International registry on factor XIII deficiency: a basis formed mostly on European data

FXIII deficiency is known as one of the rarest blood coagulation disorders. In this study, the phenotypic and in part genotypic data of 104 FXIII-deficient patients recorded from 1993 - 2005 are presented. The most common bleeding symptoms were subcutaneous bleeding (57%) followed by delayed umbilical cord bleeding (56%), muscle hematoma (49%), hemorrhage after surgery (40%), hemarthrosis (36%), and intracerebral bleeding (34%). Prophylactic treatment was initiated in about 70% of all patients. FXIII-B subunit-deficient patients had a milder phenotype than patients with FXIII-A subunit deficiency. The most frequent mutation affecting the F13A gene was a splice site mutation in intron 5 (IVS5-1G>A). This mutation was found in eight (17%) of 46 analyzed families. The haplotype analysis of patients carrying the IVS5-1A allele was consistent with a founder effect. The international registry (http://www.f13-database.de) will provide clinicians and scientists working on FXIII deficiency with a helpful tool to improve patient care and direct future studies towards better understanding and treatment of the disease.

Study of the effect of biodiesel fuel on passive oxidation in a catalyzed particulate filter

A 2007 Cummins ISL 8.9L direct-injection common rail diesel engine rated at 272 kW (365 hp) and 317 kW (425 hp) was used to load the filter to 2.2 g/L and passively oxidize particulate matter (PM) within an aftertreatment system consisting of a diesel oxidation catalyst (DOC) and catalyzed particulate filter (CPF). The tests conducted with the engine rated at 365 hp used a 2007 DOC and CPF. The tests conducted with the engine rated at 425 hp used a 2010 DOC and 2007 CPF. Understanding the passive NO2 oxidation kinetics of PM within the CPF allows for reducing the frequency of active regenerations (hydrocarbon injection) and the associated fuel penalties. Modeling the passive oxidation of accumulated PM in the CPF will lead to creating accurate state estimation strategies. The MTU 1-D CPF model will be used to simulate data collected from this study to examine differences in the PM oxidation kinetics when soy methyl ester (SME) biodiesel is used as the source of fuel for the engine, and when the engine is operated at a higher power rating. A test procedure developed by Hutton et al. [1, 2] was modified to improve the ability to model the experimental data and provide additional insight into passively oxidized PM in a partially regenerated CPF. A test procedure was developed to allow PM oxidation rates by NO2 to be determined from engine test cell data. An experimental matrix consisting of CPF inlet temperatures from 250 to 450 °C with varying NOX/PM from 25 to 583and NO2/PM ratios from 5 to 240 was used. SME biodiesel was volumetrically blended with ULSD in 10% (B10) and 20% (B20) portions. This blended fuel was then used to evaluate the effect of biodiesel on passive oxidation rates. Four tests were performed with B10 and four tests with B20. Gathering data to determine the effect of fuel type (ULSD and biodiesel blends) on PM oxidation is the primary goal. The engine used for this testing was then configured to a higher power rating and one of the tests planned was performed. Additional testing is scheduled to take place with ULSD fuel to determine the affect the engine rating has on the PM oxidation. The experimental reaction rates during passive oxidation varied based upon the average CPF temperature, NO2 concentrations, and the NOX/PM ratios for each engine rating and with all fuels. The data analysis requires a high fidelity model that includes NO2 and thermal oxidation mechanisms and back diffusion to determine the details of the PM oxidation process.

Analysis of a novel waste heat recovery mechanism for an I.C. engine

Typical internal combustion engines lose about 75% of the fuel energy through the engine coolant, exhaust and surface radiation. Most of the heat generated comes from converting the chemical energy in the fuel to mechanical energy and in turn thermal energy is produced. In general, the thermal energy is unutilized and thus wasted. This report describes the analysis of a novel waste heat recovery (WHR) system that operates on a Rankine cycle. This novel WHR system consists of a second piston within the existing piston to reduce losses associated with compression and exhaust strokes in a four-cycle engine. The wasted thermal energy recovered from the coolant and exhaust systems generate a high temperature and high pressure working fluid which is used to power the modified piston assembly. Cycle simulation shows that a large, stationary natural gas spark ignition engine produces enough waste heat to operate the novel WHR system. With the use of this system, the stationary gas compression ignition engine running at 900 RPM and full load had a net increase of 177.03 kW (240.7 HP). This increase in power improved the brake fuel conversion efficiency by 4.53%.

