatory component. At sympathetic nerve terminals, Ang II influences sympathetic transmission by enhancing norepinephrine (NE) synthesis, facilitating NE release and inhibiting NE uptake. Previously, it was demonstrated that tyrosine hydroxylase (TH) mRNA is trafficked to the distal axons of primary superior cervical ganglia (SCG) neurons, directed by a cis-acting regulatory element (i.e. zipcode) located in the 3'UTR of the transcript. Results of metabolic labeling studies established that the mRNA is locally translated. It was further shown that the axonal trafficking of the mRNA encoding the enzyme plays an important role in mediating dopamine (DA) and NE synthesis and may facilitate the maintenance of axonal catecholamine levels. In the present study, the hypothesis was tested that Ang II induces NE synthesis in rat primary SCG neurons via the modulation of the trafficking of the mRNAs encoding the catecholamine synthesizing enzymes TH and dopamine ß-hydroxylase (DBH). Treatment of SCG neurons with the Ang II receptor type 1 (AT1R) agonist, L-162,313, increases the axonal levels of TH and DBH mRNA and protein and results in elevated NE levels. Conversely, treatment of rat SCG neurons with the AT1R antagonist, Eprosartan, abolished the L-162,313-mediated increase in axonal levels of TH and DBH mRNA and protein. In a first attempt to identify the proteins involved in the Ang II-mediated axonal transport of TH mRNA, we used a biotinylated 50-nucleotide TH RNA zipcode as bait in the affinity purification of TH zipcode-associated proteins. Mass spectrometric analysis of the TH zipcode ribonucleoprotein (RNP) complex immune-purified from SCG neurons led to the identification of 163 somal and 127 axonal proteins functionally involved in binding nucleic acids, the translational machinery or acting as subunits of cytoskeletal and motor proteins. Surprisingly, immune-purification of the TH axonal trafficking complex, results in the acquisition of DBH mRNA, suggesting that these mRNAs maybe transported to the axon together, possibly in the same RNP complex. Taken together, our results point to a novel mechanism by which Ang II participates in the regulation of axonal synthesis of NE by modulating the local trafficking and expression of TH and DBH, two key enzymes involved in the catecholamine biosynthetic pathway.

The sentinel stent? A systematic review of the role of prophylactic ureteric stenting prior to colorectal resections.

PURPOSE: 'Prophylactic' ureteric stents potentially reduce rates, and facilitate intraoperative recognition, of iatrogenic ureteric injury (IUI) during colorectal resections. A lack of consensus surrounds the risk-benefit equation of this practice, and we aimed to assess the evidence base. METHODS: A systematic review was performed according to PRISMA guidelines. MEDLINE, Scopus, EMBASE and Cochrane databases were searched using terms 'ureteric/ureteral/JJ/Double J stent' or 'ureteric/ureteral catheter' and 'colorectal/prophylactic/resection/diverticular disease/diverticulitis/iatrogenic injury'. Primary outcomes were rates of ureteric injuries and their intraoperative identification. Secondary outcomes included stent complication rates. RESULTS: We identified 987 publications; 22 papers met the inclusion criteria. No randomised controlled trials were found. The total number of patients pooled for evaluation was 869,603 (102,370 with ureteric stents/catheters, 767,233 controls). The most frequent indications for prophylactic stents were diverticular disease (45.38%), neoplasia (33.45%) and inflammatory bowel disease (9.37%). Pooled results saw IUI in 1521/102,370 (1.49%) with, and in 1333/767,233 (0.17%) without, prophylactic ureteric stents. Intraoperative recognition of IUIs occurred in 10/16 injuries (62.5%) with prophylactic stents, versus 9/17 (52.94%) without stents (p = 0.579). The most serious complications of prophylactic stent use were ureteric injury (2/1716, 0.12%) and transient ureteric obstruction following stent removal (13/666, 1.95%). CONCLUSIONS: Placement of prophylactic ureteric stents has a low complication rate. There is insufficient evidence to conclude that stents decrease ureteric injury or increase intraoperative detection of IUIs. Apparently higher rates of IUI in stented patients likely reflect use in higher risk resections. A prospective registry with harmonised data collection points and stratification of intraoperative risk is needed.

The Role of Metabotropic Glutamate Receptor 1 Dependent Signaling in Glioma Viability.

Glioma refers to malignant central nervous system tumors that have histologic characteristics in common with glial cells. The most prevalent type, glioblastoma multiforme, is associated with a poor prognosis and few treatment options. On the basis of reports of aberrant expression of mGluR1 mRNA in glioma, evidence that melanoma growth is directly influenced by glutamate metabotropic receptor 1 (mGluR1), and characterization of ß-arrestin-dependent prosurvival signaling by this receptor, this study investigated the hypothesis that glioma cell lines aberrantly express mGluR1 and depend on mGluR1-mediated signaling to maintain viability and proliferation. Three glioma cell lines (Hs683, A172, and U87) were tested to confirm mGluR1 mRNA expression and the dependence of glioma cell viability on glutamate. Pharmacologic and genetic evidence is presented that suggests mGluR1 signaling specifically supports glioma proliferation and viability. For example, selective noncompetitive antagonists of mGluR1, CPCCOEt and JNJ16259685, decreased the viability of these cells in a dose-dependent manner, and glutamate metabotropic receptor 1 gene silencing significantly reduced glioma cell proliferation. Also, results of an anchorage-independent growth assay suggested that noncompetitive antagonism of mGluR1 may decrease the tumorigenic potential of Hs683 glioma cells. Finally, data are provided that support the hypothesis that a ß-arrestin-dependent signaling cascade may be involved in glutamate-stimulated viability in glioma cells and that ligand bias may exist at mGluR1 expressed in these cells. Taken together, the results strongly suggest that mGluR1 may act as a proto-oncogene in glioma and be a viable drug target in glioma treatment.