Publications by authors named "John Wood"

698 Publications

Atrial Fibrillation and Obesity: Reverse Remodeling of Atrial Substrate With Weight Reduction.

JACC Clin Electrophysiol 2021 Feb 19. Epub 2021 Feb 19.

Centre for Heart Rhythm Disorders, University of Adelaide, Adelaide, Australia; Department of Cardiology, Royal Adelaide Hospital, Adelaide, Australia. Electronic address:

Objectives: This study sought to evaluate the effect of weight loss on the atrial substrate for atrial fibrillation (AF).

Background: Whether weight loss can reverse the atrial substrate of obesity is not known.

Methods: Thirty sheep had sustained obesity induced by ad libitum calorie-dense diet over 72 weeks. Animals were randomized to 3 groups: sustained obesity and 15% and 30% weight loss. The animals randomized to weight loss underwent weight reduction by reducing the quantity of hay over 32 weeks. Eight lean animals served as controls. All were subjected to the following: dual-energy x-ray absorptiometry, echocardiogram, cardiac magnetic resonance, electrophysiological study, and histological and molecular analyses (fatty infiltration, fibrosis, transforming growth factor β1, and connexin 43).

Results: Sustained obesity was associated with increased left atrium (LA) pressure (p < 0.001), inflammation (p < 0.001), atrial transforming growth factor β1 protein (p < 0.001), endothelin-B receptor expression (p = 0.04), atrial fibrosis (p = 0.01), epicardial fat infiltration (p < 0.001), electrophysiological abnormalities, and AF burden (p = 0.04). Connexin 43 expression was decreased in the obese group (p = 0.03). In this obese ovine model, 30% weight reduction was associated with reduction in total body fat (p < 0.001), LA pressure (p = 0.007), inflammation (p < 0.001), endothelin-B receptor expression (p = 0.01), atrial fibrosis (p = 0.01), increase in atrial effective refractory period (cycle length: 400 and 300 ms; p < 0.001), improved conduction velocity (cycle length: 400 and 300 ms; p = 0.01), decreased conduction heterogeneity (p < 0.001), and decreased AF inducibility (p = 0.03). Weight loss was associated with a nonsignificant reduction in epicardial fat infiltration in posterior LA (p = 0.34).

Conclusions: Weight loss in an obese ovine model is associated with structural and electrophysiological reverse remodeling and a reduced propensity for AF. This provides evidence for the direct role of obesity in AF substrate and the role of weight reduction in patients with AF.
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http://dx.doi.org/10.1016/j.jacep.2020.11.015DOI Listing
February 2021

Pain Severity Correlates With Biopsy-Mediated Colonic Afferent Activation But Not Psychological Scores in Patients With IBS-D.

Clin Transl Gastroenterol 2021 Feb 22;12(2):e00313. Epub 2021 Feb 22.

NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK.

Introduction: Despite heterogeneity, an increased prevalence of psychological comorbidity and an altered pronociceptive gut microenvironment have repeatedly emerged as causative pathophysiology in patients with irritable bowel syndrome (IBS). Our aim was to study these phenomena by comparing gut-related symptoms, psychological scores, and biopsy samples generated from a detailed diarrhea-predominant IBS patient (IBS-D) cohort before their entry into a previously reported clinical trial.

Methods: Data were generated from 42 patients with IBS-D who completed a daily 2-week bowel symptom diary, the Hospital Anxiety and Depression score, and the Patient Health Questionnaire-12 Somatic Symptom score and underwent unprepared flexible sigmoidoscopy. Sigmoid mucosal biopsies were separately evaluated using immunohistochemistry and culture supernatants to determine cellularity, mediator levels, and ability to stimulate colonic afferent activity.

Results: Pain severity scores significantly correlated with the daily duration of pain (r = 0.67, P < 0.00001), urgency (r = 0.57, P < 0.0005), and bloating (r = 0.39, P < 0.05), but not with psychological symptom scores for anxiety, depression, or somatization. Furthermore, pain severity scores from individual patients with IBS-D were significantly correlated (r = 0.40, P < 0.008) with stimulation of colonic afferent activation mediated by their biopsy supernatant, but not with biopsy cell counts nor measured mediator levels.

Discussion: Peripheral pronociceptive changes in the bowel seem more important than psychological factors in determining pain severity within a tightly phenotyped cohort of patients with IBS-D. No individual mediator was identified as the cause of this pronociceptive change, suggesting that nerve targeting therapeutic approaches may be more successful than mediator-driven approaches for the treatment of pain in IBS-D.
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http://dx.doi.org/10.14309/ctg.0000000000000313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901800PMC
February 2021

Ionic charge distributions in silicon atomic surface wires.

Nanoscale 2021 Feb;13(5):3237-3245

Department of Physics, University of Alberta, Edmonton, Alberta T6G 2J1, Canada. and Quantum Silicon Inc., Edmonton, Alberta T6G 2M9, Canada and Nanotechnology Research Centre, National Research Council Canada, Edmonton, Alberta T6G 2M9, Canada.

Using a non-contact atomic force microscope (nc-AFM), we examine continuous dangling bond (DB) wire structures patterned on the hydrogen terminated silicon (100)-2 × 1 surface. By probing the DB structures at varying energies, we identify the formation of previously unobserved ionic charge distributions which are correlated to the net charge of DB wires and their predicted degrees of freedom in lattice distortions. Performing spectroscopic analysis, we identify higher energy configurations corresponding to alternative lattice distortions as well as tip-induced charging effects. By varying the length and orientation of these DB structures, we further highlight key features in the formation of these ionic surface phases.
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http://dx.doi.org/10.1039/d0nr08295cDOI Listing
February 2021

Total Synthesis of -Plagiochianin B.

Org Lett 2021 Feb 30;23(4):1243-1246. Epub 2021 Jan 30.

Department of Chemistry and Biochemistry, Baylor University, One Bear Place 97348, Waco, Texas 76798, United States.

