Tristability between stripes, up-hexagons, and down-hexagons and snaking bifurcation branches of spatial connections between up- and down-hexagons.

Third-order amplitude equations on hexagonal lattices can be used for predicting the existence and stability of stripes, up-hexagons, and down-hexagons in pattern-forming systems. These amplitude equations predict the nonexistence of bistable ranges between up- and down-hexagons and tristable ranges between stripes, up-, and down-hexagons. In the present work we use fifth-order amplitude equations for finding such bistable and tristable ranges for a generalized Swift-Hohenberg equation and discuss stationary front connections between up- and down-hexagons.

The Abl-1 Kinase is Dispensable for NK Cell Inhibitory Signalling and is not Involved in Murine NK Cell Education.

Natural killer (NK) cell responsiveness in the mouse is determined in an education process guided by inhibitory Ly49 and NKG2A receptors binding to MHC class I molecules. It has been proposed that inhibitory signalling in human NK cells involves Abl-1 (c-Abl)-mediated phosphorylation of Crk, lowering NK cell function via disruption of a signalling complex including C3G and c-Cbl, suggesting that NK cell education might involve c-Abl. Mice deficient in c-Abl expression specifically in murine NK cells displayed normal inhibitory and activating receptor repertoires. Furthermore, c-Abl-deficient NK cells fluxed Ca2+ normally after triggering of ITAM receptors, killed YAC-1 tumour cells efficiently and showed normal, or even slightly elevated, capacity to produce IFN-γ after activating receptor stimulation. Consistent with these results, c-Abl deficiency in NK cells did not affect NK cell inhibition via the receptors Ly49G2, Ly49A and NKG2A. We conclude that signalling downstream of murine inhibitory receptors does not involve c-Abl and that c-Abl plays no major role in NK cell education in the mouse.

Devastating Delayed Leukoencephalopathy Associated with Bath Salt Inhalation.

BACKGROUND: "Bath salts" or synthetic cathinone toxicity remains a potentially deadly clinical condition. We report a delayed leukoencephalopathy with persistent minimally conscious state. METHODS: Case report. RESULTS: A 36-year-old man presents with delayed encephalopathy, dysautonomia, fulminant hepatic failure, and renal failure from severe rhabdomyolysis after consuming bath salts. MRI showed diffusion restriction in the splenium of the corpus callosum and subcortical white matter. CONCLUSIONS: The combination of acute leukoencephalopathy, rhabdomyolysis and fulminant hepatic failure may point to bath salt inhalation and should be known to neurointensivists.

Market surveillance of in vitro diagnostics by the BfArM until end 2010: safety of IVD for therapeutic drug monitoring.

The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) regulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of incidents and field corrective actions, the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD. In this study all notifications regarding IVD for therapeutic drug monitoring (TDM) between begin 1999 until end of 2010 were analysed. A total of 2,851 notifications were received, of which 65 were related to IVD for TDM included in this study (54 tests vs. 11 analysers). Reports were received from manufacturers (58), CAs (5 cases) and users (2 cases). Most frequently IVD used for TDM of toxicologically relevant substances, antibiotics, antiepileptics and immunosuppressives were affected. Investigations of the manufacturers were able to identify the underlying root causes of product failures in 50 cases (76.9%), 40 (74.1%) of which were tests and 10 (90.9%) analysers. In 11 cases (16.9%, all tests), the root cause remained unclear and in 4 cases (6.2%, 3 tests, 1 analyser) a product failure was excluded. Product failures in tests were most commonly material defects (12 cases), interferences (7 cases) and manufacturing errors (7 cases), whereas in the analyser group software errors (5 cases) were most common. Corrective actions were performed in 56 cases (86.2%); 46 (85.2%) in tests, and 10 (90.9%) in analysers. In the group of tests these were predominantly (multiple entries) customer information (46 cases, mandatory in case of a recall), recall (29 cases), modifications in production or quality management (29 cases) and modifications of the instructions for use (9 cases). However, in the analyser group corrective actions were typically customer information (10 cases), recall (5 cases) and software-update (4 cases). The obtained data demonstrate that there are differences in the type of product failures between analysers and tests, which are followed by different corrective actions depending on the root causes of product failure accordingly. The results and the experience since 1999 suggest that the system for post marketing surveillance of IVD is an established tool to enhance product safety even though further optimisation is possible.

