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Primary hyperhidrosis affects up to 1% of the population and has a significant negative impact on quality of life. It affects the axillae in approximately 80% of cases. Hyperhidrosis results from excessive sympathetic stimulation of the eccrine sweat glands: the various treatment modalities available target points along the pathway between the central nervous system and the peripheral gland. The first line of treatment is topical aluminium chloride, which is effective in the majority of cases. Alternative treatments such as systemic anti-cholinergics and iontophoresis have significant disadvantages, while surgical sympathectomy has been regarded as the gold-standard in treatment of this condition. Recently, attention has focused on the use of intradermal botulinum toxin for the treatment of axillary hyperhidrosis. This is a highly effective, minimally-invasive treatment with few side effects, and is now recommended as the treatment of choice in isolated axillary hyperhidrosis [ABSTRACT FROM AUTHOR]

Coronaviruses exhibit many mechanisms of genetic innovation, including the acquisition of accessory genes that originate by capture of cellular genes or through duplication of existing viral genes. Accessory genes influence viral host range and cellular tropism, but little is known about how selection acts on these variable regions of virus genomes. We used experimental evolution of mouse hepatitis virus (MHV) encoding a cellular AKAP7 phosphodiesterase and an inactive native phosphodiesterase, NS2 to model the evolutionary fate of accessory genes. After courses of serial infection, the gene encoding inactive NS2, ORF2, unexpectedly remained intact, suggesting it is under cryptic constraint uncoupled from the function of NS2. In contrast, AKAP7 was retained under strong selection but rapidly lost under relaxed selection. Experimental evolution also led to altered viral replication in a cell type-specific manner and changed the relative proportions of subgenomic viral RNA in plaque-purified viral isolates, revealing additional mechanisms of adaptation. Guided by the retention of ORF2 and similar patterns in related betacoronaviruses, we analyzed ORF8 of SARS-CoV-2, which arose via gene duplication and contains premature stop codons in several globally successful lineages. As with MHV ORF2, the coding-defective SARS-CoV-2 ORF8 gene remains largely intact, mirroring patterns observed during MHV experimental evolution, challenging assumptions on the dynamics of gene loss in virus genomes and extending these findings to viruses currently adapting to humans., Competing Interests: Declaration of Interests The authors declare no competing interests.

Background:  The relationship between von Willebrand factor antigen (VWF:Ag), VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio, ADAMTS13 activity, and microembolic signal (MES) status in carotid stenosis is unknown., Methods:  This prospective, multicenter study simultaneously assessed plasma VWF:Ag levels, VWFpp levels and ADAMTS13 activity, and their relationship with MES in asymptomatic versus symptomatic moderate-to-severe (≥50-99%) carotid stenosis patients. One-hour transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES+ve or MES-ve., Results:  Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the "early phase" (≤4 weeks) and 37 patients in the "late phase" (≥3 months) after transient ischemic attack (TIA)/ischemic stroke. VWF:Ag levels were higher ( p  = 0.049) and VWFpp/VWF:Ag ratios lower ( p  = 0.006) in early symptomatic than in asymptomatic patients overall, and in early symptomatic versus asymptomatic MES-ve subgroups ( p ≤0.02). There were no intergroup differences in VWFpp expression or ADAMTS13 activity ( p ≥0.05). VWF:Ag levels and ADAMTS13 activity decreased ( p ≤ 0.048) and VWFpp/VWF:Ag ratios increased ( p  = 0.03) in symptomatic patients followed up from the early to late phases after TIA/stroke. Although there were no differences in the proportions of symptomatic and asymptomatic patients with blood group O, a combined analysis of early symptomatic and asymptomatic patients revealed lower median VWF:Ag levels in patients with blood group O versus those without blood group O (9.59 vs. 12.32 µg/mL, p  = 0.035)., Discussion:  VWF:Ag expression, a marker of endothelial ± platelet activation, is enhanced in recently symptomatic versus asymptomatic carotid stenosis patients, including in MES-ve patients, and decreases with ADAMTS13 activity over time following atherosclerotic TIA/ischemic stroke., Competing Interests: S.J.X.M. reports grants from Trinity College Dublin Innovation Bursary, Meath Foundation, Joint IICN/Merck Serono Fellowship in Neuroscience, The Vascular Neurology Research Foundation, unrestricted educational grant from Bayer HealthCare Ireland, and unrestricted educational grant from Verum Diagnostica, GmbH, outside the submitted work.S.T.L. reports grants from Meath Foundation, the Irish Institute of Clinical Neuroscience (IICN)/Novartis Ireland Fellowship Grant, the Irish Heart Foundation Stroke Prevention Bursary, the Vascular Neurology Research Foundation, Ireland, and unrestricted educational grant funding from Biogen Idec Ireland, outside the submitted work.D.J.H.M. reports grants from the Trinity College Dublin Innovation Bursary, Trinity College Dublin, Ireland, the Meath Foundation, Ireland, Joint IICN/Merck Serono Fellowship in Neuroscience, the Vascular Neurology Research Foundation, Bayer HealthCare Ireland, Verum Diagnostica, GmbH, the Irish Institute of Clinical Neuroscience (IICN)/Novartis Ireland Fellowship Grant, the Irish Heart Foundation Stroke Prevention Bursary, and Biogen Idec Ireland, during the conduct of the study., (Thieme. All rights reserved.)