Polyclonal and specific antibodies mediate protective immunity against enteric helminth infection

Anti-helminth immunity involves CD4+ T cells, yet the precise effector mechanisms responsible for parasite killing or expulsion remain elusive. We now report an essential role for antibodies in mediating immunity against the enteric helminth Heligmosomoides polygyrus (Hp), a natural murine parasite that establishes chronic infection. Polyclonal IgG antibodies, present in naive mice and produced following Hp infection, functioned to limit egg production by adult parasites. Comparatively, affinity-matured parasite-specific IgG and IgA antibodies that developed only after multiple infections were required to prevent adult worm development. These data reveal complementary roles for polyclonal and affinity-matured parasite-specific antibodies in preventing enteric helminth infection by limiting parasite fecundity and providing immune protection against reinfection, respectively. We propose that parasite-induced polyclonal antibodies play a dual role, whereby the parasite is allowed to establish chronicity, while parasite load and spread are limited, likely reflecting the long coevolution of helminth parasites with their hosts.

Decision making in patients with acute abdominal pain at a university and at a rural hospital: Does the value of abdominal sonography differ?

Introduction and objectives Abdominal sonography is regarded as a quick and effective diagnostic tool for acute abdominal pain in emergency medicine. However, final diagnosis is usually based on a combination of various clinical examinations and radiography. The role of sonography in the decision making process at a hospital with advanced imaging capabilities versus a hospital with limited imaging capabilities but more experienced clinicians is unclear. The aim of this pilot study was to assess the relative importance of sonography and its influence on the clinical management of acute abdominal pain, at two Swiss hospitals, a university hospital (UH) and a rural hospital (RH). Methods 161 patients were prospectively examined clinically. Blood tests and sonography were performed in all patients. Patients younger than 18 years and patients with trauma were excluded. In both hospitals, the diagnosis before and after ultrasonography was registered in a protocol. Certainty of the diagnosis was expressed on a scale from 0% to 100%. The decision processes used to manage patients before and after they underwent sonography were compared. The diagnosis at discharge was compared to the diagnosis 2 – 6 weeks thereafter. Results Sensitivity, specificity and accuracy of sonography were high: 94%, 88% and 91%, respectively. At the UH, management after sonography changed in only 14% of cases, compared to 27% at the RH. Additional tests were more frequently added at the UH (30%) than at the RH (18%), but had no influence on the decision making process-whether to operate or not. At the UH, the diagnosis was missed in one (1%) patient, but in three (5%) patients at the RH. No significant difference was found between the two hospitals in frequency of management changes due to sonography or in the correctness of the diagnosis. Conclusion Knowing that sonography has high sensitivity, specificity and accuracy in the diagnosis of acute abdominal pain, one would assume it would be an important diagnostic tool, particularly at the RH, where tests/imaging studies are rare. However, our pilot study indicates that sonography provides important diagnostic information in only a minority of patients with acute abdominal pain. Sonography was more important at the rural hospital than at the university hospital. Further costly examinations are generally ordered for verification, but these additional tests change the final treatment plan in very few patients.

Ability of dGEMRIC and T2 mapping to evaluate cartilage repair after microfracture: a goat study

OBJECTIVE: To investigate the ability of delayed gadolinium-enhanced magnetic resonance (MR) imaging of cartilage (dGEMRIC) and T2 mapping to evaluate the quality of repair tissue after microfracture. DESIGN: Twelve knees from 12 goats were studied. An osteochondral defect (diameter, 6mm; depth, 3mm) with microfracture was created in the weight-bearing aspect of both the medial and lateral femoral condyles. Goats were euthanized at 24 weeks (n=6) and 48 weeks (n=6) postsurgery. Pre-contrast R1 (R1pre) and post-contrast R1 (R1post) measurements for dGEMRIC and a pre-contrast T2 measurement for T2 mapping were performed with a 3T MR imaging system. MR imaging findings were compared with histological and biochemical assessments. RESULTS: In native cartilage, significant correlations were observed between the R1post and the glycosaminoglycan (GAG) concentration, as well as DeltaR1 (difference between the R1pre and R1post) and the GAG concentration (P<0.05). In repair tissue, a significant correlation was observed between DeltaR1 and the GAG concentration (P<0.05), but not between the R1post and the GAG concentration. In both repair tissue and native cartilage, no correlation was observed between T2 and the water concentration or between T2 and the hydroxyproline (HP) concentration. A zonal variation of T2 and a clear dependence of T2 on the angles relative to B0 were observed in native cartilage, but not in repair tissue. CONCLUSION: dGEMRIC with DeltaR1 measurement might be useful for the evaluation of the GAG concentration in repair tissue after microfracture. T2 mapping might be useful for the differentiation of repair tissue after microfracture from native cartilage; however, its potential to assess the specific biochemical markers in native cartilage as well as repair tissue may be limited.

