Optimization of 68Ga production at an 18 MeV medical cyclotron with solid targets by means of cross-section measurement of 66Ga, 67Ga and 68Ga.

The future development of personalized nuclear medicine relies on the availability of novel medical radionuclides. In particular, radiometals are attracting considerable interest since they can be used to label both proteins and peptides. Among them, the ß+-emitter 68Ga is widely used in nuclear medicine for positron emission tomography (PET). It is used in theranostics as the diagnostic partner of the therapeutic ß--emitters 177Lu and 90Y for the treatment of a wide range of diseases, including prostate cancer. Currently, 68Ga is usually obtained via 68Ge/68Ga generators. However, their availability, high price and limited produced radioactivity per elution are a major barrier for a wider use of the 68Ga-based diagnostic radiotracers. A promising solution is the production of 68Ga by means of proton irradiation of enriched 68Zn liquid or solid targets. Along this line, a research program is ongoing at the Bern medical cyclotron, equipped with a solid target station. In this paper, we report on the measurements of 68Ga, 67Ga and 66Ga production cross-sections using natural Zn and enriched 68Zn material, which served as the basis to perform optimized 68Ga production tests with enriched 68Zn solid targets.

Antimicrobial susceptibility in E. coli and Pasteurellaceae at the beginning and at the end of the fattening process in veal calves: Comparing 'outdoor veal calf' and conventional operations.

Animal husbandry requires practical measures to limit antimicrobial resistance (AMR). Therefore, a novel management and housing concept for veal calf fattening was implemented on 19 intervention farms (IF) and evaluated regarding its effects on AMR in Escherichia (E.) coli, Pasteurella (P.) multocida and Mannheimia (M.) haemolytica in comparison with 19 conventional control farms (CF). Treatment intensity (-80%) and mortality (-50%) were significantly lower in IF than in CF, however, production parameters did not differ significantly between groups. Rectal and nasopharyngeal swabs were taken at the beginning and the end of the fattening period. Susceptibility testing by determination of the minimum inhibitory concentration was performed on 5420 isolates. The presence of AMR was described as prevalence of resistant isolates (%), by calculating the Antimicrobial Resistance Index (ARI: number of resistance of one isolate to single drugs/total number of drugs tested), by the occurrence of pansusceptible isolates (susceptible to all tested drugs, ARI=0), and by calculating the prevalence of multidrug (≥3) resistant isolates (MDR). Before slaughter, odds for carrying pansusceptible E. coli were higher in IF than in CF (+65%, p=0.022), whereas ARI was lower (-16%, p=0.003), and MDR isolates were less prevalent (-65%, p=0.001). For P. multocida, odds for carrying pansusceptible isolates were higher in IF before slaughter compared to CF (+990%, p=0.009). No differences between IF and CF were seen regarding the prevalence of pansuceptible M. haemolytica. These findings indicate that easy-to-implement measures to improve calf management can lead to a limitation of AMR in Swiss veal fattening farms.

Effects of the novel concept 'outdoor veal calf' on antimicrobial use, mortality and weight gain in Switzerland.

The aim of the intervention study 'outdoor veal calf' was to evaluate a novel concept for calf fattening which aimed at reducing antimicrobial use without compromising animal health. Management practices such as commingling of calves from multiple birth farms, crowding, and suboptimal barn climate are responsible for high antimicrobial use and mortality in the veal calf population. The risk of selecting bacteria resistant to antimicrobials and of economic losses is accordingly elevated. The 'outdoor veal calf' concept, implemented in nineteen intervention farms (IF), is based on three main measures: 1. purchased calves are transported directly from neighboring birth farms to the fattening facility instead of commingling calves in livestock dealer trucks; 2. each calf is vaccinated against pneumonia after arrival and completes a three-week quarantine in an individual hutch; and 3. the calves spend the rest of the fattening period in outdoor hutches in groups not exceeding 10 calves. The covered and bedded paddock and the group hutches provide shelter from cold weather and direct sunshine, constant access to fresh air is warranted. Nineteen conventional calf fattening operations of similar size served as controls (CF). Every farm was visited once a month for a one-year period, and data regarding animal health, treatments, and production parameters were collected. Treatment intensity was assessed by use of the defined daily dose method (TIDDD in days per animal year), and calf mortality and daily weight gain were recorded in both farm groups. Mean TIDDD was 5.3-fold lower in IF compared to CF (5.9 ±â€¯6.5 vs. 31.5 ±â€¯27.4 days per animal year; p < 0.001). Mortality was 2.1-fold lower in IF than in CF (3.1% ± 2.3 vs. 6.3 % ± 4.9; p = 0.020). Average daily gain did not differ between groups (1.29 ±â€¯0.17 kg/day in IF vs. 1.35 ±â€¯0.16 kg/day in CF; p = 0.244). A drastic reduction in antimicrobial use and mortality was achieved in the novel 'outdoor veal calf' system without compromising animal health. The principles of risk reduction used in designing the system can be used to improve management and animal health, decrease the need for antimicrobial treatments and thus selection pressure on bacteria in veal operations.