Market surveillance of in vitro diagnostics by the BfArM until end 2010: how safe are products for tumor diagnostics?

The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) regulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of incidents and field corrective actions the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD. In this study all notifications regarding IVD (tests, calibrators, kits, and control materials, except laboratory analyzers) for tumor diagnostics received by the BfArM between begin 1999 until end of 2010 were analyzed. All notifications were analyzed in respect to the type of product, the source of notification, the underlying product defects and the corrective actions performed. In the observation period, a total of 2,851 notifications were received of which 84 were related to IVD for tumor diagnostics included in this study (clinical chemistry - 63, histology - 6, molecular biology - 3, rapid tests - 12). Reports were received from manufacturers (68 cases), CA (8 cases), users (4 cases) and other sources (4 cases). In the group of IVD based on clinical chemistry means, the affected products were mostly those for the measurement of prostate specific antigen (PSA, 14 cases), human chorion gonadotropine (13 cases), carcino embryonic antigen (6 cases), CA 19-9 (6 cases), α(1)-fetoprotein (6 cases) and CA 125 (5 cases), whereas in test strips 9 out of the 12 notifications were related to PSA. Investigations of the manufacturers were able to identify the underlying root causes of product failures in 66 cases (78.6%). In 10 cases (11.9%) the root cause remained unclear and in 6 cases and 2 cases (7.1% and 2.4%) a product failure was excluded or a user error was the underlying cause. Most common root causes of product failures were material defects (24 cases) and manufacturing errors (15 cases). Corrective actions were performed by the manufacturers in 64 cases (76.2%) and were predominantly (multiple entries possible) customer information (62 cases, mandatory in case of a recall), recalls (45 cases), modifications in production or quality management (45 cases) and design changes (14 cases). The obtained results suggest that the system for post marketing surveillance of IVD is an established tool to enhance product safety and provides valuable information on product specific problems serving for improvement of product safety.

In-vivo and in-vitro histological evaluation of two commercially available acellular dermal matrices.

PURPOSE: Post-herniation abdominal wall repair can be performed with synthetic or biologic meshes. Synthetics have been associated with complications, so biologics are promising alternatives. The methods used to decellularize biological matrices may affect the extracellular components. This study evaluated the post-implantation biological response of two allogenic acellular dermal matrices (ADMs) in a hernia model. METHODS: Testing was conducted with two ADMs from different manufacturers: RTI Biologics (ADM-R) and LifeCell (ADM-L). Samples were evaluated for collagen IV, glycosaminoglycans (GAGs), and elastin before implantation. Samples were also used to repair bilateral full-thickness defects in rat abdominal walls. Pathologist evaluations included explant dimensions, inflammation, neovascularization, mature implant tissue, fibrosis, encapsulation, necrosis, mineralization, adhesions, granulomas, and hemorrhages at four and eight weeks post-implantation. RESULTS: GAG distribution in ADM-R samples was more consistent with native dermis than that in ADM-L samples. Collagen IV was visible in ADM-R, but not in ADM-L. The four-week ADM-R explants showed primarily lymphocytic infiltrates, and less inflammation at eight weeks. The four-week ADM-L explants showed primarily lymphocytic infiltrates, and sustained inflammation at eight weeks. Fibroplasia at four and eight weeks was higher in ADM-L than in ADM-R. Encapsulation, mature connective tissue, and vascular profile scores were comparable between groups. Picrosirius red image analysis showed no significant differences between groups. CONCLUSIONS: The post-processing matrix characterization and in-vivo response showed notable differences in these ADMs, despite similar allogenic origin. Future investigations into the different matrix composition with regard to fibrosis and inflammation are warranted.

