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1.
Nat Commun ; 13(1): 6883, 2022 Nov 12.
Article in English | MEDLINE | ID: mdl-36371495

ABSTRACT

Understanding atmospheric impacts of solar energetic particle precipitation (EPP) remains challenging, from quantification of the response in ozone, to implications on temperature. Both are necessary to understand links between EPP and regional climate variability. Here we use a chemistry-climate model to assess the importance of EPP on late winter/spring polar stratosphere. In transient simulations, the impact on NOy, ozone, and temperature is underestimated when using EPP forcing from the current recommendation of the Coupled Model Intercomparison Project (CMIP6). The resulting temperature response is largely masked by overall dynamical variability. An idealised experiment with EPP forcing that reproduces observed levels of NOy results in a significant reduction of ozone (up to 25%), cooling the stratosphere (up to 3 K) during late winter/spring. Our results unravel the inconsistency regarding the temperature response to EPP-driven springtime ozone decrease, and highlight the need for an improved EPP forcing in climate simulations.

2.
Sci Rep ; 12(1): 16655, 2022 10 05.
Article in English | MEDLINE | ID: mdl-36198742

ABSTRACT

Complex parenting has been proposed to contribute to the evolutionary success of vertebrates. However, the evolutionary routes to complex parenting and the role of parenting in vertebrate diversity are still contentious. Although basal vertebrates provide clues to complex reproduction, these are often understudied. Using 181 species that represent all major lineages of an early vertebrate group, the salamanders and newts (Caudata, salamanders henceforth) here we show that fertilisation mode is tied to parental care: male-only care occurs in external fertilisers, whereas female-only care exclusively occurs in internal fertilisers. Importantly, internal fertilisation opens the way to terrestrial reproduction, because fertilised females are able to deposit their eggs on land, and with maternal care provision, the eggs could potentially develop outside the aquatic environment. Taken together, our results of a semi-aquatic early vertebrate group propose that the diversity and follow-up radiation of terrestrial vertebrates are inherently associated with a complex social behaviour, parenting.


Subject(s)
Fertilizers , Urodela , Animals , Biological Evolution , Female , Male , Reproduction , Salamandridae
3.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Article in English | MEDLINE | ID: mdl-34230096

ABSTRACT

The Toba eruption ∼74,000 y ago was the largest volcanic eruption since the start of the Pleistocene and represents an important test case for understanding the effects of large explosive eruptions on climate and ecosystems. However, the magnitude and repercussions of climatic changes driven by the eruption are strongly debated. High-resolution paleoclimate and archaeological records from Africa find little evidence for the disruption of climate or human activity in the wake of the eruption in contrast with a controversial link with a bottleneck in human evolution and climate model simulations predicting strong volcanic cooling for up to a decade after a Toba-scale eruption. Here, we use a large ensemble of high-resolution Community Earth System Model (CESM1.3) simulations to reconcile climate model predictions with paleoclimate records, accounting for uncertainties in the magnitude of Toba sulfur emissions with high and low emission scenarios. We find a near-zero probability of annual mean surface temperature anomalies exceeding 4 °C in most of Africa in contrast with near 100% probabilities of cooling this severe in Asia and North America for the high sulfur emission case. The likelihood of strong decreases in precipitation is low in most of Africa. Therefore, even Toba sulfur release at the upper range of plausible estimates remains consistent with the muted response in Africa indicated by paleoclimate proxies. Our results provide a probabilistic view of the uneven patterns of volcanic climate disruption during a crucial interval in human evolution, with implications for understanding the range of environmental impacts from past and future supereruptions.

