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Die Generalisierbarkeitstheorie (G-Theorie) ist ein Algorithmus zur Generierung allgemeiner und praziser wissenschaftlicher Theorien. In ihren G-Studien analysiert sie faktorielle Designs gekreuzter und genesteter Daten auf multiplen Ebenen und ermittelt die maximale Zahl von Effekten als zufallige Varianzkomponenten. Einerseits kann damit geforscht werden, z. B. zur Fuhrung in Unternehmen (360-Grad-Feedback; Management-Derailment). Andererseits optimiert sie in ihren D-Studien psychometrische Prognosen. Die Prazision ihrer Generalisierungen (Generalisierungskoeffizienten) ist in Erweiterung der Spearman-Brown-Prophecy-Formula der klassischen Testtheorie eine Funktion der Zahl jeder Anzahl der Bedingungen (Stufen) je Facette. Die freie Software R ermoglicht alle notwendigen Berechnungen. Zum Nachvollziehen fur den Praktiker zeigt der Beitrag die R-Syntax zur Analyse von Brennans (2001) synthetischen Datenmatrizen, namentlich mit dem R-Paket gstudy.

Figure S1. Multi-Dimensional-Scaling of the distance matrix underlying the phylogenetic tree, based on chromosomes 1, 8 and 13. (DOCX 95 kb)

ZusammenfassungMiniaturschweine (Minipigs) gehören immer häufiger zu den Patienten der Kleintierpraxis. Da sie in der Regel ein deutlich höheres Lebensalter erreichen als Schweine in der Nutztierhaltung, treten bei ihnen Alterserkrankungen auf, die bei konventionell gehaltenen Schweinen keine Rolle spielen. Hierzu gehören neoplastische Veränderungen des Uterus. Die beiden präsentierten Fallbeispiele beschreiben ein uterines Adenokarzinom sowie ein Leiomyom bei zwei Minipigsauen. Diskutiert werden Optionen und Grenzen der Diagnostik (unspezifische klinische Symptomatik, Röntgen, Ultraschall und Computertomographie), die Gefahr der Verwechslung mit häufiger vorkommenden differenzialdiagnostisch zu berücksichtigenden Erkrankungen (Obstipation, Zystitis, Endometritis) in der Schweinemedizin sowie die Therapie bei Verdacht auf Vorliegen eines Uterustumors im Rahmen der gesetzlichen Möglichkeiten.

Innate immunity is critically important for the outcome of infection in many diseases. It was previously shown that cathelicidin PR-39, an important porcine multifunctional host defence peptide, is elevated in bronchoalveolar lavage fluid and respiratory tract tissue after experimental infection with Actinobacillus pleuropneumoniae (A.pp.). To date, neutrophil polymorphonuclear leukocytes (PMNs) are thought to be the only source of PR-39. The aim of this study was to further characterize PR-39⁺ cells and selected immune cell populations in lung tissue during the peracute (7-10 hours), acute (2 days), reconvalescent (7 days) and chronic (21 days) stages of experimental infection with A.pp. serotype 2. In total, six mock-infected control pigs and 12 infected pigs were examined. Using immunofluorescence double-labeling, antibodies against PR-39 were combined with antibodies against CD3 (T-cells), CD79 (B-cells), Iba1 (activated macrophages), TTF-1 (lung epithelial cells expressing surfactant proteins), macrophage/L1 protein and myeloperoxidase (MPO, cells of the myeloid linage). In the peracute and acute phases of infection, total PR-39⁺ cells and myeloid linage cells increased, whereas CD3⁺ cells and TTF-1⁺ cells decreased. Double labeling revealed that most Macrophage/L1 protein+ cells and to a lesser extent MPO⁺ cells co-expressed PR-39. In addition, few bronchial epithelial cells and type 2 alveolar epithelial cells (both identified with TTF-1) produced PR-39. Occasionally, CD3⁺ T cells expressing PR-39 were seen in infected animals. Taken together, this study identifies cell types, other than PMNs, in lungs of A.pp.-infected pigs that are capable of producing PR-39. In addition, these findings provide further insights into the dynamics of different immune cell populations during A.pp.-infection.

