Quantum Critical Point in the Itinerant Ferromagnet Ni_{1-x}Rh_{x}.

We report a chemical substitution-induced ferromagnetic quantum critical point in polycrystalline Ni_{1-x}Rh_{x} alloys. Through magnetization and muon spin relaxation measurements, we show that the ferromagnetic ordering temperature is suppressed continuously to zero at x_{crit}=0.375 while the magnetic volume fraction remains 100% up to x_{crit}, pointing to a second order transition. Non-Fermi liquid behavior is observed close to x_{crit}, where the electronic specific heat C_{el}/T diverges logarithmically, while immediately above x_{crit} the volume thermal expansion coefficient α_{V}/T and the Grüneisen ratio Γ=α_{V}/C_{el} both diverge logarithmically in the low temperature limit, further indication of a ferromagnetic quantum critical point in Ni_{1-x}Rh_{x}.

Detection of invasive pulmonary aspergillosis in critically ill patients by combined use of conventional culture, galactomannan, 1-3-beta-D-glucan and Aspergillus specific nested polymerase chain reaction in a prospective pilot study.

Invasive pulmonary aspergillosis (IPA) is an emerging and life-threatening infectious disease in patients admitted to the intensive care unit (ICU). Most diagnostic studies are conducted in hematological patients and results cannot readily be transferred to ICU patients lacking classical host factors. In a multicenter, prospective clinical trial including 44 ICU patients, hematological (n = 14) and non-hematological patients (n = 30), concurrent serum and bronchoalveolar lavage (BAL) samples were analyzed by conventional culture, galactomannan (GM), 1-3-beta-D-glucan (BDG) as well as an Aspergillus specific nested polymerase chain reaction (PCR). Nine patients (20%) had putative IPA according to AspICU classification. GM and PCR showed superior performance in BAL with sensitivity/specificity of 56%/94% and 44%/94% compared to 33%/97% and 11%/94% in serum. Despite better sensitivity of 89%, BDG showed poor specificity of only 31% (BAL) and 26% (serum). Combination of GM and PCR (BAL) with BDG (serum) resulted in 100% sensitivity, but also reduced specificity to 23%. Whereas mean GM levels were significantly higher in hematological patients BDG and PCR did not differ between hematological and non-hematological patients. Under present clinical conditions test combinations integrating both BAL and blood samples are advantageous. BDG might best serve as possible indicator for ruling out IPA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01695499. First posted: September 28, 2012, last update posted: May 8, 2017.

Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants.

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Diagnosis of invasive fungal infections in haematological patients by combined use of galactomannan, 1,3-ß-D-glucan, Aspergillus PCR, multifungal DNA-microarray, and Aspergillus azole resistance PCRs in blood and bronchoalveolar lavage samples: results of a prospective multicentre study.

High mortality rates of invasive fungal disease (IFD), especially invasive aspergillosis (IA), in immunocompromised haematological patients and current diagnostic limitations require improvement of detection of fungal pathogens by defining the optimal use of biomarkers and clinical samples. Concurrent bronchoalveolar lavage (BAL) and peripheral blood samples of 99 haematological patients with suspected IFD were investigated within a multicentre prospective study. Diagnostic performance of a galactomannan (GM) enzyme immune assay (EIA), a 1,3-ß-D-glucan assay (BDG), an Aspergillus PCR, and a multifungal DNA-microarray (Chip) alone or in combination were calculated. IFD were classified as proven (n=3), probable (n=34), possible (n=33), and no IFD (n=29) according to EORTC/MSG criteria. GM, PCR, and Chip showed superior diagnostic performance in BAL than in blood, whereas specificity of BDG in BAL was poor (48% (14/29)). The combination of GM (BAL) with BDG (blood) showed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and DOR (diagnostic odds ratio) of 92% (34/37), 93% (27/29), 94%, 90%, and 153.0, respectively. Combining GM (BAL) with PCR (BAL) showed convincing diagnostic potential for diagnosing IA with sensitivity, specificity, PPV, NPV, and DOR of 85% (17/20), 97% (28/29), 94%, 90%, and 158.7. Addition of the DNA-microarray resulted in further detection of two mucormycetes infections. In 1 out of 15 Aspergillus DNA-positive samples a triazole resistance-mediating Cyp51A mutation was found. Combination of biomarkers is superior to their sole use in diagnosing IFD, particularly IA. Integrating blood and BAL samples into a diagnostic algorithm is an advantageous approach.