4.
Earth Space Sci ; 8(4): e2020EA001223, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33869669

ABSTRACT

The Sun provides the energy required to sustain life on Earth and drive our planet's atmospheric circulation. However, establishing a solid physical connection between solar and tropospheric variability has posed a considerable challenge. The canon of solar variability is derived from the 400 years of observations that demonstrates the waxing and waning number of sunspots over an 11(-ish) year period. Recent research has demonstrated the significance of the underlying 22 years magnetic polarity cycle in establishing the shorter sunspot cycle. Integral to the manifestation of the latter is the spatiotemporal overlapping and migration of oppositely polarized magnetic bands. We demonstrate the impact of "terminators"-the end of Hale magnetic cycles-on the Sun's radiative output and particulate shielding of our atmosphere through the rapid global reconfiguration of solar magnetism. Using direct observation and proxies of solar activity going back some six decades we can, with high statistical significance, demonstrate a correlation between the occurrence of terminators and the largest swings of Earth's oceanic indices: the transition from El Niño to La Niña states of the central Pacific. This empirical relationship is a potential source of increased predictive skill for the understanding of El Niño climate variations, a high-stakes societal imperative given that El Niño impacts lives, property, and economic activity around the globe. A forecast of the Sun's global behavior places the next solar cycle termination in mid-2020; should a major oceanic swing follow, then the challenge becomes: when does correlation become causation and how does the process work?

5.
Magn Reson Med ; 86(2): 611-624, 2021 08.
Article in English | MEDLINE | ID: mdl-33749010

ABSTRACT

PURPOSE: Achieving a desired RF transmit field ( B1+ ) in small regions of interest is critical for single-voxel MRS at ultrahigh field. Radio-frequency (RF) shimming, using parallel transmission, requires B1+ mapping and optimization, which limits its ease of use. This work aimed to generate calibration-free RF shims for predefined target regions of interest, which can be applied to any participant, to produce a desired absolute magnitude B1+ (| B1+ |). METHODS: The RF shims were found offline by joint optimization on a database comprising B1+ maps from 11 subjects, considering regions of interest in occipital cortex, hippocampus and posterior cingulate, as well as whole brain. The | B1+ | achieved was compared with a tailored shimming approach, and MR spectra were acquired using tailored and calibration-free shims in 4 participants. Global and local 10g specific-absorption-rate deposition were estimated using Duke and Ella dielectric models. RESULTS: There was no difference in the mean | B1+ | produced using calibration-free versus tailored RF shimming in the occipital cortex (p = .15), hippocampus (p = .5), or posterior cingulate (p = .98), although differences were observed in the RMS error | B1+ |. Spectra acquired using calibration-free shims had similar SNR and low residual water signal. Under identical power settings, specific-absorption-rate deposition was lower compared with operating in quadrature mode. For example, the total head specific absorption rate was around 35% less for the occipital cortex. CONCLUSION: This work demonstrates that static RF shims, optimized offline for small regions, avoid the need for B1+ mapping and optimization for each region of interest and participant. Furthermore, power settings may be increased when using calibration-free shims, to better take advantage of RF shimming.


Subject(s)
Magnetic Resonance Imaging , Radio Waves , Brain/diagnostic imaging , Calibration , Head , Humans
6.
Environ Pollut ; 262: 114284, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32443191

ABSTRACT

Concentrations of the air pollutants (NO2 and particulate matter) were measured for several months and at multiple locations inside and outside two enclosed railway stations in the United Kingdom - Edinburgh Waverly (EDB) and London King's Cross (KGX) - which, respectively, had at the time 59% and 18% of their train services powered by diesel engines. Average concentrations of NO2 were above the 40 µg m-3 annual limit value outside the stations and were further elevated inside, especially at EDB. Concentrations of PM2.5 inside the stations were 30-40% higher at EDB than outside and up to 20% higher at KGX. Concentrations of both NO2 and PM2.5 were highest closer to the platforms, especially those with a higher frequency of diesel services. A random-forest regression model was used to quantify the impact of numbers of different types of diesel trains on measured concentrations allowing prediction of the impact of individual diesel-powered rolling stock.


