Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder thought to arise in a multipotent haemopoietic stem cell. A distinct clinical feature is a tendency to thrombosis, with a particular predilection for the hepatic veins (Budd-Chiari syndrome). We report here on two patients with PNH who developed hepatic vein thrombosis (HVT) and who were treated with tissue plasminogen activator (t-PA). Both patients had a marked clinical and radiological improvement following the t-PA treatment and remain well over 2 years and 6 years after the treatment. This method of thrombolysis for HVT occurring in PNH has only been reported in two previous patients with limited follow-up. We suggest that this therapy is a useful first-line treatment for PNH patients who develop HVT.

Treatments for macular oedema following central retinal vein occlusion: systematic review

Objectives: To review systematically the randomised controlled trial (RCT) evidence for treatment of macular oedema due to central retinal vein occlusion (CRVO).

Data sources: MEDLINE, EMBASE, CDSR, DARE, HTA, NHSEED, CENTRAL and meeting abstracts (January 2005 to March 2013).

Study eligibility criteria, participants and interventions: RCTs with at least 12 months of follow-up assessing pharmacological treatments for CRVO were included with no language restrictions.

Study appraisal and synthesis methods: 2 authors screened titles and abstracts and conducted data extracted and Cochrane risk of bias assessment. Meta-analysis was not possible due to lack of comparable studies.

Results: 8 studies (35 articles, 1714 eyes) were included, assessing aflibercept (n=2), triamcinolone (n=2), bevacizumab (n=1), pegaptanib (n=1), dexamethasone (n=1) and ranibizumab (n=1). In general, bevacizumab, ranibizumab, aflibercept and triamcinolone resulted in clinically significant increases in the proportion of participants with an improvement in visual acuity of ≥15 letters, with 40–60% gaining ≥15 letters on active drugs, compared to 12–28% with sham. Results for pegaptanib and dexamethasone were mixed. Steroids were associated with cataract formation and increased intraocular pressure. No overall increase in adverse events was found with bevacizumab, ranibizumab, aflibercept or pegaptanib compared with control. Quality of life was poorly reported. All studies had a low or unclear risk of bias.

Limitations: All studies evaluated a relatively short primary follow-up (1 year or less). Most had an unmasked extension phase. There was no head-to-head evidence. The majority of participants included had non-ischaemic CRVO.

Conclusions and implications of key findings: Bevacizumab, ranibizumab, aflibercept and triamcinolone appear to be effective in treating macular oedema secondary to CRVO. Long-term data on effectiveness and safety are needed. Head-to-head trials and research to identify ‘responders’ is needed to help clinicians make the right choices for their patients. Research aimed to improve sight in people with ischaemic CRVO is required.

Central venous catheterization - An anatomical review of a clinical skill - Part 1: Subclavian vein via the infraclavicular approach.

The safe and successful performance of a central venous catheterization (CVC) requires a specific knowledge of anatomy in addition to a working knowledge. Misunderstanding the anatomy may result in failure or complications. This review aims to aid understanding of the anatomical framework, pitfalls, and complications of CVC of the subclavian (SCV). CVC is common practice amongst surgeons, anesthesiologists, and emergency room physicians during the preparations for major surgical procedures such as open-heart surgery, as well as, for intensive care monitoring and rapid restoration of blood volume. Associated with this technique are certain anatomical pitfalls and complications that can be successfully avoided if one possesses a thorough knowledge of the contraindications, regional anatomy, and rationale of the technique.

Upper limb deep vein thrombosis due to Langer's axillary arch

Langer's axillary arch is a recognized muscular anomaly characterized by an accessory muscular band crossing the axilla that rarely causes symptoms. We describe a patient who presented with an upper limb deep vein thrombosis caused by this aberrant muscle, which we believe is the first reported case. Axillary surgery with division of the aberrant muscle relieved upper limb venous obstruction in this patient. (J Vase Surg 2012;55:234-6.)

