Incidence of persistent postoperative opioid use in patients undergoing ambulatory surgery: a retrospective cohort study.

The opioid crisis remains a major public health concern. In ambulatory surgery, persistent postoperative opioid use is poorly described and temporal trends are unknown. A population-based retrospective cohort study was undertaken in Ontario, Canada using routinely collected administrative data for adults undergoing ambulatory surgery between 1 January 2013 and 31 December 2017. The primary outcome was persistent postoperative opioid use, defined using best-practice methods. Multivariable generalised linear models were used to estimate the association of persistent postoperative opioid use with prognostic factors. Temporal trends in opioid use were examined using monthly time series, adjusting for patient-, surgical- and hospital-level variables. Of 340,013 patients, 44,224 (13.0%, 95%CI 12.9-13.1%) developed persistent postoperative opioid use after surgery. Following multivariable adjustment, the strongest predictors of persistent postoperative opioid use were pre-operative: utilisation of opioids (OR 9.51, 95%CI 8.69-10.39); opioid tolerance (OR 88.22, 95%CI 77.21-100.79); and utilisation of benzodiazepines (OR 13.75, 95%CI 12.89-14.86). The time series model demonstrated a small but significant trend towards decreasing persistent postoperative opioid use over time (adjusted percentage change per year -0.51%, 95%CI -0.83 to -0.19%, p = 0.003). More than 10% of patients who underwent ambulatory surgery experienced persistent postoperative opioid use; however, there was a temporal trend towards a reduction in persistent opioid use after surgery. Future studies are needed that focus on interventions which reduce persistent postoperative opioid use.

The trend of percutaneous and open surgical procedures for peripheral arteriovenous malformations in the National Health Service England.

INTRODUCTION: This study aimed to assess the trend of percutaneous and open surgical procedures for peripheral arteriovenous malformations (AVMs) performed in NHS hospitals in England between 2012 and 2018. METHODS: Hospital Episode Statistics (HES) is a freely available data warehouse that represents the whole population of England served by the NHS. Data from the HES database was obtained and analysed for all hospital episodes between 2012 and 2018 for the total number and trend of 'primary diagnosis', and 'primary procedures and interventions' identified for peripheral AVMs. RESULTS: Over the period studied, there was an increase in the total number of admissions for peripheral AVMs; total primary diagnosis increased from 2242 to 2857 per year. Open surgery remained more commonly performed than percutaneous procedures throughout the studied period. However, the overall percentage of primary procedures and interventions being percutaneous in this period increased from 29.8% to 41.0% per year. The increase in the number of percutaneous procedures per year seemed to occur in both children (from 43 to 124) and adults (from 408 to 492) over the course of the study period. CONCLUSIONS: This study concluded that open surgery remained the most commonly performed primary procedure for peripheral AVMs, although there was an increasing trend for percutaneous procedures in NHS hospitals in England. The increase in the number and percentage of percutaneous procedures for peripheral AVMs was likely to have significant resource implications for the provision of care for patients with peripheral AVMs in NHS hospitals.

Examination of FERMT1 expression in placental chorionic villi and its role in HTR8-SVneo cell invasion.