Antibiotic and quaternary ammonium compound resistance in Escherichia coli from calves at the beginning of the -fattening period in Switzerland (2017).

INTRODUCTION: In the Swiss veal calf production, antimicrobials and disinfectants are used to control bacterial infectious diseases, leading to a risk of selecting for a resistant bacterial population. While the prevalence of antibiotic resistance in E. coli from calves has been monitored at slaughterhouses in Switzerland since 2006, the resistance situation of E. coli from young calves entering the fattening period is not known. A total of 100 calves entering the fattening period in 20 geographically distant farms in Switzerland were screened for the presence of E. coli using rectal swabs in 2017. Genetic diversity between isolates was determined using repetitive palindromic Polymerase Chain Reaction (rep-PCR) revealing a genetically diverse E. coli population. Susceptibility to 13 antibiotics and to alkyldimethylbenzylammonium (ADBAC) was determined by the measurement of the minimal inhibitory concentration. Antibiotic and quaternary ammonium compound (QAC) resistance genes were identified using microarray and Polymerase Chain Reaction (PCR). Sixty-four percent of the isolates were resistant to at least one antibiotic, and 52% also exhibited decreased susceptibility to ADBAC. Resistance to more than 3 antibiotics was found in 40% of the isolates. Isolates exhibited resistance to tetracycline (57%) associated with the presence of tet genes (tet(A), (B), (E), (G)), to sulfonamides (61%) (sul1, sul2, sul3), ampicillin (56%) (blaTEM-1), trimethoprim (32%) (dfrA), phenicols (31%) (catA1, cmlA1, floR), gentamicin (27%) (ant(2")-Ia, aac(3)-IVa, aac(3)-VIa), and cefotaxime (2%) (blaCTX-M-14 (ESBL)). Mutations in GyrA (S83L) and ParC (S80I) were found in the fluoroquinolone-resistant isolates (6%). All isolates were susceptible to colistin, tigecycline and meropenem. No association between the presence of decreased susceptibility to ADBAC and qac genes was observed. In conclusion, antibiotic and QAC resistant E. coli are present in the gastrointestinal tract of young calves at the beginning of the fattening period, emphasizing the need for appropriate and reduced use of antibiotics and QAC-containing disinfectants in order to limit further selection of these bacteria during the fattening period.

