The western redcedar genome reveals low genetic diversity in a self-compatible conifer.

We assembled the 9.8-Gbp genome of western redcedar (WRC; Thuja plicata), an ecologically and economically important conifer species of the Cupressaceae. The genome assembly, derived from a uniquely inbred tree produced through five generations of self-fertilization (selfing), was determined to be 86% complete by BUSCO analysis, one of the most complete genome assemblies for a conifer. Population genomic analysis revealed WRC to be one of the most genetically depauperate wild plant species, with an effective population size of approximately 300 and no significant genetic differentiation across its geographic range. Nucleotide diversity, π, is low for a continuous tree species, with many loci showing zero diversity, and the ratio of π at zero- to fourfold degenerate sites is relatively high (approximately 0.33), suggestive of weak purifying selection. Using an array of genetic lines derived from up to five generations of selfing, we explored the relationship between genetic diversity and mating system. Although overall heterozygosity was found to decline faster than expected during selfing, heterozygosity persisted at many loci, and nearly 100 loci were found to deviate from expectations of genetic drift, suggestive of associative overdominance. Nonreference alleles at such loci often harbor deleterious mutations and are rare in natural populations, implying that balanced polymorphisms are maintained by linkage to dominant beneficial alleles. This may account for how WRC remains responsive to natural and artificial selection, despite low genetic diversity.

Vanadium Alkylidyne Initiated Cyclic Polymer Synthesis: The Importance of a Deprotiovanadacyclobutadiene Moiety.

Reported is the catalytic cyclic polymer synthesis by a 3d transition metal complex: a V(V) alkylidyne, [(dBDI)V≡CtBu(OEt2)] (1-OEt2), supported by the deprotonated ß-diketiminate dBDI2- (dBDI2- = ArNC(CH3)CHC(CH2)NAr, Ar = 2,6-iPr2C6H3). Complex 1-OEt2 is a precatalyst for the polymerization of phenylacetylene (PhCCH) to give cyclic poly(phenylacetylene) (c-PPA), whereas its precursor, complex [(BDI)V≡CtBu(OTf)] (2-OTf; BDI- = [ArNC(CH3)]2CH, Ar = 2,6-iPr2C6H3, OTf = OSO2CF3), and the zwitterion [((C6F5)3B-dBDI)V≡CtBu(OEt2)] (3-OEt2) exhibit low catalytic activity despite having a neopentylidyne ligand. Cyclic polymer topologies were verified by size-exclusion chromatography (SEC) and intrinsic viscosity studies. A component of the mechanism of the cyclic polymerization reaction was probed by isolation and full characterization of 4- and 6-membered metallacycles as model intermediates. Metallacyclobutadiene (MCBD) and deprotiometallacyclobutadiene (dMCBD) complexes (dBDI)V[C(tBu)C(H)C(tBu)] (4-tBu) and (BDI)V[C(tBu)CC(Mes)] (5-Mes), respectively, were synthesized upon reaction with bulkier alkynes, tBu- (tBuCCH) and Mes-acetylene (MesCCH), with 1-OEt2. Furthermore, the reaction of the conjugate acid of 1-OEt2, [(BDI)V≡CtBu(OTf)] (2-OTf), with the conjugated base of phenylacetylene, lithium phenylacetylide (LiCCPh), yields the doubly deprotio-metallacycle complex, [Li(THF)4]{(BDI)V[C(Ph)CC(tBu)CC(Ph)]} (6). Protonation of the doubly deprotio-metallacycle complex 6 yields 6-H+, a catalytically active species toward the polymerization of PhCCH, for which the polymers were also confirmed to be cyclic by SEC studies. Computational mechanistic studies complement the experimental observations and provide insight into the mechanism of cyclic polymer growth. The noninnocence of the supporting dBDI2- ligand and its role in proton shuttling to generate deprotiometallacyclobutadiene (dMCBD) complexes that proposedly culminate in the formation of catalytically active V(III) species are also discussed. This work demonstrates how a dMCBD moiety can react with terminal alkynes to form cyclic polyalkynes.

General Surgery Resident Participation in a Mandatory Wellness Program: Six Years Later.

