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1.
Mol Neurobiol ; 58(5): 2158-2182, 2021 May.
Article in English | MEDLINE | ID: mdl-33411248

ABSTRACT

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by NFE2L2. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of N-acetylcysteine, coenzyme Q10 and melatonin is accompanied by increased Nrf2 activity. N-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q10, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.


Subject(s)
Brain/metabolism , Mental Disorders/drug therapy , NF-E2-Related Factor 2/metabolism , Animals , Humans , Mental Disorders/metabolism , Mitochondria/metabolism , Neuropsychiatry
2.
Mol Biol Rep ; 47(7): 5587-5620, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32564227

ABSTRACT

Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.


Subject(s)
Energy Metabolism/physiology , Mental Disorders/physiopathology , Oxidative Stress/physiology , Antioxidants/metabolism , Glutathione/metabolism , Humans , Mitochondria/metabolism , Nervous System Diseases/psychology , Niacinamide/pharmacology , Oxidation-Reduction , Oxidative Stress/genetics , Reactive Oxygen Species/metabolism , Thioredoxins/metabolism , Ubiquinone/analogs & derivatives , Ubiquinone/pharmacology
3.
J Viral Hepat ; 25(5): 442-456, 2018 05.
Article in English | MEDLINE | ID: mdl-29397014

ABSTRACT

Hepatitis C virus (HCV)-infected patients are at risk of developing hepatocellular carcinoma (HCC). Individuals at heightened risk could be targeted by intensive follow-up surveillance. We have conducted a systematic review of the literature to identify host genetic predisposition to HCC in HCV-infected patients. A comprehensive search of Medline and Embase databases was performed, and the strength of evidence of associations for each gene on development of HCC was evaluated. We identified 166 relevant studies, relating to 137 different genes, or combinations thereof. Seventeen genes were classified as having "good" evidence of an association, a significant association was observed for 37 genes but this finding had not yet been replicated, 56 genes had mixed or limited evidence of an association, and 27 genes showed no association. IFNL3/4, TNF-α and PNPLA3 genes had the most evidence of an association. There was, however, considerable heterogeneity in study design and data quality. In conclusion, we identified a number of genes with evidence of association with HCC, but also a need for more standardized approaches to address this clinically critical question. It is important to consider the underlying mechanism of these relationships and which are confounded by the presence of other HCC risk factors and response to therapy. We also identified many genes where the evidence of association is contradictory or requires replication, as well as a number where associations have been studied but no evidence found. These findings should help to direct future studies on host genetic predisposition to HCC in HCV-infected patients.


Subject(s)
Carcinoma, Hepatocellular/genetics , Genetic Predisposition to Disease , Hepatitis C, Chronic/complications , Liver Neoplasms/genetics , Genetic Association Studies , Humans
4.
Hernia ; 22(3): 447-453, 2018 06.
Article in English | MEDLINE | ID: mdl-29335910

ABSTRACT

PURPOSE: Little is known regarding the magnitude and timing of the risk of VTE following inguinal hernia surgery. We aimed to determine the absolute and relative rates of venous thromboembolism (VTE) following planned inguinal hernia repair. METHODS: We analysed male adults with a first inguinal hernia repair with no prior record of VTE from the Clinical Practice Research Datalink, linked to the Hospital Episode Statistics (2001-2011). Crude rates and adjusted hazard ratios (HR) of the first VTE were calculated using Cox regression analysis to compare specific time periods following the surgery compared to the general population. RESULTS: We identified 28,782 men who underwent an inguinal hernia repair with 53 (0.18%) having a first VTE in the 90 days following surgery. The overall rate of VTE in the first 90 days following surgery was 7.61 per 1000 person years (pyrs) (95% CI 5.82-9.96). Increasing age, a body mass index > 30 kg/m2 and an in-patient procedure were associated with an increased risk of VTE, when compared to the general population. The risk of VTE was highest in the 1st month following the surgery with a 2.3- (aHR 2.33; 95% CI 1.09-4.99) and 3.5- (aHR 3.47; 95% CI 2.07-5.83) fold increased risk compared to the general population for both day case and planned in-patient procedures, respectively. CONCLUSIONS: Reassuringly, the absolute rates of VTE following inguinal hernia repair are low. Patients should be informed that their peak risk of VTE is during the 1st month following the surgery. Further studies on the optimum duration of thromboprophylaxis following surgery are required in high-risk patients undergoing hernia repair.