Transmembrane integrin receptors mediate cell-extracellular matrix as well as cell-cell adhesion. As placental trophoblast cells undergo differentiation they display changes in integrin expression or switching, but the mechanism(s) of integrin activation that supports this differentiation is still unknown. The Fermitin family of adapter proteins (FERMT 1-3) are integrin activators that mediate integrin-mediated signaling. In this study, we examined the spatiotemporal pattern of expression of FERMT1 in human chorionic villi throughout gestation and its role in HTR8-SVneo substrate adhesion and invasion. Placental villous tissue was obtained from patients undergoing elective terminations at weeks 8-14, as well as from term deliveries at weeks 37-40 and analyzed by immunofluorescence. Additionally, HTR8-SVneo trophoblast cells were transfected with FERMT1-specific siRNA or non-targeting siRNA (control) and used in cell-substrate adhesion as well as invasion assays. FERMT1 was primarily localized to membrane-associated regions at the base or around the periphery of the villous cytotrophoblast and proximal as well as distal cell column trophoblast. FERMT1 was also localized to endothelial cells of blood vessels in chorionic villi. siRNA-mediated depletion of FERMT1 in HTR8-SVneo cells did not markedly alter HTR8-SVneo cell-substrate adhesion but did significantly decrease invasion (P < 0.05) compared to control cells. These novel findings identify the presence of the integrin activator FERMT1 in trophoblast cells and that FERMT1 can regulate HTR8-SVneo cell invasion. FERMT1 may directly influence integrin activation and the subsequent integrin-mediated signaling and differentiation that underlies the acquisition of the invasive trophoblast phenotype in vivo.

Regional anaesthesia quality indicators for adult patients undergoing non-cardiac surgery: a systematic review.

Improvement in healthcare delivery depends on the ability to measure outcomes that can direct changes in the system. An overview of quality indicators within the field of regional anaesthesia is lacking. This systematic review aims to synthesise available quality indicators, as per the Donabedian framework, and provide a concise overview of evidence-based quality indicators within regional anaesthesia. A systematic literature search was conducted using the databases MEDLINE, Embase, CINAHL and Cochrane from 2003 to present, and a prespecified search of regional anaesthesia society websites and healthcare quality agencies. The quality indicators relevant to regional anaesthesia were subdivided into peri-operative structure, process and outcome indicators as per the Donabedian framework. The methodological quality of the indicators was determined as per the Oxford Centre for Evidence-Based Medicine's framework. Twenty manuscripts met our inclusion criteria and, in total, 68 unique quality indicators were identified. There were 4 (6%) structure, 12 (18%) process and 52 (76%) outcome indicators. Most of the indicators were related to the safety (57%) and effectiveness (19%) of regional anaesthesia and were general in nature (60%). In addition, most indicators (84%) were based on low levels of evidence. Our study is an important first step towards describing quality indicators for the provision of regional anaesthesia. Future research should focus on the development of structure and process quality indicators and improving the methodological quality and usability of these indicators.

An evaluation of brigatinib as a promising treatment option for non-small cell lung cancer.

Introduction: Brigatinib is a second-line inhibitor for the treatment of rearranged anaplastic lymphoma kinase (ALK) in lung cancer patients which has significant activity against brain metastases. This tyrosine kinase inhibitor (TKI) overcomes a wide range of ALK mutations which confer therapeutic resistance and is increasingly applied in first-line therapy due to improved benefit for patients compared to crizotinib, the current standard of care. Areas covered: The authors review the development and characteristics of brigatinib and discuss the optimal clinical use and sequence of the application of ALK inhibitors in patients progressing under therapy. Expert opinion: ALK-rearranged NSCLC can be treated with a broad range of approved and novel inhibitors at various stages of therapy, including the second-line therapeutic brigatinib. Besides this TKI, the second-line ALK inhibitors alectinib and ceritinib, as well as the third-line lorlatinib are approved for the treatment of ALK-positive NSCLC patients. The main challenge is to find sequences and combinations of ALK inhibitors which provide the best benefit for the patients.

Lung nodules are reliably detectable on ultra-low-dose CT utilising model-based iterative reconstruction with radiation equivalent to plain radiography.