Identification of invasive fungal diseases in immunocompromised patients by combining an Aspergillus specific PCR with a multifungal DNA-microarray from primary clinical samples.

The increasing incidence of invasive fungal diseases (IFD), most of all invasive aspergillosis (IA) in immunocompromised patients emphasises the need to improve the diagnostic tools for detection of fungal pathogens. We investigated the diagnostic performance of a multifungal DNA-microarray detecting 15 different fungi [Aspergillus, Candida, Fusarium, Mucor, Rhizopus, Scedosporium and Trichosporon species (spp.)] in addition to an Aspergillus specific polymerase chain reaction (PCR) assay. Biopsies, bronchoalveolar lavage and peripheral blood samples of 133 immunocompromised patients (pts) were investigated by a multifungal DNA-microarray as well as a nested Aspergillus specific PCR assay. Patients had proven (n = 18), probable (n = 29), possible (n = 48) and no IFD (n = 38) and were mostly under antifungal therapy at the time of sampling. The results were compared to culture, histopathology, imaging and serology, respectively. For the non-Aspergillus IFD the microarray analysis yielded in all samples a sensitivity of 64% and a specificity of 80%. Best results for the detection of all IFD were achieved by combining DNA-microarray and Aspergillus specific PCR in biopsy samples (sensitivity 79%; specificity 71%). The molecular assays in combination identify genomic DNA of fungal pathogens and may improve identification of causative pathogens of IFD and help overcoming the diagnostic uncertainty of culture and/or histopathology findings, even during antifungal therapy.

Early hemostatic responses to trauma identified with hierarchical clustering analysis.

BACKGROUND: Trauma-induced coagulopathy is a complex multifactorial hemostatic response that is poorly understood. OBJECTIVES: To identify distinct hemostatic responses to trauma and identify key components of the hemostatic system that vary between responses. PATIENTS/METHODS: A cross-sectional observational study of adult trauma patients at an urban level I trauma center emergency department was performed. Hierarchical clustering analysis was used to identify distinct clusters of similar subjects according to vital signs, injury/shock severity, and comprehensive assessment of coagulation, clot formation, platelet function, and thrombin generation. RESULTS: Among 84 total trauma patients included in the model, three distinct trauma clusters were identified. Cluster 1 (N = 57) showed platelet activation, preserved peak thrombin generation, plasma coagulation dysfunction, a moderately decreased fibrinogen concentration and normal clot formation relative to healthy controls. Cluster 2 (N = 18) showed platelet activation, preserved peak thrombin generation, and a preserved fibrinogen concentration with normal clot formation. Cluster 3 (N = 9) was the most severely injured and shocked, and showed a strong inflammatory and bleeding phenotype. Platelet dysfunction, thrombin inhibition, plasma coagulation dysfunction and a decreased fibrinogen concentration were present in this cluster. Fibrinolytic activation was present in all clusters, but was particularly increased in cluster 3. Trauma clusters were most noticeably different in their relative fibrinogen concentration, peak thrombin generation, and platelet-induced clot contraction. CONCLUSIONS: Hierarchical clustering analysis identified three distinct hemostatic responses to trauma. Further insights into the underlying hemostatic mechanisms responsible for these responses are needed.

Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany.