Subject(s)
Elective Surgical Procedures/adverse effects , Hernia, Inguinal/epidemiology , Hernia, Inguinal/surgery , Herniorrhaphy/adverse effects , Herniorrhaphy/statistics & numerical data , Venous Thromboembolism/epidemiology , Adolescent , Adult , Aged , Cohort Studies , Databases, Factual/statistics & numerical data , Elective Surgical Procedures/methods , Elective Surgical Procedures/statistics & numerical data , Herniorrhaphy/methods , Humans , Male , Middle Aged , Risk Factors , United Kingdom/epidemiology , Venous Thromboembolism/etiology , Young Adult
5.
Mol Neurobiol ; 55(7): 5767-5786, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29052145

ABSTRACT

In the first part, the following mechanisms involved in different forms of cell death are considered, with a view to identifying potential therapeutic targets: tumour necrosis factor receptors (TNFRs) and their engagement by tumour necrosis factor-alpha (TNF-α); poly [ADP-ribose] polymerase (PARP)-1 cleavage; the apoptosis signalling kinase (ASK)-c-Jun N-terminal kinase (JNK) axis; lysosomal permeability; activation of programmed necrotic cell death; oxidative stress, caspase-3 inhibition and parthanatos; activation of inflammasomes by reactive oxygen species and the development of pyroptosis; oxidative stress, calcium dyshomeostasis and iron in the development of lysosomal-mediated necrosis and lysosomal membrane permeability; and oxidative stress, lipid peroxidation, iron dyshomeostasis and ferroptosis. In the second part, there is a consideration of the role of lethal and sub-lethal activation of these pathways in the pathogenesis and pathophysiology of neurodegenerative and neuroprogressive disorders, with particular reference to the TNF-α-TNFR signalling axis; dysregulation of ASK-1-JNK signalling; prolonged or chronic PARP-1 activation; the role of pyroptosis and chronic inflammasome activation; and the roles of lysosomal permeabilisation, necroptosis and ferroptosis. Finally, it is suggested that, in addition to targeting oxidative stress and inflammatory processes generally, neuropsychiatric disorders may respond to therapeutic targeting of TNF-α, PARP-1, the Nod-like receptor NLRP3 inflammasome and the necrosomal molecular switch receptor-interacting protein kinase-3, since their widespread activation can drive and/or exacerbate peripheral inflammation and neuroinflammation even in the absence of cell death. To this end, the use is proposed of a combination of the tetracycline derivative minocycline and N-acetylcysteine as adjunctive treatment for a range of neuropsychiatric disorders.


Subject(s)
Apoptosis , Molecular Targeted Therapy , Neurosciences , Animals , Humans , Nervous System Diseases/pathology , Nervous System Diseases/therapy , Reactive Oxygen Species/metabolism , Tumor Necrosis Factor-alpha/metabolism
6.
Transl Psychiatry ; 6(6): e842, 2016 06 21.
Article in English | MEDLINE | ID: mdl-27327257

ABSTRACT

Mitochondrial dysfunction has a critical role in the pathophysiology of mood disorders and treatment response. To investigate this, we established an animal model exhibiting a state of antidepressant treatment resistance in male Wistar rats using 21 days of adrenocorticotropic hormone (ACTH) administration (100 µg per day). First, the effect of ACTH treatment on the efficacy of imipramine (10 mg kg(-1)) was investigated alongside its effect on the prefrontal cortex (PFC) mitochondrial function. Second, we examined the mood-regulatory actions of chronic (7 day) high-frequency nucleus accumbens (NAc) deep-brain stimulation (DBS; 130 Hz, 100 µA, 90 µS) and concomitant PFC mitochondrial function. Antidepressant-like responses were assessed in the open field test (OFT) and forced swim test (FST) for both conditions. ACTH pretreatment prevented imipramine-mediated improvement in mobility during the FST (P<0.05). NAc DBS effectively improved FST mobility in ACTH-treated animals (P<0.05). No improvement in mobility was observed for sham control animals (P>0.05). Analyses of PFC mitochondrial function revealed that ACTH-treated animals had decreased capacity for adenosine triphosphate production compared with controls. In contrast, ACTH animals following NAc DBS demonstrated greater mitochondrial function relative to controls. Interestingly, a proportion (30%) of the ACTH-treated animals exhibited heightened locomotor activity in the OFT and exaggerated escape behaviors during the FST, together with general hyperactivity in their home-cage settings. More importantly, the induction of this mania-like phenotype was accompanied by overcompensative increased mitochondrial respiration. Manifestation of a DBS-induced mania-like phenotype in imipramine-resistant animals highlights the potential use of this model in elucidating mechanisms of mood dysregulation.