Subject(s)
Air Pollutants/analysis , Air Pollution/analysis , Environmental Monitoring , London , Particulate Matter/analysis , United Kingdom , Vehicle Emissions/analysis
7.
BMJ Open ; 9(12): e033247, 2019 12 23.
Article in English | MEDLINE | ID: mdl-31874887

ABSTRACT

INTRODUCTION: Early identification and appropriate treatment of child and adolescent mental health disorders can often be hampered by patchwork services with poorly planned or unclear pathways. The Choice and Partnership Approach (CAPA) is an evidence-based transformational model of community (community-based or outpatient) mental health and addictions services for children and adolescents that aims to better match services to needs and to improve timely access to care. CAPA has been variably implemented across jurisdictions but has not been comprehensively evaluated for its impact on system and client outcomes. Our research question is, 'To what degree does CAPA work, for whom and under what circumstances?'. The purpose of this review is twofold: (1) to gain an understanding of the extent and outcomes of the implementation of CAPA in community mental health and addictions services; and (2) to identify the role of context as it influences the implementation of CAPA and resulting client and system outcomes. METHODS AND ANALYSIS: We will conduct a realist-informed scoping review of the literature related to CAPA in either child and adolescent or adult community mental health and addictions services. Relevant studies, reports and documentation will be identified by searching the following online databases: MEDLINE, Embase, CINAHL, PsycINFO, Academic Search Premier, ERIC, Web of Science, Cochrane, Dissertations Abstracts, NCBI Bookshelf, PubMed Central and the Canadian Health Research Collection. The search strategy was developed by a health sciences library scientist and informed by a multidisciplinary team comprising methodological and content knowledge experts. The search will gather evidence from multiple online databases of peer-reviewed literature and grey literature repositories. All articles will be independently assessed for inclusion by pairs of reviewers. The key themes derived from a thematic analysis of extracted data will be presented in a narrative overview. ETHICS AND DISSEMINATION: Research ethics review is not required for this scoping review. The results will be disseminated through meetings with stakeholders (including clients and families, clinicians and decision-makers), conference presentations and peer-reviewed publication. The results of this review will inform an overarching programme of research, policy and quality indicator development to ultimately improve mental health and addictions care and subsequent mental health outcomes for children and adolescents.


Subject(s)
Addiction Medicine/organization & administration , Community Mental Health Centers/organization & administration , Adolescent , Child , Humans , Needs Assessment/organization & administration , Review Literature as Topic
8.
Blood Purif ; 45(1-3): 236-244, 2018.
Article in English | MEDLINE | ID: mdl-29478044

ABSTRACT

BACKGROUND/AIMS: Neighborhood walkability is associated with indicators of health in the general population. We explored the association between neighborhood walkability and daily steps in hemodialysis (HD) patients. METHODS: We measured daily steps over 5 weeks using Fitbit Flex (Fitbit, San Francisco, CA, USA) and retrieved Walk Score® (WS) data by patient's home ZIP code (www.walkscore.com; 0 = poorest walkability; 100 = greatest walkability). RESULTS: HD patients took a mean of 6,393 ± 3,550 steps/day (n = 46). Median WS of the neighborhood where they resided was 28. Patients in an above-median WS (n = 27) neighborhood took significantly more daily steps compared to those (n = 19) in a below-median WS neighborhood (7,514 ± 3,900 vs. 4,800 ± 2,228 steps/day; p < 0.001, t test). Daily steps and WS were directly correlated (R = 0.425; p = 0.0032, parametric test; R = 0.359, p = 0.0143, non-parametric test). CONCLUSION: This is the first study conducted among HD patients to indicate a direct relationship between neighborhood walkability and the actual steps taken. These results should be considered when designing initiatives to increase and improvise exercise routines in HD populations.


Subject(s)
Renal Dialysis , Walking , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective Studies
10.
Blood Purif ; 43(1-3): 235-243, 2017.
Article in English | MEDLINE | ID: mdl-28114147