ZusammenfassungÜber Staphylococcus(S.)-aureus-Infektionen beim Schwein wurde im Zusammenhang mit Septikämien, Mastitiden, Vaginitiden, Metritiden, Osteomyelitiden und Endokarditiden in der Vergangenheit mehrfach berichtet. Dieser Fallbericht beschreibt eine durch S. aureus hervorgerufene septikämische Erkrankung von Saugferkeln. Am dritten Lebenstag traten bei Saugferkeln eines Wurfes Zyanosen und ekchymale Blutungen auf der Hautoberfläche auf. Etwa die Hälfte der Tiere verendete, die andere Hälfte wurde zu einer anderen Sau gesetzt, verendete jedoch einen Tag später. Fremde, an die Muttersau angesetzte Ferkel zeigten bereits nach einem Tag ebenfalls die beschriebene Sympto matik. Blutuntersuchungen bei den Ferkeln ergaben eine Anämie, eine Thrombozytopenie und eine Leukopenie, sodass weder eine Septikämie noch eine isohämolytische Anämie ausgeschlossen werden konnte. Bei der Sektion wurden petechiale Blutungen auf Oberflächen der inneren Organe sowie Einblutungen in die Körperhöhlen festgestellt. Durch die bakteriologische Untersuchung von Sauenmilch sowie der Milz eines Ferkels konnte eine Infektion mit einem Methicillinresistenten S. aureus (MRSA CC398) nachgewiesen werden, die mit großer Wahrscheinlichkeit die Ursache für das septikämische Krankheitsbild darstellte. Die Differenzialdiagnosen zu dem klinischen Bild werden besprochen.

Rat C regions mu, gamma 1, gamma 2a, gamma 2b, gamma 2c, epsilon, and alpha have been characterized by means of chimeric antibody technology. A set of rat/mouse Ag-specific (anti-4-hydroxy-3-nitrophenacetyl) antibodies was constructed that differ only in the H chain constant region but carry identical V region and L chain, both of which are of mouse origin. All rat constant regions could be expressed and m.w. were as expected from the protein sequence. A slight variation in mobility within the IgG subclasses allowed us to establish a hierarchy for the sizes of the four gamma H chains; gamma 2b greater than gamma 1 greater than gamma 2c greater than gamma 2a. Rat IgG2c and IgG2b could be purified on both protein A and protein G while rat IgG2a could only be purified on protein G. Rat IgM and IgG2b were the most potent in C-mediated hemolysis. This was not simply a consequence of the amount of C1q bound because IgG2c bound C1q efficiently but was relatively poor in cell lysis. In ADCC using human effector and target cells, IgG2b and IgG1 were the most effective.

IL-18 (also known as IFN-gamma-inducing factor), although structurally unrelated to IL-12, shares with it the role of activating NK cells and polarizing T cells toward Th1 cell function. To understand how the IL-18 gene (and consequently Th1 function) is regulated, we have determined the gene structure and investigated the mechanisms of transcriptional control and cell type expression. The mouse IL-18 gene comprises seven exons distributed over 26 kb. Exons 1 and 2 of this gene are 5'-noncoding exons. Promoter activity was detected upstream of these noncoding exons in two distinct regions. Both promoters are TATA-less and not G+C rich. The promoter activity located upstream of exon 2 was shown to act constitutively, while the activity located upstream of exon 1 was up-regulated in activated macrophage and T cell lines. IL-18 gene expression may be regulated in a wide range of cell types by the activities of these two distinct promoters. IL-18 is known to be synthesized as a precursor, pro-IL-18, and its maturation is controlled by IL-1beta-converting enzyme (ICE). We observed concordant expression of IL-18 and ICE mRNAs in a wide range of cell types, unlike the more restricted expression of IL-12 p40 mRNA. The widespread IL-18 mRNA distribution and the special relationship with ICE lead us to the hypothesis that IL-18 expression may be coupled with apoptotic processes involving activation of ICE or ICE-like proteinase.

Zusammenfassung Gegenstand und Ziel: In der Veterinärmedizin hat die computertomographische (CT-) Bildgebung in den letzten Jahren für die Diagnostik bei Liebhabertieren, aber auch für Verlaufsuntersuchungen an Tiermodellen für die Humanmedizin an Bedeutung gewonnen. In dieser Studie wurde die Eignung der CT als bildgebendes Verfahren für die Darstellung des Thorax und insbesondere der Lunge beim Schwein geprüft. Material und Methoden: An 11 gesunden Schweinen zweier Altersgruppen erfolgten CT-Untersuchungen. Die erhobenen Befunde wurden zu klinischen, röntgenologischen, makroskopischen und mikroskopischen Untersuchungsbefunden sowie zur Erregerdiagnostik in Beziehung gesetzt und evaluiert. Ergebnisse: Anhand transversaler Schnittbilder wurden klinisch relevante anatomische Strukturen dargestellt und beschrieben. Die Dichtemessungen des Lungenparenchyms in Höhe des zweiten, vierten und siebten Brustwirbels zeigten in Bauchlagerung der Tiere eine signifikant höhere Lungenparenchymdichte der ventralen Quadranten im Vergleich zu den dorsalen Quadranten. Schlussfolgerung und klinische Relevanz: Die CT-Untersuchung eignet sich zur kontrastreichen und überlagerungsfreien Darstellung der Lunge des Schweines. Diese Referenz für die Lunge gesunder Schweine stellt eine Bewertungsgrundlage dar, um zukünftig anatomische Strukturen der Schweinelunge im CT-Querschnittbild identifizieren und pathologische Veränderungen bewerten zu können.