Subject(s)
Adenosine Triphosphate/metabolism , Adrenocorticotropic Hormone/pharmacology , Deep Brain Stimulation/methods , Depression/physiopathology , Depression/therapy , Mitochondria/drug effects , Nucleus Accumbens/physiopathology , Affect/drug effects , Affect/physiology , Animals , Bipolar Disorder/physiopathology , Depression/psychology , Drug Resistance , Escape Reaction/drug effects , Escape Reaction/physiology , Imipramine/pharmacology , Male , Mitochondria/physiology , Motor Activity/drug effects , Motor Activity/physiology , Nucleus Accumbens/drug effects , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiopathology , Premedication , Rats , Rats, Wistar
7.
Br J Surg ; 103(4): 443-50, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26818405

ABSTRACT

BACKGROUND: Appendicectomy is the commonest intra-abdominal emergency surgical procedure, and little is known regarding the magnitude and timing of the risk of venous thromboembolism (VTE) after surgery. This study aimed to determine absolute and relative rates of symptomatic VTE following emergency appendicectomy. METHODS: A cohort study was undertaken using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data of patients who had undergone emergency appendicectomy from 2001 to 2011. Crude rates and adjusted incidence rate ratios (IRRs) for VTE were calculated using Poisson regression, compared with baseline risk in the year before appendicectomy. RESULTS: A total of 13 441 patients were identified, of whom 56 (0·4 per cent) had a VTE in the first year after surgery. The absolute rate of VTE was highest during the in-hospital period, with a rate of 91·29 per 1000 person-years, which was greatest in those with a length of stay of 7 days or more (267·12 per 1000 person-years). This risk remained high after discharge, with a 19·1- and 6·6-fold increased risk of VTE in the first and second months respectively after discharge, compared with the year before appendicectomy (adjusted IRR: month 1, 19·09 (95 per cent c.i. 9·56 to 38·12); month 2, 6·56 (2·62 to 16·44)). CONCLUSION: The risk of symptomatic VTE following appendicectomy is relatively high during the in-hospital admission and remains increased after discharge. Trials of extended thromboprophylaxis are warranted in patients at particularly high risk.


Subject(s)
Appendectomy/adverse effects , Emergencies , Postoperative Complications/epidemiology , Risk Assessment/methods , Venous Thromboembolism/epidemiology , Adolescent , Adult , Female , Follow-Up Studies , Humans , Male , Middle Aged , Postoperative Complications/etiology , Prognosis , Retrospective Studies , Risk Factors , Time Factors , United Kingdom/epidemiology , Venous Thromboembolism/etiology , Young Adult
8.
Bull Volcanol ; 78(8): 56, 2016.
Article in English | MEDLINE | ID: mdl-32355391

ABSTRACT

Several broadly circular structures up to 16 m in diameter, into which higher strata have sagged and locally collapsed, are present in a tephra outcrop on southwest Öræfajökull, southern Iceland. The tephra was sourced in a nearby basaltic tuff cone at Varða. The structures have not previously been described in tuff cones, and they probably formed by the melting out of large buried blocks of ice emplaced during a preceding jökulhlaup that may have been triggered by a subglacial eruption within the Öræfajökull ice cap. They are named ice-melt subsidence structures, and they are analogous to kettle holes that are commonly found in proglacial sandurs and some lahars sourced in ice-clad volcanoes. The internal structure is better exposed in the Varða examples because of an absence of fluvial infilling and reworking, and erosion of the outcrop to reveal the deeper geometry. The ice-melt subsidence structures at Varða are a proxy for buried ice. They are the only known evidence for a subglacial eruption and associated jökulhlaup that created the ice blocks. The recognition of such structures elsewhere will be useful in reconstructing more complete regional volcanic histories as well as for identifying ice-proximal settings during palaeoenvironmental investigations.