INTRODUCTION: Following the approval of a resident-created physician wellness program in 2016, an initial survey demonstrated majority support for the implementation of a mandatory curriculum. The purpose of this study is to survey surgical residents about the wellness curriculum six years after implementation and re-evaluate preference for mandatory participation. METHODS: In 2016, the CORE7 Wellness Program didactic sessions were integrated into the general surgery resident education curriculum. A comparison between 2016 and 2022 resident survey results was done to examine overall approval and resident experience. RESULTS: A total of 25 general surgery residents responded to the 2022 survey which equaled to a response rate of 67.5% compared to a response rate of 87.1% in 2016. Similar to the results in 2016, there was unanimous support (100%, n = 25) in favor of the ongoing development of a general surgery wellness program. The majority of residents (88% versus 85.2% in 2016) preferred quarterly "wellness half-days" remain a mandatory component of the program. In 2016, most of the residents (50%) stated that the reason for mandatory preference for wellness half-days was ease of explanation to faculty. In 2022, the reason changed to a combination of reasons with most residents (59%) selecting ease of explanation to attendings, feeling too guilty otherwise to leave the shift, and forcing the resident to think about self-care. Complaints about taking a wellness half-day from other team members increased from 29% in 2016 to 48% in 2022. CONCLUSIONS: Six years after implementation, there is unanimous support for the mandatory components of a general surgery residency wellness curriculum. Increased perceived complaints from faculty and staff about resident wellness present an opportunity for improvement.

Ynamide and Azaalleneyl. Acid-Base Promoted Chelotropic and Spin-State Rearrangements in a Versatile Heterocumulene [(Ad)NCC(tBu)].

We introduce the heterocumulene ligand [(Ad)NCC(tBu)]- (Ad=1-adamantyl (C10H15), tBu=tert-butyl, (C4H9)), which can adopt two forms, the azaalleneyl and ynamide. This ligand platform can undergo a reversible chelotropic shift using Brønsted acid-base chemistry, which promotes an unprecedented spin-state change of the [VIII] ion. These unique scaffolds are prepared via addition of 1-adamantyl isonitrile (C≡NAd) across the alkylidyne in complexes [(BDI)V≡CtBu(OTf)] (A) (BDI-=ArNC(CH3)CHC(CH3)NAr), Ar=2,6-iPr2C6H3) and [(dBDI)V≡CtBu(OEt2)] (B) (dBDI2-=ArNC(CH3)CHC(CH2)NAr). Complex A reacts with C≡NAd, to generate the high-spin [VIII] complex with a κ1-N-ynamide ligand, [(BDI)V{κ1-N-(Ad)NCC(tBu)}(OTf)] (1). Conversely, B reacts with C≡NAd to generate a low-spin [VIII] diamagnetic complex having a chelated κ2-C,N-azaalleneyl ligand, [(dBDI)V{κ2-N,C-(Ad)NCC(tBu)}] (2). Theoretical studies have been applied to better understand the mechanism of formation of 2 and the electronic reconfiguration upon structural rearrangement by the alteration of ligand denticity between 1 and 2.

Metallacyclobuta-(2,3)-diene: A Bidentate Ligand for Stream-line Synthesis of First Row Transition Metal Catalysts for Cyclic Polymerization of Phenylacetylene.

Described here is a direct entry to two examples of 3d transition metal catalysts that are active for the cyclic polymerization of phenylacetylene, namely, [(BDI)M{κ2 -C,C-(Me3 SiC3 SiMe3 )}] (2-M) (BDI=[ArNC(CH3 )]2 CH- , Ar=2,6-i Pr2 C6 H3 ; M=Ti, V). Catalysts are prepared in one step by the treatment of [(BDI)MCl2 ] (1-M, M=Ti, V) with 1,3-dilithioallene [Li2 (Me3 SiC3 SiMe3 )]. Complexes 2-M have been spectroscopically and structurally characterized and the polymers that are catalytically formed from phenylacetylene were verified to have a cyclic topology based on a combination of size-exclusion chromatography (SEC) and intrinsic viscosity studies. Two-electron oxidation of 2-V with nitrous oxide (N2 O) cleanly yields a [VV ] alkylidene-alkynyl oxo complex [(BDI)V(=O){κ1 -C-(=C(SiMe3 )CC(SiMe3 ))}] (3), which lends support for how this scaffold in 2-M might be operating in the polymerization of the terminal alkyne. This work demonstrates how alkylidynes can be circumvented using 1,3-dianionic allene as a segue into M-C multiple bonds.