A study to determine the occurrence of pathogenic Yersinia enterocolitica on surfaces of slaughtered pig livers and the antimicrobial resistant pattern of the isolates was carried out in a slaughterhouse in Lower Saxony, Germany. During the slaughtering process, 1,500 surfaces of pig livers from 50 fattening herds were swabbed in order to isolate and characterize Y. enterocolitica isolates by serotyping, detecting the virulence plasmid coding the yopT gene, and resistance testing. Of the livers tested, 4.7% were positive for Y. enterocolitica O:3, which was the only identified serotype. The virulence gene yopT was found in 90.0% of these isolates. Antimicrobial susceptibility was tested by the broth dilution method, and the MICs were determined for 13 antimicrobials. All isolates were resistant to ampicillin and sulfamethoxazole but were susceptible to ciprofloxacin, nalidixic acid, gentamicin, ceftiofur, tetracycline, kanamycin, cefotaxime, and chlorphenicol. Up to now, resistance to florfenicol has always been described in combination with resistance to chloramphenicol. In the present study, 15.3% of the isolates were resistant to florfenicol, while no chloramphenicol-resistant strains could be identified. Multiresistance to three or more antimicrobials was detected in 22 strains (27.3%). Nevertheless, third-generation cephalosporines or fluoroquinolones, which were recommended for extraintestinal Y. enterocolitica infection in humans, were not affected.

CD40L antibodies have proven to be powerful immunosuppressive agents in nonhuman primates but unfortunately perturb blood coagulation. Neither the therapeutic nor the prothrombotic mechanism of anti-CD40L is defined sufficiently to determine whether these effects can be uncoupled. Recent evidence suggests that the Fc region of anti-CD40L antibodies interacting with Fc receptors plays an important role in stabilizing platelet aggregates. An Fc-disabled, aglycosylated anti-CD40L heavy chain variant was therefore created to determine whether it might still be useful in promoting transplantation tolerance. In a number of mouse models an engineered aglycosyl anti-CD40L recapitulated the effects of the intact anti-CD40L antibody in tolerance protocols involving transplantation of allogeneic bone marrow and skin. In contrast, another anti-CD40L variant with a conventional rat gamma2b heavy chain was less effective in ensuring long-term skin graft survival, possibly associated with its faster clearance from the circulation. These results show that short pulses of anti-CD40L antibody therapy may still be useful in tolerance protocols even when the Fc region is disabled.

Summary In bronchoalveolar lavage fluid (BALF) of pigs originating from different herds bacteria, cells and the antibacterial peptide PR‐39 were examined to gain information about the lung health status. In a high health nucleus herd 56% and in low health herds 20–100% of the examined pigs were found positive for potentially pathogenic bacteria. Based on these findings, a novel definition for bacterial respiratory tract disease was established using an 8% cut‐off for the relative number of neutrophils in bronchoscopic and a 40% cut‐off in transtracheal BALF in combination with the occurrence of potentially pathogenic microorganisms. The antibacterial peptide PR‐39 was highly correlated to this definition of respiratory disease. An assessment of the bacteriological respiratory health status appears to be possibly based on the determination of PR‐39 concentrations in BALF using different cut‐off values according to the lavage method (2.5 nM for bronchoscopic and 5 nM for transtracheal BALF).

We consider a countable state Markov decision process with bounded reward function and an absorbing set. At first we generalize known properties and derive new properties of the critical discount factor, which is roughly defined as the maximal discount factor under which for V, the maximal expected infinite-stage discounted reward, there is guaranteed existence, boundedness, and computability by the successive approximation method. The emphasis of the paper is on algorithms for computing V exactly (recursion in state space and policy iteration) or approximately (value iteration combined with an extrapolation and finite state approximation). Our extrapolation method is motivated by and based on the Perron--Frobenius theory for nonlinear operators. As a by-product we obtain an efficient algorithm for determining the distribution of the entrance time of a Markov chain into an absorbing set. Further results concern asymptotically $\epsilon$-optimal policies and a new turnpike theorem. Some of the results need tightness of the transition law, which turns out to be equivalent to compactness of a nonlinear operator, which is crucial for our study.