9.
Br J Surg ; 102(13): 1629-38, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26387670

ABSTRACT

BACKGROUND: Guidelines recommend extended thromboprophylaxis following colectomy for malignant disease, but not for non-malignant disease. The aim of this study was to determine absolute and relative rates of venous thromboembolism (VTE) following colectomy by indication, admission type and time after surgery. METHODS: A cohort study of patients undergoing colectomy in England was undertaken using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data (2001-2011). Crude rates and adjusted hazard ratios (HRs) were calculated for the risk of first VTE following colectomy using Cox regression analysis. RESULTS: Some 12,388 patients were identified; 312 (2·5 per cent) developed VTE after surgery, giving a rate of 29·59 (95 per cent c.i. 26·48 to 33·06) per 1000 person-years in the first year after surgery. Overall rates were 2·2-fold higher (adjusted HR 2·23, 95 per cent c.i. 1·76 to 2·50) for emergency compared with elective admissions (39·44 versus 25·78 per 1000 person-years respectively). Rates of VTE were 2·8-fold higher in patients with malignant disease versus those with non-malignant disease (adjusted HR 2·84, 2·04 to 3·94). The rate of VTE was highest in the first month after emergency surgery, and declined from 121·68 per 1000 person-years in the first month to 25·65 per 1000 person-years during the rest of the follow-up interval. Crude rates of VTE were similar for malignant and non-malignant disease (114·76 versus 120·98 per 1000 person-years respectively) during the first month after emergency surgery. CONCLUSION: Patients undergoing emergency colectomy for non-malignant disease have a similar risk of VTE as patients with malignant disease in the first month after surgery.


Subject(s)
Colectomy/adverse effects , Postoperative Complications/epidemiology , Risk Assessment/methods , Venous Thromboembolism/epidemiology , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Incidence , Male , Middle Aged , Postoperative Complications/etiology , Proportional Hazards Models , Retrospective Studies , Risk Factors , Survival Rate/trends , Time Factors , United Kingdom/epidemiology , Venous Thromboembolism/etiology
10.
J Thromb Haemost ; 12(5): 641-9, 2014 May.
Article in English | MEDLINE | ID: mdl-24977288

ABSTRACT

BACKGROUND: Patients with colorectal cancer are at high risk of developing venous thromboembolism(VTE), and recent international guidelines have advised extended prophylaxis for some of these patients following surgery or during chemotherapy. However, our understanding of which patients are at increased risk, and to what extent, is limited. OBJECTIVES: To determine absolute and relative rates of VTE among patients with colorectal cancer according to Dukes stage, surgical intervention,and chemotherapy. METHODS: We analyzed data from four linked databases from 1997 to 2006: the Clinical Practice Research Datalink, linked to Hospital Episode Statistics, Cancer Registry data, and Office for National Statistics cause of death data, all from England. Rates were compared by the use of Cox regression. RESULTS: There were 10 309 patients with colorectal cancer, and 555 developed VTE (5.4%). The incidence varied by Dukes stage, being three-fold higher among Dukes D patients than among Dukes A patients (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.95­4.84), and 40% higher for those receiving chemotherapy than for those not receiving chemotherapy(HR 1.39, 95% CI 1.14­1.69). The risk following surgery varied by stage of disease and chemotherapy, with Dukes A patients having a low incidence of VTE (0.74%; 95% CI 0.28­1.95) at 6 months,with all events occurring within 28 days of surgery, as compared with Dukes B and Dukes C patients, whose risk at 6 months was ~ 2%. CONCLUSION: Twenty-eight days of prophylaxis following surgery for colorectal cancer is appropriate for Dukes A patients. However, Dukes B and Dukes C patients receiving postoperative chemotherapy have a longer duration of risk.


