Neuroprotective Strategies Can Prevent Permanent Paraplegia in the Majority of Patients Who Develop Spinal Cord Ischaemia After Endovascular Repair of Thoracoabdominal Aortic Aneurysms.

OBJECTIVES: Spinal cord ischaemia (SCI) following endovascular thoracoabdominal aortic aneurysm (TAAA) repair is a devastating and unpredictable complication. This study describes a single unit's experience of SCI in patients who have had endovascular TAAA repair. METHODS: A prospectively maintained database of patients having endovascular TAAA repair using branched and fenestrated stent grafts between 2008 and 2014 at a single high volume centre was reviewed. Patients who developed neurological symptoms and signs related to SCI were identified and factors associated with onset and recovery of neurology were analysed. RESULTS: Sixty-nine patients (median age 73 years, 52 male; Crawford classification type I [n = 4], type II [n = 11], type III [n = 33], type IV [n = 14], type V [n = 7]) underwent endovascular TAAA repair. Twelve patients developed neurological symptoms/signs related to SCI but this was successfully reversed in eight patients, leaving four (5.8%) with permanent paraplegia. The median length of aorta covered was not significantly different in the 12 patients who developed SCI compared with the cohort that did not. Eleven of the patients who developed SCI had an intraoperative mean arterial pressure (MAP) below 80 mmHg. Cutaneous atheroemboli were noted in half of the patients in the SCI group compared with 11% of the non-SCI group (p < .05). Strategies used to reverse SCI included raising MAP, cerebrospinal fluid drainage, angioplasty of stenosed internal iliac arteries, and restoring perfusion to the aneurysm sac. CONCLUSIONS: This series highlights some of the risk factors associated with the development of SCI after endovascular repair of TAAAs. It also illustrates the importance of a dedicated institutional protocol aimed at ensuring the early diagnosis of SCI and prompt intervention to reverse permanent paraplegia in the majority of cases.

Editor's choice--Angulation of the C-arm during complex endovascular aortic procedures increases radiation exposure to the head.

OBJECTIVES/BACKGROUND: The increased complexity of endovascular aortic repair necessitates longer procedural time and higher radiation exposure to the operator, particularly to exposed body parts. The aims were to measure directly exposure to radiation of the bodies and heads of the operating team during endovascular repair of thoracoabdominal aortic aneurysms (TAAA), and to identify factors that may increase exposure. METHODS: This was a single-centre prospective study. Between October 2013 and July 2014, consecutive elective branched and fenestrated TAAA repairs performed in a hybrid operating room were studied. Electronic dosimeters were used to measure directly radiation exposure to the primary (PO) and assistant (AO) operator in three different areas (under-lead, over-lead, and head). Fluoroscopy and digital subtraction angiography (DSA) acquisition times, C-arm angulation, and PO/AO height were recorded. RESULTS: Seventeen cases were analysed (Crawford II-IV), with a median operating time of 280 minutes (interquartile range 200-330 minutes). Median age was 76 years (range 71-81 years); median body mass index was 28 kg/m(2) (25-32 kg/m(2)). Stent-grafts incorporated branches only, fenestrations only, or a mixture of branches and fenestrations. A total of 21 branches and 38 fenestrations were cannulated and stented. Head dose was significantly higher in the PO compared with the AO (median 54 µSv [range 24-130 µSv] vs. 15 µSv [range 7-43 µSv], respectively; p = .022), as was over-lead body dose (median 80 µSv [range 37-163 µSv] vs. 32 µSv [range 6-48 µSv], respectively; p = .003). Corresponding under-lead doses were similar between operators (median 4 µSv [range 1-17 µSv] vs. 1 µSv [range 1-3 µSv], respectively; p = .222). Primary operator height, DSA acquisition time in left anterior oblique (LAO) position, and degrees of LAO angulation were independent predictors of PO head dose (p < .05). CONCLUSIONS: The head is an unprotected area receiving a significant radiation dose during complex endovascular aortic repair. The deleterious effects of exposure to this area are not fully understood. Vascular interventionalists should be cognisant of head exposure increasing with C-arm angulation, and limit this manoeuvre.

Steady-state sulfur critical loads and exceedances for protection of aquatic ecosystems in the U.S. Southern Appalachian Mountains.