ABSTRACT

BACKGROUND/AIMS: Hemodialysis (HD) patients are less active than their healthy counterparts. They are often plagued with sleep disorders that affect the quality of their sleep. Our aim was to objectively quantify activity and sleep quality among HD patients in a suburban HD population. METHODS: Activity and sleep parameters were measured using a commercially available activity tracker in 29 HD patients from Baton Rouge, LA, USA. Patients in the feedback group received their activity and sleep data at each dialysis treatment. In addition, questionnaires were administered at the beginning and end of the study period. Patients were stratified based on activity levels and sleep quality. RESULTS: Patients walked an average of 5,281 steps/day and slept 370.5 min/night. Informing patients about their daily number of steps taken, did not increase activity. Only 3% of the population followed were active, defined as walking more than 10,000 steps per day. Patients walked significantly less on dialysis days compared to the other days of the week. Many of the patients experienced poor sleep quality, with patients in the first shift experiencing the greatest disturbance to their sleep/wake cycle. CONCLUSION: Patients in a suburban environment walked much less than those in a previously studied urban population. They rarely met the recommended goal of 10,000 steps/day, even on non-dialysis days. Interventions to increase physical activity may target any day of the week, particularly HD days. Prospective, long-term studies are needed to evaluate the use of activity trackers in dialysis patients and their impact on physical activity.


Subject(s)
Exercise , Renal Dialysis/adverse effects , Renal Insufficiency, Chronic/physiopathology , Sleep , Suburban Health , Adult , Aged , Feedback , Fitness Trackers , Humans , Middle Aged , Renal Insufficiency, Chronic/therapy , Sleep Wake Disorders/etiology , Surveys and Questionnaires , Walking
11.
Gland Surg ; 5(2): 150-7, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27047783

ABSTRACT

BACKGROUND: Advances in mobile telecommunication, improved mobile internet and affordability have led to a significant increase in smartphone use within medicine. The capability of instant messaging, photography, videography, word processing, drawing and internet access allow significant potential in this small portable device. Smartphone use within medicine has grown tremendously worldwide given its affordability, improved internet and capabilities. METHODS: We have searched for apps specifically helpful in the perioperative care of microsurgical breast reconstructive patients. RESULTS: The useful apps have been subdivided: (I) communication apps-multimedia messaging, WhatsApp, PicSafeMedi: allow efficient communication via text, picture and video messages leading to earlier assessment and definitive management of free flaps; (II) storage apps-Notability, Elogbook: electronic storage of patient notes and logbooks of case which can be shared with others if required; (III) educational apps-FlapApp, Touch Surgery, PubMed on tap: step by step guides to surgical procedures to aid learning and medical journal database; (IV) flap monitoring app-SilpaRamanitor: free flap monitoring app based on photographic analysis for earlier detection of compromised flaps. CONCLUSIONS: There has been remarkable growth in smartphones use among surgeons. Apps are being developed for every conceivable use. The future will be in wearable smart devices that allow continuous monitoring with the potential to instigate change should deviations from the norm occur. The smart watch is the start of this digital revolution.

13.
Environ Sci Process Impacts ; 18(2): 208-21, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26705547

ABSTRACT

Construction activities are common across cities; however, the studies assessing their contribution to airborne PM10 (≤10 µm) and PM2.5 (≤2.5 µm) particles on the surrounding air quality are limited. Herein, we assessed the impact of PM10 and PM2.5 arising from construction works in and around London. Measurements were carried out at 17 different monitoring stations around three construction sites between January 2002 and December 2013. Tapered element oscillating microbalance (TEOM 1400) and OSIRIS (2315) particle monitors were used to measure the PM10 and PM2.5 fractions in the 0.1-10 µm size range along with the ambient meteorological data. The data was analysed using bivariate concentration polar plots and k-means clustering techniques. Daily mean concentrations of PM10 were found to exceed the European Union target limit value of 50 µg m(-3) at 11 monitoring stations but remained within the allowable 35 exceedences per year, except at two monitoring stations. In general, construction works were found to influence the downwind concentrations of PM10 relatively more than PM2.5. Splitting of the data between working (0800-1800 h; local time) and non-working (1800-0800 h) periods showed about 2.2-fold higher concentrations of PM10 during working hours when compared with non-working hours. However, these observations did not allow to conclude that this increase was from the construction site emissions. Together, the polar concentration plots and the k-means cluster analysis applied to a pair of monitoring stations across the construction sites (i.e. one in upwind and the other in downwind) confirmed the contribution of construction sources on the measured concentrations. Furthermore, pairing the monitoring stations downwind of the construction sites showed a logarithmic decrease (with R(2) about 0.9) in the PM10 and PM2.5 concentration with distance. Our findings clearly indicate an impact of construction activities on the nearby downwind areas and a need for developing mitigation measures to limit their escape from the construction sites.