An enantioselective total synthesis of plagiochianin B is described that employs (+)-3-carene as its point of departure and delivers the enantiomer of the natural product. Key features of the synthesis include a palladium-mediated regioselective oxidative cleavage of an olefin residing on a pyridine derived from a 6π-azatriene electrocyclization.
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http://dx.doi.org/10.1021/acs.orglett.0c04219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901668PMC
February 2021

Correction: Significant Determinants of Mouse Pain Behaviour.

PLoS One 2021 15;16(1):e0245813. Epub 2021 Jan 15.

[This corrects the article DOI: 10.1371/journal.pone.0104458.].
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245813PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810306PMC
January 2021

Tract-specific analysis and neurocognitive functioning in sickle cell patients without history of overt stroke.

Brain Behav 2021 Jan 12:e01978. Epub 2021 Jan 12.

CIBORG Laboratory, Department of Radiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Introduction: Sickle cell disease (SCD) is a hereditary blood disorder in which the oxygen-carrying hemoglobin molecule in red blood cells is abnormal. SCD patients are at increased risks for strokes and neurocognitive deficit, even though neurovascular screening and treatments have lowered the rate of overt strokes. Tract-specific analysis (TSA) is a statistical method to evaluate microstructural WM damage in neurodegenerative disorders, using diffusion tensor imaging (DTI).

Methods: We utilized TSA and compared 11 major brain WM tracts between SCD patients with no history of overt stroke, anemic controls, and healthy controls. We additionally examined the relationship between the most commonly used DTI metric of WM tracts and neurocognitive performance in the SCD patients and healthy controls.

Results: Disruption of WM microstructure orientation-dependent metrics for the SCD patients was found in the genu of the corpus callosum (CC), cortico-spinal tract, inferior fronto-occipital fasciculus, right inferior longitudinal fasciculus, superior longitudinal fasciculus, and left uncinate fasciculus. Neurocognitive performance indicated slower processing speed and lower response inhibition skills in SCD patients compared to controls. TSA abnormalities in the CC were significantly associated with measures of processing speed, working memory, and executive functions.

Conclusion: Decreased DTI-derived metrics were observed on six tracts in chronically anemic patients, regardless of anemia subtype, while two tracks with decreased measures were unique to SCD patients. Patients with WMHs had more significant FA abnormalities. Decreased FA values in the CC significantly correlated with all nine neurocognitive tests, suggesting a critical importance for CC in core neurocognitive processes.
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http://dx.doi.org/10.1002/brb3.1978DOI Listing
January 2021

Juvenile recurrent parotitis: Review and proposed management algorithm.

Int J Pediatr Otorhinolaryngol 2021 Mar 4;142:110617. Epub 2021 Jan 4.

Dept of Paediatric ORL, Starship Children's Hospital, Grafton, Auckland, New Zealand; Dept of Surgery & Dept of Paediatrics, University of Auckland, New Zealand.

Introduction: Despite being the second most common salivary disease in childhood, the aetiology and appropriate management of juvenile recurrent parotitis (JRP) remains uncertain. Consequently patients may be misdiagnosed, or even undergo indeterminate or potentially invasive procedures without benefit. This article reviews the current understanding of the epidemiology and pathophysiology of JRP, and to appraise the management options available.

Methods And Results: Medline and Google Scholar databases were searched and peer reviewed journal articles assessed. The epidemiology of JRP remains uncertain, and the clinical presentation of JRP can vary widely in frequency and severity. Diagnosis is still largely based on clinical signs and symptoms including parotid swelling, pain and fever. Investigation typically focuses on the exclusion of other diseases and immunodeficiencies, however there are noted typical radiological findings on both ultrasound and magnetic resonance imaging. The ideal management of this condition still remains unclear, however symptoms typically resolve by puberty. Treatment focuses on minimally invasive procedures such as sialography and sialendoscopy to reduce the frequency and severity of acute episodes.

Conclusions: Acute episodes of JRP can occur up to 30 times per year and have a significant impact on the quality of life of an affected child. Consequently a management algorithm is proposed based on the exclusion of other pathology. There is increasing evidence for non-ablative, minimally invasive approaches such as sialography and sialendoscopy to reduce the impact of this disease.
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http://dx.doi.org/10.1016/j.ijporl.2021.110617DOI Listing
March 2021

Staurosporine Analogs Via C-H Borylation.

ACS Med Chem Lett 2020 Dec 30;11(12):2441-2445. Epub 2020 Oct 30.

Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76798, United States.

Staurosporine is among the most potent naturally occurring kinase inhibitors isolated to date and has served as a lead compound for numerous drug development efforts in several therapeutic areas. Herein we report that C-H borylation chemistry provides access to analogs of staurosporine that were previously inaccessible to medicinal chemists who, in the past four decades, have prepared over 1000 semisynthetic staurosporine analogs.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734790PMC
December 2020

Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin.

Proc Natl Acad Sci U S A 2020 12 14;117(52):33619-33627. Epub 2020 Dec 14.

The Jackson Laboratory, Bar Harbor, ME 04609;

Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Here, we used RNA-sequencing and metabolomics to examine early glaucoma in DBA/2J mice. We demonstrate gene expression changes that significantly impact pathways mediating the metabolism and transport of glucose and pyruvate. Subsequent metabolic studies characterized an intraocular pressure (IOP)-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Remarkably, retinal glucose levels were elevated 50-fold, consistent with decreased glycolysis but possibly including glycogen mobilization and other metabolic changes. Oral supplementation of the glycolytic product pyruvate strongly protected from neurodegeneration in both rat and mouse models of glaucoma. Investigating further, we detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration, supporting a damaging role for IOP-induced mTOR activation in perturbing metabolism and promoting glaucoma. Together, these findings support the use of treatments that limit metabolic disturbances and provide bioenergetic support. Such treatments provide a readily translatable strategy that warrants investigation in clinical trials.
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http://dx.doi.org/10.1073/pnas.2014213117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776900PMC
December 2020

Acute respiratory infections in hospitalised infants with congenital heart disease.