The relationship between plaque morphology, cerebral micro-embolic signals (MES) and platelet biomarkers in carotid stenosis patients warrants investigation.We combined data from two prospective, observational studies to assess carotid plaque morphology and relationship with cerebral MES and platelet biomarkers in patients with recently symptomatic (≤4 weeks of transient ischaemic attack (TIA)/ischaemic stroke) versus asymptomatic carotid stenosis. Plaque morphology on ultrasound was graded with Grey-Scale Median (GSM) and Gray-Weale (GW) scoring. Bilateral transcranial Doppler ultrasound classified patients as 'MES+ve' or 'MES-ve'. Full blood counts were analysed and flow cytometry quantified CD62P and CD63 expression, leucocyte-platelet complexes and reticulated platelets.Data from 42 recently symptomatic carotid stenosis patients were compared with those from 36 asymptomatic patients. There were no differences in median GSM scores between symptomatic and asymptomatic patients (25 vs. 30; P  = 0.31) or between MES+ve vs. MES-ve symptomatic patients (36 vs. 25; P  = 0.09). Symptomatic patients with GSM-echodense plaques (GSM ≥25) had higher platelet counts (228 vs. 191 × 10 9 /L), neutrophil-platelet (3.3 vs. 2.7%), monocyte-platelet (6.3 vs. 4.55%) and lymphocyte-platelet complexes (2.91 vs. 2.53%) than ' asymptomatic patients with GSM-echodense plaques ' ( P ≤ 0.03).Recently, symptomatic carotid stenosis patients with 'GSM-echodense plaques' have enhanced platelet production/secretion/activation compared with their asymptomatic counterparts. Simultaneous assessment with neurovascular imaging and platelet biomarkers may aid risk-stratification in carotid stenosis.

Background: Assessment of 'high on-treatment platelet reactivity (HTPR)' could enhance understanding of the pathophysiology of first or recurrent vascular events in carotid stenosis patients on antiplatelet therapy., Methods: This prospective, multi-centre study assessed antiplatelet-HTPR status and its relationship with micro-emboli signals (MES) in asymptomatic vs. symptomatic ≥ 50-99% carotid stenosis. Platelet function/reactivity was assessed under 'moderately high shear stress' with the PFA-100 ® and 'low shear stress' with VerifyNow ® and Multiplate ® analysers. Bilateral 1-h transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES + ve or MES - ve., Results: Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the 'early phase' (≤ 4 weeks) and 37 patients in the 'late phase' (≥ 3 months) after TIA/ischaemic stroke. Median daily aspirin doses were higher in early symptomatic (225 mg; P < 0.001), but not late symptomatic (75 mg; P = 0.62) vs. asymptomatic patients (75 mg). There was a lower prevalence of aspirin-HTPR in early (28.6%; P = 0.028), but not late symptomatic (38.9%; P = 0.22) compared with asymptomatic patients (56.7%) on the PFA-100 ® , but not on the VerifyNow ® or Multiplate ® (P ≤ 0.53). Early symptomatic patients had a higher prevalence of aspirin-HTPR on the PFA-100 ® (28.6%) vs. VerifyNow ® (9.5%; P = 0.049), but not Multiplate ® assays (11.9%, P = 0.10). There was no difference in aspirin-HTPR prevalence between any symptomatic vs. asymptomatic MES + ve or MES - ve subgroup., Discussion: Recently symptomatic moderate-severe carotid stenosis patients had a lower prevalence of aspirin-HTPR than their asymptomatic counterparts on the PFA-100 ® , likely related to higher aspirin doses. The prevalence of antiplatelet-HTPR was positively influenced by higher shear stress levels, but not MES status.