Subject(s)
Air Pollutants/analysis , Environmental Monitoring , Particulate Matter/analysis , Vehicle Emissions/analysis , Cities , Construction Industry , Humans , London , Particle Size
14.
J Pathol ; 223(4): 470-81, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21294121

ABSTRACT

Worldwide, approximately 405 000 cases of oral cancer (OSCC) are diagnosed each year, with a rising incidence in many countries. Despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained largely unchanged for decades, with a 5-year survival rate of around 50%. OSCC is a heterogeneous disease, staged currently using the TNM classification, supplemented with pathological information from the primary tumour and loco-regional lymph nodes. Although patients with advanced disease show reduced survival, there is no single pathological or molecular feature that identifies aggressive, early-stage tumours. We retrospectively analysed 282 OSCC patients for disease mortality, related to clinical, pathological, and molecular features based on our previous functional studies [EGFR, αvß6 integrin, smooth muscle actin (SMA), p53, p16, EP4]. We found that the strongest independent risk factor of early OSCC death was a feature of stroma rather than tumour cells. After adjusting for all factors, high stromal SMA expression, indicating myofibroblast transdifferentiation, produced the highest hazard ratio (3.06, 95% CI 1.65-5.66) and likelihood ratio (3.6; detection rate: false positive rate) of any feature examined, and was strongly associated with mortality, regardless of disease stage. Functional assays showed that OSCC cells can modulate myofibroblast transdifferentiation through αvß6-dependent TGF-ß1 activation and that myofibroblasts promote OSCC invasion. Finally, we developed a prognostic model using Cox regression with backward elimination; only SMA expression, metastasis, cohesion, and age were significant. This model was independently validated on a patient subset (detection rate 70%; false positive rate 20%; ROC analysis 77%, p < 0.001). Our study highlights the limited prognostic value of TNM staging and suggests that an SMA-positive, myofibroblastic stroma is the strongest predictor of OSCC mortality. Whether used independently or as part of a prognostic model, SMA identifies a significant group of patients with aggressive tumours, regardless of disease stage.


Subject(s)
Carcinoma, Squamous Cell/pathology , Mouth Neoplasms/pathology , Stromal Cells/pathology , Actins/metabolism , Aged , Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/secondary , Carcinoma, Squamous Cell/therapy , Epidemiologic Methods , Female , Humans , Male , Middle Aged , Mouth Neoplasms/diagnosis , Mouth Neoplasms/therapy , Myofibroblasts/physiology , Neoplasm Invasiveness , Neoplasm Proteins/metabolism , Neoplasm Staging , Prognosis , Stromal Cells/metabolism
15.
J Pathol ; 223(3): 366-77, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21171082

ABSTRACT

Oral submucous fibrosis (OSF) is a premalignant, fibrosing disorder of the mouth, pharynx, and oesophagus, with a malignant transformation rate of 7-13%. OSF is strongly associated with areca (betel) nut chewing and worldwide, over 5 million people are affected. As αvß6 integrin is capable of promoting both tissue fibrosis and carcinoma invasion, we examined its expression in fibroepithelial hyperplasia and OSF. αvß6 was markedly up-regulated in OSF, with high expression detected in 22 of 41 cases (p < 0.001). We investigated the functional role of αvß6 using oral keratinocyte-derived cells genetically modified to express high αvß6 (VB6), and also NTERT-immortalized oral keratinocytes, which express low αvß6 (OKF6/TERT-1). VB6 cells showed significant αvß6-dependent activation of TGF-ß1, which induced transdifferentiation of oral fibroblasts into myofibroblasts and resulted in up-regulation of genes associated with tissue fibrosis. These experimental in vitro findings were confirmed using human clinical samples, where we showed that the stroma of OSF contained myofibroblasts and that TGF-ß1-dependent Smad signalling was detectable both in keratinocytes and in myofibroblasts. We also found that arecoline, the major alkaloid of areca nuts, up-regulated keratinocyte αvß6 expression. This was modulated through the M(4) muscarinic acetylcholine receptor and was suppressed by the M(4) antagonist, tropicamide. Arecoline-dependent αvß6 up-regulation promoted keratinocyte migration and induced invasion, raising the possibility that this mechanism may support malignant transformation. Over 80% of OSF-related oral cancers examined had moderate/high αvß6 expression. These data suggest that the pathogenesis of OSF may be epithelial-driven and involve arecoline-dependent up-regulation of αvß6 integrin.