AIM: To determine if ultra-low-dose (ULD) computed tomography (CT) utilising model-based iterative reconstruction (MBIR) with radiation equivalent to plain radiography allows the detection of lung nodules. MATERIALS AND METHODS: Ninety-nine individuals undergoing surveillance of solid pulmonary nodules undertook a low-dose (LD) and ULD CT during the same sitting. Image pairs were read blinded, in random order, and independently by two experienced thoracic radiologists. With LD-CT as the reference standard, the number, size, and location of nodules was compared, and inter-rater agreement was established. RESULTS: There was very good inter-rater agreement with regards nodules ≥4mm for both the LD- (k=0.931) and ULD-CT (k=0.869). One hundred and ninety-nine nodules were reported on the LD-CT by both radiologists and 196 reported on the ULD-CT, with no nodules reported only on the ULD-CT. This gives a sensitivity of 98.5% and specificity of 100% for ULD-CT with MBIR. The effective dose of radiation was significantly different between the two scans (p<0.0001), 1.67 mSv for the LD-CT and 0.13 mSv for the ULD-CT. CONCLUSION: ULD-CT utilising MBIR and delivering radiation equivalent to plain radiography, allows detection of lung nodules with high sensitivity. The attendant 10-fold reduction in radiation may allow for dramatic reductions in cumulative radiation exposure.

Saddle nose deformity and septal perforation in granulomatosis with polyangiitis.

BACKGROUND: Patients who have granulomatosis with polyangiitis (GPA, syn. M. Wegener) often develop an external nose deformity which may have devastating psychological effects. Therefore, reconstruction of nasal deformities by rhinoplasty may become necessary to achieve a normal appearance. OBJECTIVE OF REVIEW: The aim of this systematic review was to investigate the efficacy and safety of surgical reconstruction in external nasal deformities and septal perforation in GPA patients. SEARCH STRATEGY: A systematic literature search with defined search terms was performed for scientific articles archived in the MEDLINE-Database up to 10 June 2016 (PubMed Advanced MEDLINE Search), describing management of cases or case series in GPA patients with saddle nose deformity and/or septal perforation. RESULTS: Eleven of 614 publications met the criteria for this analysis including 41 GPA patients undergoing external nasal reconstruction and/or septal reconstruction with a median follow-up of 2.6 years. Overall, saddle nose reconstruction in GPA patients is safe even if an increased rate of revision surgery has to be expected compared with individuals without GPA undergoing septorhinoplasty. Most implanted grafts were autografts of calvarial bone or costal cartilage. For septal perforation reconstruction, few studies were available. Therefore, based on the available data for surgical outcomes, it is impossible to make evidence-based recommendations. All included GPA patients had minimal or no local disease at the time of reconstructive surgery. Therefore, the relationship between disease activity and its impact on surgical outcomes remains unanswered. The potential impact of immune-modulating medications on increased complication rates and the impact of prophylactic antibiotics are unknown. CONCLUSIONS: This study systematically reviews the efficacy and safety of surgical reconstruction of external nasal deformities in GPA patients for the first time. Saddle nose reconstruction in GPA patients with minimal or no local disease is a safe procedure despite an increased rate of revision surgery. Further research is required regarding the impact of antibiotic prophylaxis, immune-modulating therapy, long-term outcomes and functional outcomes measured with subjective and objective parameters.

Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics.

Pulmonary thrombosis is a significant cause of patient mortality; however, there are no effective in vitro models of thrombi formation in human lung microvessels that could also assess therapeutics and toxicology of antithrombotic drugs. Here, we show that a microfluidic lung alveolus-on-a-chip lined by human primary alveolar epithelium interfaced with endothelium and cultured under flowing whole blood can be used to perform quantitative analysis of organ-level contributions to inflammation-induced thrombosis. This microfluidic chip recapitulates in vivo responses, including platelet-endothelial dynamics and revealed that lipopolysaccharide (LPS) endotoxin indirectly stimulates intravascular thrombosis by activating the alveolar epithelium, rather than acting directly on endothelium. This model is also used to analyze inhibition of endothelial activation and thrombosis due to a protease activated receptor-1 (PAR-1) antagonist, demonstrating its ability to dissect complex responses and identify antithrombotic therapeutics. Thus, this methodology offers a new approach to study human pathophysiology of pulmonary thrombosis and advance drug development.

Retrograde Extrusion of Coronary Thrombus During Urgent Aortocoronary Bypass Surgery: A Case Report.

