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1.  The Archaeal Proteasome Is Regulated by a Network of AAA ATPases* 
The Journal of Biological Chemistry  2012;287(46):39254-39262.
Background: The AAA ATPases of the PAN/Rpt1–6 group regulate access of substrates to the 20S proteasome.
Results: Two groups of AAA proteins, CDC48 and AMA, function as novel proteasomal ATPases in archaea.
Conclusion: This network of regulatory ATPases increases the capacity of proteasomal protein degradation in archaea.
Significance: Diversification at the level of the regulatory ATPase provides a contrast to the fully differentiated 26S proteasome of eukaryotes.
The proteasome is the central machinery for targeted protein degradation in archaea, Actinobacteria, and eukaryotes. In its basic form, it consists of a regulatory ATPase complex and a proteolytic core particle. The interaction between the two is governed by an HbYX motif (where Hb is a hydrophobic residue, Y is tyrosine, and X is any amino acid) at the C terminus of the ATPase subunits, which stimulates gate opening of the proteasomal α-subunits. In archaea, the proteasome-interacting motif is not only found in canonical proteasome-activating nucleotidases of the PAN/ARC/Rpt group, which are absent in major archaeal lineages, but also in proteins of the CDC48/p97/VAT and AMA groups, suggesting a regulatory network of proteasomal ATPases. Indeed, Thermoplasma acidophilum, which lacks PAN, encodes one CDC48 protein that interacts with the 20S proteasome and activates the degradation of model substrates. In contrast, Methanosarcina mazei contains seven AAA proteins, five of which, both PAN proteins, two out of three CDC48 proteins, and the AMA protein, function as proteasomal gatekeepers. The prevalent presence of multiple, distinct proteasomal ATPases in archaea thus results in a network of regulatory ATPases that may widen the substrate spectrum of proteasomal protein degradation.
PMCID: PMC3493965  PMID: 22992741
Archaea; ATP-dependent Protease; ATPases; Proteasome; Protein Degradation
2.  Peer reviewing critical care: a pragmatic approach to quality management 
Critical care medicine frequently involves decisions and measures that may result in significant consequences for patients. In particular, mistakes may directly or indirectly derive from daily routine processes. In addition, consequences may result from the broader pharmaceutical and technological treatment options, which frequently involve multidimensional aspects. The increasing complexity of pharmaceutical and technological properties must be monitored and taken into account. Besides the presence of various disciplines involved, the provision of 24-hour care requires multiple handovers of significant information each day. Immediate expert action that is well coordinated is just as important as a professional handling of medicine's limitations.
Intensivists are increasingly facing professional quality management within the ICU (Intensive Care Unit). This article depicts a practical and effective approach to this complex topic and describes external evaluation of critical care according to peer reviewing processes, which have been successfully implemented in Germany and are likely to gain in significance.
PMCID: PMC2975265  PMID: 21063473
peer review; quality management; intensive care medicine; evidence based medicine; effectiveness
3.  Quality indicators in intensive care medicine: why? Use or burden for the intensivist 
In order to improve quality (of therapy), one has to know, evaluate and make transparent, one’s own daily processes. This process of reflection can be supported by the presentation of key data or indicators, in which the real as-is state can be represented. Quality indicators are required in order to depict the as-is state.
Quality indicators reflect adherence to specific quality measures. Continuing registration of an indicator is useless once it becomes irrelevant or adherence is 100%.
In the field of intensive care medicine, studies of quality indicators have been performed in some countries. Quality indicators relevant for medical quality and outcome in critically ill patients have been identified by following standardized approaches.
Different German societies of intensive care medicine have finally agreed on 10 core quality indicators that will be valid for two years and are currently recommended in German intensive care units (ICUs).
PMCID: PMC2975264  PMID: 21063472
quality indicators; quality management; intensive care medicine; quality of therapy; outcome
4.  Evidence and consensus-based German guidelines for the management of analgesia, sedation and delirium in intensive care – short version 
Targeted monitoring of analgesia, sedation and delirium, as well as their appropriate management in critically ill patients is a standard of care in intensive care medicine. With the undisputed advantages of goal-oriented therapy established, there was a need to develop our own guidelines on analgesia and sedation in intensive care in Germany and these were published as 2nd Generation Guidelines in 2005. Through the dissemination of these guidelines in 2006, use of monitoring was shown to have improved from 8 to 51% and the use of protocol-based approaches increased to 46% (from 21%).