Field safety notices released by manufacturers in cases of failure of products for infection testing: analysis of cases reported to the BfArM between 2005 and 2007.

The European Directive 98/79/EC for in vitro diagnostic medical devices (IVD) regulates marketing and post marketing surveillance of IVD in the European Economic Area. Manufacturers have to inform the responsible Competent Authorities (CA) about incidents and field safety corrective actions (FSCA) related to IVD. In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD, only few IVD as specified in Annex II of the Directive are under the responsibility of the Paul Ehrlich Institute (PEI). In case of a FSCA manufacturers have to inform customers by means of a Field Safety Notice (FSN) which should be sent to BfArM prior to release and is published on the BfArM homepage. Between beginning of 2005 and end of 2007 the BfArM received a total of 1025 reports regarding IVD. From these, 38 related to tests, reagents, calibrators, and control materials for infection testing, 13 related to analysers and general consumables (n = 8 and n = 5, respectively) based on culture techniques, and 7 related to analysers and general consumables (n = 5 and n = 2, respectively) based on molecular biological methods. FSCA were performed in Germany in 32 (84.2%) of all notifications related to tests reagents, calibrators, and control materials as well as in 13 (100%) and 7 (100%) of notifications related to analysers and consumables based on culture techniques and molecular biological methods, respectively. A number of relevant deficiencies regarding the quality of the FSN were separately demonstrated for FSN in German and English language. In brief, manufacturers often sent their FSN to the BfArM with delay. Additionally, a subset of FSN provided insufficient information on the product related risks or the measures to be performed by the customer to mitigate product related risks. Furthermore, customer confirmation forms often were missing in the FSN sent to the BfArM. Our data suggest that for IVD for infection testing FSCA and FSN are frequently performed. For better vigilance performance, manufacturers could shorten the time until release and improve the contents of FSN to ensure the safety of IVD in cases of product related corrective actions.

Safety of laboratory analyzers for infection testing - results of the market surveillance by the BfArM until End 2007.

The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) stipulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of issues and field corrective actions, the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD, with a small subset of IVD for immune hematological and infectiological testing as well as tissue typing as specified in Annex II of the Directive, being within the responsibility of the Paul-Ehrlich-Institute (PEI). In this study, all issues regarding laboratory analyzers for infection testing and their consumables, but not reagents, kits and general culture media, reported to the BfArM between begin 1999 and end of 2007 were analyzed in respect to the sources of report, the underlying product failure and the performed corrective actions. Within the observation period a total of 1471 reports for IVD were received of which 73 related to the IVD for infection testing were included in our study. Reports were predominantly received from manufacturers (56) and competent authorities (15). Affected products were most frequently those for immunological analysis (42) whereas those based on culturing techniques (17) and molecular biological techniques (14) played only minor roles. In all these groups, laboratory analyzers (55) were more frequently affected than their consumables (18). Investigations of the manufacturers were able to identify the underlying root causes of product failures in 62 cases (84.9%). In 2 cases (2.7%) the root cause remained unclear and in 9 cases (12.3%) a product failure was excluded or a user error was the underlying cause. Product failures in laboratory analyzers were most frequently caused by software errors (31) and constructional faults (8) whereas the predominant cause of product failure in consumables were errors in production and quality control (8). Manufacturers issued corrective measures in 66 cases (90.4%) from which 49 and 17 were related to laboratory analyzers and their consumables, respectively. Based on the underlying root causes of product failures these were predominantly customer information (48), recalls (40), software-updates (30) and design changes (9) in the product group of laboratory analyzers as well as customer information (16), recalls (12) and modifications of production and quality management (11) in the group of consumables. The results and experiences obtained since 1999 suggest that the system for post marketing surveillance of IVD is an established tool to ensure product safety, even though the current system can be further enhanced.