Transferrin (TF)-mediated provision of iron is essential for a productive infection by many bacterial pathogens, and iron-depletion of TF is a first line defence against bacterial infections. Therefore, the transferrin (TF) gene can be considered a candidate gene for disease resistance. We obtained the complete DNA sequence of the porcine TF gene, which spans 40 kb and contains 17 exons. We identified polymorphisms on a panel of 10 different pig breeds. Comparative intra- and interbreed sequence analysis revealed 62 polymorphisms in the TF gene including one microsatellite. Ten polymorphisms were located in the coding sequence of the TF gene. Four SNPs (c.902A>T, c.980G>A, c.1417A>G, c.1810A>C) were predicted to cause amino acid exchanges (p.Lys301Ile, p.Arg327Lys, p.Lys473Glu, p.Asn604His). We performed association analyses using six selected TF markers and 116 pigs experimentally infected with Actinobacillus pleuropneumoniae serotype 7. The analysis showed breed-specific TF allele frequencies. In German Landrace, we found evidence for a possible association of the severity of A. pleuropneumoniae infection with TF genotypes.

Miniature pet pigs are becoming ever more common among the patients of small animal practices. Due to an advanced age attained in these animals in comparison with conventional pigs in pork production, miniature pet pigs develop age-related diseases that are infrequently observed in farm pigs, including neoplastic alterations of the uterus. We describe two cases of a uterine adenocarcinoma and a leiomyoma, respectively, in two miniature pet pig sows. Options and limits of diagnostic measures (unspecific clinical symptoms, x-ray, sonography and computed tomography) and therapy within the legal limits as well as the risk of an incorrect diagnosis based upon the more common differential diagnoses in swine medicine, including obstipation, cystitis and endometritis, are discussed.

Scoring schemes for clinical, ultrasonographic and radiographic findings in pigs were developed based upon a standardized animal model for Actinobacillus pleuropneumoniae infection.The results of these methods were compared to each other as well as with the corresponding pathomorphological findings during necropsy. Altogether 69 pigs of different breeding lines (Hampshire, Pietrain and German Landrace were examined. Positive correlations were found between the results of all three methods as well as with the necropsy scores (p0.0001). Different pathomorphological findings were detected either by radiographic or by ultrasonographic examination dependent upon the type of lung tissue alterations: Alterations of the pleura as well as sequestration of lung tissue on the lung surface could be clearly identified during the ultrasonographic examination while deep tissue alterations with no contact to the lung surface could be detected reliably by radiographic examination. Both methods complement each other, and the application of a combined ultrasonographic and radiographic examination of the thorax allows a comprehensive inspection of the lung condition. Particularly during the acute phase of the disease the extent of lung tissue damage can be estimated more precisely than by clinical examination alone.

The elective treatment of patients with multiple sclerosis, using a humanized anti-leukocyte (CD52) monoclonal antibody (Campath-1H), has illuminated mechanisms that underlie the clinical course of the disease. Twenty-seven patients were studied clinically and by magnetic resonance imaging (MRI) before and for 18 months after a single pulse of Campath-1H. The first dose of monoclonal antibody was associated with a transient rehearsal of previous symptoms caused by the release of mediators that impede conduction at previously demyelinated sites; this effect remained despite selective blockade of tumor necrosis factor-alpha. Disease activity persisted for several weeks after treatment but thereafter radiological markers of cerebral inflammation were suppressed for at least 18 months during which there were no new symptoms or signs. However, about half the patients experienced progressive disability and increasing brain atrophy, attributable on the basis of MRI spectroscopy to axonal degeneration, which correlated with the extent of cerebral inflammation in the pretreatment phase. These data support the formulation that inflammation and demyelination are responsible for relapses of multiple sclerosis; that inflammatory mediators, but not tumor necrosis factor-alpha, cause symptomatic reactivation of previously demyelinated lesions; and that axonal degeneration, conditioned by prior inflammation but proceeding despite its suppression, contributes to the progressive phase of disability. These results provide evidence supporting the emerging view that treatment in multiple sclerosis must be given early in the course, before the consequences of inflammation are irretrievably established.

Diese Arbeit fokussiert sich auf die nicht-medikamentosen ambulanten Therapiemasnahmen und erlautert eine Stadieneinteilung der Drogenabhangigkeit. Sie ist somit komplementar zu anderen Arbeiten dieses Hefts. Anschaulich und plausibel werden die Bindungen zwischen dem Ich des Drogenabhangigen und seiner Interessenssphare dargestellt, die auf Suchtstoff(e), die eigene Person und den eigenen Korper, Bezugspersonen und Sozialbezuge gerichtet sind. Die Schwierigkeiten des Drogenentzugs durch zunachst alleinige passive Hilfestellung und sukzessiv auch durch aktive Mitarbeit der Abhangigen wird aus dieser Ubersicht deutlich. Insbesondere mit Blick auf Nicht-Spezialisten wird dadurch das Verstandnis fur Drogenabhangige und nicht zuletzt auch fur die Kolleginnen und Kollegen, die sich dieser diffizilen Aufgabe stellen, gefordert.