Stepped osteotomy of the trochanter for stable, anatomic refixation

Refixation of a trochanteric osteotomy carries a high complication rate. To enhance stability and facilitate anatomic reduction of the trochanteric fragment, we have introduced a stepped osteotomy. Between April 2006 and June 2007, we performed surgical hip dislocations using the modified trochanteric osteotomy combined with a relatively aggressive rehabilitation program. Full weightbearing was allowed at a mean of 42 days (range, 33-54 days). The minimum followup was 8 months (median, 13 months; range, 8-24 months). Postoperative radiographs were assessed prospectively for consolidation or the appearance of malreduction/nonunion/malunion of the osteotomy and heterotopic ossification. In 110 of 113 hips, the trochanteric osteotomy healed in the anatomic position. Two patients had a trochanteric delayed union with loss of anatomic position, and one additional patient underwent revision surgery for a pseudarthrosis and cranial migration of the trochanteric fragment. All three complications related to healing occurred in the first 60 patients when the step height was 3 to 4 mm. After increasing the step heights to 6 mm, we observed no healing complications. Despite more aggressive postoperative mobilization, the incidence of malunion or nonunion related to the new stepped osteotomy is low and approaches zero for steps of 6 mm. It is now our technique of choice.

Novel autoantigens immunogenic in COPD patients

Background Chronic obstructive pulmonary disease (COPD) is a respiratory inflammatory condition with autoimmune features including IgG autoantibodies. In this study we analyze the complexity of the autoantibody response and reveal the nature of the antigens that are recognized by autoantibodies in COPD patients. Methods An array of 1827 gridded immunogenic peptide clones was established and screened with 17 sera of COPD patients and 60 healthy controls. Protein arrays were evaluated both by visual inspection and a recently developed computer aided image analysis technique. By this computer aided image analysis technique we computed the intensity values for each peptide clone and each serum and calculated the area under the receiver operator characteristics curve (AUC) for each clone and the separation COPD sera versus control sera. Results By visual evaluation we detected 381 peptide clones that reacted with autoantibodies of COPD patients including 17 clones that reacted with more than 60% of the COPD sera and seven clones that reacted with more than 90% of the COPD sera. The comparison of COPD sera and controls by the automated image analysis system identified 212 peptide clones with informative AUC values. By in silico sequence analysis we found an enrichment of sequence motives previously associated with immunogenicity. Conclusion The identification of a rather complex humoral immune response in COPD patients supports the idea of COPD as a disease with strong autoimmune features. The identification of novel immunogenic antigens is a first step towards a better understanding of the autoimmune component of COPD.

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

BACKGROUND: Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. METHODS: Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. FINDINGS: Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. INTERPRETATION: Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.

Discontinuous Galerkin finite element approximation of quasilinear elliptic boundary value problems II: Strongly monotone quasi-Newtonian flows

In this article, we develop the a priori and a posteriori error analysis of hp-version interior penalty discontinuous Galerkin finite element methods for strongly monotone quasi-Newtonian fluid flows in a bounded Lipschitz domain Ω ⊂ ℝd, d = 2, 3. In the latter case, computable upper and lower bounds on the error are derived in terms of a natural energy norm, which are explicit in the local mesh size and local polynomial degree of the approximating finite element method. A series of numerical experiments illustrate the performance of the proposed a posteriori error indicators within an automatic hp-adaptive refinement algorithm.

Towards a consensus on a hearing preservation classification system

The comprehensive Hearing Preservation classification system presented in this paper is suitable for use for all cochlear implant users with measurable pre-operative residual hearing. If adopted as a universal reporting standard, as it was designed to be, it should prove highly beneficial by enabling future studies to quickly and easily compare the results of previous studies and meta-analyze their data. Objectives: To develop a comprehensive Hearing Preservation classification system suitable for use for all cochlear implant users with measurable pre-operative residual hearing. Methods: The HEARRING group discussed and reviewed a number of different propositions of a HP classification systems and reviewed critical appraisals to develop a qualitative system in accordance with the prerequisites. Results: The Hearing Preservation Classification System proposed herein fulfills the following necessary criteria: 1) classification is independent from users' initial hearing, 2) it is appropriate for all cochlear implant users with measurable pre-operative residual hearing, 3) it covers the whole range of pure tone average from 0 to 120 dB; 4) it is easy to use and easy to understand.