[Are test systems for diagnostics of infectious diseases safe? Experiences of the BfArM based on all notifications received until end of 2005]. / Wie sicher sind Testsysteme zur Diagnostik von Infektionskrankheiten? Erfahrungen des Bundesinstitutes für Arzneimittel und Medizinprodukte mit den dort bis Ende 2005 eingegangenen Meldungen.

The European Directive 98/79/EC for in vitro diagnostic medical devices (IVD) regulates the marketing and post marketing surveillance of IVD in the European Economic Area. Manufacturers have to inform the responsible Competent Authorities about incidents and field corrective actions related to IVD. In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible Competent Authority for most IVD, while a small subset of IVD, specified in Annex II of the Directive 98/79/EC for immune hematological and infectiological testing as well as tissue typing, is under the responsibility of the Paul-Ehrlich-Institute (PEI). Until the end of 2005 the BfArM received a total of 653 notifications regarding IVD. From these 115 related to IVD for analysis of the infection status (reagents, control materials, calibrators, culture media and analyzing equipment). Most of the reports originated from manufacturers (57.4 %), while other sources of reports played only minor roles. Product failures of test reagents, control materials, calibrators as well as culture media were frequently caused by manufacturing errors and biological contamination. Analyzing equipment was typically affected by software malfunction. Through the investigations of the manufacturers product failures were confirmed in most cases and consequently corrective actions were performed in the large majority of incidents. The corrective actions frequently included customer information, product recalls, changes in the production process and/or the quality management or software upgrades for the analyzing equipment. Our data suggest that the existing system for post marketing surveillance is an important tool to ensure product safety of IVD even though it should be further optimized in the future.

Safety of reagents for infection testing: results of the market surveillance by the Federal Institute for Drugs and Medicinal Devices until end 2006.

The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) stipulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of issues and field corrective actions, the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD, with a small subset of IVD for immune hematological and infection testing as well as tissue typing as specified in Annex II of the Directive, being within the responsibility of the Paul-Ehrlich-Institute (PEI). In this study, all issues regarding reagents for infection testing, but not laboratory analyzers, reported to the BfArM between begin 1999 and end of 2006 were analyzed in respect to the source of report, the underlying product defects, and the performed corrective actions. Within the observation period a total of 888 reports on IVD were received of which 90 related to the IVD for infection testing included in our study. Reports were predominantly received from manufacturers (55) and Competent Authorities (29). Affected products were most frequently those for serological analysis (42) and culturing techniques (36), whereas molecular biological tests played only a minor role (12). Investigations of the manufacturers were able to identify the underlying root causes of product failures in 68 cases (75.6%). In 16 cases (17.8%) the root cause remained unclear and in 6 cases (6.6%) a product failure was excluded or a user error was the underlying cause. Most frequently product failures were caused by material defects (25), production errors (11), microbial contamination (6), and labelling errors (5). Manufacturers issued corrective measures in 73 cases (81.1%). Based on the underlying root causes of product failures, these were predominantly (multiple entries) customer information (71), recall (58), modifications in production or quality management (50), modifications of the raw materials (17), and modifications of the instructions for use (12). The results and experience obtained since 1999 suggest that the system for post marketing surveillance of IVD is an established tool to ensure product safety even though the current system can be further optimised.

[Safety of in-vitro diagnostics used in transfusion medicine. Experience of the BfArM until end 2005]. / Sicherheit von In-vitro-Diagnostika zum Gebrauch in der Transfusionsmedizin. Erfahrungen des BfArM bis Ende 2005.