In an internal campaign, a large Swiss company carried out an instruction programme with employees concerning ergonomics at a VDU. Before and after this campaign, the existing conditions were recorded regarding ergonomics at the VDU workplace. At the same time, complaints, as well as individual knowledge and interest in ergonomics, were recorded. Based on the information at hand, it can be assumed that the campaign improved the existing conditions of ergonomics, as well as the self-responsibility on the part of those involved. A compilation of the work involved indicates that a training course with the objective of influencing ergonomics at the place of work was cost effective.

Staphylococcus (S.) aureus has been associated with septicaemia, mastitis, vaginitis, metritis, osteomyelitis, and endocarditis. This case report demonstrates S. aureus-induced septicaemia in suckling pig- lets. Three days after birth, littermates displayed severe ecchymosis and cyanosis, with a 50% mortality rate. The surviving littermates were cross-fostered, but died 1 day later. Other piglets, which were allowed to suck at the sow, developed similar clinical signs. Haematological findings were anaemia, thrombocytopenia, and leukopenia; therefore, neither isohaemolytic anaemia nor septicaemia could be excluded as differential diagnoses. At necropsy, petechial bleeding on inner organ surfaces and free blood in body cavities were found. Bacteriological examination of the sow's milk and of the spleen of one piglet detected a methicillin-resistent S. aureus strain (MRSA CC398), which was in all likelihood the cause of the disease. Potential differential diagnoses are discussed.

Castration of piglets with the use of isoflurane-anaesthesia in combination with an analgesic has been proven to be a welfare-friendly approach. However, castration is performed with an equipped anaesthetic device which is not profitable for small farms. Thus, this study aimed at investigating whether sharing the anaesthetic device among farms results in an elevated risk of bacteriological contamination and further spreading in spite of a thorough disinfection. The study included two groups of organic farms. Piglets (n = 1579) were anaesthetised with isoflurane supplied from an equipped device and castrated. Stationary anaesthetic devices were used in the first group of farms, whereas farms in the second group shared one device. Each farm was visited four times and the colony forming units (CFU) of total mesophilic bacteria, Staphylococcus spp., Methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli were determined. Sampling took place before castration and after disinfection, and included snout masks, retaining fixtures, pedals and wheels of the device (n = 376). The results indicated presence of Staphylococcus species in 56.5% and 40.3% of samples obtained from farms using stationary and shared devices, respectively. MRSA was detected in 2.4% of the samples and only one pathogenic Shiga toxin-producing E. coli (Stx2e, F18) could be detected. Bacterial counts were lower on the shared device than on the stationary devices (p = 0.038), particularly on restraining fixtures (p0.05). In both groups wheels were the most and pedals the least contaminated materials (p0.05). It is concluded that sharing an anaesthetic device on several farms does not increase bacteriological contamination after a thorough disinfection and thus imposing no additional hygiene risk to farms with similar hygienic conditions.