Introduction:  Cerebral micro-embolic signals (MES) predict risk of stroke in carotid stenosis patients. However, MES-negative 'recently symptomatic patients' also have a higher stroke risk than 'asymptomatic patients'. Differences in platelet activation status may contribute to this disparity in risk., Methods:  This prospective, observational study assessed platelet biomarkers and their relationship with MES in asymptomatic versus symptomatic moderate (≥50-69%) or severe (≥70-99%) carotid stenosis patients. Full blood count parameters were measured and whole-blood flow cytometry was used to quantify platelet surface CD62P and CD63 expression and leucocyte-platelet complex formation. Bilateral simultaneous transcranial Doppler ultrasound of the middle cerebral arteries classified patients as 'MES positive' or 'MES negative'., Results:  Data from 34 asymptomatic patients were compared with those from 43 symptomatic patients in the 'early phase' (≤ 4 weeks) and 37 of these symptomatic patients in the 'late phase' (≥ 3 months) after transient ischaemic attack/ischaemic stroke. There were no differences in %CD62P or %CD63 expression between early or late symptomatic and asymptomatic patients overall ( p  > 0.05). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic patients (2.8 vs. 2.16%; p  < 0.001). MES were more commonly observed in early symptomatic (31.4%; p  = 0.027) but not in late symptomatic (6.7%; p  = 0.996) versus asymptomatic patients (7.1%). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic MES-negative patients (2.7 vs. 2.17%; p  = 0.02)., Conclusion: These data add to the evidence that leucocyte-platelet complex formation/platelet activation is increased in recently symptomatic versus asymptomatic patients, and may contribute to the pathogenesis of first and subsequent strokes in carotid stenosis patients, including those who are MES negative., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: The relationship between on-treatment platelet reactivity and cerebral micro-embolic signals (MES) is unknown, and has not been previously simultaneously assessed in asymptomatic and symptomatic carotid stenosis patients., Methods: Consecutive eligible patients with ≥50% asymptomatic or recently symptomatic carotid stenosis (≤4weeks following TIA/ischaemic stroke) were recruited to this pilot study. Symptomatic patients were followed up to the 'late' phase (≥3months) following symptom onset or carotid intervention; longitudinal data were analysed from symptomatic patients with data available at both time-points. Platelet function/reactivity was assessed with the PFA-100® to measure collagen-ADP (C-ADP) and collagen-epinephrine (C-EPI) closure times in citrate-anticoagulated whole blood. Bilateral simultaneous 1-hour transcranial Doppler ultrasound (TCD) monitoring of the middle cerebral arteries was performed to classify patients as MES +ve or MES -ve., Results: 31 patients with ≥50% asymptomatic and 46 with early symptomatic carotid stenosis or occlusion were included. 35 symptomatic patients were followed up to the late phase (23 following carotid intervention). Prevalence of 'high on-treatment platelet reactivity' (HTPR) on the C-EPI cartridge did not differ between asymptomatic and symptomatic patients overall, but was lower in 'symptomatic post-intervention' than asymptomatic patients on aspirin monotherapy (10% vs. 50%; p=0.03). The prevalence of HTPR on the C-EPI cartridge decreased between the early and late phases in symptomatic patients (63% vs. 34%; p=0.017), including those on aspirin monotherapy (p=0.016). There were no significant differences in HTPR status between asymptomatic vs. early or late symptomatic MES +ve or MES -ve patients., Discussion: Carotid interventional treatment, presumably in combination with resolution of the acute phase response, may decrease the prevalence of HTPR in patients with recently symptomatic carotid stenosis over time. Preliminary subgroup analysis suggests that successful intervention may reduce the prevalence of aspirin-HTPR in symptomatic patients to lower levels than asymptomatic medically-treated patients on aspirin monotherapy. Larger, longitudinal studies are warranted to reassess the impact of more intensive secondary preventive treatment on ex vivo platelet function at different levels of shear stress in carotid stenosis patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: The importance of thrombin generation in the pathogenesis of TIA or stroke and its relationship with cerebral microembolic signals (MES) in asymptomatic and symptomatic carotid stenosis has not been comprehensively assessed., Methods: Plasma thrombin generation parameters from patients with moderate or severe (≥ 50%) asymptomatic carotid stenosis were compared with those from patients with symptomatic carotid stenosis in the early (≤ 4 weeks) and late phases (≥ 3 months) after TIA or stroke in this prospective, pilot observational study. Thrombin generation profile was longitudinally assessed in symptomatic patients with data at each time point. Bilateral transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed whenever possible to classify patients as MES-positive or MES-negative., Results: Data from 31 asymptomatic, 46 'early symptomatic' and 35 'late symptomatic' patients were analysed. Peak thrombin (344.2 nM vs 305.3 nM; p = 0.01) and endogenous thrombin potential (1772.4 vs 1589.7; p = 0.047) were higher in early symptomatic than asymptomatic patients. Peak thrombin production decreased in symptomatic patients followed up from the early to late phase after TIA or stroke (339.7 nM vs 308.6 nM; p = 0.02). Transcranial Doppler ultrasound data were available in 25 asymptomatic, 31 early symptomatic and 27 late symptomatic patients. Early symptomatic MES-positive patients had a shorter 'time-to-peak thrombin' than asymptomatic MES-positive patients (p=0.04), suggesting a more procoagulant state in this early symptomatic subgroup., Discussion: Thrombin generation potential is greater in patients with recently symptomatic than asymptomatic carotid stenosis, and decreases over time following TIA or stroke associated with carotid stenosis. These data improve our understanding of the haemostatic/thrombotic biomarker profile in moderate-severe carotid stenosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The impact of commencing or changing antiplatelet therapy on von Willebrand factor antigen (VWF:Ag) and von Willebrand factor propeptide (VWF:Ag II) levels has not been comprehensively assessed following TIA or ischaemic stroke. In this pilot, longitudinal, observational analytical study, VWF:Ag and VWF:Ag II levels were simultaneously quantified in platelet poor plasma by ELISA in patients within 4 weeks of TIA or ischaemic stroke (baseline), and then 14 days (14d) and >90 days (90d) after altering antiplatelet therapy. Ninety-one patients were recruited. Eighteen were initially assessed on no antiplatelet therapy, and then after 14d (N = 17) and 90d (N = 8) on aspirin monotherapy; 21 patients were assessed on aspirin and after 14d and 90d on clopidogrel; 52 were assessed on aspirin monotherapy, and after 14d and 90d on aspirin and dipyridamole combination therapy. VWF:Ag, VWF:Ag II levels and VWF:Ag/VWF:Ag II ratio were unchanged at 14d and 90d in the overall study population (p ≥ 0.1). VWF:Ag and VWF:Ag II levels remained stable at 14d and 90d after commencing aspirin (p ≥ 0.054), and after changing from aspirin to clopidogrel (p ≥ 0.2). Following the addition of dipyridamole MR to aspirin, there was a significant reduction in VWF:Ag levels at 14d (p = 0.03) and 90d (p = 0.005), but not in VWF:Ag II levels (p ≥ 0.3). The addition of dipyridamole to aspirin led to a persistent reduction in VWF:Ag but not in VWF:Ag II levels, suggesting that dipyridamole may inhibit release of platelet-derived VWF:Ag following TIA or ischaemic stroke.