OBJECTIVES: Aspergillus fumigatus is the most common agent of invasive aspergillosis (IA). In recent years, resistance to triazoles, the mainstay of IA therapy, has emerged in different countries worldwide. IA caused by azole-resistant A. fumigatus (ARAF) shows an exceedingly high mortality. In this study, IA due to ARAF isolates in HSCT recipients in Germany was investigated. METHODS: The epidemiology of azole resistance in IA was analysed in two German haematology departments. Between 2012 and 2013, 762 patients received HSCT in Essen (n = 388) and Cologne (n = 374). Susceptibility testing of A. fumigatus isolates was performed by Etest, followed by EUCAST broth microdilution testing if elevated MICs were recorded. In all ARAF isolates the cyp51A gene was sequenced and the genotype was determined by microsatellite typing using nine short tandem repeats. RESULTS: In total, A. fumigatus was recovered from 27 HSCT recipients. Eight patients had azole-resistant IA after HSCT, and seven of the cases were fatal (88%). All except one patient received antifungal prophylaxis (in five cases triazoles). TR34/L98H was the most common mutation (n = 5), followed by TR46/Y121F/T289A (n = 2). In one resistant isolate no cyp51A mutation was detected. Genotyping revealed genetic diversity within the German ARAF isolates and no clustering with resistant isolates from the Netherlands, India and France. CONCLUSIONS: This report highlights the emergence of azole-resistant IA with TR34/L98H and TR46/Y121F/T289A mutations in HSCT patients in Germany and underscores the need for systematic antifungal susceptibility testing of A. fumigatus.

Assessment of Aspergillus-specific PCR as a screening method for invasive aspergillosis in paediatric cancer patients and allogeneic haematopoietic stem cell recipients with suspected infections.

Invasive aspergillosis (IA) remains difficult to diagnose in immunocompromised patients, because diagnostic EORTC/MSG criteria are often not met. As biomarkers might elucidate the pathogen, we analysed the performance of an Aspergillus PCR assay in blood for diagnosis of IA in immunocompromised paediatric patients with suspected infections. Ninety-five haemato-oncological paediatric patients were included over a period of 3 years, the underlying diseases consisting of acute leukaemia, solid tumours, non-malignant immunocompromising disorders and haematopoietic stem cell transplantation recipients. We retrospectively analysed 253 consecutive episodes of suspected infections. Thirty-eight patients had possible IA, none of the patients fulfilled EORTC/MSG criteria of probable/proven IA. PCR positivity was observed in 97/967 analyses. Sensitivity, specificity, positive and negative predictive value of the PCR per episode were 34%, 78%, 31% and 81% using possible IA as endpoint. Taken together, an undirected blood screening by Aspergillus-specific PCR is of little diagnostic value in a heterogenous paediatric patient cohort. Harnessing PCR for diagnosis of IA should thus be focused on blood analyses of more homogenous high-risk patients and/or analyses of bronchoalveolar lavage, tissue or cerebrospinal fluid specimens.

Performance of galactomannan, beta-d-glucan, Aspergillus lateral-flow device, conventional culture, and PCR tests with bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis.

Galactomannan detection in bronchoalveolar lavage (BAL) fluid samples (GM test) is currently considered the gold standard test for diagnosing invasive pulmonary aspergillosis (IPA). The limitations, however, are the various turnaround times and availability of testing. We compared the performance of GM testing with that of conventional culture, an Aspergillus lateral-flow-device (LFD) test, a beta-d-glucan (BDG) test, and an Aspergillus PCR assay by using BAL fluid samples from immunocompromised patients. A total of 78 BAL fluid samples from 78 patients at risk for IPA (74 samples from Graz and 4 from Mannheim) collected between December 2012 and May 2013 at two university hospitals in Austria and Germany were included. Three patients had proven IPA, 14 probable IPA, and 17 possible IPA, and 44 patients had no IPA. The diagnostic accuracies of the different methods for probable/proven IPA were evaluated. The diagnostic odds ratios were the highest for the GM, PCR, and LFD tests. The sensitivities for the four methods (except culture) were between 70 and 88%. The combination of the GM (cutoff optical density index [ODI], >1.0) and LFD tests increased the sensitivity to 94%, while the combination of the GM test (>1.0) and PCR resulted in 100% sensitivity (specificity for probable/proven IPA, 95 to 98%). The performance of conventional culture was limited by low sensitivity, while that of the BDG test was limited by low specificity. We evaluated established and novel diagnostic methods for IPA and found that the Aspergillus PCR, LFD, and GM tests were the most useful methods for diagnosing the disease by using BAL fluid samples. In particular, the combination of the GM test and PCR or, if PCR is not available, the LFD test, allows for sensitive and specific diagnosis of IPA.