S | Hair and Other Adnexal Structures 216 Human hair follicles can “smell”: OR2AT4-mediated hair growth regulation J Cheret, LM Ponce Moya, M Bertolini, T Tsai, M Alam, H Hatt and R Paus 1 Monasterium Laboratory, Muenster, Germany, 2 Ruhr-Uni-Bochum, Bochum, Germany and 3 Dermatology Research Centre, Manchester, United Kingdom Olfactory receptors (OR) are part of an evolutionarily ancient chemosensory signaling system, which regulates many cell functions beyond olfaction, incl. keratinocyte (KC) proliferation. Since hair follicle (HF) growth requires proliferation, we asked whether ORs play a role in human HF growth. We focused on OR2AT4, since OR2AT4 stimulation promotes human epidermal KC growth/migration. Human scalp HFs prominently express OR2AT4 (IF) in situ, namely in basal layer KCs of the central outer root sheath. When human scalp anagen VI HFs were treated with the specific synthetic OR2AT4 agonist, Sandalore , this significantly retarded spontaneous catagen development of HFs ex vivo and significantly decreased hair matrix KC apoptosis (TUNEL/caspase-3), possibly via down-regulating the expression of the catagen-promoting growth factor TGFb2 and up-regulating the expression of the key anagenmaintenance growth factor, IGF-1. Most of these effects were counteracted by co-administering the OR2AT4 antagonist, Phenirat . When OR2AT4 expression was silenced in human scalp HFs (the knock-down efficiency ex vivo was low), HF cycling appeared unaffected by it in short-term HF organ culture. However, OR2AT4 silencing significantly enhanced both HF KC apoptosis and TGFb2 expression. This supports that OR-mediated signalling regulates human HF KC biology in situ and suggests that OR2AT4 stimulation by (as yet unknown) endogenous ligands is required to down-regulate KC apoptosis and TGFb2 expression in human anagen HFs. These data constitute the first evidence that human HFs can “smell” in the sense that they engage in OR2AT4-mediated chemosensation to regulate their own growth. If the odorant, Sandalore , is also topically effective, it may become an adjuvant therapy for managing hair growth disorders characterized by premature catagen entry (e.g. telogen effluvium, alopecia areata). S198 Journal of Investigative Dermatology (2016), Volume 136 217 The adenosine-generating ecto-enzyme CD73 regulates human hair growth LM Ponce Moya, M Bertolini, Y Uchida, K Figlak, J Cheret, H Waldmann and R Paus 1 Dermatology, University of Munster, Munster, Germany, 2 Queen Mary University of London, London, United Kingdom, 3 Monasterium Laboratory, Munster, Germany, 4 Pathology, Oxford University, Oxford, United Kingdom and 5 Dermatology Rs Ctr, University of Manchester, Manchester, United Kingdom The immunoihibitory ecto-5’-nucleotidase CD73 metabolizes pericellular AMP to adenosine, with the latter being implicated in hair follicle (HF) growth modulation. Therefore, we hypothesized that CD73 may be expressed in human HFs and might impact on their growth. Our results revealed that CD73 is strongly expressed in HF mesenchyme, namely in endothelial and immune cells, and in the HF epithelium, in cytokeratin 74+ keratinocytes. The CD73-specific antagonist, adenosine 50-(a,b-methylene)diphosphate (APCP), strongly inhibited hair shaft production and induced catagen development (demonstrated by hair cycle staging). Interestingly, the concentration to which this effect was seen in each patient differed from 25mM to 100mM. In addition, HFs that showed reduced elongation after treatment with APCP, revealed also decreased adenosine concentration (0.1-0.2 mM) in the medium, suggesting that the APCP-dependent elongation inhibition may result from a reduction of adenosine production by CD73. This hypothesis is further confirmed by the fact that CD73-dependent elongation inhibition is reversed in pilot experiments upon treatment of HFs with APCP in combination of 0.1mM adenosine. In addition, hair shaft production and catagen transition were unaffected by silencing CD73 in the mesenchyme, suggesting the intriguing concept that only the intrafollicular CD73 activity associated with HF epithelium is functionally important for human hair growth control. Thus, our study reveals CD73 activity as a novel endogenous regulator of human growth, most likely by modulating the production of anagen-prolonging adenosine within the HF epithelium. Therefore, CD73 deserves to be explored as a novel therapeutic target in the management of human hair growth disorders, e.g. by the topical administration of CD73 inhibitors as candidate anti-hirsutism agents. 218 Chemokine receptor CCR5 is the novel target for the treatment of alopecia areata T Ito, T Suzuki, A Funakoshi, T Fujiyama and Y Tokura 1 Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan and 2 Dermatology, Fujinomiya City General Hospital, Fujinomiya, Japan Alopecia areata (AA) is an organ-specific autoimmune disease with cell-mediated autoimmune reactions. T lymphocytes densely surround hair bulbs in the lesion of acute-phase AA, referred to as “swarm of bees”. The pathological mechanisms of “swarm of bees”, can be induced by the upregulation of Th1 chemokine expression from hair follicles that result in the resultant infiltration of CXCR3 and CCR5 Th1 or Tc1 cells into AA lesions. Here, C3H/HeJ mice with AA were treated with CCR5 inhibitor, Maraviroc, that is HIV drug by negative allosteric modulator of the CCR5 receptor. Specifically, maraviroc is a negative allosteric modulator of the CCR5 receptor. At first, AA lesions were experimentally induced in C3H/HeJ by subcutaneous injection of T cells that were derived from LNs of AA-bearing syngeneic mice and stimulated IL-2, IL-7, and IL-15. Then, maraviroc is orally administrated. Interestingly, 4/5 maraviroc-treated C3H/HeJ mice with AA showed improvement of hair loss lesions after 2 weeks. Immunohistological assessments revealed decreased number of CD4CCR5 and CD8CCR5 T cells in the lesions after maraviroc treatment. Furthermore, FACS analysis also supports revealed the reduced frequency of CD4CCR5 T cells in skin-infiltrating cells. Next, CD4+ T cells from LN cells were incubated with 0, 1 and 10 mM maraviroc for 8 hours. Then, chemotactic activity was analyzed by EZTaxiscan. Interestingly, the significant inhibition of the velocity of CD4 LN cells toward RANTES by maraviroc was found compared to PBS-treated LN cells. Mean intensity of CCR5 was slightly downregulated by maraviroc treatments in CD4 T cells. In conclusion, inhibition of chemokine receptors/chemokines can be the novel target for the treatment of AA. 219 STAT5 activation in the dermal papilla is important for hair follicle growth phase induction, hair follicle regeneration and wound healing J Legrand, R Villani, E Roy and K Khosrotehrani Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia Hair follicles are skin appendages that undergo periods of growth (anagen), regression (catagen) and rest (telogen), regulated by their mesenchymal component, the dermal papilla (DP). Based on reports of its specific expression in the DP, we investigated STAT5 activation during hair development and cycling. STAT5 activation in the DP began in late catagen, reaching a peak in early anagen before disappearing for the rest of the cycle. This was confirmed by the expression profile of SOCS2, a STAT5 target in the DP. This pattern of expression starts after the first postnatal hair cycle. In order to conditionally ablate STAT5A and B in the DP, we used Sox18Cre/ER mice. Indeed Sox18 was expressed in developing dermal placodes for all three hair waves at E14.5, E16.5 and E18.5. Its expression post-natally was associated with zigzag hairs only. Remarkably dominant negative loss of function mutants of Sox18 did not display any Auchene or zigzag hair. Quantification of hair cycling using the Flash canonical Wnt signalling in vivo bioluminescence reporter found that conditional knockout of STAT5A/B in the DP targeted through Cre recombinase under the control of the Sox18 promoter induced at birth, resulted in delayed anagen entry compared to control. Of note, this method did not delete STAT5 in Sox2 expressing HFs. Microarray analysis of STAT5deletion versus control revealed key changes in TNFalpha, Wnt and FGF ligands, known for their role in inducing anagen entry. Pharmacological inhibition of Jak1-2 did not alter STAT5 activation in the DP. Finally, the use of DP spheroids with active STAT5 resulted in more robust hair follicle regeneration in patch assays and more robust engraftment and acceleration of wound healing in vivo. We conclude that STAT5 activation acts as a mesenchymal switch to trigger natural anagen entry in post-developmental hair follicle cycling.