Background and Purpose: von Willebrand factor propeptide (VWF:Ag II) is potentially a more sensitive marker of acute endothelial activation than von Willebrand factor antigen (VWF:Ag). These biomarkers have not been simultaneously assessed in asymptomatic versus symptomatic carotid stenosis patients. The relationship between endothelial activation and cerebral microembolic signals (MESs) detected on transcranial Doppler ultrasound is unknown., Methods: In this multicentre observational analytical study, plasma VWF:Ag and VWF:Ag II levels in patients with ≥50% asymptomatic carotid stenosis were compared with those from patients with ≥50% symptomatic carotid stenosis in the 'early' (≤4 weeks) and 'late' (≥3 months) phases after transient ischaemic attack or ischaemic stroke. Endothelial activation was also longitudinally assessed in symptomatic patients during follow-up. Transcranial Doppler ultrasound monitoring classified patients as MES-positive or MES-negative., Results: Data from 31 asymptomatic patients were compared with those from 46 early symptomatic and 35 late phase symptomatic carotid stenosis patients, 23 of whom had undergone carotid intervention. VWF:Ag II levels were higher in early (12.8 μg/ml; P < 0.001), late (10.6 μg/ml; P = 0.01) and late post-intervention (10.6 μg/ml; P = 0.038) symptomatic patients than asymptomatic patients (8.9 μg/ml). VWF:Ag levels decreased in symptomatic patients followed up from the early to late phase after symptom onset (P = 0.048). Early symptomatic MES-negative patients had higher VWF: Ag II levels (13.3 vs. 9.0 μg/ml; P < 0.001) than asymptomatic MES-negative patients., Conclusions: Endothelial activation is enhanced in symptomatic versus asymptomatic carotid stenosis patients, in early symptomatic versus asymptomatic MES-negative patients, and decreases over time in symptomatic patients. VWF:Ag II levels are a more sensitive marker of endothelial activation than VWF:Ag levels in carotid stenosis. The potential value of endothelial biomarkers and concurrent cerebral MES detection at predicting stroke risk in carotid stenosis warrants further study., (© 2014 The Author(s) European Journal of Neurology © 2014 EAN.)

Objectives: To identify possible cases of occupational asthma and assess accidental skin and inhalation exposures to aliphatic diisocyanates., Methods: Seventy-three employees from two plants, manufacturing or producing aliphatic diisocyanates, were surveyed using a detailed respiratory history questionnaire with additional questions on accidental skin and inhalation exposures. Further reviews of medical records and interviews were used to determine whether any of 15 employees with questionable responses had developed occupational asthma., Results: No cases of occupational asthma were identified. Nevertheless, many employees reported occasional accidental unprotected skin exposures and/or detecting the odor of 1,6-hexamethylene diisocyanate or isophorone diisocyanate., Conclusions: Consistent with a previous study, no cases of occupational asthma were identified from exposure to 1,6-hexamethylene diisocyanate, isophorone diisocyanate, methylene bis(4-cyclohexyl isocyanate), or their polyisocyanates even though many employees reported detection of odors (93%) or skin exposures (53%).

Background: Cerebral microembolic signals (MES) may predict increased stroke risk in carotid stenosis. However, the relationship between platelet counts or platelet activation status and MES in symptomatic vs. asymptomatic carotid stenosis has not been comprehensively assessed., Setting: University teaching hospitals., Methods: This prospective, pilot observational study assessed platelet counts and platelet activation status, and the relationship between platelet activation and MES in asymptomatic vs. early (≤ 4 weeks after TIA/stroke) and late phase (≥ 3 months) symptomatic moderate or severe (≥ 50%) carotid stenosis patients. Full blood count measurements were performed, and whole blood flow cytometry was used to quantify platelet surface activation marker expression (CD62P and CD63) and circulating leucocyte-platelet complexes. Bilateral simultaneous transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed for 1 h to classify patients as MES positive or MES negative., Results: Data from 31 asymptomatic patients were compared with 46 symptomatic patients in the early phase, and 35 of these patients were followed up to the late phase after symptom onset. The median platelet count (211 vs. 200 × 10(9)  L(-1) ; P = 0.03) and the median percentage of lymphocyte-platelet complexes was higher in early symptomatic than asymptomatic patients (2.8 vs. 2.4%; P = 0.001). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic patients with ≥ 70% carotid stenosis (P = 0.0005) and symptomatic patients recruited within 7 days of symptom onset (P = 0.028). Complete TCD data were available in 25 asymptomatic, 31 early phase symptomatic and 27 late phase symptomatic patients. Twelve per cent of asymptomatic vs. 32% of early phase symptomatic (P = 0.02) and 19% of late phase symptomatic patients (P = 0.2) were MES positive. Early symptomatic MES-negative patients had a higher percentage of lymphocyte-platelet complexes than asymptomatic MES-negative patients (2.8 vs. 2.3%; P = 0.0085)., Discussion: Recently, symptomatic carotid stenosis patients have had higher platelet counts (potentially reflecting increased platelet production, mobilization or reduced clearance) and platelet activation status than asymptomatic patients. MES were more frequently detected in early symptomatic than asymptomatic patients, but the differences between late symptomatic and asymptomatic groups were not significant. Increased lymphocyte-platelet complex formation in recently symptomatic vs. asymptomatic MES-negative patients indicates enhanced platelet activation in this early symptomatic subgroup. Platelet biomarkers, in combination with TCD, have the potential to aid risk-stratification in asymptomatic and symptomatic carotid stenosis patients., (© 2013 International Society on Thrombosis and Haemostasis.)

Background: Foot ulceration which may result in lower limb amputation is one of the most feared complications among patients with diabetes and the prevention of both ulceration and amputation is a major challenge facing the health service. Many studies have proposed dedicated diabetic foot teams as the future of diabetic foot care., Aims: We aimed to quantify the cost benefit and sustainability of a multi-disciplinary foot protection clinic (MDFPC) in an Irish university hospital setting., Methods: A dedicated bi-weekly consultant-led MDFPC including Vascular Surgery, Endocrinology, Orthopaedic Surgery, Podiatry, Orthotics and Tissue Viability was established in June 2008., Results: Between 2006 and 2010, a total of 221 lower limb procedures (major/minor amputations and debridement) were performed. The number of major amputations decreased from 12 during the control period (2 years before the clinic) to 7 in the study period (2 years after the clinic). After costing all activity associated with the clinic, there was an overall saving of €114,063 per year associated with the introduction of the MDFPC., Conclusion: This is the first study in an Irish context, and one of few international studies, to demonstrate that an aggressive-coordinated approach to diabetic foot care is both cost effective and clinically efficient in reducing the burden of foot-related complications in a diabetic population.