A 73-year-old man underwent urgent coronary artery bypass grafting after an acute myocardial infarction. An angiogram had revealed multivessel disease with a circumflex artery lesion suspected as the primary culprit. On separation from cardiopulmonary bypass, transesophageal echocardiography revealed a new mobile mass in the aortic root. Cardiopulmonary bypass was reinstituted and a large thrombus emanating from the left coronary ostium was surgically removed. We hypothesize that the thrombus had originated from coronary retrograde extrusion during venous grafting. This case illustrates an unusual source of emboli during coronary artery bypass grafting and emphasizes the importance of perioperative transesophageal echocardiography for the prevention of potentially catastrophic outcomes.

Assessment of treatment response in non-alcoholic steatohepatitis using advanced magnetic resonance imaging.

BACKGROUND: Magnetic resonance imaging-derived measures of liver fat and volume are emerging as accurate, non-invasive imaging biomarkers in non-alcoholic steatohepatitis (NASH). Little is known about these measures in relation to histology longitudinally. AIM: To examine any relationship between MRI-derived proton-density fat-fraction (PDFF), total liver volume (TLV), total liver fat index (TLFI), vs. histology in a NASH trial. METHODS: This is a secondary analysis of a 24-week randomised, double-blind, placebo-controlled trial of 50 patients with biopsy-proven NASH randomised to oral ezetimibe 10 mg daily (n = 25) vs. placebo (n = 25). Baseline and post-treatment anthropometrics, biochemical profiling, MRI and biopsies were obtained. RESULTS: Baseline mean PDFF correlated strongly with TLFI (Spearman's ρ = 0.94, n = 45, P < 0.0001) and had good correlation with TLV (ρ = 0.57, n = 45, P < 0.0001). Mean TLV correlated strongly with TLFI (ρ = 0.78, n = 45, P < 0.0001). After 24 weeks, PDFF remained strongly correlated with TLFI (ρ = 0.94, n = 45, P < 0.0001), maintaining good correlation with TLV (ρ = 0.51, n = 45, P = 0.0004). TLV remained strongly correlated with TLFI (ρ = 0.74, n = 45, P < 0.0001). Patients with Grade 1 vs. 3 steatosis had lower PDFF, TLV, and TLFI (P < 0.0001, P = 0.0003, P < 0.0001 respectively). Regression analysis of changes in MRI-PDFF vs. TLV indicates that 10% reduction in MRI-PDFF predicts 257 mL reduction in TLV. CONCLUSIONS: The MRI-PDFF and TLV strongly correlated with TLFI. Decreases in steatosis were associated with an improvement in hepatomegaly. Lower values of these measures reflect lower histologic steatosis grades. MRI-derived measures of liver fat and volume may be used as dynamic and more responsive imaging biomarkers in a NASH trial, than histology.

Bone marrow fat content is correlated with hepatic fat content in paediatric non-alcoholic fatty liver disease.

AIM: To investigate the relationship between bone marrow fat content and hepatic fat content in children with known or suspected non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This was an institutional review board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant, cross-sectional, prospective analysis of data collected between October 2010 to March 2013 in 125 children with known or suspected NAFLD. Written informed consent was obtained for same-day research magnetic resonance imaging (MRI) of the lumbar spine, liver, and abdominal adiposity. Lumbar spine bone marrow proton density fat fraction (PDFF) and hepatic PDFF were estimated using complex-based MRI (C-MRI) techniques and magnitude-based MRI (M-MRI), respectively. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT) were quantified using high-resolution MRI. All images were acquired by two MRI technologists. Hepatic M-MRI images were analysed by an image analyst; all other images were analysed by a single investigator. The relationship between lumbar spine bone marrow PDFF and hepatic PDFF was assessed with and without adjusting for the presence of covariates using correlation and regression analysis. RESULTS: Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD prior to adjusting for covariates (r=0.33, p=0.0002). Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD (r=0.24, p=0.0079) after adjusting for age, sex, body mass index z-score, VAT, and SCAT in a multivariable regression analysis. CONCLUSION: Bone marrow fat content is positively associated with hepatic fat content in children with known or suspected NAFLD. Further research is needed to confirm these results and understand their clinical and biological implications.