The magnetic hyperfine fields at Br and Kr nuclei in nickel have been measured by heavy ion implantation techniques. Extrapolating to 0 K, H = −0.7(1) T is obtained for Kr and H = +8.0(1) T for Br, in qualitative agreement with theoretical values. The temperature dependences deviate strongly from that of the lattice magnetization.

The most commonly used method for producing highly charged metal ion beams in ECRIS are 1) insertion techniques vapourizing the metal by the ECR-plasma, 2) oven techniques. A new method using volatile, in most cases organic metal compounds as a starting material was developed by Arje et al. [1]. Due to its high vapour pressure the metal compound evaporates and diffuses into the plasma chamber where it dissociates. With the help of this technique ion beams of several transition metals were produced. At the same time charged fragments of the residual organic molecule were obtained. It turned out that this method is a powerful tool to produce stable and reliable metal ion beams with a high yield. Typical spectra of charge states of ions of some transition metals taken at the 14.5 GHz ECRIS at the HMI Berlin are shown. The achieved ion yield is given and the advantages compared to the “classical” methods are presented.

This study was conducted to assess the antimicrobial susceptibility rate of Salmonella and Campylobacter spp. isolated from Northern German fattening pigs. From 540 lymph node samples, 16 Salmonella Typhimurium, 1 Salmonella Brandenburg, 37 Campylobacter coli, and 11 Campylobacter jejuni strains were isolated. Antibiotic susceptibility testing was carried out by the broth dilution method. The 14 tested antibiotics for Salmonella were ampicillin, cefotaxime, ceftazidime, chloramphenicol, ciprofloxacin, colistin, florfenicol, gentamicin, kanamycin, nalidixic acid, streptomycin, sulfamethoxazole, tetracycline, and trimethoprim. The eight tested antibiotics for Campylobacter spp. were ampicillin, ampicillin-sulbactam (2:1), ciprofloxacin, erythromycin, gentamicin, nalidixic acid, sulfamethoxazole-trimethoprim (1:19), and tetracycline. In total, 93.7% (n = 16) of Salmonella Typhimurium, 75.7% (n = 37) of C. coli, and 54.5% (n = 11) of C. jejuni isolates were resistant to at least one of the tested antibiotics. Multiresistance to three antibiotics was observed in 75% of Salmonella Typhimurium, 16.2% of C. coli, and 0% of C. jejuni isolates. Pansusceptibility was detected in 6.3% of Salmonella Typhimurium, 24.3% of C. coli, and 45.5% of C. jejuni isolates. Multiresistance is defined as resistance to three or more antibiotics, and pansusceptibility is defined as not having resistance to any antibiotic. Regarding drugs of last resort--cefotaxime, ciprofloxacin, and nalidixic acid--resistance was not common among Salmonella (6.3%). The resistance rate of Campylobacter spp. to last-resort drugs--erythromycin, ciprofloxacin, and nalidixic acid--varied between species. The observed trend was not statistically significant. No C. coli isolates and few C. jejuni isolates (9.1%) were resistant to erythromycin. In contrast to C. jejuni, the C. coli isolates were more likely to be resistant to ciprofloxacin (9.1 and 18.9%, respectively) and nalidixic acid (0 and 13.5%, respectively). The same phenomenon was detected for tetracycline (27.3 and 62.2%, respectively), sulfamethoxazole (9.1 and 43.2%, respectively), and ampicillin (9.1 and 21.6%, respectively).