Background and Purpose: The prevalence of ex vivo 'high on-treatment platelet reactivity' (HTPR) to antiplatelet regimens in patients with ischaemic cerebrovascular disease (CVD) is uncertain., Methods: HTPR was assessed with PFA-100 collagen-epinephrine (C-EPI) and collagen-ADP (C-ADP) cartridges. Platelet activation (CD62P, CD63 and leucocyte-platelet complex formation) was assessed with whole-blood flow cytometry. Patients were assessed at baseline [≤ 4 weeks of transient ischaemic attack (TIA) or ischaemic stroke], and at 14 days and ≥ 90 days after changing treatment from (i) no medication to aspirin monotherapy (N = 26) or (ii) aspirin to clopidogrel monotherapy (N = 22). HTPR was defined in a novel, 'longitudinal fashion' as failure to prolong relevant closure times compared with the patient's 'baseline value' before he/she underwent an antiplatelet change by more than twice the coefficient of variation of the assay., Results: (i) C-EPI closure times increased at 14 days and 90 days after commencing aspirin (P = 0.002); 24% at 14 days and 18% at 90 days demonstrated HTPR on aspirin. (ii) C-ADP closure times increased at 14 days (P = 0.001) but not 90 days (P = 0.09) after changing from aspirin to clopidogrel; 41% at 14 days, and 35% at 90 days demonstrated HTPR on clopidogrel. Platelet activation was unaffected by aspirin (P = 0.09). The percentage neutrophil-platelet complexes decreased at 14 days (P = 0.02), but this reduction was not maintained 90 days after changing to clopidogrel (P = 0.3). No patient had a recurrent vascular event during prospective follow-up., Conclusions: Longitudinal definitions of HTPR in patients with ischaemic CVD who are undergoing a change in antiplatelet therapy have the potential to provide more clinically meaningful information than traditional 'cross-sectional definitions' of HTPR which are usually based on the comparison of patients' values with those in healthy controls. Using our novel, longitudinal definition of HTPR, the PFA-100 could be used to monitor ex vivo responsiveness to aspirin, and larger, prospective studies are warranted to assess the clinical predictive value of this and other platelet function tests in patients with ischaemic CVD., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

The impact of changing antiplatelet therapy on thrombin generation potential in patients with ischaemic cerebrovascular disease (CVD) is unclear. We assessed patients within 4 weeks of TIA or ischaemic stroke (baseline), and then 14 days (14d) and >90 days (90d) after altering antiplatelet therapy. Thrombin generation was assessed in platelet poor plasma. Ninety-one patients were recruited. Twenty-four were initially assessed on no antiplatelet therapy, and then after 14d (N = 23) and 90d (N = 8) on aspirin monotherapy; 52 were assessed on aspirin monotherapy, and after 14 and 90 days on aspirin and dipyridamole combination therapy; 21 patients were assessed on aspirin and after 14 days (N = 21) and 90 days (N = 19) on clopidogrel. Peak thrombin generation and endogenous thrombin potential were reduced at 14 and 90 days (p ≤ 0.04) in the overall cohort. We assessed the impact of individual antiplatelet regimens on thrombin generation parameters to investigate the cause of this effect. Lag time and time-to-peak thrombin generation were unchanged at 14 days, but reduced 90 days after commencing aspirin (p ≤ 0.009). Lag time, peak thrombin generation and endogenous thrombin potential were reduced at both 14 and 90 days after adding dipyridamole to aspirin (p ≤ 0.01). Lag time was reduced 14 days after changing from aspirin to clopidogrel (p = 0.045), but this effect was not maintained at 90 days (p = 0.2). This pilot study did not show any consistent effects of commencing aspirin, or of changing from aspirin to clopidogrel on thrombin generation potential during follow-up. The addition of dipyridamole to aspirin led to a persistent reduction in peak and total thrombin generation ex vivo, and illustrates the diverse, potentially beneficial, newly recognised 'anti-coagulant' effects of dipyridamole in ischaemic CVD.

Background: Little is known of the actual understanding that underlies patient choices with regard to their surgical treatment. This review explores current knowledge of patient understanding and techniques that may be used to improve this understanding., Methods: MEDLINE and PubMed were searched using the terms "patient understanding," "patient comprehension," "consent," "video," "multimedia," "patient information leaflet," "internet," "test-feedback," "extended discussion," "shared decision making," and "decision aid." All retrieved peer-reviewed studies were included in the review., Results: Understanding in surgical patients is poor. There is little evidence to support the use of information leaflets, although multimedia appears to be effective in improving patient understanding. The internet is not used effectively as an aid to consent by health care providers. Patients with lower educational levels may gain most from additional interventions. Improving patient understanding does not impact on their satisfaction with the treatment they have received but may reduce periprocedural anxiety., Conclusions: There is a need for greater awareness of patients' information needs, and novel approaches that may enhance decision making through improved understanding are required., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Critical limb ischaemia due to distal arterial disease represents a significant challenge. Randomised controlled evidence suggests that open surgery may be superior to endovascular intervention but there is limited data on the specific clinical cohort with exclusively infra-popliteal disease., Aim: We analysed indications for, and outcome from all, popliteo-pedal bypass procedures performed between July 1998 to November 2008., Patients and Methods: Twenty-eight bypass procedures were performed in 24 patients. Autologous vein was used exclusively. The proximal anastomosis was to the below-knee popliteal artery in all the patients; the distal anastomosis was to plantar artery (n = 15) or dorsalis pedis artery (n = 13). Mean patient age was 63.Eight years of age (range 37-92 years). Indications for surgery were tissue loss (n = 21) and rest pain (n = 7). Ultrasound graft surveillance was performed every 6-months., Results: Using life table analysis, primary graft patency was 63.3% at 1-, 3- and 5-years and secondary patency (after three interventions) was 74.6% at 1-, 3- and 5-years. Limb salvage rate was 81.8% after 1-, 3- and 5-years as all five limb amputations were performed in the first 3-months following the surgery. Overall survival was 75, 75 and 47.1% at 1-, 3- and 5-years, respectively. The major amputation free survival rate was 54.2, 54.2 and 21.3% at 1-, 3- and 5-years, respectively. Seventy-nine percent (n = 19) patients were diabetic., Conclusion: Our data supports popliteo-pedal bypass as an effective treatment for distal vascular disease. Comparison with endovascular treatment in a randomised trial needs to be performed.