Vertebral Tortuosity Index in Patients with Non-Connective Tissue Disorder-Related Aneurysm Disease.

OBJECTIVE: The vertebral tortuosity index (VTI) predicts increased risk of acute aortic events in patients with known genetic aortopathies. This study describes the VTI in a cohort of patients with non-connective tissue disorder-related large aneurysms. METHODS: Hospital imaging records from July 2012 to March 2016 were interrogated to identify patients with aneurysmal disease who had undergone computed tomographic angiography that included imaging of vertebral arteries. A control group of consecutive patients undergoing carotid and vertebral imaging was also assessed. VTI was calculated using the formula: [(centre-line distance) / (straight-line distance)-1] ×100 for all patients, and statistical analysis undertaken to determine whether measured VTI was statistically different in patients of younger age, with larger aneurysms, or an acute presentation. Comparison was made with patients who had no aneurysm disease. RESULTS: Sixty-five patients were identified with adequate imaging to assess the entire aorta, including vertebral arteries. The majority of patients were male (71%, 46/65) and mean age at the time of the CT scan was 71 years (SD 11.1 years). There were 11 patients under the age of 60 years in this cohort. The mean VTI was 33.17 (SD 20.43). There was no statistically significant difference between different territories of presentation (proximal vs. distal aneurysm, p=.94), age of patient (>60 years vs. <60 years, p=.2), or size of aneurysm (>6 cm vs. <6 cm, p=.09). Acuity of presentation was not predicted by a higher VTI (p=.69). The VTI in patients with aneurysms was higher than in patients without aneurysm disease (VTI = 16.1, p<.005) CONCLUSIONS: An elevated VTI is consistently present in patients with degenerative aneurysms and has potential as a universally available predictive measurement. However, the increased VTI in the older cohort without connective tissue disease may not carry the same predictive value for acute presentations as has been demonstrated in younger patients with a known genetic basis for their aortopathy.

A Comparison of Accuracy of Image- versus Hardware-based Tracking Technologies in 3D Fusion in Aortic Endografting.

OBJECTIVES: Fusion of three-dimensional (3D) computed tomography and intraoperative two-dimensional imaging in endovascular surgery relies on manual rigid co-registration of bony landmarks and tracking of hardware to provide a 3D overlay (hardware-based tracking, HWT). An alternative technique (image-based tracking, IMT) uses image recognition to register and place the fusion mask. We present preliminary experience with an agnostic fusion technology that uses IMT, with the aim of comparing the accuracy of overlay for this technology with HWT. METHOD: Data were collected prospectively for 12 patients. All devices were deployed using both IMT and HWT fusion assistance concurrently. Postoperative analysis of both systems was performed by three blinded expert observers, from selected time-points during the procedures, using the displacement of fusion rings, the overlay of vascular markings and the true ostia of renal arteries. The Mean overlay error and the deviation from mean error was derived using image analysis software. Comparison of the mean overlay error was made between IMT and HWT. The validity of the point-picking technique was assessed. RESULTS: IMT was successful in all of the first 12 cases, whereas technical learning curve challenges thwarted HWT in four cases. When independent operators assessed the degree of accuracy of the overlay, the median error for IMT was 3.9 mm (IQR 2.89-6.24, max 9.5) versus 8.64 mm (IQR 6.1-16.8, max 24.5) for HWT (p = .001). Variance per observer was 0.69 mm(2) and 95% limit of agreement ±1.63. CONCLUSION: In this preliminary study, the error of magnitude of displacement from the "true anatomy" during image overlay in IMT was less than for HWT. This confirms that ongoing manual re-registration, as recommended by the manufacturer, should be performed for HWT systems to maintain accuracy. The error in position of the fusion markers for IMT was consistent, thus may be considered predictable.