Cardiol Young 2020 Dec 14:1-9. Epub 2020 Dec 14.

Division of Hospital Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Objectives: To assess the overall burden and outcomes of acute respiratory infections in paediatric inpatients with congenital heart disease (CHD).

Methods: This is a retrospective cross-sectional study of non-neonates <1 year with CHD in the Kid's Inpatient Database from 2012. We compared demographics, clinical characteristics, cost, length of stay, and mortality rate for those with and without respiratory infections. We also compared those with respiratory infections who had critical CHD versus non-critical CHD. Multi-variable regression analyses were done to look for associations between respiratory infections and mortality, length of stay, and cost.

Results: Of the 28,696 infants with CHD in our sample, 26% had respiratory infections. Respiratory infection-associated hospitalisations accounted for $440 million in costs (32%) for all CHD patients. After adjusting for confounders including severity, mortality was higher for those with respiratory infections (OR 1.5, p = 0.003), estimated mean length of stay was longer (14.7 versus 12.2 days, p < 0.001), and estimated mean costs were higher ($53,760 versus $46,526, p < 0.001). Compared to infants with respiratory infections and non-critical CHD, infants with respiratory infections and critical CHD had higher mortality (4.5 versus 2.3%, p < 0.001), longer mean length of stay (20.1 versus 15.5 days, p < 0.001), and higher mean costs ($94,284 versus $52,585, p < 0.001).

Conclusion: Acute respiratory infections are a significant burden on infant inpatients with CHD and are associated with higher mortality, costs, and longer length of stay; particularly in those with critical CHD. Future interventions should focus on reducing the burden of respiratory infections in this population.
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http://dx.doi.org/10.1017/S1047951120004333DOI Listing
December 2020

Study protocol for evaluation of aid to diagnosis for developmental dysplasia of the hip in general practice: controlled trial randomised by practice.

BMJ Open 2020 12 2;10(12):e041837. Epub 2020 Dec 2.

Research Department of Primary Care and Population Health, UCL, London, UK.

Introduction: In the UK, a compulsory '6-week hip check' is performed in primary care for the detection of developmental dysplasia of the hip (DDH). However, missed diagnoses and infants incorrectly labelled with DDH remain a problem, potentially leading to adverse consequences for infants, their families and the National Health Service. National policy states that infants should be referred to hospital if the 6-week check suggests DDH, though there is no available tool to aid examination or offer guidelines for referral. We developed standardised diagnostic criteria for DDH, based on international Delphi consensus, and a 9-item checklist that has the potential to enable non-experts to diagnose DDH in a manner approaching that of experts.

Methods And Analysis: We will conduct a controlled trial randomised by practice that will compare a diagnostic aid against standard care for the hip check. The primary objective is to determine whether an aid to the diagnosis of DDH reduces the number of clinically insignificant referrals from primary care to hospital and the number of late diagnosed DDH. The trial will include a qualitative process evaluation, an assessment of professional behavioural change and a full health economic evaluation. We will recruit 152 general practitioner practices in England. These will be randomised to conduct the hip checks with use of the study diagnostic aid and/or as per usual practice. The total number of infants seen during a 15-month recruitment period will be 110 per practice. Two years after the 6-week hip check, we will measure the number of referred infants that are (1) clinically insignificant for DDH and (2) those that constitute appropriate referrals.

Ethics And Dissemination: This study has approval from the Health Research Authority (16/1/2020) and the Confidentiality Advisory Group (18/2/2020). Results will be published in peer-reviewed academic journals, disseminated to patient organisations and the media.

Trial Registration Number: NCT04101903; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-041837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713187PMC
December 2020

Sensitization of Cutaneous Primary Afferents in Bone Cancer Revealed by In Vivo Calcium Imaging.

Cancers (Basel) 2020 Nov 24;12(12). Epub 2020 Nov 24.

Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.

Cancer-induced bone pain (CIBP) is a complex condition, comprising components of inflammatory and neuropathic processes, but changes in the physiological response profiles of bone-innervating and cutaneous afferents remain poorly understood. We used a combination of retrograde labelling and in vivo calcium imaging of bone marrow-innervating dorsal root ganglia (DRG) neurons to determine the contribution of these cells in the maintenance of CIBP. We found a majority of femoral bone afferent cell bodies in L3 dorsal root ganglia (DRG) that also express the sodium channel subtype Na1.8-a marker of nociceptive neurons-and lack expression of parvalbumin-a marker for proprioceptive primary afferents. Surprisingly, the response properties of bone marrow afferents to both increased intraosseous pressure and acid were unchanged by the presence of cancer. On the other hand, we found increased excitability and polymodality of cutaneous afferents innervating the ipsilateral paw in cancer bearing animals, as well as a behavioural phenotype that suggests changes at the level of the DRG contribute to secondary hypersensitivity. This study demonstrates that cutaneous afferents at distant sites from the tumour bearing tissue contribute to mechanical hypersensitivity, highlighting these cells as targets for analgesia.
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http://dx.doi.org/10.3390/cancers12123491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760605PMC
November 2020

Loss of alpha-globin genes in human subjects is associated with improved nitric oxide-mediated vascular perfusion.

Am J Hematol 2021 Mar 12;96(3):277-281. Epub 2020 Dec 12.

Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California, USA.

Alpha thalassemia is a hemoglobinopathy due to decreased production of the α-globin protein from loss of up to four α-globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co-inherit the loss of one or two α-globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α-globin gene deletions affect sickle red cell deformability, the α-globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of α-globin due to α-thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow-mediated dilation and microvascular post-occlusive reactive hyperemia in 27 human subjects (15 missing one or two α-globin genes and 12 healthy controls). Flow-mediated dilation was significantly higher in subjects with α-trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in α-globin gene status. This may explain the beneficial effect of α-globin gene loss in sickle cell disease and suggests that α-globin gene status may play a role in other vascular diseases.
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http://dx.doi.org/10.1002/ajh.26058DOI Listing
March 2021

Progression in Fontan conduit stenosis and hemodynamic impact during childhood and adolescence.