Subject(s)
Antigens, Neoplasm/biosynthesis , Areca/chemistry , Arecoline/pharmacology , Integrins/biosynthesis , Keratinocytes/drug effects , Oral Submucous Fibrosis/metabolism , Actins/metabolism , Antigens, Neoplasm/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Differentiation/drug effects , Cell Movement/drug effects , Cells, Cultured , Coculture Techniques , Humans , Integrins/genetics , Keratinocytes/metabolism , Mouth Neoplasms/metabolism , Mouth Neoplasms/pathology , Myofibroblasts/cytology , Myofibroblasts/drug effects , Oral Submucous Fibrosis/pathology , Precancerous Conditions/metabolism , Precancerous Conditions/pathology , Reverse Transcriptase Polymerase Chain Reaction/methods , Transforming Growth Factor beta1/metabolism , Up-Regulation/drug effects
16.
J Neurotrauma ; 27(10): 1805-18, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20698759

ABSTRACT

Autonomic dysreflexia consistently develops in patients and in rats after severe upper thoracic spinal cord injury (SCI) as a result of exaggerated spinal sympathetic excitation. In this study we induced episodic hypertension in rats after varying degrees of SCI severity to investigate the contribution of serotonergic bulbospinal axons to the development of autonomic dysreflexia after SCI. Female Wistar rats (250-300 g) were used in all experiments in the following groups: (1) uninjured, (2) clip compression at T4 of 20, 35, or 50 g, (3) spinal cord transection at T4, and (4) intrathecal 5,7-dihydroxytryptamine creatinine sulfate (5,7-DHT). Immunohistochemistry for choline acetyl transferase and serotonin (5-HT) was performed on T8-T12 spinal segments to identify sympathetic preganglionic neurons, and to assess 5-HT-containing axons in the intermediolateral cell column (IMLC), respectively. Testing for autonomic dysreflexia was conducted by measuring mean arterial pressure (MAP) at rest and after colon distension-induced hypertension. We observed that the magnitude of the pressor response seen after colon distension correlated with SCI severity and density of 5-HT-immunoreactive axons in the IMLC. Intrathecal administration of the 5-HT(2A) agonist dimethoxy-4-iodamphetamine increased resting MAP and blocked colon distension-induced hypertension, whereas the 5-HT(2A) antagonist ketanserin decreased resting MAP and was permissive to the colon distension-induced pressor response in SCI rats. These results suggest that the SCI-induced loss of serotonergic inputs into the spinal cord IMLC is proportional to the pathogenesis of autonomic dysreflexia and hypotension seen after SCI. We thus conclude that sparing of serotonergic axons beyond a critical threshold preserves cardiovascular regulation and prevents the development of autonomic dysreflexia.


Subject(s)
Autonomic Dysreflexia/etiology , Autonomic Dysreflexia/physiopathology , Axons/metabolism , Serotonin/metabolism , Spinal Cord Injuries/complications , Analysis of Variance , Animals , Autonomic Dysreflexia/metabolism , Axons/drug effects , Blood Pressure/drug effects , Blood Pressure/physiology , Choline O-Acetyltransferase/metabolism , Female , Heart Rate/drug effects , Heart Rate/physiology , Immunohistochemistry , Indophenol/analogs & derivatives , Indophenol/pharmacology , Injections, Spinal , Ketanserin/pharmacology , Motor Activity/physiology , Rats , Rats, Wistar , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/physiopathology
17.
Int J Exp Pathol ; 91(3): 244-55, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20353423