Aspergillus PCR-based investigation of fresh tissue and effusion samples in patients with suspected invasive Aspergillosis enhances diagnostic capabilities.

Although it is a severe complication in immunocompromised patients, diagnosing invasive fungal disease (IFD), especially invasive aspergillosis (IA), remains difficult. In certain clinical scenarios, examining tissue samples for identification of the infectious organism becomes important. As culture-based methods rarely yield results, the performance of an Aspergillus-specific nested PCR in fresh tissue or pleural effusion samples was evaluated. Fresh tissue (n = 59) and effusion (n = 47) specimens from 79 immunocompromised patients were subjected to an Aspergillus-specific PCR assay. Twenty-six patients had proven (n = 20) or probable (n = 6) IFD, according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria, while the remaining patients were classified as having either possible IFD (n = 30) or no IFD (n = 23). IA was identified as the underlying IFD in 21/26 proven/probable cases. PCR positivity was observed for 18/21 proven/probable and 6 possible IA cases; cases classified as no IA did not show positive signals. Patients with proven IFD (n = 5) with cultures positive for non-Aspergillus molds also had negative Aspergillus PCR results. Aspergillus PCR performance analysis yielded sensitivity and specificity values of 86% (95% confidence interval [CI], 65% to 95%) and 100% (95% CI, 86% to 100%), respectively, thus leading to a diagnostic odds ratio of >200. In this analysis, good diagnostic performance of the PCR assay for detection of IA was observed for tissue samples, while effusion samples showed lower sensitivity rates. PCR testing represents a complementary tool; a positive PCR result strengthens the likelihood of IA, whereas IA seems unlikely in cases with negative results but findings could indicate non-Aspergillus IFD. Thus, PCR testing of these specimens enhances the diagnostic capabilities.

Equine keratomycosis in Switzerland: a retrospective evaluation of 35 horses (January 2000-August 2011).

REASON FOR PERFORMING STUDY: Keratomycosis is a severe disease in horses. Geographical differences in fungi causing keratomycosis and susceptibility of the organisms to antifungal drugs exist but few previous publications on this disease originate from Europe. OBJECTIVE: To retrospectively compare the clinical data of 36 eyes with keratomycosis, diagnosed in 35 horses between January 2000 and August 2011 at the Vetsuisse Faculty of Switzerland. Case history, season, prior treatment, clinical appearance, surgical and medical treatment, treatment duration, and globe survival were evaluated. STUDY DESIGN: Retrospective case series. METHODS: Medical records of horses with a definitive cytological or histological diagnosis of keratomycosis were reviewed. RESULTS: Thirty-one of 36 eyes (86.1%) presented with ulcerative keratitis, 2/36 (5.55%) had diffuse corneal infiltration, 2/36 (5.55%) had superficial punctate keratitis and 1/36 (2.8%) had a fluorescein-negative fungal plaque. Two of 6 fungal cultures produced Aspergillus spp. Thirty eyes received medical and surgical treatment, while 3 eyes were treated medically only. In 3 horses the globe was removed at the time of first presentation. Sex, age, prior treatment with antimicrobials or steroids, or type of surgical approach did not significantly influence the outcome. Twenty-three of 36 eyes (63.9%) were at least partially visual, 11/36 eyes (30.5%) were enucleated and 2 horses (2/36 eyes, 5.6%) were subjected to euthanasia. Treatment protocols were compared in the 31 eyes with ulcerative keratitis. In this group, 3/31 globes were immediately enucleated, 16/31 eyes were treated topically with voriconazole or voriconazole/fluconazole and 12/31 with other antifungal drug combinations. The different medication protocols did not significantly affect the outcome. CONCLUSIONS: There were no significant differences in outcome between different medical treatment protocols or types of surgical approach. POTENTIAL RELEVANCE: Future studies in central Europe should focus on the identification of fungal pathogens, susceptibility patterns and the efficacy of antifungal drug therapies.

Azole-resistant invasive aspergillosis in a patient with acute myeloid leukaemia in Germany.