Subject(s)
Colorectal Neoplasms/complications , Colorectal Neoplasms/physiopathology , Venous Thromboembolism/complications , Venous Thromboembolism/diagnosis , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Cohort Studies , Colorectal Neoplasms/drug therapy , Comorbidity , Databases, Factual , England , Female , Hospitalization , Humans , Incidence , Male , Middle Aged , Proportional Hazards Models , Registries , Risk Factors , Treatment Outcome
11.
Br J Cancer ; 107(9): 1602-7, 2012 Oct 23.
Article in English | MEDLINE | ID: mdl-23011483

ABSTRACT

BACKGROUND: Aspirin has been widely reported to reduce the incidence of colorectal cancer. Recently, a survival benefit after diagnosis has also been suggested. Data regarding such a benefit are to date contradictory. This study examines the effect of non-steroidal anti-inflammatory drug (NSAID) use on mortality in colorectal cancer in a larger patient cohort than previously to further clarify this effect, especially in terms of exposure timing and dosing. METHODS: A study using the General Practice Research Database assessed whether aspirin or NSAID exposure in the year immediately following diagnosis affected all-cause mortality in a cohort of 13 994 colorectal cancer patients. Cox proportional hazards modelling adjusted for age, gender, smoking, body mass index and comorbidity. RESULTS: Overall mortality was slightly lower in patients treated with aspirin, (hazard ratio (HR)=0.91; 95% confidence interval (CI)=0.82-1.00). This effect was observed only in patients treated with prophylaxis-dose aspirin (HR=0.89, CI=0.80-0.98) and only in patients taking aspirin before diagnosis (HR=0.86, CI=0.76-0.98). Differential effects were observed depending on the time after diagnosis. Up to 5 years, a reduction in mortality was observed for aspirin users (HR=0.83, CI=0.75-0.92), whereas after 10 years there was an increase in mortality (HR=1.94, CI=1.26-2.99). For NSAID use, no significant effect was observed on overall mortality (HR=1.07, CI=0.98-1.15). High-dose NSAID use was associated with a slight increase in mortality (HR=1.41, CI=1.26-1.56). INTERPRETATION: These findings provide further indication that aspirin may be beneficial in reducing mortality in colorectal cancer during the first 5 years. The same cannot be said for other NSAIDs, where a small increase in mortality was observed.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Aspirin/administration & dosage , Colorectal Neoplasms/mortality , Aged , Cohort Studies , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/prevention & control , Female , Humans , Incidence , Male , Prospective Studies , Risk Factors , Survival Analysis , United Kingdom/epidemiology
12.
Parasitology ; 139(6): 744-54, 2012 May.
Article in English | MEDLINE | ID: mdl-22309997

ABSTRACT

The 3 post-marsupial juvenile stages of the gnathiid isopod, Paragnathia formica, are haematophagous ectoparasites of fishes that may, in heavy infestations, cause host mortality. Protein digestion in fed stage 3 juveniles is accomplished by cysteine proteinases, but what bioactive compounds attenuate host haemostatic, inflammatory and immunological responses during feeding is unknown. Trypsin inhibitory activity and anticoagulant activity were detected in crude extracts of unfed P. formica stage 1 juveniles; fractionation of stage 1 crude extracts by ion exchange chromatography resulted in 3 preparations each displaying these bioactivities. Further characterization revealed anti-thrombin activity in 2 of these preparations, whilst the third displayed the strongest anticoagulant activity that targeted a factor of the intrinsic coagulation pathway. Three trypsin inhibitors (18 kDa, 21 kDa, and 22 kDa) were also detected using reverse zymography. In parallel, homogenates of fed stage 2 and 3 juveniles were used to identify their fish hosts by amplifying the 16S mitochondrial rDNA and 18S genomic rDNA vertebrate gene regions. Blood from at least 4 fish families had been ingested by separate individuals during feeding. This study demonstrates that trypsin inhibitors and anticoagulants are present in P. formica juveniles which could suppress host haemostatic, inflammatory and immunological responses during feeding, and that juveniles are not host specific.


Subject(s)
Anticoagulants/chemistry , Ectoparasitic Infestations/veterinary , Feeding Behavior/physiology , Fishes/blood , Fishes/classification , Isopoda/physiology , Trypsin Inhibitors/chemistry , Animals , Anticoagulants/metabolism , Behavior, Animal/physiology , DNA, Ribosomal/analysis , DNA, Ribosomal/genetics , Ectoparasitic Infestations/parasitology , Fish Diseases/parasitology , Fishes/genetics , Fishes/parasitology , Host-Parasite Interactions/physiology , Isopoda/classification , RNA, Ribosomal, 16S/genetics , RNA, Ribosomal, 18S/genetics , Trypsin Inhibitors/metabolism
13.
J Appl Physiol (1985) ; 110(3): 610-8, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21148341