ABSTRACT

Regeneration of skeletal muscle following injury is dependent on numerous factors including age, the inflammatory response, revascularization, gene expression of myogenic and growth factors and the activation and proliferation of endogenous progenitor cells. It is our hypothesis that oxidative stress preceding a contusion injury to muscle modulates the inflammatory response to inhibit muscle regeneration and enhance fibrotic scar formation. Male F344/BN rats were assigned to one of four groups. Group 1: uinjured control; Group 2: ischaemic occlusion of femoral vessels for 2 h followed by reperfusion (I-R); Group 3: contusion injury of the tibialis anterior (TA); Group 4: I-R, then contusion injury. The acute inflammatory response (8 h, 3 days) was determined by expression of the chemokine CINC-1, TGF-beta1, IFN-gamma and markers of neutrophil (myeloperoxidase) and macrophage (CD68) activity and recruitment. Acute oxidative stress caused by I-R and/or contusion, was determined by measuring GP91(phox) and lipid peroxidation. Muscle recovery (21 days) was assessed by examining the fibrosis after I-R and contusion injuries to the TA with Sirius Red staining and quantification of collagen I expression. Consistent with our hypothesis, I-R preceding contusion increased all markers of the acute inflammatory response and oxidative stress after injury and elevated the expression of collagen. We conclude that ischaemia-induced oxidative stress exacerbated the inflammatory response and enhanced fibrotic scar tissue formation after injury. This response may be attributable to increased levels of TGF-beta1 and diminished expression of IFN-gamma in the ischaemic contused muscle.


Subject(s)
Contusions/physiopathology , Inflammation/physiopathology , Muscle, Skeletal/physiology , Regeneration/physiology , Reperfusion Injury/physiopathology , Animals , Contusions/complications , Contusions/pathology , Fibrosis , Inflammation/etiology , Interferon-gamma/metabolism , Male , Muscle, Skeletal/pathology , Oxidative Stress/physiology , Rats , Rats, Inbred F344 , Reperfusion Injury/complications , Transforming Growth Factor beta/metabolism
18.
Exp Gerontol ; 45(5): 381-8, 2010 May.
Article in English | MEDLINE | ID: mdl-20211238

ABSTRACT

Inflammation is an integral component of the response of skeletal muscle to a contusion injury that can be modulated by acute oxidative stress. Less is known regarding the effect of aging-associated oxidative stress on the inflammatory response in injured skeletal muscle. The purpose of this project was to assess the level of oxidative stress in skeletal muscles of young, adult, and old rats and determine its effect on the acute inflammatory response to a contusion injury. Inherent oxidative stress in the muscle was determined by measuring the glutathione:glutathione disulfide ratio, and levels of GP91(phox). Elevated oxidative stress was observed in uninjured muscles of adult and old rats and was accompanied by increased levels of lipid peroxidation and neutrophil chemoattractant CINC-1. After injury, the acute inflammatory response (8h, 3 d) was determined from markers of neutrophil (myeloperoxidase) and macrophage (CD68) content and by expression of NFkappaB, CINC-1 and TGF-beta1. Compared to injured muscles of young rats, NFkappaB, myeloperoxidase activity (8h), macrophage content (3 d), and TGF-beta1 (8h and 3 d) were significantly greater in injured muscles of old rats. We conclude that aging-associated oxidative stress in muscles of old rats exacerbated the inflammatory response to contusion injury and leads to increased TGF-beta1-induced collagen content.


Subject(s)
Aging/metabolism , Contusions/metabolism , Inflammation/etiology , Muscle, Skeletal/metabolism , Oxidative Stress , Animals , Glutathione/analysis , Glutathione Disulfide/analysis , Lipid Peroxidation , Male , Muscle, Skeletal/pathology , Neutrophil Infiltration , Peroxidase/metabolism , Rats , Rats, Inbred BN , Rats, Inbred F344 , Transforming Growth Factor beta1/physiology
19.
J Neurotrauma ; 27(4): 729-37, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20059302