Drug treatment of macular oedema secondary to central retinal vein occlusion: a network meta-analysis

Objective
To indirectly compare aflibercept, bevacizumab, dexamethasone, ranibizumab and triamcinolone for treatment of macular oedema secondary to central retinal vein occlusion using a network meta-analysis (NMA).

Design
NMA.

Data sources
The following databases were searched from January 2005 to March 2013: MEDLINE, MEDLINE In-process, EMBASE; CDSR, DARE, HTA, NHSEED, CENTRAL; Science Citation Index and Conference Proceedings Citation Index-Science.

Eligibility criteria for selecting studies
Only randomised controlled trials assessing patients with macular oedema secondary to central retinal vein occlusion were included. Studies had to report either proportions of patients gaining ≥3 lines, losing ≥3 lines, or the mean change in best corrected visual acuity. Two authors screened titles and abstracts, extracted data and undertook risk of bias assessment. Bayesian NMA was used to compare the different interventions.

Results
Seven studies, assessing five drugs, were judged to be sufficiently comparable for inclusion in the NMA. For the proportions of patients gaining ≥3 lines, triamcinolone 4 mg, ranibizumab 0.5 mg, bevacizumab 1.25 mg and aflibercept 2 mg had a higher probability of being more effective than sham and dexamethasone. A smaller proportion of patients treated with triamcinolone 4 mg, ranibizumab 0.5 mg or aflibercept 2 mg lost ≥3 lines of vision compared to those treated with sham. Patients treated with triamcinolone 4 mg, ranibizumab 0.5 mg, bevacizumab 1.25 mg and aflibercept 2 mg had a higher probability of improvement in the mean best corrected visual acuity compared to those treated with sham injections.

Conclusions
We found no evidence of differences between ranibizumab, aflibercept, bevacizumab and triamcinolone for improving vision. The antivascular endothelial growth factors (VEGFs) are likely to be favoured because they are not associated with steroid-induced cataract formation. Aflibercept may be preferred by clinicians because it might require fewer injections.

Systemic recruitment of osteoblastic cells in fracture healing

We hypothesise that following a bone fracture there is systemic recruitment of bone forming cells to a fracture site. A rabbit ulnar osteotomy model was adapted to trace the movement of osteogenic cells. Bone marrow mesenchymal stem cells from 41 NZW rabbits were isolated, culture-expanded and fluorescently labelled. The labelled cells were either re-implanted into the fracture gap (Group A); into a vein (Group B); or into a remote tibial bone marrow cavity 48 h after the osteotomy (Group C) or 4 weeks before the osteotomy was established (Group D), and a control group (Group E) had no labelled cells given. To quantify passive leakage of cells to an injury site, inert beads were also co-delivered in Group B. Samples of the fracture callus tissue and various organs were harvested at discrete sacrifice time-points to trace and quantify the labelled cells. At 3 weeks following osteotomy, the number of labelled cells identified in the callus of Group C, was significantly greater than following IV delivery, Group B, and there was no difference in the number of labelled cells in the callus tissues, between Groups C and A, indicating the labelled bone marrow cells were capable of migrating to the fracture sites from the remote bone marrow cavity. Significantly fewer inert beads than labelled cells were identified in Group B callus, suggesting some of the bone-forming cells were actively recruited and selectively chosen to the fracture site, rather than passively leaked into the circulation and to bone injury site. This investigation supports the hypothesis that some osteoblasts involved in fracture healing were systemically mobilised and recruited to the fracture from remote bone marrow sites. © 2005 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

Relationship between G894T polymorphism (Glu 298 Asp variant) in endothelial nitric oxide synthase and nitric oxide mediated endothelial function in human atherosclerosis.

Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), plays important roles in normal vascular homeostasis, and reduced endothelial NO bioactivity is an important feature of vascular disease states. The Glu298Asp (G894T) polymorphic variant of eNOS has been associated with vascular disease, but functional data are lacking. Accordingly, we examined the relationships between NO-mediated endothelial function, the presence of the eNOS Glu298Asp variant, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations to different agonists were determined in human saphenous veins obtained from patients with coronary artery disease and identified risk factors (n = 104). Patients were genotyped for the eNOS G894T polymorphism. Nitric oxide-mediated endothelial vasorelaxations were highly variable between patients. Reduced vasorelaxations were associated with increased number of clinical risk factors for atherosclerosis (r = - 0.54, P

Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

Bailey DM, Taudorf S, Berg RMG, Lundby C, McEneny J, Young IS, Evans KA, James PE, Shore A, Hullin DA, McCord JM, Pedersen BK, Moller K. Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness? Am J Physiol Regul Integr Comp Physiol 297: R1283-R1292, 2009. First published September 2, 2009; doi: 10.1152/ajpregu.00366.2009.-This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein and radial artery blood samples during normoxia and 9-h passive exposure to hypoxia (12.9% O-2). Cerebral blood flow was determined by the Kety-Schmidt technique with net exchange calculated by the Fick principle. AMS and headache were determined with clinically validated questionnaires. Electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide metabolites. Neuron-specific enolase (NSE), S100 beta, and 3-nitrotyrosine (3-NT) were determined by ELISA. Hypoxia increased the arterio-jugular venous concentration difference (a-v(D)) and net cerebral output of lipid-derived alkoxyl-alkyl free radicals and lipid hydroperoxides (P

Adrenomedullin Gene Delivery is Cardio-protective in a Model of Chronic Nitric Oxide Deficiency Combining Pressure Overload, Oxidative Stress and Cardiomyocyte Hypertrophy

BACKGROUND/AIMS:
Chronic inhibition of nitric oxide (NO) synthesis is associated with hypertension, myocardial ischemia, oxidative stress and hypertrophy; expression of the vasodilator peptide, adrenomedullin (AM) and its receptors is augmented in cardiomyocytes, indicating that the myocardial AM system may be activated in response to pressure loading and ischemic insult to serve a counter-regulatory, cardio-protective role. The study examined the hypothesis that oxidative stress and hypertrophic remodeling in NO-deficient cardiomyocytes are attenuated by adenoviral vector-mediated delivery of the human adrenomedullin (hAM) gene in vivo.

METHODS:
The NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 15mg . kg(-1) . day(-1)) was given to rats for 4 weeks following systemic administration via the tail vein of a single injection of either adenovirus harbouring hAM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM-4F2), or for comparison, adenovirus alone (Ad.Null) or saline. Cardiomyocytes were subsequently isolated for assessment of the influence of each intervention on parameters of oxidative stress and hypertrophic remodelling.

RESULTS: Cardiomyocyte expression of the transgene persisted for > or =4 weeks following systemic administration of adenoviral vector. In L-NAME treated rats, relative to Ad.Null or saline administration, Ad.CMV-hAM-4F2 (i) reduced augmented cardiomyocyte membrane protein oxidation and mRNA expression of pro-oxidant (p22phox) and anti-oxidant (SOD-3, GPx) genes; (ii) attenuated increased cardiomyocyte width and mRNA expression of hypertrophic (sk-alpha-actin) and cardio-endocrine (ANP) genes; (iii) did not attenuate hypertension.

CONCLUSIONS: Adenoviral vector mediated delivery of hAM resulted in attenuation of myocardial oxidative stress and hypertrophic remodelling in the absence of blood pressure reduction in this model of chronic NO-deficiency. These findings are consistent with a direct cardio-protective action in the myocardium of locally-derived hAM which is not dependant on NO generation.