ABSTRACT

Hyperoxia has been shown to attenuate the increase in pulmonary artery (PA) pressure associated with immersed exercise in thermoneutral water, which could serve as a possible preventive strategy for the development of immersion pulmonary edema (IPE). We tested the hypothesis that the same is true during exercise in cold water. Six healthy volunteers instrumented with arterial and PA catheters were studied during two 16-min exercise trials during prone immersion in cold water (19.9-20.9°C) in normoxia [0.21 atmospheres absolute (ATA)] and hyperoxia (1.75 ATA) at 4.7 ATA. Heart rate (HR), Fick cardiac output (CO), mean arterial pressure (MAP), pulmonary artery pressure (PAP), pulmonary artery wedge pressure (PAWP), central venous pressure (CVP), arterial and venous blood gases, and ventilatory parameters were measured both early (E, 5-6 min) and late (L, 15-16 min) in exercise. During exercise at an average oxygen consumption rate (Vo(2)) of 2.38 l/min, [corrected] CO, CVP, and pulmonary vascular resistance were not affected by inspired (Vo(2)) [corrected] or exercise duration. Minute ventilation (Ve), alveolar ventilation (Va), and ventilation frequency (f) were significantly lower in hyperoxia compared with normoxia (mean ± SD: Ve 58.8 ± 8.0 vs. 65.1 ± 9.2, P = 0.003; Va 40.2 ± 5.4 vs. 44.2 ± 9.0, P = 0.01; f 25.4 ± 5.4 vs. 27.2 ± 4.2, P = 0.04). Mixed venous pH was lower in hyperoxia compared with normoxia (7.17 ± 0.07 vs. 7.20 ± 0.07), and this result was significant early in exercise (P = 0.002). There was no difference in mean PAP (MPAP: 28.28 ± 8.1 and 29.09 ± 14.3 mmHg) or PAWP (18.0 ± 7.6 and 18.7 ± 8.7 mmHg) between normoxia and hyperoxia, respectively. PAWP decreased from early to late exercise in hyperoxia (P = 0.002). These results suggest that the increase in pulmonary vascular pressures associated with cold water immersion is not attenuated with hyperoxia.


Subject(s)
Cold Temperature/adverse effects , Exercise , Hyperoxia/complications , Hyperoxia/physiopathology , Hypertension, Pulmonary/physiopathology , Immersion/adverse effects , Pulmonary Edema/physiopathology , Adult , Female , Humans , Hypertension, Pulmonary/complications , Male , Middle Aged , Prone Position , Pulmonary Edema/complications , Young Adult
14.
Br J Cancer ; 104(1): 193-7, 2011 Jan 04.
Article in English | MEDLINE | ID: mdl-21081933

ABSTRACT

BACKGROUND: Several studies suggest links between cancer and tricyclic antidepressant use. METHODS: A case-control study using the General Practice Research Database examined whether previous tricyclic usage was associated with reduced incidence of brain (with glioma as a sub-category), breast, colorectal, lung and prostate cancers. Conditional logistic regression adjusted for age, gender, general practice, depression, smoking, body mass index, alcohol use and non-steroidal anti-inflammatory drug use. RESULTS: A total of 31 953 cancers were identified, each matched with up to two controls. We found a statistically significant reduction in tricyclic prescriptions compared with controls in glioma (odds ratio (OR) =0.59, 95% confidence interval (CI)=0.42-0.81) and colorectal cancer patients (OR=0.84, CI=0.75-0.94). These effects were dose-dependent (P-values for trend, glioma=0.0005, colorectal=0.001) and time-dependant (P-values for trend glioma=0.0005, colorectal=0.0086). The effects were cancer-type specific, with lung, breast and prostate cancers largely unaffected by antidepressant use. CONCLUSION: The biologically plausible, specific and dose- and time-dependant inverse association that we have found suggests that tricyclics may have potential for prevention of both colorectal cancer and glioma.