Between 2006–2009, the existing guidelines from the DGAI (Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin) and DIVI (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin) were developed into 3rd Generation Guidelines for the securing and optimization of quality of analgesia, sedation and delirium management in the intensive care unit (ICU). In collaboration with another 10 professional societies, the literature has been reviewed using the criteria of the Oxford Center of Evidence Based Medicine. Using data from 671 reference works, text, diagrams and recommendations were drawn up. In the recommendations, Grade “A” (very strong recommendation), Grade “B” (strong recommendation) and Grade “0” (open recommendation) were agreed.
As a result of this process we now have an interdisciplinary and consensus-based set of 3rd Generation Guidelines that take into account all critically illness patient populations.
The use of protocols for analgesia, sedation and treatment of delirium are repeatedly demonstrated. These guidelines offer treatment recommendations for the ICU team. The implementation of scores and protocols into routine ICU practice is necessary for their success.
PMCID: PMC2830566  PMID: 20200655
guideline; evidence; analgesia; sedation; delirium; monitoring; treatment; intensive care
5.  prlF and yhaV encode a new toxin-antitoxin system in Escherichia coli 
Journal of molecular biology  2007;372(4):894-905.
Toxin-antitoxin systems consist of a stable toxin, frequently with endonuclease activity, and a small, labile antitoxin, which sequesters the toxin into an inactive complex. Under unfavorable conditions, the antitoxin is degraded, leading to activation of the toxin and resulting in growth arrest, possibly also in bacterial programmed cell death. Correspondingly, these systems are generally viewed as agents of the stress response in prokaryotes. Here we show that prlF and yhaV encode a novel toxin-antitoxin system in Escherichia coli. YhaV, a ribonuclease of the RelE superfamily, causes reversible bacteriostasis that is counteracted by PrlF, a swapped-hairpin transcription factor homologous to MazE. The two proteins form a tight, hexameric complex, which binds with high specificity to a conserved sequence in the promotor region of the prlF-yhaV operon. As homologs of MazE and RelE, respectively, PrlF and YhaV provide an evolutionary connection between the two best-characterized toxin-antitoxin systems in E. coli, mazEF and relEB.
PMCID: PMC2699681  PMID: 17706670
mRNA decay; RelE superfamily ribonuclease; stress response; swapped-hairpin barrel; toxin-antitoxin system
6.  Structure of the Head of the Bartonella Adhesin BadA 
PLoS Pathogens  2008;4(8):e1000119.
Trimeric autotransporter adhesins (TAAs) are a major class of proteins by which pathogenic proteobacteria adhere to their hosts. Prominent examples include Yersinia YadA, Haemophilus Hia and Hsf, Moraxella UspA1 and A2, and Neisseria NadA. TAAs also occur in symbiotic and environmental species and presumably represent a general solution to the problem of adhesion in proteobacteria. The general structure of TAAs follows a head-stalk-anchor architecture, where the heads are the primary mediators of attachment and autoagglutination. In the major adhesin of Bartonella henselae, BadA, the head consists of three domains, the N-terminal of which shows strong sequence similarity to the head of Yersinia YadA. The two other domains were not recognizably similar to any protein of known structure. We therefore determined their crystal structure to a resolution of 1.1 Å. Both domains are β-prisms, the N-terminal one formed by interleaved, five-stranded β-meanders parallel to the trimer axis and the C-terminal one by five-stranded β-meanders orthogonal to the axis. Despite the absence of statistically significant sequence similarity, the two domains are structurally similar to domains from Haemophilus Hia, albeit in permuted order. Thus, the BadA head appears to be a chimera of domains seen in two other TAAs, YadA and Hia, highlighting the combinatorial evolutionary strategy taken by pathogens.
Author Summary
The ability to adhere is an important aspect of the interaction between bacteria and their environment. Adhesion allows them to aggregate into colonies, form biofilms with other species, and colonize surfaces. Where the surfaces are provided by other organisms, adhesion can lead to a wide range of outcomes, from symbiosis to pathogenicity. In Proteobacteria, colonization of the host depends on a wide range of adhesive surface molecules, among which Trimeric Autotransporter Adhesins (TAAs) represent a major class. In electron micrographs, TAAs resemble lollipops projecting from the bacterial surface, and in all investigated cases, the adhesive properties reside in their heads. We have determined the head structure of BadA, the major adhesin of Bartonella henselae. This pathogen causes cat scratch disease in humans, but can lead to much more severe disease in immunosuppressed patients, e.g., during chemotherapy or after HIV infection. Surprisingly, domains previously seen in other TAA heads are combined in a novel assembly, illustrating how pathogens rearrange available building blocks to create new adhesive surface molecules.