Tocilizumab for the treatment of chronic antibody mediated rejection in kidney transplant recipients.

BACKGROUND: Chronic active antibody-mediated rejection (CAAMR) constitutes a dominant form of late allograft failure. Several treatment strategies directed at CAAMR have been attempted but proven ineffective at delaying kidney function decline or reducing donor-specific antibodies (DSA). We describe our single-center experience using tocilizumab in patients with CAAMR. METHODS: This is a retrospective analysis using electronic medical records. 38 kidney transplant recipients at Columbia University Irving Medical Center who had been prescribed tocilizumab and followed for at least 3 months between August 2013 through December 2019 were included. RESULTS: Tocilizumab use was associated with a decrease in the rate of estimated glomerular filtration rate (eGFR) decline in the 6 months following treatment initiation as compared to the 3 months before tocilizumab was initiated (difference between slopes before and after initiation of treatment = 2.6 mL/min/1.73 m2 (SE = .8, p = .002) per month for up to 6 months following Tocilizumab initiation). Allograft biopsies showed significant improvement in interstitial inflammation scores (score 1(0,1) to 0 (0,1), p = .03) while other histologic scores remained stable. There was no significant change in proteinuria or DSA titers post-treatment with tocilizumab. CONCLUSIONS: Treatment of CAAMR with tocilizumab was associated with a decrease in the rate of eGFR decline and a reduction in interstitial inflammation scores in patients with CAAMR.

Astrocyte-T cell crosstalk regulates region-specific neuroinflammation.

During multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system (CNS), symptoms, and outcomes are determined by the location of inflammatory lesions. While we and others have shown that T cell cytokines differentially regulate leukocyte entry into perivascular spaces and regional parenchymal localization in murine models of MS, the molecular mechanisms of this latter process are poorly understood. Here, we demonstrate that astrocytes exhibit region-specific responses to T cell cytokines that promote hindbrain versus spinal cord neuroinflammation. Analysis of cytokine receptor expression in human astrocytes showed region-specific responsiveness to Th1 and Th17 inflammatory cytokines. Consistent with this, human and murine astrocytes treated with these cytokines exhibit differential expression of the T cell localizing molecules VCAM-1 and CXCR7 that is both cytokine and CNS region-specific. Using in vivo models of spinal cord versus brain stem trafficking of myelin-specific T cells and astrocyte-specific deletion strategies, we confirmed that Th1 and Th17 cytokines differentially regulate astrocyte expression of VCAM-1 and CXCR7 in these locations. Finally, stereotaxic injection of individual cytokines into the hindbrain or spinal cord revealed region- and cytokine-specific modulation of localizing cue expression by astrocytes. These findings identify a role for inflammatory cytokines in mediating local astrocyte-dependent mechanisms of immune cell trafficking within the CNS during neuroinflammation.

Small Phosphine Ligands Enable Selective Oxidative Addition of Ar-O over Ar-Cl Bonds at Nickel(0).

Current methods for Suzuki-Miyaura couplings of nontriflate phenol derivatives are limited by their intolerance of halides including aryl chlorides. This is because Ni(0) and Pd(0) often undergo oxidative addition of organohalides at a similar or faster rate than most Ar-O bonds. DFT and stoichiometric oxidative addition studies demonstrate that small phosphines, in particular PMe3, are unique in promoting preferential reaction of Ni(0) with aryl tosylates and other C-O bonds in the presence of aryl chlorides. This selectivity was exploited in the first Ni-catalyzed C-O-selective Suzuki-Miyaura coupling of chlorinated phenol derivatives where the oxygen-containing leaving group is not a fluorinated sulfonate such as triflate. Computational studies suggest that the origin of divergent selectivity between PMe3 and other phosphines differs from prior examples of ligand-controlled chemodivergent cross-couplings. PMe3 effects selective reaction at tosylate due to both electronic and steric factors. A close interaction between nickel and a sulfonyl oxygen of tosylate during oxidative addition is critical to the observed selectivity.

Giving a good start to a new life via maternal brain allostatic adaptations in pregnancy.