Subject(s)
Antidepressive Agents, Tricyclic/adverse effects , Depression/chemically induced , Neoplasms/drug therapy , Neoplasms/epidemiology , Aged , Case-Control Studies , Databases, Factual , Female , Follow-Up Studies , Humans , Incidence , Male , Middle Aged , Neoplasms/pathology , Prospective Studies , Risk Factors , United Kingdom/epidemiology
15.
J Phys Condens Matter ; 22(32): 325106, 2010 Aug 18.
Article in English | MEDLINE | ID: mdl-21386488

ABSTRACT

A dynamic theory for compressible smectic C (SmC) liquid crystals is postulated following previous work by Leslie et al (1991 Mol. Cryst. Liq. Cryst. 198 443-54), Nakagawa (1996 J. Phys. Soc. Japan 65 100-6; 2004 J. Non-Newtonian Fluid Mech. 119 123-9) and de Gennes and Prost (1993 The Physics of Liquid Crystals 2nd edn (Oxford: Oxford University Press)). This theory is then implemented with a constructed bulk elastic energy and asymmetric stress tensor to describe a system of planar layered SmC liquid crystals undergoing various modes of undulation. We show that previous work on smectic A (SmA) liquid crystals by de Gennes and Prost (1993 The Physics of Liquid Crystals 2nd edn (Oxford: Oxford University Press)) can be expanded for SmC and consolidated. Novel and confirming estimates for SmC material parameter values are produced by considering the dependence of the system on these parameters.

16.
J Appl Physiol (1985) ; 106(2): 691-700, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19023017

ABSTRACT

Immersion pulmonary edema (IPE) is a condition with sudden onset in divers and swimmers suspected to be due to pulmonary arterial or venous hypertension induced by exercise in cold water, although it does occur even with adequate thermal protection. We tested the hypothesis that cold head immersion could facilitate IPE via a reflex rise in pulmonary vascular pressure due solely to cooling of the head. Ten volunteers were instrumented with ECG and radial and pulmonary artery catheters and studied at 1 atm absolute (ATA) during dry and immersed rest and exercise in thermoneutral (29-31 degrees C) and cold (18-20 degrees C) water. A head tent varied the temperature of the water surrounding the head independently of the trunk and limbs. Heart rate, Fick cardiac output (CO), mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), pulmonary artery wedge pressure (PAWP), and central venous pressure (CVP) were measured. MPAP, PAWP, and CO were significantly higher in cold pool water (P < or = 0.004). Resting MPAP and PAWP values (means +/- SD) were 20 +/- 2.9/13 +/- 3.9 (cold body/cold head), 21 +/- 3.1/14 +/- 5.2 (cold/warm), 14 +/- 1.5/10 +/- 2.2 (warm/warm), and 15 +/- 1.6/10 +/- 2.6 mmHg (warm/cold). Exercise values were higher; cold body immersion augmented the rise in MPAP during exercise. MAP increased during immersion, especially in cold water (P < 0.0001). Except for a transient additive effect on MAP and MPAP during rapid head cooling, cold water on the head had no effect on vascular pressures. The results support a hemodynamic cause for IPE mediated in part by cooling of the trunk and extremities. This does not support the use of increased head insulation to prevent IPE.


Subject(s)
Body Temperature Regulation , Cold Temperature , Diving/adverse effects , Exercise , Hemodynamics , Immersion , Pulmonary Edema/etiology , Water , Adult , Atmospheric Pressure , Carbon Dioxide/blood , Cardiac Output , Central Venous Pressure , Extremities , Female , Head , Heart Rate , Humans , Male , Middle Aged , Oxygen/blood , Pulmonary Circulation , Pulmonary Edema/blood , Pulmonary Edema/physiopathology , Pulmonary Wedge Pressure , Respiration , Young Adult
17.
J Appl Physiol (1985) ; 106(1): 316-25, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18787095