PMCID: PMC2483945  PMID: 18688279
7.  Changes in sedation management in German intensive care units between 2002 and 2006: a national follow-up survey 
Critical Care  2007;11(6):R124.
The aim of this study, conducted in 2006, was to find out whether changes in sedation management in German intensive care units took place in comparison with our survey from 2002.
We conducted a follow-up survey with a descriptive and comparative cross-sectional multi-center design. A postal survey was sent between January and May 2006, up to four times, to the same 269 hospitals that participated in our first survey in 2002. The same questionnaire as in 2002 was used with a few additional questions.
Two hundred fourteen (82%) hospitals replied. Sixty-seven percent of the hospitals carried out changes in sedation management since the 2002 survey. Reasons for changes were published literature (46%), national guidelines (29%), and scientific lectures (32%). Sedation protocols (8% versus 52%) and a sedation scale (21% versus 46%) were used significantly more frequently. During sedation periods of up to 24 hours, significantly less midazolam was used (46% versus 35%). In comparison to 2002, sufentanil and epidural analgesia were used much more frequently in all phases of sedation, and fentanyl more rarely. For periods of greater than 72 hours, remifentanil was used more often. A daily sedation break was introduced by 34% of the hospitals, and a pain scale by 21%.
The increased implementation of protocols and scoring systems for the measurement of sedation depth and analgesia, a daily sedation break, and the use of more short-acting analgesics and sedatives account for more patient-oriented analgesia and sedation in 2006 compared with 2002.
PMCID: PMC2246220  PMID: 18062820
8.  Bartonella Adhesin A Mediates a Proangiogenic Host Cell Response 
The Journal of Experimental Medicine  2004;200(10):1267-1278.
Bartonella henselae causes vasculoproliferative disorders in humans. We identified a nonfimbrial adhesin of B. henselae designated as Bartonella adhesin A (BadA). BadA is a 340-kD outer membrane protein encoded by the 9.3-kb badA gene. It has a modular structure and contains domains homologous to the Yersinia enterocolitica nonfimbrial adhesin (Yersinia adhesin A). Expression of BadA was restored in a BadA-deficient transposon mutant by complementation in trans. BadA mediates the binding of B. henselae to extracellular matrix proteins and to endothelial cells, possibly via β1 integrins, but prevents phagocytosis. Expression of BadA is crucial for activation of hypoxia-inducible factor 1 in host cells by B. henselae and secretion of proangiogenic cytokines (e.g., vascular endothelial growth factor). BadA is immunodominant in B. henselae–infected patients and rodents, indicating that it is expressed during Bartonella infections. Our results suggest that BadA, the largest characterized bacterial protein thus far, is a major pathogenicity factor of B. henselae with a potential role in the induction of vasculoproliferative disorders.
PMCID: PMC2211922  PMID: 15534369
pilus; endothelial cells; HIF-1; VEGF; angiogenesis
9.  Practice of sedation and analgesia in German intensive care units: results of a national survey 
Critical Care  2005;9(2):R117-R123.
Sedation and analgesia are provided by using different agents and techniques in different countries. The goal is to achieve early spontaneous breathing and to obtain an awake and cooperative pain-free patient. It was the aim of this study to conduct a survey of the agents and techniques used for analgesia and sedation in intensive care units in Germany.
A survey was sent by mail to 261 hospitals in Germany. The anesthesiologists running the intensive care unit were asked to fill in the structured questionnaire about their use of sedation and analgesia.
A total of 220 (84%) questionnaires were completed and returned. The RAMSAY sedation scale was used in 8% of the hospitals. A written policy was available in 21% of hospitals. For short-term sedation in most hospitals, propofol was used in combination with sufentanil or fentanyl. For long-term sedation, midazolam/fentanyl was preferred. Clonidine was a common part of up to two-thirds of the regimens. Epidural analgesia was used in up to 68%. Neuromuscular blocking agents were no longer used.
In contrast to the US 'Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult', our survey showed that in Germany different agents, and frequently neuroaxial techniques, were used.
PMCID: PMC1175921  PMID: 15774043

Results 1-9 (9)