In 1890 it was shown that resistance to diphtheria toxin could be transferred from one animal to another by transfer of serum (1). From this discovery, passive antibody therapy was developed as an effective treatment for infectious diseases and for neutralization of toxins, and continues to be used to this day. Meanwhile, there have been continued efforts to use antibodies for cancer therapy, starting with the pioneering work of Hericourt and Richet in 1895 (2), which was the forerunner of the "magic bullet" concept. However, all of the early work on tumor therapy led ultimately to disappointment (3). The problems were readily acknowledged, i.e., lack of specificity and reproducibility, lack of purity, and the xenogeneic immune response. Developments over the past 20 years, as described throughout this book, have effectively overcome all of these technical problems, often in very ingenious ways. The difficulty we have now is different. There are just too many potential new antibody-based treatments for them all to be properly evaluated in the clinic. Many will still fail because of factors that are hard to predict from experiments: unexpected toxicity, biological heterogeneity of the target disease, or lack of access to the appropriate tissue.

Prospects for the Application of Antibodies in Medicine.

In veterinary medicine computed tomography (CT) imaging has gained importance in recent years, especially for diagnostics in pets, but also during the course of experimental studies in animal models for human medicine. In this study the applicability of CT as an imaging method for the depiction of the porcine thorax and in particular of the pig lung was evaluated.CT examinations were performed with 11 healthy pigs of two age groups. For evaluation, CT findings were related to clinical, radiological, macroscopical, microscopical, and microbiological findings.Clinically relevant anatomical structures were determined and recorded using transverse slices. In ventral recumbency, lung parenchyma density measurements at the levels of the second, fourth and seventh thoracic vertebrae resulted in significantly higher densities of the ventral in comparison to those of the dorsal lung quadrants.Computed tomography is a valuable tool for the high-contrast depiction of the porcine lung without superposition. In future studies this CT reference base for unaltered pig lungs may facilitate the identification of anatomical structures within the porcine lung as well as the assessment of pathological lung alterations.

Perturbed angular distribution (PAD) measurements were performed on Zn 1− x Mn x S ( x = 0.05, 0.06, 0.10, 0.18, 0.21 and 0.23). In our PAD experiments recoil-implanted 54 Fe ions were used as nuclear probes. By the local magnetic behaviour of the isolated 54 Fe nuclei we obtained information on the probe environment. The crystal having the lowest manganese concentration ( x =0.05) shows only one hyperfine component. The temperature dependence of this component is the same as in that case of pure ZnS. For samples with concentrations x ⪖0.06 two additional hyperfine components are observed. One of them is attributed to β- or γ-MnS clusters, respectively. The other additional component occurs for crystals having Mn-concentrations x ⪖0.10. The behaviour of this component is similar to the one observed with pure α-MnS. From our data we conclude that the additional components observed with Mn concentrations x ⪖0.06 are due to the formation of different types of MnS clusters. Our experimental findings are compared with the data of magnetic susceptibility, photoluminescence and EPR.

The local magnetic behaviours of isolated Fe and Ni impurities in the II-VI semiconductors ZnS and ZnTe have been studied directly after recoil implantation. From the measured magnetic properties, ...

Perturbed angular distribution experiments on19F implanted into fullerites revealed a large fraction of fluorine atoms which are not subject to static quadrupole interactions in contrast to other allotropic forms of carbon.

A study to determine the occurrence of pathogenic Yersinia enterocolitica on surfaces of slaughtered pig livers and the antimicrobial resistant pattern of the isolates was carried out in a slaughterhouse in Lower Saxony, Germany. During the slaughtering process, 1,500 surfaces of pig livers from 50 fattening herds were swabbed in order to isolate and characterize Y. enterocolitica isolates by serotyping, detecting the virulence plasmid coding the yopT gene, and resistance testing. Of the livers tested, 4.7% were positive for Y. enterocolitica O:3, which was the only identified serotype. The virulence gene yopT was found in 90.0% of these isolates. Antimicrobial susceptibility was tested by the broth dilution method, and the MICs were determined for 13 antimicrobials. All isolates were resistant to ampicillin and sulfamethoxazole but were susceptible to ciprofloxacin, nalidixic acid, gentamicin, ceftiofur, tetracycline, kanamycin, cefotaxime, and chlorphenicol. Up to now, resistance to florfenicol has always been described in combination with resistance to chloramphenicol. In the present study, 15.3% of the isolates were resistant to florfenicol, while no chloramphenicol-resistant strains could be identified. Multiresistance to three or more antimicrobials was detected in 22 strains (27.3%). Nevertheless, third-generation cephalosporines or fluoroquinolones, which were recommended for extraintestinal Y. enterocolitica infection in humans, were not affected.