ABSTRACT

During diving, arterial Pco(2) (Pa(CO(2))) levels can increase and contribute to psychomotor impairment and unconsciousness. This study was designed to investigate the effects of the hypercapnic ventilatory response (HCVR), exercise, inspired Po(2), and externally applied transrespiratory pressure (P(tr)) on Pa(CO(2)) during immersed prone exercise in subjects breathing oxygen-nitrogen mixes at 4.7 ATA. Twenty-five subjects were studied at rest and during 6 min of exercise while dry and submersed at 1 ATA and during exercise submersed at 4.7 ATA. At 4.7 ATA, subsets of the 25 subjects (9-10 for each condition) exercised as P(tr) was varied between +10, 0, and -10 cmH(2)O; breathing gas Po(2) was 0.7, 1.0, and 1.3 ATA; and inspiratory and expiratory breathing resistances were varied using 14.9-, 11.6-, and 10.2-mm-diameter-aperture disks. During exercise, Pa(CO(2)) (Torr) increased from 31.5 +/- 4.1 (mean +/- SD for all subjects) dry to 34.2 +/- 4.8 (P = 0.02) submersed, to 46.1 +/- 5.9 (P < 0.001) at 4.7 ATA during air breathing and to 49.9 +/- 5.4 (P < 0.001 vs. 1 ATA) during breathing with high external resistance. There was no significant effect of inspired Po(2) or P(tr) on Pa(CO(2)) or minute ventilation (Ve). Ve (l/min) decreased from 89.2 +/- 22.9 dry to 76.3 +/- 20.5 (P = 0.02) submersed, to 61.6 +/- 13.9 (P < 0.001) at 4.7 ATA during air breathing and to 49.2 +/- 7.3 (P < 0.001) during breathing with resistance. We conclude that the major contributors to increased Pa(CO(2)) during exercise at 4.7 ATA are increased depth and external respiratory resistance. HCVR and maximal O(2) consumption were also weakly predictive. The effects of P(tr), inspired Po(2), and O(2) consumption during short-term exercise were not significant.


Subject(s)
Carbon Dioxide/blood , Diving/adverse effects , Exercise , Hypercapnia/etiology , Prone Position , Respiratory Physiological Phenomena , Adaptation, Physiological , Adult , Airway Resistance , Atmospheric Pressure , Exhalation , Female , Humans , Hypercapnia/blood , Hypercapnia/physiopathology , Immersion , Inhalation , Male , Middle Aged , Models, Biological , Oxygen/blood , Oxygen Consumption , Partial Pressure , Pulmonary Ventilation , Respiratory Dead Space , Risk Factors , Up-Regulation , Young Adult
18.
J Phys Condens Matter ; 21(15): 155101, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-21825354

ABSTRACT

This paper considers the dynamics of cylindrically arranged parallel layers of smectic A liquid crystal subjected to Couette flow. Governing equations are constructed using a recently developed dynamic theory for smectic A (Stewart 2007 Contin. Mech. Thermodyn. 18 343-60). These equations are solved to provide analytical solutions for the smectic layer undulations and velocity profiles. Results show the dependence of the response time of the smectic layers upon the permeation constant and the layer compression modulus. The relaxation times for the flow profiles are shown to depend upon two viscosities; estimates for these times are shown to be shorter than that for a typical approximation to the relaxation time of the smectic layer undulations.

19.
Parasitology ; 135(3): 337-45, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18053291

ABSTRACT

Molecular interplay during snail-schistosome interactions is poorly understood and there is much to discover concerning the effect of snail host molecules on molecular processes in schistosomes. Using the Biomphalaria glabrata - Schistosoma mansoni host-parasite system, the effects of exposure to haemolymph, derived from schistosome-resistant and susceptible snail strains, on protein tyrosine phosphorylation in miracidia have been investigated. Western blotting revealed several tyrosine phosphorylated proteins in this larval stage. Exposure of miracidia to haemolymph from susceptible snails for 60 min resulted in a striking, 5-fold, increase in the tyrosine phosphorylation of a 56 kDa (p56) S. mansoni protein. In contrast, haemolymph from resistant snails had little effect on protein tyrosine phosphorylation levels in miracidia. Confocal microscopy revealed that tyrosine phosphorylation was predominantly associated with proteins present in the tegument. Finally, treatment of miracidia with the tyrosine kinase inhibitor genistein significantly impaired their development into primary sporocysts. The results open avenues for research that focus on the potential importance of phospho-p56 to the outcome of schistosome infection in snails, and the significance of protein tyrosine kinase-mediated signalling events to the transformation of S. mansoni larvae.


Subject(s)
Biomphalaria/parasitology , Hemolymph/physiology , Host-Parasite Interactions/immunology , Schistosoma mansoni/metabolism , Tyrosine/metabolism , Animals , Biomphalaria/immunology , Blotting, Western , Electrophoresis, Polyacrylamide Gel , Genistein/pharmacology , Hemolymph/immunology , Larva , Microscopy, Confocal , Phosphorylation , Protein-Tyrosine Kinases/metabolism , Schistosoma mansoni/growth & development , Schistosoma mansoni/immunology , Signal Transduction , Tyrosine/antagonists & inhibitors
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