Atmospherically deposited sulfur (S) causes stream water acidification throughout the eastern U.S. Southern Appalachian Mountain (SAM) region. Acidification has been linked with reduced fitness and richness of aquatic species and changes to benthic communities. Maintaining acid-base chemistry that supports native biota depends largely on balancing acidic deposition with the natural resupply of base cations. Stream water acid neutralizing capacity (ANC) is maintained by base cations that mostly originate from weathering of surrounding lithologies. When ambient atmospheric S deposition exceeds the critical load (CL) an ecosystem can tolerate, stream water chemistry may become lethal to biota. This work links statistical predictions of ANC and base cation weathering for streams and watersheds of the SAM region with a steady-state model to estimate CLs and exceedances. Results showed that 20.1% of the total length of study region streams displayed ANC <100 µeq∙L(-1), a level at which effects to biota may be anticipated; most were 4th or lower order streams. Nearly one-third of the stream length within the study region exhibited CLs of S deposition <50 meq∙m(-2)∙yr(-1), which is less than the regional average S deposition of 60 meq∙m(-2)∙yr(-1). Owing to their geologic substrates, relatively high elevation, and cool and moist forested conditions, the percentage of stream length in exceedance was highest for mountain wilderness areas and in national parks, and lowest for privately owned valley bottom land. Exceedance results were summarized by 12-digit hydrologic unit code (subwatershed) for use in developing management goals and policy objectives, and for long-term monitoring.

Hybrid repair of complex thoracic aortic arch pathology: long-term outcomes of extra-anatomic bypass grafting of the supra-aortic trunk.

PURPOSE: Hybrid repair constitutes supra-aortic debranching before thoracic endovascular aortic repair (TEVAR). It offers improved short-term outcome compared with open surgery; however, longer-term studies are required to assess patient outcomes and patency of the extra-anatomic bypass grafts. METHODS: A prospectively maintained database of 380 elective and urgent patients who had undergone TEVAR (1997-2011) was analyzed retrospectively. Fifty-one patients (34 males; 17 females) underwent hybrid repair. Median age was 71 (range, 18-90) years with mean follow-up of 15 (range, 0-61) months. RESULTS: Perioperative complications included death: 10 % (5/51), stroke: 12 % (6/51), paraplegia: 6 % (3/51), endoleak: 16 % (8/51), rupture: 4 % (2/51), upper-limb ischemia: 2 % (1/51), bypass graft occlusion: 4 % (2/51), and cardiopulmonary complications in 14 % (7/51). Three patients (6 %) required emergency intervention for retrograde dissection: (2 aortic root repairs; 2 innominate stents). Early reintervention was performed for type 1 endoleak in two patients (2 proximal cuff extensions). One patient underwent innominate stenting and revision of their bypass for symptomatic restenosis. At 48 months, survival was 73 %. Endoleak was detected in three (6 %) patients (type 1 = 2; type 2 = 1) requiring debranching with proximal stent graft (n = 2) and proximal extension cuff (n = 1). One patient had a fatal rupture of a mycotic aneurysm and two arch aneurysms expanded. No bypass graft occluded after the perioperative period. CONCLUSIONS: Hybrid operations to treat aortic arch disease can be performed with results comparable to open surgery. The longer-term outcomes demonstrate low rates of reintervention and high rates of graft patency.

Total endovascular repair of thoracoabdominal aortic aneurysms.

BACKGROUND: Endovascular graft designs incorporating sidebranches, fenestrations and scallops offer a minimally-invasive alternative to open surgery and hybrid approaches for thoracoabdominal aortic aneurysms (TAAA). Our unit has offered total endovascular TAAA repair to selected higher-risk patients since 2008. We report the largest UK series to date of total endovascular TAAA repair. METHODS: Retrospective analysis of a prospectively-maintained operative database. RESULTS: 31 patients (21 male, 10 female) median age 71 years (range 58-84), with TAAA (12 Crawford type I, 13 type III, 6 type IV), median diameter 6.4 (4.3 (mycotic)- 9.9) underwent endovascular TAAA repair (total 48 sidebranches, 26 fenestrations, 13 scallops) between July 2008 and January 2011. Median operating time 225 min (65-540 min), X-ray screening time 58 min (4-212 min), contrast dose 175 ml (70-500 ml), blood loss 325 ml (100-400 ml). Median post-operative length of hospital stay 6 days (2-22 days). Three patients (3/31, 9.7%) died within 30 days of operation: multisystem organ failure (1) acute renal failure and paraplegia (1) and paraplegia (1). There were no other cases of in-hospital organ failure, paraplegia or major complications. The median change in pre-discharge from pre-operative renal function was 3.4% deterioration in eGFR (range: 32.7% deterioration to 73.0% improvement) One patient presented with late-onset paraparesis, a second developed acute renal failure 8 months after repair. One early high-pressure endoleak (type 3) required correction. Three patients had died by median follow-up 12 months (1-36), 2 from heart disease and one from haemopericardium secondary to acute dissection of the ascending aorta (the dissection did not involve, nor extend close to, the endovascular graft). CONCLUSIONS: Total endovascular repair of TAAA offers patients a minimally-invasive alternative to open surgery with early results at least comparable to those seen with open or hybrid surgical approaches.