Successful pregnancy requires adjustments to multiple maternal homeostatic mechanisms, governed by the maternal brain to support and enable survival of the growing fetus and placenta. Such adjustments fit the concept of allostasis (stability through change) and have a cost: allostatic load. Allostasis is driven by ovarian, anterior pituitary, placental and feto-placental hormones acting on the maternal brain to promote adaptations that support the pregnancy and protect the fetus. Many women carry an existing allostatic load into pregnancy, from socio-economic circumstances, poor mental health and in 'developed' countries, also from obesity. These pregnancies have poorer outcomes indicating negative interactions (failing allostasis) between pre-pregnancy and pregnancy allostatic loads. Use of animal models, such as adult prenatally stressed female offspring with abnormal neuroendocrine, metabolic and behavioural phenotypes, to probe gene expression changes, and epigenetic mechanisms in the maternal brain in adverse pregnancies are discussed, with the prospect of ameliorating poor pregnancy outcomes.

CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial.

BACKGROUND: Oral CXC chemokine receptor 2 (CXCR2) antagonists have been shown to inhibit neutrophil migration and activation in the lung in preclinical and human models of neutrophilic airway inflammation. A previous study with danirixin, a reversible CXCR2 antagonist, demonstrated a trend for improved respiratory symptoms and health status in patients with COPD. METHODS: This 26-week, randomised, double-blind, placebo-controlled phase IIb study enrolled symptomatic patients with mild-to-moderate COPD at risk for exacerbations. Patients received danirixin 5, 10, 25, 35 or 50 mg twice daily or placebo in addition to standard of care. Primary end-points were the dose response of danirixin compared with placebo on the incidence and severity of respiratory symptoms (Evaluating Respiratory Symptoms in COPD [E-RS:COPD] scores) and safety. Secondary end-points included the incidence of moderate-severe exacerbations, health status (COPD Assessment test, CAT) and health-related quality of life HRQoL (St. George Respiratory Questionnaire-COPD, SGRQ-C). RESULTS: A total of 614 participants were randomized to treatment. There were no improvements in E-RS:COPD, CAT or SGRQ-C scores in participants treated with any dose of danirixin compared to placebo; a larger than expected placebo effect was observed. There was an increased incidence of exacerbation in the danirixin-treated groups and an increased number of pneumonias in participants treated with danirixin 50 mg. CONCLUSIONS: The robust placebo and study effects prohibited any conclusions on the efficacy of danirixin. However, the absence of a clear efficacy benefit and the observed increase in exacerbations in danirixin-treated groups suggests an unfavorable benefit-risk profile in patients with COPD. TRIAL REGISTRATION: This study was registered with clinicaltrials.gov, NCT03034967.

Edge-Localized Biodeterioration and Secondary Microplastic Formation by Papiliotrema laurentii Unsaturated Biofilm Cells on Polyurethane Films.

Painted environmental surfaces are prone to microbiological colonization with potential coating deterioration induced by the microorganisms. Accurate mechanistic models of these interactions require an understanding of the heterogeneity in which the deterioration processes proceed. Here, unsaturated biofilms (i.e., at air/solid interfaces) of the yeast Papiliotrema laurentii were prepared on polyether polyurethane (PEUR) and polyester-polyether polyurethane (PEST-PEUR) coatings and incubated for up to 33 days at controlled temperature and humidity with no additional nutrients. Transmission micro-Fourier transform infrared microscopy (µFTIR) confirmed preferential hydrolysis of the ester component by the biofilm. Atomic force microscopy combined with infrared nanospectroscopy (AFM-IR) was used to analyze initial PEST-PEUR coating deterioration processes at the single-cell level, including underlying surfaces that became exposed following cell translocation. The results revealed distinct deterioration features that remained localized within ∼10 µm or less of the edges of individual cells and cell clusters. These features comprised depressions of up to ∼300 nm with locally reduced ester/urethane ratios. They are consistent with a formation process initiated by enzymatic ester hydrolysis followed by erosion from water condensation cycles. Further observations included particle accumulation in the broader biofilm vicinity. AFM-IR spectroscopy indicated these to be secondary microplastics consisting of urethane-rich oligomeric aggregates. Overall, multiple contributing factors have been identified that can facilitate differential deterioration rates across the PEST-PEUR surface. Effects of the imposed nutrient conditions on Papiliotrema laurentii physiology were also apparent, with cells developing the characteristics of starvation response, despite the availability of polyester metabolites as a carbon source. The combined results provide new laboratory insights into field-relevant microbiological polymer deterioration mechanisms and biofilm physiology at polymer coating interfaces.