INTRODUCTION: Dans la production de veaux en Suisses, des antimicrobiens et des désinfectants sont utilisés pour contrôler les maladies infectieuses bactériennes, ce qui entraîne un risque de sélection d'une population bactérienne résistante. Si la prévalence de la résistance de E. coli aux antibiotiques chez les veaux est surveillée dans les abattoirs suisses depuis 2006, la situation de la résistance de E. coli chez les jeunes veaux au début de la période d'engraissement n'est pas connue. Un total de 100 veaux entrant dans la période d'engraissement dans 20 exploitations géographiquement éloignées de Suisse ont été testés en 2017 pour détecter la présence de E. Coli à l'aide de prélèvements rectaux. La diversité génétique entre les isolats a été déterminée à l'aide de la réaction de polymérase en chaîne répétitive palindrome (rep-PCR) révélant une population de E.coli génétiquement diversifié. La sensibilité à 13 antibiotiques et au chlorure d'alkyldiméthylbenzylammonium (ADBAC) a été déterminée par la mesure de la concentration inhibitrice minimale. Les gènes de résistance aux antibiotiques et aux composés d'ammonium quaternaire (QAC) ont été identifiés à l'aide d'une puce à ADN et de la réaction de polymérase en chaîne (PCR). Soixante-quatre pour cent des isolats étaient résistants à au moins un antibiotique et 52% présentaient également une diminution de la sensibilité à l'ADBAC. Une résistance à plus de 3 antibiotiques a été trouvée dans 40% des isolats. Les isolats présentaient une résistance à la tétracycline (57%) associée à la présence de gènes tet (tet (A), (B), (E), (G)), aux sulfonamides (61%) (sul1, sul2, sul3), à l'ampicilline (56%) (blaTEM-1), au triméthoprime (32%) (dfrA), aux phénicols (31%) (catA1, cmlA1, floR), à la gentamicine (27%) (ant(2'')-Ia, aac (3) -IVa, aac (3) -VIa) et à la céfotaxime (2%) (blaCTX-M-14 (BLSE)). Les isolats résistants aux fluoroquinolones (6%) présentaient des mutations dans GyrA (S83L) et ParC (S80I). Tous les isolats étaient sensibles à la colistine, à la tigécycline et au méropénème. Aucune association entre la présence d'une sensibilité diminuée à l'ADBAC et les gènes qac n'a été observée. En conclusion, des E. coli résistants aux antibiotiques et aux QAC sont présents dans le tractus gastro-intestinal des jeunes veaux au début de la période d'engraissement, ce qui souligne la nécessité d'un usage approprié et réduit d'antibiotiques et de désinfectants contenant un QAC afin de limiter la sélection ultérieure de ces bactéries au cours de la période d'engraissement.

First clinical case of KPC-3-producing Klebsiella michiganensis in Europe.

Klebsiella michiganensis is a newly emerging human pathogen. We describe a case of bloodstream infection in an immunocompromised patient. The pathogen was repeatedly isolated from blood and one rectal swab, and was identified using routine standard procedures. Further investigations revealed that the K. michiganensis was multidrug resistant, carrying a plasmid harbouring a Klebsiella pneumoniae carbapenemase (KPC)-3 carbapenemase gene. This plasmid has been frequently encountered in K. pneumoniae isolates in Europe but has never been described in K. michiganensis.

Three alternative promoters of the rat gamma-glutamyl transferase gene are active in developing lung and are differentially regulated by oxygen after birth.

The rat gamma-glutamyl transferase mRNA transcripts I, II, and III are derived from three alternative promoters, P(I), P(II), and P(III). In the adult only mRNA III is expressed in the lung. We show that mRNA III gene expression is developmentally regulated in the fetal lung; it is first expressed in gestation. In contrast to the adult lung, the fetal lung expresses mRNA I, II, and III. The switch from the fetal to the adult pattern of gammaGT mRNA expression begins within the first 24 h of birth and is complete by 10 d of age. gammaGT mRNA II disappears within 24 h, mRNA I disappears by 10 d leaving mRNA III as the sole transcript. Alveolar epithelial type 2 cells (AT2) isolated from the adult lung express only mRNA III. When cultured in 21% O2 mRNA III is maintained, but when cultured in 3% O2 the fetal pattern of mRNA I, II and III expression is induced. When AT2 cells in hypoxia are exposed to carbon monoxide, mRNA II is suppressed suggesting that a heme-binding protein (responsive to oxygen) may suppress mRNA II expression and may be responsible for the decrease in lung mRNA II seen after birth. A reporter gene under the control of DNA sequences from the gammaGT P(III) promoter is activated in transient transfection studies in response to hyperoxia, while a deletion construct retaining an antioxidant responsive element is not. Oxygen appears to regulate each of the alternative promoters of the gammaGT gene, such that P(II) is rapidly repressed by a heme-dependent mechanism, P(I), is more gradually repressed by a nonheme mechanism and P(III) is activated by a putative oxygen response element. We hypothesize that similar oxygen-dependent mechanisms regulate other genes in the developing lung at birth.

Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia.