Evaluation of alkaline phosphatase detection in dairy products using a modified rapid chemiluminescent method and official methods.

Alkaline phosphatase is a ubiquitous milk enzyme that historically has been used to verify adequate pasteurization of milk for public health purposes. Current approved methods for detection of alkaline phosphatase in milk include the use of enzyme photoactivated substrates to give readings in milliunits per liter. The U.S. and European public health limit for alkaline phosphatase in pasteurized drinks is 350 mU/liter. A modified chemiluminescent method, fast alkaline phosphatase, was compared with the approved fluorometric and chemiluminescent alkaline phosphatase methods to determine whether the modified method was equivalent to the approved methods and suitable for detecting alkaline phosphatase in milk. Alkaline phosphatase concentrations in cow's, goat's, and sheep's milk and in flavored drinks and cream were determined by three methods. Evaluations in each matrix were conducted with pasteurized samples spiked with raw milk to produce alkaline phosphatase concentrations of 2 to 5,000 mU/liter. The tests were performed by the method developer and then reproduced at a laboratory at the National Center for Food Safety and Technology following the criteria for a single laboratory validation. The results indicated that the fast alkaline phosphatase method was not significantly different from the approved chemiluminescent method, with a limit of detection of 20 to 50 mU/liter in all the studied matrices. This modified chemiluminescent method detects alkaline phosphatase in the 350 mU/liter range with absolute differences from triplicate data that are lower and within the range of the allowed intralaboratory repeatability values published for the approved chemiluminescent method.

A case-control study of elderly patients with acute respiratory illness: effect of influenza vaccination on admission to hospital in winter 2003-2004.

Every winter, hospitals face a large increase in emergency respiratory admissions in elderly people. A case-control study was undertaken to assess the effect of routine influenza vaccine in preventing such admissions among a cohort of UK elderly presenting with acute respiratory illness during winter 2003-2004. 157 hospitalised cases and 639 controls (matched for age, sex and week of consultation) were interviewed. In a winter typical of levels of circulating influenza in recent years, influenza vaccine did not show a protective effect on emergency respiratory admissions overall (adjusted OR 1.2 (95%CI 0.8, 1.9). Policy makers should not rely solely on influenza vaccine routinely having a large effect on winter pressures, and should focus on additional preventive strategies.

Ethics of refusing parental requests to withhold or withdraw treatment from their premature baby.

In the United Kingdom women have access to termination of pregnancy for maternal reasons until 24 weeks' completed gestation, but it is accepted practice for children born at or beyond 25 weeks' gestation to be treated according to the child's perceived best interests even if this is not in accordance with parental wishes. The authors present a case drawn from clinical practice which highlights the discomfort that parents may feel about such an abrupt change in their rights over their child, and argue that parents should have greater autonomy over treatment decisions regarding their prematurely born children.

Comparison of estimates and calculations of risk of coronary heart disease by doctors and nurses using different calculation tools in general practice: cross sectional study.

OBJECTIVE: To assess the effect of using different risk calculation tools on how general practitioners and practice nurses evaluate the risk of coronary heart disease with clinical data routinely available in patients' records. DESIGN: Subjective estimates of the risk of coronary heart disease and results of four different methods of calculation of risk were compared with each other and a reference standard that had been calculated with the Framingham equation; calculations were based on a sample of patients' records, randomly selected from groups at risk of coronary heart disease. SETTING: General practices in central England. PARTICIPANTS: 18 general practitioners and 18 practice nurses. MAIN OUTCOME MEASURES: Agreement of results of risk estimation and risk calculation with reference calculation; agreement of general practitioners with practice nurses; sensitivity and specificity of the different methods of risk calculation to detect patients at high or low risk of coronary heart disease. RESULTS: Only a minority of patients' records contained all of the risk factors required for the formal calculation of the risk of coronary heart disease (concentrations of high density lipoprotein (HDL) cholesterol were present in only 21%). Agreement of risk calculations with the reference standard was moderate (kappa=0.33-0.65 for practice nurses and 0.33 to 0.65 for general practitioners, depending on calculation tool), showing a trend for underestimation of risk. Moderate agreement was seen between the risks calculated by general practitioners and practice nurses for the same patients (kappa=0.47 to 0.58). The British charts gave the most sensitive results for risk of coronary heart disease (practice nurses 79%, general practitioners 80%), and it also gave the most specific results for practice nurses (100%), whereas the Sheffield table was the most specific method for general practitioners (89%). CONCLUSIONS: Routine calculation of the risk of coronary heart disease in primary care is hampered by poor availability of data on risk factors. General practitioners and practice nurses are able to evaluate the risk of coronary heart disease with only moderate accuracy. Data about risk factors need to be collected systematically, to allow the use of the most appropriate calculation tools.