The financial impact of an enhanced recovery after surgery (ERAS) protocol in an academic gynecologic oncology practice.

OBJECTIVE: To determine the financial impact of an enhanced recovery after surgery (ERAS) protocol in gynecologic oncology patients. METHODS: This study identified gynecologic oncology patients who were placed on the ERAS protocol after elective laparotomy from 10/2016-6/2017. A control group was identified from the year prior to ERAS implementation. Financial experts assisted in procuring data for these patient encounters, including payer status, direct and indirect costs, contribution margin, and length of stay (LOS). SPSS Statistics v. 24 was used for statistical analysis. RESULTS: 376 patients met criteria for inclusion: 179 in the ERAS group and 197 in the control group. Patient demographics were similar between the two cohorts. Payer status across the groups was not statistically significant in patients with private insurance (control 43.7% vs. ERAS 41.3%), Medicare (38.1% vs. 31.8%), or self-pay patients (12.2% vs. 15.1%). There was a significantly higher number of Medicaid patients in the ERAS group (6.1% vs. 11.7%; p = 0.05). Hospital direct costs ($5596 vs. 5346) and indirect costs ($5182 vs. $4954) per encounter were similar between groups. However, overall contribution margin per encounter decreased in the ERAS group ($11,619 vs. $8528; p = 0.01). LOS was significantly lower in the ERAS group (4.1 vs. 2.9 days; p = 0.04). CONCLUSIONS: Implementation of the ERAS protocol in gynecologic oncology patients does not lead to increased costs for the patient or hospital system. The decreased contribution margin is likely due to a reduction in per diem payments caused by the reduction in LOS. On a per-patient-day basis, contribution margin was the same for both groups ($2877 vs $2857). The reduction in LOS also created capacity for additional cases, the financial impact of which was not evaluated.

Reducing dropout in acceptance and commitment therapy, mindfulness-based cognitive therapy, and problem-solving therapy for chronic pain and cancer patients using motivational interviewing.

OBJECTIVE: Acceptance and commitment therapy, mindfulness-based cognitive therapy, and problem-solving therapy are types of cognitive-behavioural therapy (CBT) group that improve physical and mental health in chronic pain or cancer. However, dropout is high due to group demands alongside physical impairments. Motivational interviewing (MI) is a well-evidenced means of enhancing treatment adherence. Few studies have investigated MI as an adjunct to CBT in cancer or chronic pain, and none have established the minimum MI duration required for adherence improvement. This study evaluated minimal-duration MI to improve adherence in three CBT group types for cancer and chronic pain. METHODS: In a cohort study of 99 cancer and chronic pain patients, 47 were given a 10- to 15-min structured MI telephone intervention (MI-call) after the first session. The remaining 52 received a CBT group without MI (no-MI). RESULTS: Odds of completing group CBTs were five times greater for patients in the MI-call cohort versus no-MI. Effects remained when controlling for age, gender, diagnosis, group type, and baseline quality of life. The MI-call cohort attended one extra session per patient compared to no-MI, controlling for age, gender, and diagnosis. CONCLUSIONS: A brief MI telephone intervention may improve adherence to group CBTs in cancer and chronic pain. PRACTITIONER POINTS: A brief motivational interviewing (MI) telephone intervention may reduce dropout from group cognitive-behavioural therapies (CBTs) for cancer and chronic pain patients when administered after the first group session in routine care. Recipients of this intervention were five times more likely to complete a group CBT programme than those who did not receive it. Therefore, a minimal-dose MI intervention can have clinically important effects on dropout in group CBTs for patients with long-term conditions. It is unclear whether this intervention would also result in greater outcome improvements.

Fronto-orbital advancement and reconstruction using reverse frontal bone graft without the use of orbital bar: a technical note.