J Thorac Cardiovasc Surg 2020 Oct 29. Epub 2020 Oct 29.

Division of Pediatric Cardiology, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, Calif. Electronic address:

Objective: To characterize changes in Fontan conduit size over time and determine if cross-sectional area (CSA) affects cardiac output, pulmonary artery growth, and exercise capacity.

Methods: We conducted a retrospective cross-sectional study of patients with Fontan physiology who underwent cardiac magnetic resonance imaging or cardiac catheterization between January 2013 and October 2019. We collected Fontan and pulmonary artery measurements, hemodynamic data, and cardiopulmonary exercise test data. We identified 158 patients with an extracardiac Fontan. We measured minimum and mean Fontan conduit CSA and assessed whether these correlated with Nakata index, cardiac index, or exercise capacity.

Results: Minimum Fontan CSA decreased by a median of 33% (24%, 40%) during a mean follow-up of 9.6 years. Median percentage decrease in Fontan CSA did not differ among 16-, 18-, and 20-mm conduits (P = .29). There was a significant decrease in the minimum Fontan CSA (33% [25%, 41%]) starting less than 1-year post-Fontan. Median Nakata index was 177.6 mm/m (149.1, 210.8) and was not associated with Fontan CSA/BSA (ρ = 0.09, P = .29). Fontan CSA/BSA was not associated with cardiac index (ρ = -0.003, P = .97). A larger Fontan CSA/BSA had a modest correlation with % predicted oxygen consumption (ρ = 0.31, P = .013).

Conclusions: Fontan conduit CSA decreases as early as 6 months post-Fontan. The minimum Fontan CSA/BSA was not associated with cardiac index or pulmonary artery size but did correlate with % predicted peak oxygen consumption.
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http://dx.doi.org/10.1016/j.jtcvs.2020.09.140DOI Listing
October 2020

Kidney iron deposition by R2* is associated with haemolysis and urinary iron.

Br J Haematol 2020 Nov 20. Epub 2020 Nov 20.

Department of Pediatrics, Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Kidney iron deposition measured by R2* (magnetic resonance imaging) MRI is posited to result from tubular reabsorption of filtered haemoglobin due to intravascular haemolysis. In chronically transfused sickle cell disease (SCD), R2* is elevated and positively correlated with lactate dehydrogenase (LDH). To account for contributions to renal iron from systemic iron overload, we evaluated kidney R2*, urinary iron and haemolysis markers in 62 non-transfused SCD patients. On multivariate analysis, kidney R2* was associated with urinary iron and LDH (R  = 0·55, P < 0·0001). Our study confirms that kidney R2* is associated with intravascular haemolysis and raises important questions regarding the role of iron in SCD nephropathy.
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http://dx.doi.org/10.1111/bjh.17085DOI Listing
November 2020

Physiologic osteoclasts are not sufficient to induce skeletal pain in mice.

Eur J Pain 2021 Jan 12;25(1):199-212. Epub 2020 Oct 12.

Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK.

Background: Increased bone resorption is driven by augmented osteoclast activity in pathological states of the bone, including osteoporosis, fracture and metastatic bone cancer. Pain is a frequent co-morbidity in bone pathologies and adequate pain management is necessary for symptomatic relief. Bone cancer is associated with severe skeletal pain and dysregulated bone remodelling, while increased osteoclast activity and bone pain are also observed in osteoporosis and during fracture repair. However, the effects of altered osteoclast activity and bone resorption on nociceptive processing of bone afferents remain unclear.

Methods: This study investigates whether physiologic osteoclasts and resulting changes in bone resorption can induce skeletal pain. We first assessed correlation between changes in bone microarchitecture (through µCT) and skeletal pain using standardized behavioural phenotyping assays in a mouse model of metastatic bone cancer. We then investigated whether increased activity of physiologic osteoclasts, and the associated bone resorption, is sufficient to induce skeletal pain using mouse models of localized and widespread bone resorption following administration of exogenous receptor activator of nuclear factor kappa-B ligand (RANKL).

Results: Our data demonstrates that mice with bone cancer exhibit progressive pain behaviours that correlate with increased bone resorption at the tumour site. Systemic RANKL injections enhance osteoclast activity and associated bone resorption, without producing any changes in motor function or pain behaviours at both early and late timepoints.

Conclusion: These findings suggest that activation of homeostatic osteoclasts alone is not sufficient to induce skeletal pain in mice.

Significance Statement: The role of osteoclasts in peripheral sensitization of sensory neurones is not fully understood. This study reports on the direct link between oestrogen-independent osteoclast activation and skeletal pain. Administration of exogenous receptor activator of nuclear factor kappa-B ligand (RANKL) increases bone resorption, but does not produce pro-nociceptive changes in behavioural pain thresholds. Our data demonstrates that physiologic osteoclasts are not essential for skeletal pain behaviours.
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http://dx.doi.org/10.1002/ejp.1662DOI Listing
January 2021

Tricuspid regurgitant jet velocity and myocardial tissue Doppler parameters predict mortality in a cohort of patients with sickle cell disease spanning from pediatric to adult age groups - revisiting this controversial concept after 16 years of additional evidence.

Am J Hematol 2021 01 12;96(1):31-39. Epub 2020 Oct 12.

Cardiology, Children's Hospital Los Angeles, Los Angeles, California, USA.

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi-level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S') and diastole (E'), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty-eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional-hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end-organ failure. On Cox proportional-hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S' results in a 91% increase, and 1 cm/s decrease in E' results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers.
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http://dx.doi.org/10.1002/ajh.26003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746595PMC
January 2021

Software for Quantifying and Batch Processing Images of Brn3a and RBPMS Immunolabelled Retinal Ganglion Cells in Retinal Wholemounts.

Transl Vis Sci Technol 2020 05 27;9(6):28. Epub 2020 May 27.

Ophthalmic Research Laboratories, Discipline of Ophthalmology and Visual Sciences, University of Adelaide, Adelaide Health and Medical Sciences Building, North Terrace, Adelaide, Australia.