Charm Safe-Level beta-Lactam Test for amoxicillin, ampicillin, ceftiofur, cephapirin, and penicillin G in raw commingled milk.

The Charm Safe-Level beta-Lactam Test was evaluated by a U.S. Food and Drug Administration (FDA) test protocol administered by the AOAC-Research Institute. The sensitivity and selectivity of the test were evaluated with >800 negative raw commingled and drug-fortified milk samples by the manufacturer and an independent laboratory. Probit analysis by the independent laboratory determined the following 90% positive levels with 95% confidence: amoxicillin, 5.6 ppb; ampicillin, 8.5 ppb; cephapirin, 13.7 ppb; ceftiofur, 46.2 ppb; and penicillin G, 3.6 ppb. These values were within a range of +/- 20% of the manufacturer's data. Selection of negative samples met confidence specifications. Ruggedness parameters were studied and defined, and the stability of frozen milk was verified. There were no interferences from somatic cells (1,000,000 somatic cell count/mL) or bacteria (300,000 colony-forming units/mL), or from 27 other non-beta-lactam animal drugs. Test performance with raw milk samples containing incurred penicillin, ampicillin, and amoxicillin was consistent with the dose responses determined with fortified milk samples. Incurred cephalosporin in raw milk samples was detected at lower levels than was cephalosporin in fortified milk samples, presumably because of the presence of metabolite, as verified by other test methods. Quality control data support consistency in manufacture between batches and the stability of refrigerated test reagents for up to 1 year. Successful fulfillment of these criteria led to FDA certification of the test when used with a reader in U.S. milk testing programs.

Presentation with influenza-like illness in general practice: implications for use of neuraminidase inhibitors.

General practitioners in the Midlands Research Practice Consortium (MidReC), combined list size 140,000, completed questionnaires about 918 patients in whom they had made working diagnoses of influenza-like illness during an outbreak of influenza A H3N2 from 1 December 1999 to 4 February 2000. Adults, more females than males consulted most, reflecting the age and sex distribution reported to the Royal College of General Practitioners Weekly Returns Service. Illness at presentation was considered severe in 4%, moderately severe in 49%, mild in 45%, and asymptomatic (for example, attended for certificates) in 1% of patients. In seven tenths of patients, the practitioner estimated that the likelihood of influenza was 70% or more and in just over half, 80% or more. Half of patients aged over 75 years were seen at home, but only 7% of those under 55 years. Less than a quarter of patients consulted within two days of having become ill, with the highest consultation frequency on the third and fourth days. Preschool children presented earliest: 75% were seen within two days, compared with only 17% of adults over 75 years. Four fifths of patients were seen on the same day as they contacted the practice, and 12% on the following day. Given the brief time window for effective antiviral treatment, only a small proportion of patients are likely to be prescribed these drugs unless consulting behaviour, especially in elderly people, changes considerably.

Modification of the amino terminus of a class II epitope confers resistance to degradation by CD13 on dendritic cells and enhances presentation to T cells.

Dendritic cells and human B cell lines were compared for ability to present synthetic peptides corresponding to residues 145-159 and 188-203 of human Ig kappa-chains to peptide-specific mouse T cell hybridomas restricted by HLA-DR4Dw4. B cell lines presented both peptides, but dendritic cells could only efficiently present the latter epitope. In this paper, we show that dendritic cells degrade the 145-159 peptide, removing four residues from the amino terminus. Binding of the peptide to the class II restriction element is not required for this process. The degradation product is resistant to further cleavage, accumulates in the culture supernatant, and does not bind to HLA-DR4Dw4 or stimulate T cell reactivity. Cleavage can be blocked with bestatin, but not with other protease inhibitors tested, or by a mAb directed against aminopeptidase N (CD13). Addition of an acetyl group to the amino terminus of peptide 145-159 also blocks degradation, and allows dendritic cells to present the peptide to specific T cells with greatly increased efficiency. These results demonstrate that CD13 on dendritic cells is able to selectively and efficiently degrade exogenously provided peptide Ags, in a process that can be blocked by addition of an acetyl group to the amino terminus of the peptide. Modification of the amino terminus of peptide epitopes susceptible to degradation may prove to be useful as a general strategy for enhancing their immunogenicity.