Vascular smooth muscle cell (VSMC) proliferation and migration are responses to arterial injury that are highly important to the processes of restenosis and atherosclerosis. In the arterial balloon injury model in the rat, platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) are induced in the vessel wall and regulate these VSMC activities. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit insulin and epidermal growth factor-induced growth of VSMCs. We hypothesized that these agents might also inhibit the effect of PDGF and bFGF on cultured VSMCs and intimal hyperplasia in vivo. Troglitazone (1 microM), a member of the thiazolidinedione class, produced a near complete inhibition of both bFGF-induced DNA synthesis as measured by bromodeoxyuridine incorporation (6.5+/-3.9 vs. 17.6+/-4.3% cells labeled, P < 0.05) and c-fos induction. This effect was associated with an inhibition (by 73+/-4%, P < 0.01) by troglitazone of the transactivation of the serum response element, which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via a blockade of the MAP kinase pathway at a point downstream of MAP kinase activation by MAP kinase kinase. At this dose, troglitazone also inhibited PDGF-BB-directed migration of VSMC (by 70+/-6%, P < 0.01). These in vitro effects were operative in vivo. Quantitative image analysis revealed that troglitazone-treated rats had 62% (P < 0.001) less neointima/media area ratio 14 d after balloon injury of the aorta compared with injured rats that received no troglitazone. These results suggest troglitazone is a potent inhibitor of VSMC proliferation and migration and, thus, may be a useful agent to prevent restenosis and possibly atherosclerosis.

A microcomputer-based device to simulate biomechanical environments for cultured cells.

We describe software and hardware for a microcomputer-based cyclic strain device which applies programmed cycles of elongation and relaxation to cultured cells. This system has the potential to simulate many of the complex mechanically active environments found in living systems. As a sample application, we use it to simulate the cyclic stresses to which vascular smooth muscle cells in the arterial system are exposed.

[Fulminant purpura in Still's disease and bacteremia with Xanthomonas maltophilia and coagulase-negative staphylococci]. / Purpura fulminans bei Morbus Still und Bakteriämie mit Xanthomonas maltophilia und koagulasenegativen Staphylokokken.

We describe the case of a 31-year-old man with a long history of juvenile rheumatoid arthritis who was admitted to the hospital because of painful purple skin lesions on hands and feet. On admission he presented the classical picture of "purpura fulminans" with extensive acrocyanosis and large blisters on the lower limbs which evolved into symmetrical peripheral gangrene. Laboratory findings revealed activated intravascular coagulation and bacteremia with coagulase-negative staphylococci and Xanthomonas maltophilia which was thought to be catheter-related. His condition improved markedly under therapy with antibiotics, intravenous heparin, iloprost and intensive local debridement including amputation of several toes. Coagulation studies two months after the acute phase of the disease revealed chronic activated coagulation with a significant protein S deficiency. Clinical findings, etiology, significance of impaired coagulation and therapeutic action in "purpura fulminans" are discussed.

Increased expression of Axl tyrosine kinase after vascular injury and regulation by G protein-coupled receptor agonists in rats.

Axl is a receptor tyrosine kinase originally identified as a transforming gene product in human myeloid leukemia cells. Cultured rat vascular smooth muscle cells also express Axl, where it has been proposed that Axl may play a role in cell proliferation. In the current study, we tested the hypotheses that Axl expression would parallel neointima formation in balloon-injured rat carotid, and that Axl expression would be regulated by growth factors present at sites of vascular injury. Ribonuclease protection assay showed dynamic increases in Axl mRNA in vessels, with peak expression 7 and 14 days after injury. Immunohistochemical analysis confirmed these results and demonstrated that Axl protein expression was localized primarily to cells of the neointima after injury. Northern blot analysis indicated increased mRNA expression for the secreted Axl ligand, Gas6, in injured carotids, with a time course paralleling that of Axl upregulation. Axl and Gas6 expression were temporally correlated with neointima formation, suggesting a role for Axl signaling in this process. Other studies, performed in cultured rat vascular smooth muscle cells, revealed positive regulation of Axl mRNA expression by thrombin or angiotensin II but not by basic fibroblast growth factor, platelet-derived growth factor-BB, or transforming growth factor-ss1. Western blot analysis confirmed these results, showing that Axl protein expression was specifically increased by thrombin or angiotensin II. Our results implicate Axl as a potential mediator of vascular smooth muscle migration and proliferation caused by vascular injury and G protein-coupled receptor agonists.