Purpose: The ability to accurately quantify immunohistochemically labeled retinal ganglion cells (RGCs) on wholemounts is an important histopathological determinant in experimental retinal research. Traditionally, this has been performed by manual or semi-automated counting of RGCs. Here, we describe an automated software that accurately and efficiently counts immunolabeled RGCs with the ability to batch process images and perform whole-retinal analysis to permit isodensity map generation.

Methods: Retinal wholemounts from control rat eyes, and eyes subjected to either chronic ocular hypertension or N-methyl-D-aspartate (NMDA)-induced excitotoxicity, were labeled by immunohistochemistry for two different RGC-specific markers, Brn3a and RNA-binding protein with multiple splicing (RBPMS). For feasibility of manual counting, images were sampled from predefined retinal sectors, totaling 160 images for Brn3a and 144 images for RBPMS. The automated program was initially calibrated for each antibody prior to batch analysis to ensure adequate cell capture. Blinded manual RGC counts were performed by three independent observers.

Results: The automated counts of RGCs labeled for Brn3a and RBPMS closely matched manual counts. The automated script accurately quantified both physiological and damaged retinas. Efficiency in counting labeled RGC wholemount images is accelerated 40-fold with the automated software. Whole-retinal analysis was demonstrated with integrated retinal isodensity map generation.

Conclusions: This automated cell counting software dramatically accelerates data acquisition while maintaining accurate RGC counts across different immunolabels, methods of injury, and spatial heterogeneity of RGC loss. This software likely has potential for wider application.

Translational Relevance: This study provides a valuable tool for preclinical RGC neuroprotection studies that facilitates the translation of neuroprotection to the clinic.
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http://dx.doi.org/10.1167/tvst.9.6.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409150PMC
May 2020

Safety Profile of Slit-Lamp-Delivered Retinal Laser Photobiomodulation.

Transl Vis Sci Technol 2020 03 23;9(4):22. Epub 2020 Mar 23.

Ophthalmic Research Laboratories, Discipline of Ophthalmology and Visual Sciences, University of Adelaide, Adelaide, South Australia, Australia.

Purpose: Photobiomodulation (PBM) refers to therapeutic irradiation of tissue with low-energy, 630- to 1000-nm wavelength light. An increasing body of evidence supports a beneficial effect of PBM in retinal disorders. To date, most studies have utilized light-emitting diode irradiation sources. Slit-lamp-mounted retinal lasers produce a coherent beam that can be delivered with precisely defined dosages and predetermined target area; however, the use of retinal lasers raises safety concerns that warrant investigation prior to clinical application. In this study, we determined safe dosages of laser-delivered PBM to the retina.

Methods: A custom-designed, slit-lamp-delivered, 670-nm, red/near-infrared laser was used to administer a range of irradiances to healthy pigmented and non-pigmented rat retinas. The effects of PBM on various functional and structural parameters of the retina were evaluated utilizing a combination of electroretinography, Spectral Domain Optical Coherence (SD-OCT), fluorescein angiography, histology and immunohistochemistry.

Results: In non-pigmented rats, no adverse events were identified at any irradiances up to 500 mW/cm. In pigmented rats, no adverse events were identified at irradiances of 25 or 100 mW/cm; however, approximately one-third of rats that received 500 mW/cm displayed very localized photoreceptor damage in the peripapillary region, typically adjacent to the optic nerve head.

Conclusions: A safety threshold exists for laser-delivered PBM in pigmented retinas and was identified as 500 mW/cm irradiance; therefore, caution should be exercised in the dosage of laser-delivered PBM administered to pigmented retinas.

Translational Relevance: This study provides important data necessary for clinical translation of laser-delivered PBM for retinal diseases.
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http://dx.doi.org/10.1167/tvst.9.4.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396177PMC
March 2020

Quantitative perfusion mapping with induced transient hypoxia using BOLD MRI.

Magn Reson Med 2021 01 27;85(1):168-181. Epub 2020 Jul 27.

Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.

Purpose: Gadolinium-based dynamic susceptibility contrast (DSC) is commonly used to characterize blood flow in patients with stroke and brain tumors. Unfortunately, gadolinium contrast administration has been associated with adverse reactions and long-term accumulation in tissues. In this work, we propose an alternative deoxygenation-based DSC (dDSC) method that uses a transient hypoxia gas paradigm to deliver a bolus of paramagnetic deoxygenated hemoglobin to the cerebral vasculature for perfusion imaging.

Methods: Through traditional DSC tracer kinetic modeling, the MR signal change induced by this hypoxic bolus can be used to generate regional perfusion maps of cerebral blood flow, cerebral blood volume, and mean transit time. This gas paradigm and blood-oxygen-level-dependent (BOLD)-MRI were performed concurrently on a cohort of 66 healthy and chronically anemic subjects (age 23.5 ± 9.7, female 64%).

Results: Our results showed reasonable global and regional agreement between dDSC and other flow techniques, such as phase contrast and arterial spin labeling.

Conclusion: In this proof-of-concept study, we demonstrated the feasibility of using transient hypoxia to generate a contrast bolus that mimics the effect of gadolinium and yields reasonable perfusion estimates. Looking forward, optimization of the hypoxia boluses and measurement of the arterial-input function is necessary to improve the accuracy of dDSC. Additionally, a cross-validation study of dDSC and DSC in brain tumor and ischemic stroke subjects is warranted to evaluate the clinical diagnostic utility of this approach.
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http://dx.doi.org/10.1002/mrm.28422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728454PMC
January 2021

New Guinea has the world's richest island flora.