The European Directive 98/79/EC on in-vitro diagnostic medical devices (IVD) stipulates the marketing and post marketing surveillance of IVD in the European Economic Area. In cases of incidents and field corrective actions related to IVD, manufacturers have to inform the responsible Competent Authorities. In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible Competent Authority for most IVD. Only a small subset of IVD for immune hematological and infectiological testing, as well as tissue typing specified in Annex II of the Directive, is under the responsibility of the Paul-Ehrlich-Institute (PEI). Until the end of 2005 the BfArM received a total of 653 notifications regarding IVD. From these 48 related to IVD used for diagnostics in transfusion medicine and tissue typing which are subject of this study. The investigated products included reagents (tests, calibrators and controls) used for immune hematological analysis as far as they are not under the responsibility of the PEI, analyzing instruments used for immune hematological testing, liquid handling systems for sample preparation and a small subset of analysing instruments and reagents for tissue typing. Most of the reports originated from manufacturers (n=27, 56.3%) and Competent Authorities (n=20; 41.7%) whereas other sources played only minor roles. Product failures were confirmed by the investigations of the manufacturers in 36 (75%) of the reported incidents. Reagents were frequently subject of manufacturing errors and biological contaminations, whereas analysing instruments were typically affected by software errors. In consequence, corrective actions were performed in the large majority of cases (n=37; 77.1%). These included customer information, product recalls, changes in production or quality management and software upgrades (the latter predominantly in cases of failures of analysing instruments). Our data suggest that the governmental system for marketing surveillance is an established tool to ensure product safety for IVD used in transfusion medicine.

[Transformation of general measures by patients in heart failure]. / Umsetzung von Allgemeinmassnahmen bei Herzinsuffizienz.

BACKGROUND AND OBJECTIVE: Non-pharmacological treatment (NPT) and immunization with influenzal and pneumococcal vaccines are an integral part in the management of heart failure (HF). However, few data are available about the implementation of NPT in real life. The aim of this study was to analyse long-term changes in behavior and the use of self-care strategies by patients with HF. PATIENTS AND METHODS: 91 of 151 patients in HF (77 men, 14 women; mean age 68) at the Göttingen University Hospital were recruited to the study. Implementation of NPT was assessed during the hospital stay and one year after discharge by standardized interviews. Additionally, patients were also asked about their preferred sources of information about HF. RESULTS: Compared with the baseline data, NPT were more frequently named after one year (significant increase for "See the doctor in case of weight gain" [24.3% vs. 57.1%; p<0.001] and "Dietary salt restriction" [41.4% vs. 70.0%; p<0.001]. Patients who had been readmitted reported NPT more frequently than those who had not previously been admitted to hospital (3.6 vs. 3.1, n.s). The majority of patients considered general practitioners to be the most important source for information on HF. CONCLUSIONS: One year after discharge more patients had become aware of NPT. On the whole lifestyle modification is still relatively uncommon. General practitioners are seen as the most important informants on the management of HF and could use this trust to promote greater implementation of NPT by their patients.

Preparation of soybean seed samples for FT-IR microspectroscopy.

Typical preparation of seed samples for infrared (IR) microspectroscopy involves imbibition of the seed for varying time periods followed by cryosectioning. Imbibition, however, may initiate germination even at 4 degrees C with associated changes in the chemistry of the sample. We have found that it is possible to section seeds that are sufficiently hard, such as soybeans, on a standard laboratory microtome without imbibition. The use of dry sectioning of unimbibed seeds is reported here, as well as a comparison of different mounting media and modes of analysis. Glycerol, Tissue-Tek, and ethanol were used as mounting media, and the quality of the resulting spectra was assessed. Ethanol was the preferred mountant, because it dried quickly with no residue and thus did not interfere with the spectrum of interest. Analysis in transmission mode using barium fluoride windows to hold the samples was compared with transmission-reflection analysis with sections mounted on special infrared-reflecting slides. The two modes of analysis performed well in different regions of the spectrum. The mode of analysis (transmission vs. transmission-reflection) should be based on the components of greatest interest in the sample.

Cercosporin-deficient mutants by plasmid tagging in the asexual fungus Cercospora nicotianae.