Immunotherapy of NOD mice with bone marrow-derived dendritic cells.

We evaluated two bone marrow-derived dendritic cell (DC) populations from NOD mice, the murine model for type 1 human diabetes. DCs derived from GM-CSF [granulocyte/macrophage colony-stimulating factor] + interleukin (IL)-4 cultures expressed high levels of major histocompatibility complex (MHC) class II, CD40, CD80, and CD86 molecules and were efficient stimulators of naive allogeneic T-cells. In contrast, DCs derived from GM-CSF cultures had low levels of MHC class II costimulation/activation molecules, were able to take up mannosylated bovine serum albumin more efficiently than GM + IL-4 DCs, and were poor T-cell stimulators. The two DC populations migrated to the spleen and pancreas after intravenous injection. To determine the ability of the two DC populations to modulate diabetes development, DCs were pulsed with a mixture of three islet antigen-derived peptides or with medium before injection into prediabetic NOD mice. Despite phenotypic and functional differences in vitro, both populations prevented in vivo diabetes development. Pulsing of the DCs with peptide in vitro did not significantly improve the ability of DCs to prevent disease, which suggests that DCs may process and present antigen to T-cells in vivo. In addition, we detected GAD65 peptide-specific IgG1 antibody responses in DC-treated mice. Overall, these results suggest that a Th2 response was generated in DC-treated mice. This response was optimal when using GM + IL-4 DCs, which suggests that the balance between regulatory Th2 and effector Th1 cells may have been altered in these mice.

Binding and uptake of agalactosyl IgG by mannose receptor on macrophages and dendritic cells.

Increased levels of agalactosyl IgG (G0 IgG) are found in several autoimmune diseases, including rheumatoid arthritis, in which they are correlated with severity of the disease. To investigate whether structural alteration of IgG may lead to aberrant processing and presentation of IgG peptides as autoantigens, we have studied uptake of G0 IgG by human dendritic cells and macrophages cultured from PBMC. We found that enzymatic removal of terminal galactose residues, which exposes N-acetylglucosamine residues, increases uptake of soluble IgG mediated by mannose receptor on macrophages and dendritic cells. Efficient uptake appears to require recycling of the receptor, can be blocked by saccharides or Abs reactive with mannose receptor, and is dependent upon the state of maturation of the dendritic cells. No differences between IgG isotypes in ability to be internalized by APC were identified, suggesting that uptake would not be limited to a particular subset of Abs. These results suggest a novel pathway by which Abs or Ag-Ab complexes can be taken into dendritic cells and macrophages, and potentially generate epitopes recognized by T cells. These findings may have particular relevance for autoimmune disorders characterized by high levels of G0 IgG.

Peptide-conformed beta2m-free class I heavy chains are intermediates in generation of soluble HLA by the membrane-bound metalloproteinase.

Molecular mechanisms of soluble HLA-release by a membrane-bound metalloproteinase (MPase) are not defined. We have investigated the possibility that certain beta2-microglobulin (beta2m)-free heavy chains (HC) retain peptide-induced conformations before and after the cleavage by using mutant HLA-A2.242K HC with reduced affinity for beta2m. We show that dissociation of HC/beta2m complexes on the surface of C1R lymphoblastoid cells generates both conformed and non-conformed beta2m-free HC recognized by conformation-dependent antibodies. Conformed HC, having bound the HLA-A2-specific peptide HTLV-1 tax 11-19, can retain their proper conformations after dissociation of beta2m. Further, conformed and non-conformed surface beta2m-free HC are cleaved by the MPase, and some released HC preserve their conformations. Exogenous beta2m binds only to conformed HC, and protects them from cleavage as effectively as the MPase inhibitor BB-2116. We propose that soluble HLA-release requires generation of peptide-conformed beta2m-free HC intermediates on the cell surface, which are then cleaved by the MPase and in solution may reassociate with beta2m. Given the role of soluble HLA in the indirect allorecognition, the activity of this MPase may be important in transplant rejection.