Authors:
Rodrigo Cámara-Leret David G Frodin Frits Adema Christiane Anderson Marc S Appelhans George Argent Susana Arias Guerrero Peter Ashton William J Baker Anders S Barfod David Barrington Renata Borosova Gemma L C Bramley Marie Briggs Sven Buerki Daniel Cahen Martin W Callmander Martin Cheek Cheng-Wei Chen Barry J Conn Mark J E Coode Iain Darbyshire Sally Dawson John Dransfield Clare Drinkell Brigitta Duyfjes Atsushi Ebihara Zacky Ezedin Long-Fei Fu Osia Gideon Deden Girmansyah Rafaël Govaerts Helen Fortune-Hopkins Gustavo Hassemer Alistair Hay Charlie D Heatubun D J Nicholas Hind Peter Hoch Peter Homot Peter Hovenkamp Mark Hughes Matthew Jebb Laura Jennings Tiberius Jimbo Michael Kessler Ruth Kiew Sandra Knapp Penniel Lamei Marcus Lehnert Gwilym P Lewis Hans Peter Linder Stuart Lindsay Yee Wen Low Eve Lucas Jeffrey P Mancera Alexandre K Monro Alison Moore David J Middleton Hidetoshi Nagamasu Mark F Newman Eimear Nic Lughadha Pablo H A Melo Daniel J Ohlsen Caroline M Pannell Barbara Parris Laura Pearce Darin S Penneys Leon R Perrie Peter Petoe Axel Dalberg Poulsen Ghillean T Prance J Peter Quakenbush Niels Raes Michele Rodda Zachary S Rogers André Schuiteman Pedro Schwartsburd Robert W Scotland Mark P Simmons David A Simpson Peter Stevens Michael Sundue Weston Testo Anna Trias-Blasi Ian Turner Timothy Utteridge Lesley Walsingham Bruce L Webber Ran Wei George D Weiblen Maximilian Weigend Peter Weston Willem de Wilde Peter Wilkie Christine M Wilmot-Dear Hannah P Wilson John R I Wood Li-Bing Zhang Peter C van Welzen

Nature 2020 08 5;584(7822):579-583. Epub 2020 Aug 5.

Naturalis Biodiversity Center, Leiden, The Netherlands.

New Guinea is the world's largest tropical island and has fascinated naturalists for centuries. Home to some of the best-preserved ecosystems on the planet and to intact ecological gradients-from mangroves to tropical alpine grasslands-that are unmatched in the Asia-Pacific region, it is a globally recognized centre of biological and cultural diversity. So far, however, there has been no attempt to critically catalogue the entire vascular plant diversity of New Guinea. Here we present the first, to our knowledge, expert-verified checklist of the vascular plants of mainland New Guinea and surrounding islands. Our publicly available checklist includes 13,634 species (68% endemic), 1,742 genera and 264 families-suggesting that New Guinea is the most floristically diverse island in the world. Expert knowledge is essential for building checklists in the digital era: reliance on online taxonomic resources alone would have inflated species counts by 22%. Species discovery shows no sign of levelling off, and we discuss steps to accelerate botanical research in the 'Last Unknown'.
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http://dx.doi.org/10.1038/s41586-020-2549-5DOI Listing
August 2020

Retinal energy metabolism in health and glaucoma.

Prog Retin Eye Res 2020 Jul 23:100881. Epub 2020 Jul 23.

Ophthalmic Research Laboratories, University of Adelaide, Adelaide Health and Medical Sciences Building, North Terrace, Adelaide, SA, 5000, Australia.

Energy metabolism refers to the processes by which life transfers energy to do cellular work. The retina's relatively large energy demands make it vulnerable to energy insufficiency. In addition, evolutionary pressures to optimize human vision have been traded against retinal ganglion cell bioenergetic fragility. Details of the metabolic profiles of the different retinal cells remain poorly understood and are challenging to resolve. Detailed immunohistochemical mapping of the energy pathway enzymes and substrate transporters has provided some insights and highlighted interspecies differences. The different spatial metabolic patterns between the vascular and avascular retinas can account for some inconsistent data in the literature. There is a consilience of evidence that at least some individuals with glaucoma have impaired RGC energy metabolism, either due to impaired nutrient supply or intrinsic metabolic perturbations. Bioenergetic-based therapy for glaucoma has a compelling pathophysiological foundation and is supported by recent successes in animal models. Recent demonstrations of visual and electrophysiological neurorecovery in humans with glaucoma is highly encouraging and motivates longer duration trials investigating bioenergetic neuroprotection.
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http://dx.doi.org/10.1016/j.preteyeres.2020.100881DOI Listing
July 2020

Preclinical and clinical studies of photobiomodulation therapy for macular oedema.

Diabetologia 2020 09 14;63(9):1900-1915. Epub 2020 Jul 14.

Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW, 2000, Australia.

Aims/hypothesis: Diabetic macular oedema (DME) is the leading cause of visual impairment in people with diabetes. Intravitreal injections of vascular endothelial growth factor inhibitors or corticosteroids prevent loss of vision by reducing DME, but the injections must be given frequently and usually for years. Here we report laboratory and clinical studies on the safety and efficacy of 670 nm photobiomodulation (PBM) for treatment of centre-involving DME.

Methods: The therapeutic effect of PBM delivered via a light-emitting diode (LED) device was tested in transgenic mice in which induced Müller cell disruption led to photoreceptor degeneration and retinal vascular leakage. We also developed a purpose-built 670 nm retinal laser for PBM to treat DME in humans. The effect of laser-delivered PBM on improving mitochondrial function and protecting against oxidative stress was studied in cultured rat Müller cells and its safety was studied in pigmented and non-pigmented rat eyes. We then used the retinal laser to perform PBM in an open-label, dose-escalation Phase IIa clinical trial involving 21 patients with centre-involving DME. Patients received 12 sessions of PBM over 5 weeks for 90 s per treatment at a setting of 25, 100 or 200 mW/cm for the three sequential cohorts of 6-8 patients each. Patients were recruited from the Sydney Eye Hospital, over the age of 18 and had centre-involving DME with central macular thickness (CMT) of >300 μm with visual acuity of 75-35 Log minimum angle of resolution (logMAR) letters (Snellen visual acuity equivalent of 20/30-20/200). The objective of this trial was to assess the safety and efficacy of laser-delivered PBM at 2 and 6 months. The primary efficacy outcome was change in CMT at 2 and 6 months.