INTRODUCTION: We describe our technique of using reverse frontal bone graft for FOAR for patients with metopic or coronal synostosis and present our complications using the Leeds classification system for complications in craniosynostosis surgery. METHODS: Since April 2015, seventeen patients have been operated using this technique. We perform a frontal bone graft that is then reversed, and supraorbital margins are drilled out. The orbital bar is then removed and drilled down to make bone dust and on-lay bone grafts which are then used to fill gaps on exposed dura and fill in around the temporal region. RESULTS: All 17 patients who underwent this technique have good cosmetic results. We report 5 (29%) complications and 8 (47%) blood transfusions (7 exposures, 1 cell salvage).

Mucosal Schwann cell hamartoma of the gastroesophageal junction: A series of 6 cases and comparison with colorectal counterpart.

Mucosal Schwann cell hamartoma (MSCH) is an uncommon neural lesion characterized by an ill-defined proliferation of S100-positive Schwann cells in the lamina propria, with reported cases exclusively occurring in the colorectum. Here we describe the first series of MSCHs arising in the gastroesophageal junction (GEJ) and discuss their clinicopathologic features in comparison with their colorectal counterparts. We searched the UCLA pathology database from 01/2014 to 12/2018 to identify cases carrying the diagnosis of MSCH. A total of 48 cases (45 in-house, 3 consults) of colorectal MSCHs and 6 cases (1 in-house, 5 consults) of GEJ MSCHs were identified. For GEJ MSCHs, there were 4 males and 2 females with an average age of 70.2 years (range: 57-76 years). Clinical indications for endoscopy included history of gastroesophageal reflux disease (n = 2), heartburn (n = 2), dysphagia (n = 1), and iron deficiency anemia (n = 1). Endoscopic findings at the GEJ were available for 5 patients including irregular Z-line (n = 3), mild nodular carditis (n = 1), and normal (n = 1). None of them showed a polyp or nodule. The mean size of the lesion was 2.8 mm (range: 2-4 mm) microscopically. None of the colorectal or GEJ MSCH cases had an association with inherited syndromes. In conclusion, MSCH of the gastrointestinal tract is predominantly seen in the colorectum, but also infrequently seen in the GEJ. GEJ MSCH shares histologic and immunohistochemical features with its colorectal counterpart, but is usually an incidental finding with no endoscopically visible lesion. As there is no syndromic association with MSCH, additional treatment, work-up and follow-up are unnecessary.

Outcome of congenital tracheal stenosis in children over two decades in a national cardiothoracic surgical unit.

OBJECTIVE: To assess the outcomes of congenital tracheal stenosis among children. MATERIALS AND METHODS: A retrospective review of all children who underwent surgical repair of congenital tracheal stenosis reviewing charts, operative notes, echocardiograms, CT and MRI data from January 2002 to February 2019. RESULTS: Twenty-six children underwent surgical treatment for tracheal stenosis. The median age was 3 months (range 0.3-35 months) and the median weight was 4.7 kg (range 2.5-13 kg) at the time of surgical intervention. Stridor was the most common presenting symptom in 17 patients (65% of patients). Twenty-one patients (81%) had concurrent cardiac anomalies, with pulmonary arterial sling being the most common, present in nine patients (34%). Extracorporeal life support was utilised in seven patients (27%) pre-operatively. Laryngeal release was required in 16 patients. In 7 patients an end-to-end anastomosis was performed, in 18 patients slide tracheoplasty, and 1 patient had a double slide tracheoplasty. The median cardiopulmonary bypass time was 106 minutes (range 25-255 minutes). The median cross-clamp time was 30 minutes (range 5-67 minutes). The median post-operative duration of ventilation was 5 days (range 0.5-16 days). The median ICU length of stay was 12.5 days (range 2-60 days). There were three hospital mortalities with 88% survival. One patient only required reintervention with balloon dilation. Twenty-two patients (85%) remained symptom-free on median follow-up at 7.6 years (range 0.2-17 years). Two patients since 2017 had 3D printed tracheas produced from CT imaging to assist surgical planning. CONCLUSION: Congenital tracheal stenosis can be managed effectively with excellent outcomes and 3D printed models assist in planning the optimal surgical intervention.

Exploring the Potential of RET Kinase Inhibition for Irritable Bowel Syndrome: A Preclinical Investigation in Rodent Models of Colonic Hypersensitivity.

Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here, we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor, rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RET-cyan fluorescent protein [(CFP) RetCFP/+] mice, thoracic and lumbosacral dorsal root ganglia were shown to express RET, which colocalized with calcitonin gene-related peptide. To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia, quantified as exaggerated visceromotor response to graded pressures (0-60 mm Hg) of isobaric colorectal distension (CRD), was produced in multiple rat models induced 1) by colonic irritation, 2) following acute colonic inflammation, 3) by adulthood stress, and 4) by early life stress. In all the rat models, RET inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity.

Effect of neuromuscular electrical stimulation frequency on muscles of the tongue.

INTRODUCTION: Neuromuscular electrical stimulation (NMES) for the treatment of swallowing disorders is delivered at a variety of stimulation frequencies. We examined the effects of stimulation frequency on tongue muscle plasticity in an aging rat model. METHODS: Eighty-six young, middle-aged, and old rats were assigned to either bilateral hypoglossal nerve stimulation at 10 or 100 Hz (5 days/week, 8 weeks), sham, or no-implantation conditions. Muscle contractile properties and myosin heavy chain (MyHC) composition were determined for hyoglossus (HG) and styloglossus (SG) muscles. RESULTS: Eight weeks of 100-Hz stimulation resulted in the greatest changes in muscle contractile function with significantly longer contraction and half-decay times, the greatest reduction in fatigue, and a transition toward slowly contracting, fatigue-resistant MyHC isoforms. DISCUSSION: NMES at 100-Hz induced considerable changes in contractile and phenotypic profiles of HG and SG muscles, suggesting higher frequency NMES may yield a greater therapeutic effect. Muscle Nerve, 2018.

Basic Research Advances on Pituitary Stem Cell Function and Regulation.

As a central regulator of major physiological processes, the pituitary gland is a highly dynamic organ, capable of responding to hormonal demand and hypothalamic influence, through adapting secretion as well as remodelling cell numbers among its seven populations of differentiated cells. Stem cells of the pituitary have been shown to actively generate new cells during postnatal development but remain mostly quiescent during adulthood, where they persist as a long-lived population. Despite a significant body of research characterising attributes of anterior pituitary stem cells, the regulation of this population is poorly understood. A better grasp on the signalling mechanisms influencing stem proliferation and cell fate decisions can impact on our future treatments of pituitary gland disorders such as organ failure and pituitary tumours, which can disrupt endocrine homeostasis with life-long consequences. This minireview addresses the current methodologies aiming to understand better the attributes of pituitary stem cells and the normal regulation of this population in the organ, and discusses putative future avenues to manipulate pituitary stem cells during disease states or regenerative medicine approaches.

A retrospective observational study of acquired subglottic stenosis using low-pressure, high-volume cuffed endotracheal tubes.

INTRODUCTION: The safety of cuffed endotracheal tubes in the neonatal and critically ill pediatric population continues to be questioned due to the theoretical risk of acquired subglottic stenosis. The incidence of acquired subglottic stenosis in the high-risk mixed surgical and medical critically ill pediatric cohort using high-volume, low-pressure cuffed endotracheal tube policy has not yet been described. The aim of our study was to describe and evaluate the use and complication rate of cuffed ETT's in our unit over a 5-year period. METHODS: We defined clinically significant subglottic stenosis as a positive stenotic finding of endotracheal tube-related pathology on a microlaryngoscopy within 6 months of invasive ventilation. All patients admitted through our pediatric critical care unit from January 10, 2012 to January 25, 2017 were matched against our theater management system database for the same period. We reviewed all matching patients' baseline demographics, comorbidities, intubation/endotracheal tube history, and subsequent surgical management. RESULTS: Of 5309 pediatric critical care unit admissions (61% ventilated) and 1251 microlaryngoscopies, 23 children had endoscopic findings of clinically significant endotracheal tube-related pathology, reflecting 0.68% of all intubated patients. Eight patients developed acquired subglottic stenosis. All those requiring major surgical correction were ex-premature neonates initially intubated with uncuffed tubes in an external neonatal intensive care. No patient initially intubated with a cuffed endotracheal tube developed subglottic stenosis requiring surgical correction. CONCLUSION: We report no single case of acquired subglottic stenosis in our cohort that required major surgical correction from a cuffed endotracheal tube during a 5-year period. The introduction of a policy of appropriate placement and maintenance of low-pressure, high-volume cuffed endotracheal tubes in the pediatric critical care unit was not associated with an increased rate of endotracheal tube-related subglottic trauma.