We have successfully adapted plasmid insertion and restriction enzyme-mediated integration (REMI) to produce cercosporin toxin-deficient mutants in the asexual phytopathogenic fungus Cercospora nicotianae. The use of pre-linearized plasmid or restriction enzymes in the transformation procedure significantly decreased the transformation frequency, but promoted a complicated and undefined mode of plasmid integration that leads to mutations in the C. nicotianae genome. Vector DNA generally integrated in multiple copies, and no increase in single-copy insertion was observed when enzymes were added to the transformation mixture. Out of 1873 transformants tested, 39 putative cercosporin toxin biosynthesis ( ctb) mutants were recovered that showed altered levels of cercosporin production. Seven ctb mutants were recovered using pre-linearized plasmids without the addition of enzymes, and these were considered to be non-REMI mutants. The correlation between a specific insertion and a mutant phenotype was confirmed using rescued plasmids as gene disruption vectors in the wild-type strain. Six out of fifteen rescued plasmids tested yielded cercosporin-deficient transformants when re-introduced into the wild-type strain, suggesting a link between the insertion site and the cercosporin-deficient phenotype. Sequence analysis of a fragment flanking the insert site recovered from one insertion mutant showed it to be disrupted in sequences with high homology to the acyl transferase domain of polyketide synthases from other fungi. Disruption of this polyketide synthase gene ( CTB1) using a rescued plasmid resulted in mutants that were defective in cercosporin production. Thus, we provide the first molecular evidence that cercosporin is synthesized via a polyketide pathway as previously hypothesized.

Enhanced potential for metabolic studies using narrow-band sensitized FT-IR microspectroscopy.

The ability to detect and measure the relative concentration of deuterated substance found in tissue specimens is enhanced by adding a custom made-to-order 50 microm narrow MCT band that has an optimized response profile for the CD, ND and OH absorption bands. In the short range of interest it has a 2:1 signal advantage over the stock MCT detector and the steep cut off before the finger print region significantly diminishing the noise. The result is that levels of specific deuterated compounds experimentally administered to biological systems and dispersed by the host organism can be detected and measured The custom small target size narrow-band detector with increased signal and reduced noise enhances the potential for the use of FT-IR microspectoscopy as a novel way to study metabolism without the use of radioactive materials.

[Robotic and navigation systems: surgical practicability and benefit for the patient?]. / Roboter- und Navigationssysteme: Praktikabilität für den Operateur--Nutzen für den Patienten?

The use of robotics and navigated systems to prepare, perform and reinforce surgical interventions is described by the term "computer aided surgery" (CAS). CAS is expected to make surgery even more precise, safer and cheaper. It comprehends computer based supporting systems (e. g. therapy planning, simulation, navigation), assisting systems, programmable automates and the so called master-slave-systems. When introducing technical innovations, the potential benefit of the patient is the essential issue. Then only practicability under clinical conditions, and additional aspects can be discussed. Conclusively, less spectacular applications of CAS like computer based supporting or assisting systems are more relevant for current practical use than visionary robotic systems.

Actin filament polymerization regulates gliding motility by apicomplexan parasites.

Host cell entry by Toxoplasma gondii depends critically on actin filaments in the parasite, yet paradoxically, its actin is almost exclusively monomeric. In contrast to the absence of stable filaments in conventional samples, rapid-freeze electron microscopy revealed that actin filaments were formed beneath the plasma membrane of gliding parasites. To investigate the role of actin filaments in motility, we treated parasites with the filament-stabilizing drug jasplakinolide (JAS) and monitored the distribution of actin in live and fixed cells using yellow fluorescent protein (YFP)-actin. JAS treatment caused YFP-actin to redistribute to the apical and posterior ends, where filaments formed a spiral pattern subtending the plasma membrane. Although previous studies have suggested that JAS induces rigor, videomicroscopy demonstrated that JAS treatment increased the rate of parasite gliding by approximately threefold, indicating that filaments are rate limiting for motility. However, JAS also frequently reversed the normal direction of motility, disrupting forward migration and cell entry. Consistent with this alteration, subcortical filaments in JAS-treated parasites occurred in tangled plaques as opposed to the straight, roughly parallel orientation observed in control cells. These studies reveal that precisely controlled polymerization of actin filaments imparts the correct timing, duration, and directionality of gliding motility in the Apicomplexa.