A review of the role of surgery for small cell lung cancer and the potential prognostic value of enumeration of circulating tumor cells.

Small cell lung cancer (SCLC) is disseminated in the majority of patients at first presentation and, thus, treated with chemoradiotherapy. Despite initial high response rates, chemoresistance appears rapidly and results in a dismal prognosis. However, patients with limited cancer may exhibit better disease control upon surgical treatment. Correct staging is highly critical in the selection of those patients which are likely to benefit from surgery. Studies of the inclusion of surgery in the multimodal treatment of SCLC vary widely in number of patients, selection, treatment and follow-up. Nevertheless surgical therapy for confined SCLCs achieves favorable long-term survival compared to chemoradiotherapy, depending on a precise assessment of the degree of tumor dissemination. Recently, extremely high counts of circulating tumor cells (CTCs) were reported in patients with SCLC compared to other malignancies. In several studies the number of CTCs was found to constitute a prognostic parameter and a marker of response to therapy. Therefore, the assessment of CTCs as so-called "Liquid Biopsy" seems to constitute a more precise method to detect tumor dissemination earlier when compared to clinical staging. In conclusion, in the era of precision oncology enumeration and identification of CTCs of SCLC patients have the potential to help in the selection of patients most suitable for tumor surgery.

Nanotopography and plasma treatment: redesigning the surface for vascular graft endothelialisation.

INTRODUCTION: Vascular graft materials in clinical use, such as polytetrafluoroethylene (PTFE) and Dacron, do not endothelialise and have low patency rates. The importance of an endothelial cell layer on the luminal surface of a vascular graft is well-known with surface topography and chemistry playing an important role. The aim of this study was to investigate the potential of plasma treatment and topographical structures on the luminal graft surface to enhance the self-endothelialisation potential of a nanocomposite vascular graft. METHODS: POSS-PCU is a polycarbonate urea urethane (PCU) with a nanoparticle, polyhedral oligomeric silsesquioxane (POSS) incorporated within it. Planar, microgrooved, and nanopit patterned polymer films were fabricated using photolithography, electron beam lithography, reactive ion etching, and replication by solvent casting. Films were then exposed to oxygen plasma treatment at different powers for a fixed time (40 W, 60 W, 80 W/60 seconds). Effects of plasma treatment were assessed using scanning electron microscopy, atomic force microscopy and water contact angle analysis. Human umbilical vein endothelial cell (HUVEC) proliferation and morphology were characterised using immunostaining, live/dead staining, and Coomassie blue staining. RESULTS: Successful embossing of the micro- and nanostructures was confirmed. Oxygen plasma treatment of the different samples showed that increasing power significantly increased the hydrophilicity of the samples (p < .0001). Improved HUVEC adhesion was seen on plasma modified compared with untreated samples (p < .0001). Coomassie blue staining showed that after 5 days, cells started to form monolayers and live/dead staining showed the cells were viable. Immunostaining showed that HUVECs expressed nitric oxide synthase on all topographies with focal adhesions appearing more pronounced on nanopit surfaces, showing retention of morphology and function. CONCLUSION: These encouraging results indicate a future important role for plasma treatment and nanotopography in the development of endothelialised vascular grafts.

Luminal surface engineering, 'micro and nanopatterning': potential for self endothelialising vascular grafts?

OBJECTIVE: New technologies are being explored to meet the clinical need for an 'off-the-shelf' small diameter vascular graft with superior or at least equivalent properties to autologous vessel. The field of nanotechnology and fabrication promises major advances in biomaterial design and wall structure to deliver biomimetic grafts. This review brings together recent work on this topic. METHODS: A literature search was conducted of PubMed and ISI Web of Knowledge using relevant keywords. Articles published after January 2005 were given preference. Personal communications and PhD theses were also used as sources. RESULTS: An evolving focus on surface patterning of biomaterials has been found to carry great potential. Influencing cellular behaviour on prosthetic grafts using graft luminal surface modulation at the micro- and nano-levels is the basis of this recent concept in vascular graft development. CONCLUSION: This technology may deliver small diameter grafts with the potential for spontaneous in situ endothelialisation without the need for prior 'seeding', with the potential to open a new chapter in vascular graft development.