Results: LED-delivered PBM enhanced photoreceptor mitochondrial membrane potential, protected Müller cells and photoreceptors from damage and reduced retinal vascular leakage resulting from induced Müller cell disruption in transgenic mice. PBM delivered via the retinal laser enhanced mitochondrial function and protected against oxidative stress in cultured Müller cells. Laser-delivered PBM did not damage the retina in pigmented rat eyes at 100 mW/cm. The completed clinical trial found a significant reduction in CMT at 2 months by 59 ± 46 μm (p = 0.03 at 200 mW/cm) and significant reduction at all three settings at 6 months (25 mW/cm: 53 ± 24 μm, p = 0.04; 100 mW/cm: 129 ± 51 μm, p < 0.01; 200 mW/cm: 114 ± 60 μm, p < 0.01). Laser-delivered PBM was well tolerated in humans at settings up to 200 mW/cm with no significant side effects.

Conclusions/interpretation: PBM results in anatomical improvement of DME over 6 months and may represent a safe and non-invasive treatment. Further testing is warranted in randomised clinical trials.

Trial Registration: ClinicalTrials.gov NCT02181400 Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05189-2DOI Listing
September 2020

Transient Hypoxia Model Revealed Cerebrovascular Impairment in Anemia Using BOLD MRI and Near-Infrared Spectroscopy.

J Magn Reson Imaging 2020 11 9;52(5):1400-1412. Epub 2020 Jul 9.

Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA.

Background: Obstructive sleep apnea and nocturnal oxygen desaturations, which are prevalent in sickle cell disease (SCD) and chronic anemia disorders, have been linked to risks of stroke and silent cerebral infarcts (SCI). Cerebrovascular response to intermittent desaturations has not been well studied and may identify patients at greatest risk.

Purpose: To investigate the cerebral dynamic response to induced desaturation in SCD patients with and without SCI, chronic anemia, and healthy subjects.

Study Type: Prospective.

Subjects: Twenty-six SCD patients (age = 21 ± 8.2, female 46.2%), including 15 subjects without SCI and nine subjects with SCI, 15 nonsickle anemic patients (age = 22 ± 5.8, female 66.7%), and 31 controls (age = 28 ± 12.3, female 77.4%).

Field Strength/sequence: 3T, gradient-echo echo-planar imaging.

Assessment: A transient hypoxia challenge of five breaths of 100% nitrogen gas was performed with blood oxygen level-dependent (BOLD) MRI and near-infrared spectroscopy (NIRS) acquisitions. Hypoxia responses were characterized by desaturation depth, time-to-peak, return-to-baseline half-life, and posthypoxia recovery in the BOLD and NIRS time courses. SCI were documented by T fluid-attenuation inversion recovery (FLAIR).

Statistical Tests: Univariate and multivariate regressions were performed between hypoxic parameters and anemia predictors. Voxelwise two-sample t-statistic maps were used to assess the regional difference in hypoxic responses between anemic and control groups.

Results: Compared to controls, SCD and chronically anemic patients demonstrated significantly higher desaturation depth (P < 0.01) and shorter return-to-baseline timing response (P < 0.01). Patients having SCI had shorter time-to-peak (P < 0.01), return-to-baseline (P < 0.01), and larger desaturation depth (P < 0.01) in both white matter regions at risk and normal-appearing white matter than patients without infarcts. On multivariate analysis, desaturation depth and timing varied with age, sex, blood flow, white blood cells, and cell-free hemoglobin (r = 0.25 for desaturation depth; r = 0.18 for time-to-peak; r = 0.37 for return-to-baseline).

Data Conclusion: Transient hypoxia revealed global and regional response differences between anemic and healthy subjects. SCI was associated with extensive heterogeneity of desaturation dynamics, consistent with extensive underlying microvascular remodeling.
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http://dx.doi.org/10.1002/jmri.27210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655661PMC
November 2020

A foundation monograph of (Convolvulaceae) in the New World.

PhytoKeys 2020 16;143:1-823. Epub 2020 Mar 16.

University of Oxford, Oxford, UK University of Oxford Oxford United Kingdom.

A monograph of the 425 New World species of is presented. All 425 species are described and information is provided on their ecology and distribution, with citations from all countries from which they are reported. Notes are provided on salient characteristics and taxonomic issues related to individual species. A full synonymy is provided and 272 names are lectotypified. An extensive introduction discusses the delimitation and history of arguing that a broad generic concept is the only rational solution in the light of recent phylogenetic advances. Although no formal infrageneric classification is proposed, attention is drawn to the major clades of the genus and several morphologically well-defined clades are discussed including those traditionally treated under the names , , , and , sometimes as distinct genera, subgenera, sections or series. Identification keys are provided on a regional basis including multi-entry keys for the main continental blocks. Six species are described as new, J.R.I. Wood & Scotland from Peru, J.R.I. Wood & Scotland from Brazil, J.R.I. Wood & Scotland, J.R.I. Wood & Scotland, J.R.I. Wood & Scotland and J.R.I. Wood & Scotland from Mexico, while var. australis of is raised to specific status as (O'Donell) J.R.I. Wood & P. Muñoz. New subspecies for (subsp. krapovickasii J.R.I. Wood & Scotland) and for (subsp. bellator J.R.I. Wood & Scotland) are described. The status of previously recognized species and varieties is changed so the following new subspecies are recognized: I. amnicola subsp. chiliantha (Hallier f.) J.R.I. Wood & Scotland, I. chenopodiifolia subsp. signata (House) J.R.I. Wood & Scotland, I. orizabensis subsp. collina (House) J.R.I. Wood & Scotland, I. orizabensis subsp. austromexicana (J.A. McDonald) J.R.I. Wood & Scotland, I. orizabensis subsp. novogaliciana (J.A. McDonald) J.R.I. Wood & Scotland, I. setosa subsp. pavonii (Hallier f.) J.R.I. Wood & Scotland, I. setosa subsp. melanotricha (Brandegee) J.R.I. Wood & Scotland, I. setosa subsp. sepacuitensis (Donn. Sm.) J.R.I. Wood & Scotland, I. ternifolia subsp. leptotoma (Torr.) J.R.I. Wood & Scotland. and I. subincana are treated as var. angustata (Brandegee) J.R.I. Wood & Scotland and var. subincana (Choisy) J.R.I. Wood & Scotland of and respectively. Attention is drawn to a number of hitherto poorly recognized phenomena in the genus including a very large radiation centred on the Parana region of South America and another on the Caribbean Islands, a strong trend towards an amphitropical distribution in the New World, the existence of a relatively large number of species with a pantropical distribution and of many species in different clades with storage roots, most of which have never been evaluated for economic purposes. The treatment is illustrated with over 200 figures composed of line drawings and photographs.
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http://dx.doi.org/10.3897/phytokeys.143.32821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298354PMC
March 2020

Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease.

Blood 2020 Sep;136(10):1191-1200

Division of Hematology/Oncology, Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA.

Persons with sickle cell disease (SCD) exhibit subjective hypersensitivity to cold and heat perception in experimental settings, and triggers such as cold exposure are known to precipitate vaso-occlusive crises by still unclear mechanisms. Decreased microvascular blood flow (MBF) increases the likelihood of vaso-occlusion by increasing entrapment of sickled red blood cells in the microvasculature. Because those with SCD have dysautonomia, we anticipated that thermal exposure would induce autonomic hypersensitivity of their microvasculature with an increased propensity toward vasoconstriction. We exposed 17 patients with SCD and 16 control participants to a sequence of predetermined threshold temperatures for cold and heat detection and cold and heat pain via a thermode placed on the right hand. MBF was measured on the contralateral hand by photoplethysmography, and cardiac autonomic balance was assessed by determining heart rate variability. Thermal stimuli at both detection and pain thresholds caused a significant decrease in MBF in the contralateral hand within seconds of stimulus application, with patients with SCD showing significantly stronger vasoconstriction (P = .019). Furthermore, patients with SCD showed a greater progressive decrease in blood flow than did the controls, with poor recovery between episodes of thermal stimulation (P = .042). They had faster vasoconstriction than the controls (P = .033), especially with cold detection stimulus. Individuals with higher anxiety also experienced more rapid vasoconstriction (P = .007). Augmented vasoconstriction responses and progressive decreases in perfusion with repeated thermal stimulation in SCD are indicative of autonomic hypersensitivity in the microvasculature. These effects are likely to increase red cell entrapment in response to clinical triggers such as cold or stress, which have been associated with vaso-occlusive crises in SCD.
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http://dx.doi.org/10.1182/blood.2020005045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472716PMC
September 2020

Mortality Among Persons with Both Asthma and Chronic Obstructive Pulmonary Disease Aged ≥25 Years, by Industry and Occupation - United States, 1999-2016.

MMWR Morb Mortal Wkly Rep 2020 Jun 5;69(22):670-679. Epub 2020 Jun 5.

Respiratory Health Division, National Institute for Occupational Safety and Health, CDC.

Patients with asthma typically have chronic airway inflammation, variable airflow limitation, and intermittent respiratory symptoms; patients with chronic obstructive pulmonary disease (COPD) often have fixed airflow limitation and persistent respiratory symptoms. Some patients exhibit features suggesting that they have both conditions, which is termed asthma-COPD overlap. These patients have been reported to have worse health outcomes than do those with asthma or COPD alone (1). To describe mortality among persons aged ≥25 years with asthma-COPD overlap, CDC analyzed 1999-2016 National Vital Statistics multiple-cause-of-death mortality data* extracted from the National Occupational Mortality System (NOMS), which included industry and occupation information collected from 26 states for the years 1999, 2003, 2004, and 2007-2014. Age-adjusted death rates per one million persons and proportionate mortality ratios (PMRs)** were calculated. During 1999-2016, 6,738 male decedents (age-adjusted rate per million = 4.30) and 12,028 female decedents (5.59) had both asthma and COPD assigned on their death certificate as the underlying or contributing cause of death. The annual age-adjusted death rate per million among decedents with asthma-COPD overlap declined from 6.70 in 1999 to 3.01 in 2016 (p<0.05) for men and from 7.71 in 1999 to 4.01 in 2016 (p<0.05) for women. Among adults aged 25-64 years, asthma-COPD overlap PMRs, by industry, were significantly elevated among nonpaid workers, nonworkers, and persons working at home for both men (1.72) and women (1.40) and among male food, beverage, and tobacco products workers (2.64). By occupation, asthma-COPD overlap PMRs were significantly elevated among both men (1.98) and women (1.79) who were unemployed, had never worked, or were disabled workers and among women bartenders (3.28) and homemakers (1.34). The association between asthma-COPD overlap mortality and nonworking status among adults aged 25-64 years suggests that asthma-COPD overlap might be associated with substantial morbidity. Increased risk for asthma-COPD overlap mortality among adults in certain industries and occupations suggests targets for public health interventions (e.g., elimination of or removal from exposures, engineering controls, and workplace smoke-free policies) to prevent asthma and COPD in and out of the workplace.
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http://dx.doi.org/10.15585/mmwr.mm6922a3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272111PMC
June 2020

Total Synthesis of (±)-Phyllantidine: Development and Mechanistic Evaluation of a Ring Expansion for Installation of Embedded Nitrogen-Oxygen Bonds.

Angew Chem Int Ed Engl 2020 06 8;59(24):9757-9766. Epub 2020 May 8.

Department of Chemistry and Biochemistry, Baylor University, One Bear Place 97348, Waco, TX, 76798, USA.

The development of a concise total synthesis of (±)-phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen-oxygen (N-O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early-stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N-O bond cleavage, and the rapid assembly of the butenolide found in (1) via use of the Bestmann ylide.
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http://dx.doi.org/10.1002/anie.202003829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448577PMC
June 2020