Vascular stem cells and ischaemic retinopathies

Retinal ischaemic disorders such as diabetic retinopathy and retinal vein occlusion are common. The hypoxia-related stimuli from oxygen-deprived neural and glial networks can drive expression of growth factors and cytokines which induce leakage from the surviving vasculature and/or pre-retinal and papillary neovascularisation. If left untreated, retinal vascular stasis, hypoxia or ischaemia can lead to macular oedema or fibro-vascular scar formation which are associated with severe visual impairment, and even blindness. Current therapies for ischaemic retinopathies include laser photocoagulation, injection of corticosteroids or VEGF-antibodies and vitreoretinal surgery, however they carry significant side effects. As an alternative approach, we propose that if reparative intra-retinal angiogenesis can be harnessed at the appropriate stage, ischaemia could be contained or reversed. This review provides evidence that reperfusion of ischaemic retina and suppression of sight-threatening sequelae is possible in both experimental and clinical settings. In particular, there is emphasis on the clinical potential for endothelial progenitor cells (EPCs) to promote vascular repair and reversal of ischaemic injury in various tissues including retina. Gathering evidence from an extensive published literature, we outline the molecular and phenotypic nature of EPCs, how they are altered in disease and provide a rationale for harnessing the vascular reparative properties of various cell sub-types. When some of the remaining questions surrounding the clinical use of EPCs are addressed, they may provide an exciting new therapeutic option for treating ischaemic retinopathies. (C) 2011 Elsevier Ltd. All rights reserved.

Functional effect of the C242T polymorphism in the NAD(P)H oxidase p22phox gene on vascular superoxide production in atherosclerosis.

BACKGROUND:

Increased superoxide anion production increases oxidative stress and reduces nitric oxide bioactivity in vascular disease states. NAD(P)H oxidase is an important source of superoxide in human blood vessels, and some studies suggest a possible association between polymorphisms in the NAD(P)H oxidase CYBA gene and atherosclerosis; however, no functional data address this hypothesis. We examined the relationships between the CYBA C242T polymorphism and direct measurements of superoxide production in human blood vessels.

METHODS AND RESULTS:

Vascular NAD(P)H oxidase activity was determined in human saphenous veins obtained from 110 patients with coronary artery disease and identified risk factors. Immunoblotting, reverse-transcription polymerase chain reaction, and DNA sequencing showed that p22phox protein, mRNA, and 242C/T allelic variants are expressed in human blood vessels. Vascular superoxide production, both basal and NADH-stimulated, was highly variable between patients, but the presence of the CYBA 242T allele was associated with significantly reduced vascular NAD(P)H oxidase activity, independent of other clinical risk factors for atherosclerosis.

CONCLUSIONS:

Association of the CYBA 242T allele with reduced NAD(P)H oxidase activity in human blood vessels suggests that genetic variation in NAD(P)H oxidase components may play a significant role in modulating superoxide production in human atherosclerosis.

Cardiovascular actions of trout urotensin II in the conscious trout, Oncorhynchus mykiss

The central and peripheral cardiovascular effects of synthetic trout urotensin II (UII) were investigated in the conscious rainbow trout. Intracerebroventricular injection of 50 pmol UII produced a slight (3%) but significant (P < 0.05) increase in heart rate but had no effect on mean arterial blood pressure. Injection of 500 pmol UII icy produced a significant (P < 0.05) rise (8%) in blood pressure with no change in heart rate. In contrast to the weak presser effect of centrally administered UII, intra-arterial injection of UII produced a dose-dependent increase in arterial blood pressure and decrease in heart rate with significant (P < 0.05) effects on both parameters observed at a dose of 25 pmol. Higher doses of the peptide produced a sustained decrease in cardiac output that accompanied the bradycardia and rise in arterial blood pressure. The UII-induced bradycardia, but not the increase in pressure, was abolished by pretreatment with phentolamine. Trout UII produced a sustained and dose-dependent contraction of isolated vascular rings prepared from trout efferent branchial [-log 50% of the concentration producing maximal contraction (pD(2)) = 8.30] and celiacomesenteric (pD(2) = 8.22) arteries but was without effects on vascular rings from the anterior cardinal vein. The data indicate that the presser effect of UII in trout is mediated predominantly, if not exclusively, by an increase in systemic vascular resistance. The UII-induced hypertensive response does not seem to involve release of catecholamines, but the bradycardia may arise from adrenergic-mediated activation of cardioinhibitory baroreflexes.