Ex vivo dipyridamole 'non-responsiveness' has not been extensively studied in ischaemic cerebrovascular disease. Platelet surface marker expression, leucocyte-platelet complex formation and inhibition of platelet function at high shear stress as detected by the PFA-100® Collagen-Adenosine-diphosphate (C-ADP) and Collagen-Epinephrine cartridges was assessed in 52 patients within 4 weeks of transient ischaemic attack (TIA) or ischaemic stroke on aspirin, and then 14 d (14 d) and >90 d (90 d) after adding dipyridamole. A novel definition of 'Dipyridamole non-responsiveness' was used. The median C-ADP closure time increased following addition of dipyridamole, remained elevated at 90 d (P ≤ 0·03), and was unaffected by aspirin dose. 59% at 14 d and 56% at 90 d were 'dipyridamole non-responders' on the PFA-100. The proportion of non-responders at 14 and 90 d was similar (P= 0·9). Compared with baseline (4·6%), median monocyte-platelet complexes increased at 14 d (5·0%, P= 0·03) and 90 d (4·9%, P= 0·04). Low C-ADP closure times were associated with increased monocyte-platelet complexes at 14 d (r= -0·32, P= 0·02) and 90 d (r= -0·33, P = 0·02). Monocyte-platelet complexes increased in the subgroup of dipyridamole non-responders on the PFA-100 (P≤ 0·045), but not in responders (P ≥ 0·5), at 14 and 90 d versus baseline. Additional inhibition of platelet function has been detected with the PFA-100 when dipyridamole is added to aspirin. Elevated monocyte-platelet complexes may contribute to ex vivo dipyridamole non-responsiveness., (© 2011 Blackwell Publishing Ltd.)

Objective: To identify if 1,6-hexamethylene diisocyanate (HDI) workers demonstrated an increased prevalence of occupational asthma or accelerated decline in pulmonary function., Methods: Employees from two plants manufacturing or producing 1,6-HDI monomer and/or HDI polyisocyanates were matched to a control population by age, gender, race, and smoking status. A random coefficient regression analysis compared the decline in pulmonary function test values over time. Retrospective medical review was used to identify potential cases of occupationally induced asthma., Results: No significantly accelerated annual decline in force expiratory volume after 1 second in the HDI exposure group compared to the matched control group was observed. No cases of adult onset asthma, beyond those present at time of hire, and no cases of occupational asthma were identified., Conclusions: This study provides support for the current American Conference of Governmental Industrial Hygienists threshold limit value time-weighted average of 5 ppb.

Background: Carotid endarterectomy (CEA) is a well-established method of stroke prevention in patients with symptomatic, high-grade internal carotid artery stenosis., Aims: To assess the change in carotid surgery practice in health board regions in Ireland over two different time periods in the past 11 years (1996-1998/2001-2003)., Methods: Numbers of discharges of patients with a procedure code CEA (38.12) between 1996-1998 and 2001-2003 were obtained from the Hospital In-Patient Enquiry (HIPE) database maintained by the Economic and Social Research Institute (ESRI). Population data was obtained from national censuses., Results: There has been considerable change in the level of carotid surgery activity in specific health board regions between the two periods., Conclusions: Still no region comes close to achieving levels of CEA recommended by population studies. This is important in the context of the MRC asymptomatic carotid surgery trial (ACST), as the numbers suitable for CEA will probably increase further in the future.

Aim: It is particularly important that patients have reasonable understanding of the risks, benefits and nature of elective surgery. This study sought to analyse this level of understanding in patients undergoing varicose vein surgery, Methods: Eighty two patients completed a questionnaire in the vascular outpatient clinic and were asked to complete a telephone questionnaire following the clinic., Results: Pain (n = 46) was the primary reason patients considered varicose vein surgery followed by appearance (n = 32). Most patients felt that varicose veins placed them at high risk of leg ulcers (n = 46) and DVT (n = 41). A high level of expectation that surgery would significantly affect pain and flares was recorded. While the outpatient visit did not materially change these misconceptions, an educational leaflet significantly enhanced the recall of complications (p = 0.028) in patients who remembered receiving a leaflet., Conclusion: Patients attending varicose vein clinics have an unrealistic expectation of the benefits of surgery and fail to understand the benign nature of their condition. The outpatient process has little effect on patient-held beliefs.