Antibodies trap tissue migrating helminth larvae and prevent tissue damage by driving IL-4Rα-independent alternative differentiation of macrophages

Approximately one-third of the world's population suffers from chronic helminth infections with no effective vaccines currently available. Antibodies and alternatively activated macrophages (AAM) form crucial components of protective immunity against challenge infections with intestinal helminths. However, the mechanisms by which antibodies target these large multi-cellular parasites remain obscure. Alternative activation of macrophages during helminth infection has been linked to signaling through the IL-4 receptor alpha chain (IL-4Rα), but the potential effects of antibodies on macrophage differentiation have not been explored. We demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae and prevent tissue necrosis following challenge infection with the natural murine parasite Heligmosomoides polygyrus bakeri (Hp). Mice lacking antibodies (JH (-/-)) or activating Fc receptors (FcRγ(-/-)) harbored highly motile larvae, developed extensive tissue damage and accumulated less Arginase-1 expressing macrophages around the larvae. Moreover, Hp-specific antibodies induced FcRγ- and complement-dependent adherence of macrophages to larvae in vitro, resulting in complete larval immobilization. Antibodies together with helminth larvae reprogrammed macrophages to express wound-healing associated genes, including Arginase-1, and the Arginase-1 product L-ornithine directly impaired larval motility. Antibody-induced expression of Arginase-1 in vitro and in vivo occurred independently of IL-4Rα signaling. In summary, we present a novel IL-4Rα-independent mechanism of alternative macrophage activation that is antibody-dependent and which both mediates anti-helminth immunity and prevents tissue disruption caused by migrating larvae.

OSL and TL dating of the Middle Stone Age sequence at Diepkloof Rock Shelter (South Africa): a clarification

Diepkloof Rock Shelter offers an exceptional opportunity to study the onset and evolution of both Still Bay (SB) and Howiesons Poort (HP) techno-complexes. However, previous age estimates based on luminescence dating of burnt quartzites (Tribolo et al., 2009) and of sediments (Jacobs et al., 2008) were not in agreement. Here, we present new luminescence ages for 17 rock samples (equivalent dose estimated with a SAR-ITL protocol instead of classical MAAD-TL) as well as for 5 sediment samples (equivalent dose estimated with SAR-single grain OSL protocol) and an update of the 22 previous age estimates for burnt lithics (modified calibration and beta dose estimates). While a good agreement between the rock and sediment ages is obtained, these estimates are still significantly older than those reported by Jacobs et al. (2008). After our own analyses of the sediment from Diepkloof, it is suspected that these authors did not correctly chose the parameters for the equivalent dose determination, leading to an underestimate of the equivalent doses, and thus of the ages. From bottom to top, the mean ages are 100 ± 10 ka for stratigraphic unit (SU) Noël and 107 ± 11 ka for SU Mark (uncharacterized Lower MSA), 100 ± 10 ka for SU Lynn-Leo (Pre-SB type Lynn), 109 ± 10 ka for SUs Kim-Larry (SB), 105 ± 10 ka for SUs Kerry-Kate and 109 ± 10 ka for SU Jess (Early HP), 89 ± 8 ka for SU Jude (MSA type Jack), 77 ± 8 ka for SU John, 85 ± 9 ka for SU Fox, 83 ± 8 ka for SU Fred and 65 ± 8 ka for SU OB5 (Intermediate HP), 52 ± 5 ka for SUs OB2-4 (Late HP). This chronology, together with the technological analyses, greatly modifies the current chrono-cultural model regarding the SB and the HP and has important archaeological implications. Indeed, SB and HP no longer appear as short-lived techno-complexes with synchronous appearances for each and restricted to Oxygen Isotopic Stage (OIS) 4 across South Africa, as suggested by Jacobs et al. (2008, 2012). Rather, the sequence of Diepkloof supports a long chronology model with an early appearance of both SB and HP in the first half of OIS 5 and a long duration of the HP into OIS 3. These new dates imply that different technological traditions coexisted during OIS 5 and 4 in southern Africa and that SB and HP can no longer be considered as horizon markers.