Cholesterol and perhaps estradiol protect against corticosterone-induced hippocampal CA3 dendritic retraction in gonadectomized female and male rats.

Chronic stress or glucocorticoid exposure simplifies hippocampal Cornu Ammonis region 3 (CA3) apical dendritic arbors in male rats. In contrast to males, chronic stress either reduces CA3 basal branching or exerts no observable morphological effects in gonadally intact female rats. Under conditions that females display stress-induced CA3 dendritic retraction, such as that following ovariectomy, chronic exposure to 17ß-estradiol or cholesterol can negate these changes. Whether glucocorticoids produce CA3 dendritic retraction in ovariectomized females and whether neuroprotection from 17ß-estradiol or cholesterol is sex-specific remains unknown. The current study examined the effects of chronic glucocorticoid exposure, in conjunction with 17ß-estradiol or cholesterol administration, on hippocampal CA3 dendritic complexity. Adult male and female Sprague-Dawley rats were gonadectomized and implanted with 25% 17ß-estradiol in cholesterol, 100% cholesterol, or blank Silastic capsules. Rats were then assigned to either a 21-day corticosterone (CORT) drink (400µg/ml CORT, 2.4% ethanol in tap water) or tap water (Tap, 2.4% ethanol in tap water) treatment. Brains were processed for Golgi staining, and hippocampal CA3 dendritic architecture was quantified. Results showed 21-day CORT administration reduced hippocampal CA3 apical dendritic branch points, CA3 apical dendritic length, body weight gain, and adrenal weights compared to male and female control counterparts. Furthermore, male and female rats implanted with Silastic capsules containing cholesterol or 25% 17ß-estradiol in cholesterol were protected from CORT-induced CA3 apical dendritic branch reduction. No effects were observed in the CA3 basal dendritic arbors. The present results demonstrate that CORT produces hippocampal CA3 dendritic retraction in gonadectomized male and female rats and that cholesterol and 25% 17ß-estradiol in cholesterol prevent this dendritic simplification.

Sequential oxidations of thiolates and the cobalt metallocenter in a synthetic metallopeptide: implications for the biosynthesis of nitrile hydratase.

Cobalt nitrile hydratases (Co-NHase) contain a catalytic cobalt(III) ion coordinated in an N2S3 first coordination sphere composed of two amidate nitrogens and three cysteine-derived sulfur donors: a thiolate (-SR), a sulfenate (-S(R)O(-)), and a sulfinate (-S(R)O2(-)). The sequence of biosynthetic reactions that leads to the post-translational oxidations of the metal and the sulfur ligands is unknown, but the process is believed to be initiated directly by oxygen. Herein we utilize cobalt bound in an N2S2 first coordination sphere by a seven amino acid peptide known as SODA (ACDLPCG) to model this oxidation process. Upon exposure to oxygen, Co-SODA is oxidized in two steps. In the first fast step (seconds), magnetic susceptibility measurements demonstrated that the metallocenter remains paramagnetic, that is, Co(2+), and sulfur K-edge X-ray absorption spectroscopy (XAS) is used to show that one of the thiolates is oxidized to sulfinate. In a second process on a longer time scale (hours), magnetic susceptibility measurements and Co K-edge XAS show that the metal is oxidized to Co(3+). Unlike other model complexes, additional slow oxidation of the second thiolate in Co-SODA is not observed, and a catalytically active complex is never formed. The likely reason is the absence of the axial thiolate ligand. In essence, the reactivity of Co-SODA can be described as between previously described models which either quickly convert to final product or are stable in air, and it offers a first glimpse into a possible oxidation pathway for nitrile hydratase biosynthesis.