Background: This study was designed to document the surgical anatomy of the saphenofemoral junction (SFJ)., Methods: The anatomy of the SFJ was recorded diagrammatically in 2089 consecutive groin dissections performed to treat primary varicose veins. The number of primary tributaries, bifid systems, junctional tributaries and the relationship of the external pudendal artery (EPA) to the long saphenous vein (LSV) were recorded., Results: The LSV was bifid in 18.1 per cent of legs. The number of tributaries at the SFJ varied from one to ten. In 33.4 per cent one or more (junctional) tributaries joined the LSV or common femoral vein deep to the deep fascia. The EPA crossed anterior to 16.8 per cent of LSVs. In 4.6 per cent it passed posterior to one large tributary or trunk of a bifid LSV and anterior to the second trunk, making identification of the second trunk particularly difficult., Conclusion: A thorough understanding of the anatomical variations of the SFJ is important in ensuring that the junction is managed safely and adequately in patients with varicose veins. Failure to appreciate these variations may account for a significant proportion of inadequate primary varicose vein surgery.

The management of obstructing left-sided colonic and rectal lesions has traditionally been by a staged procedure. The introduction of 'on-table lavage', has made primary resection and anastomosis of the large bowel feasible for patients presenting as emergencies. We have studied the perioperative course of 28 patients who presented with left colonic obstruction to determine whether primary anastomosis conferred additional morbidity. The patients ranged in age from 29 to 89 years (mean 66 years) at presentation. The ASA status of patients was comparable in both groups (Table 1). Fourteen patients underwent resection, on-table lavage, and primary anastomosis (PA) and 14 a Hartmann's procedure (HP). The mean operative time for the PA procedure was 200 minutes compared to 110 minutes for the HP group. There was no significant difference in the postoperative complication rate nor mean hospital stay rate for the primary procedures between the two groups. There was no clinical anastomotic leak in patients undergoing primary anastomosis. However secondary surgery for patients undergoing colorectal reconnection conferred added morbidity for patients who had a HP. We conclude that resection, on-table lavage, and primary anastomosis is safe in the management of left-sided colonic obstruction and in most cases is the treatment of choice.

Two-hundred and twenty-four infrainguinal polytetrafluoroethylene reconstructions were performed for critical ischemia over a 10 year period: 48 to the above-knee popliteal artery, 113 to the below-knee popliteal artery, and 63 to the tibial vessels. The cumulative patency rates were 84 +/- 6% and 63 +/- 9% for above-knee popliteal, 53 +/- 5% and 35 +/- 7% for below-knee popliteal, 45 +/- 6% and 30 +/- 9% for tibial vessels at one and five years respectively. Limb salvage rates were 81 +/- 6% and 73 +/- 9% (above-knee popliteal), 69 +/- 5% and 57 +/- 9% (below-knee popliteal), 64 +/- 7% and 32 +/- 10% (tibial vessels) at one and five years respectively. Graft occlusion did not result in limb loss in 32 cases. Preoperatively, 54% of the patients had limited mobility while 43% were regarded as severely restricted. At follow-up, 57% of the patients were considered to be independent, 26% had limited mobility, and 17% were still severely restricted. Polytetrafluoroethylene provides good short-term limb salvage and improved mobility in patients with critical ischemia and poor life expectancy. Its use is well worth the effort.

Many recent reports in the North American literature have documented an increase in the ratio of proximal to distal colorectal cancers with an increase in right-sided lesions. In order to assess trends in the distribution of large bowel carcinoma at our hospital we reviewed the files of 1553 patients who presented with primary colorectal carcinoma over a 30-year period. Thirty-nine percent of patients were over 70 years old and 51% were in the 50-69 year age group. Seventy five percent of the carcinomas were left-sided, 22% right-sided and caecal carcinomas accounted for 18%. This distribution varied only slightly over the study period. Left-sided lesions were more common in males (55%: p less than 0.005), and right-sided lesions were more common in females (57%: p less than 0.005). Caecal carcinoma was more common in patients over 69 years old than in younger patients (p less than 0.001). In elderly females (greater than 69 years) 30% of colorectal carcinomas occurred in the caecum. These findings may have important implications for the investigation of patients with suspected colorectal disease or for screening programmes.

Carotid plaque characteristics associated with the production of symptoms were identified with quantification of carotid plaque constituents in high-grade stenotic asymptomatic (n = 8) and symptomatic (n = 44) plaques. Asymptomatic plaques contained significantly more fibrous/collagen material (88%) than symptomatic plaques (66%) (p less than 0.05). Hemorrhage constituted 2% and 1% of asymptomatic and symptomatic plaques, respectively. The predominant nonfibrous material was a pink amorphous material mixed with cholesterol, which composed 7% of asymptomatic and 27% of symptomatic plaques (p less than 0.05). No relationship was found between plaque composition and the number of ipsilateral ischemic neurologic events, nor was there evidence of a healing process. B-mode ultrasound scanning had a sensitivity of 94% in identifying plaque with greater than 80% fibrous content. We believe that plaque composition may be a useful discriminating factor in selecting asymptomatic patients for carotid endarterectomy.

Despite advances in the design and care of in-dwelling catheters, sepsis remains a significant problem in patients on long-term parenteral nutrition. In recent years there have been a number of reports concerning the successful use of totally implanted subcutaneous venous access devices in the management of patients requiring long-term intermittent intravenous administration of cytotoxic therapy and frequent blood sampling. The use of such a system for the administration of supplementary home parenteral nutrition in a patient with short-bowel syndrome is reported.

We report on the management of a patient with intractable venous claudication and ulceration due to bilateral iliac vein and inferior vena cava occlusion. An inverted V graft was constructed from two 8 mm diameter reinforced PTFE grafts. The upper end was anastomosed to the inferior infrarenal vena cava and the lower ends anastomosed to the common femoral veins. Bilateral arteriovenous fistulas were fashioned. Nine months later the graft is patent and the patient's only symptom is mild ankle edema. The theoretical advantage of this type of graft is that occlusion of one limb will not compromise the other, thus leaving a number of secondary options open if this should happen.