ABSTRACT

Abstract In this study we explore if loss of GABAergic inhibitory interneurons in the superficial dorsal horn of the spinal cord contributes to reduced GABAergic tone and neuropathic pain following spinal cord injury (SCI). A moderate contusion injury to T11 resulted in the development of mechanical hyperalgesia and thermal hyperalgesia below the level of the lesion in gad1:GFP mice that were alleviated by IP administration of the GABA transporter antagonist tiagabine. Six weeks following SCI a decreased number of GFP(+) neurons were observed in the dorsal horn of SCI animals relative to sham mice. Tissue from a mouse 2 weeks post-SCI was subsequently observed to express activated caspase-3, indicative of apoptosis, co-localized to some GFP(+) GABAergic neurons. Glutamate decarboxylase (GAD)65 and GAD67 immunohistochemical staining was reduced in the dorsal horn of SCI animals. This observation was confirmed in Western blots showing reduced immunoreactivity for GAD67, as well as GABA transporter (GAT)1. Reversal of post-SCI neuropathic pain by tiagabine suggests that reduced GABAergic tone may contribute to hyperalgesia symptoms. This is supported by the subsequent observation that SCI reduced the number of GFP(+) inhibitory neurons, and the finding that some GABAergic GFP(+) neurons undergo cell death at a time point consistent with the development of neuropathic pain following SCI. Concordantly, reductions in both GAD65 and GAD67 and GAT1 immunoreactivity also support the observation of a loss of GABAergic inhibition and the associated spinal interneurons.


Subject(s)
Interneurons/metabolism , Nerve Degeneration/metabolism , Neuralgia/metabolism , Posterior Horn Cells/metabolism , Spinal Cord Injuries/metabolism , gamma-Aminobutyric Acid/deficiency , Animals , Apoptosis/genetics , Caspase 3/metabolism , Cell Count , Disease Models, Animal , Down-Regulation/genetics , GABA Agonists/pharmacology , GABA Plasma Membrane Transport Proteins/metabolism , GABA Uptake Inhibitors , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/metabolism , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Interneurons/pathology , Male , Mice , Mice, Transgenic , Nerve Degeneration/etiology , Nerve Degeneration/physiopathology , Neural Inhibition/drug effects , Neural Inhibition/genetics , Neuralgia/etiology , Neuralgia/physiopathology , Nipecotic Acids/pharmacology , Pain Measurement , Pain Threshold/physiology , Posterior Horn Cells/pathology , Promoter Regions, Genetic/genetics , Spinal Cord Injuries/complications , Spinal Cord Injuries/physiopathology , Tiagabine
20.
J Plast Reconstr Aesthet Surg ; 63(1): 120-5, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19019746

ABSTRACT

BACKGROUND: The anterolateral thigh flap is becoming the flap of choice for reconstruction of soft tissue defects. By applying the chimaeric principle, we describe a technique to achieve primary donor-site closure in the use of the anterolateral thigh for the reconstruction of very large defects. METHODS: A long anterolateral thigh flap is marked out using standard points of reference. At least two separate cutaneous perforator vessels are identified on hand-held Doppler and dissected in a retrograde fashion back to the descending branch of the lateral circumflex femoral artery. The skin paddle is then divided between the two cutaneous perforators to give two separate paddles with a common vascular supply. The skin paddles can now be stacked side by side on a flap inset, effectively doubling the width of the flap, whilst still allowing for primary donor-site closure. RESULTS: We have used this flap to reconstruct chest-wall and extremity defects on six patients (mean age: 28.6 years; range: 24-35 years). The largest defect was 30x18cm and the smallest 11x12cm in diameter. In each case, the width of the defect was too great to allow for direct closure of the donor site had a conventional anterolateral flap design been used. There were no cases of flap failure or re-exploration, and in all cases the donor site was closed primarily. CONCLUSIONS: The split-skin paddle anterolateral thigh flap provides bespoke cover for large soft tissue defects with improved morbidity and cosmesis of the donor site.


Subject(s)
Plastic Surgery Procedures/methods , Surgical Flaps/blood supply , Thigh , Adult , Female , Humans , Lower Extremity/surgery , Male , Thoracic Wall/surgery , Treatment Outcome , Upper Extremity/surgery
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