The presence of haemorrhage in carotid bifurcation atheromatous plaques is widely believed to be associated with the production of ischaemic neurological events. This study set out to characterise plaque composition in symptomatic (SYM) and asymptomatic (ASYM) patients and to identify, if possible, the origin of intra-plaque haemorrhage. Fifty-nine plaques (50 SYM and 9 ASYM) were serially sectioned and examined for haemorrhage, haemosiderin, fibrin, cholesterol and collagen. Immunoperoxidase and electron microscopy studies were carried out on sections from five plaques in order to identify blood breakdown products. Intra-plaque haemorrhage was identified in 40 (68%) plaques and was similar in SYM and ASYM plaques. In only one did it constitute more than 15% of plaque content, and in the remainder it consisted of small collections of erythrocytes constituting greater than 1% of plaque content in only 21 (35%) plaques. The predominant non-fibrous component was a pink amorphous material mixed with cholesterol. Apart from traces of platelet breakdown products there was no evidence of haemorrhage in this pink material. Plaque roof rupture or ulceration was seen in 39 (66%) and in almost all cases overlay the amorphous/cholesterol material. Blood vessels were identified in 51 87%) plaques but were in close proximity to haemorrhage in only nine (15%).

Management of intractable venous ulceration remains an unrewarding task which is increasingly delegated to the realm of the vascular surgeon. The purpose of this pilot study was to assess the ulcer-healing effects of the newest form of biostimulation--the low power laser. Twelve patients with chronic venous ulcers unresponsive to conservative measures were treated with infrared laser irradiation for twelve weeks. Two ulcers healed completely and there was a 27% (p less than 0.01) reduction in size of the remaining ulcers. Treatment resulted in a 44% (p less than 0.01) increase in ulcer floor area occupied by healthy granulation tissue. The most dramatic effect of laser treatment was the reduction in ulcer pain, from 7.5 to 3.5 (linear analogue scale) (p less than 0.001). Laser irradiation had no effect on TcPO2, number of skin capillaries or pericapillary fibrin deposition in the lipodermatosclerotic area around the ulcer. The results of this pilot study are encouraging and a carefully controlled randomized study is indicated to compare low power laser irradiation to conventional treatment in the management of venous ulcers.

The effects of histamine receptor stimulation on the motility of diseased human gallbladder and cystic duct were studied on tissue strips in vitro. Histamine produced concentration-dependent contractions in normal tissues and in tissues from each disease group, but the sensitivity of the strips to histamine as measured by the median effective dose was dependent upon the grade of disease: normal, 90.0 microM; mild chronic cholecystitis, 32.4 microM; advanced chronic cholecystitis, 12.5 microM; and acute cholecystitis, 3.0 microM. There were no differences in histamine sensitivity among different regions (body, neck, and cystic duct) of the biliary system. Studies with receptor-selective agonists and antagonists indicated that the contractile effects were mediated via histamine H1 receptors. Histamine H2 receptor agonists caused only small relaxant responses in about 30% of strips from gallbladder body, but were without effect in gallbladder neck and cystic duct. We conclude that the effects of histamine on the motility of diseased human gallbladder may depend upon the severity of the cholecystitis.

The effects of several preparations of vasoactive intestinal polypeptide (VIP) on the motility of strips of human and guinea pig gallbladder were investigated in vitro. VIP (10(-12) to 10(-6) M) had no measurable effects on the spontaneous activity, resting tone or cholecystokinin-octapeptide induced tone of human gallbladder strips. However, VIP (10(-12) to 10(-6) M) caused biphasic effects on the tone of guinea pig gallbladder strips. At low concentrations (10(-12) to 10(-10) M) contractions were observed that became smaller at higher concentrations (10(-9) to 10(-8) M). At still higher concentrations (10(-7) to 10(-6) M) relaxations were elicited. It appears that VIP is not as potent a relaxant of gallbladder muscle as first described. Human gallbladder tissue was totally unresponsive to the VIP preparations tested.

Percentage of carotid stenosis and plaque morphology as determined by duplex scanning were correlated with symptoms and CT evidence of infarction in 108 patients. Severity of carotid stenosis less than 49% or greater than 50% narrowing was not associated with an increased risk of ipsilateral symptoms or CT infarction. However, a heterogeneous plaque appearance, suggesting intraplaque hemorrhage, did correlate with ipsilateral cerebral symptoms. Heterogeneous plaque appearance may be a more reliable indication for carotid endarterectomy than a hemodynamically significant stenosis.

This study examined the effects of transmural nerve stimulation, acetylcholine, adrenoceptor agonists and several peptides on the contractility of strips of human gallbladder in vitro. Acetylcholine caused concentration-related contractions of the tissues and the sensitivity to acetylcholine was similar in gallbladders with mild and severe chronic cholecystitis. Noradrenaline and adrenaline relaxed gallbladder strips, probably via beta 2-adrenoceptor stimulation. Transmural nerve stimulation always caused contractions, but in the presence of atropine inhibitory responses were demonstrable and these were antagonized by propranolol. There was no evidence of non-adrenergic inhibitory neural responses. Of the peptides tested, only cholecystokinin octapeptide (CCK-OP), gastrin, pentagastrin, substance P and caerulein caused contractions. Responses to CCK-OP, gastrin and pentagastrin were antagonized by dibutyryl cyclic GMP. Hormones which had no effect upon human gallbladder strips included motilin, secretin, bombesin, neurotensin, glucagon, vasopressin, VIP and somatostatin. Considerable differences therefore exist between human tissues and those from experimental animals with respect to the direct actions of neural and hormonal stimuli on gallbladder contractility.