We report the first culture-proven case of invasive aspergillosis (IA) caused by azole-resistant Aspergillus fumigatus in a patient with acute myeloid leukaemia in Germany. IA presented as breakthrough infection under posaconazole prophylaxis. Analysis of the resistance mechanism revealed the TR/L98H mutation in the cyp51A gene, which indicates an environmental origin of the strain. This case underscores the need for monitoring azole resistance in Aspergillus spp. and for routine susceptibility testing of moulds.

Direct detection of Ehrlichia canis by PCR in the conjunctiva of a dog with bilateral anterior uveitis.

The following report describes the direct detection of Ehrlichia canis by real-time PCR in the conjunctiva of a 1-year-old female Maltese dog. After being imported from Brazil, the dog was presented because of anorexia, dehydration, fever, and palpable mandibular lymph nodes. A few days later, the dog developed bilateral blepharospasm, photophobia and anterior uveitis. Monocytic ehrlichia was diagnosed by a positive PCR result and the detection of IgM and IgG antibodies. Because of the massive uveitis a conjunctival sample was taken with a cytobrush, which also tested positive for Ehrlichia canis DNA by real-time PCR. Only one week after starting treatment with systemic doxycycline and local anti-inflammatory and cyclopalgic therapy the dog recovered from systemic and eye diseases. After therapy the follow-up examination revealed a full remission of clinical and hematological parameters and negative PCR result.

Bilateral congenital lacrimal fistula in a Brown Swiss bull.

A five-year-old Brown Swiss bull was referred to the Department of Farm Animals, University of Zurich, because of bilateral epiphora that was unresponsive to treatment. Clinical examination revealed a fistulous opening medial to the medial canthus of both eyes and mucopurulent discharge from both openings. Attempts to flush the nasolacrimal duct via the lacrimal points resulted in the fluid exiting via the fistulous opening. Retrograde flushing of the nasolacrimal duct from the nasolacrimal opening resulted in the flush fluid flowing back out the nasolacrimal opening. Bilateral lacrimal fistula medial to the medial canthus of the eye was diagnosed based on the findings. The same anomaly was diagnosed a year later in 4 related female animals referred to our Department for other reasons. Three of the cases were sired by the bull described above and one was sired by his half-brother. Therefore, an autosomal recessive mode of inheritance of this anomaly was assumed. Clinical, epidemiological and molecular studies of the offspring of both bulls are underway to further investigate this anomaly.

[Increased occurrence of nuclear cataract in the calf after erection of a mobile phone base station]. / Vermehrtes Auftreten von nukleärer Katarakt beim Kalb nach Erstellung einer Mobilfunkbasisstation.

We examined and monitored a dairy farm in which a large number of calves were born with nuclear cataracts after a mobile phone base station had been erected in the vicinity of the barn. Calves showed a 3.5 times higher risk for heavy cataract if born there compared to Swiss average. All usual causes such as infection or poisoning, common in Switzerland, could be excluded. The real cause of the increased incidence of cataracts remains unknown.

[Transportation of veal calves in Switzerland]. / Schlachtkälbertransporte in der Schweiz.

The analysis and optimization of transportation routes of calves to slaughterhouses by means of a GIS (geographical information system) route planning and time limitation software for the fleet management in transportation industry was performed. As basic data the farms (last locations of the calves) and the slaughterhouses were available in each case with addresses and coordinates. 150 data records from 258 veal calves could be evaluated. None of the calves was transported longer than 6 hours. Therefore, in all cases the Swiss law for animal protection was obeyed concerning maximum length of transportation time. In the road model, 82% of calves were transported too far.

[Hereditary eye dieseas in the Entlebucher Mountaindog in Switzerland: a retrospective study from 1999 to 2009]. / Vererbte Augenerkrankungen beim Entlebucher Sennenhund in der Schweiz: Eine Retrospektive Studie von 1999 bis 2009.

The aim of this study was to analyze the prevalence and the incidence of hereditary cataract and progressive retinal atrophy (PRA) in the Entlebucher Mountaindog (EMD) and to evaluate possible changes over time. In addition, the influence of selective breeding programs and DNA-testing for PRA was also investigated. Data of eye certifications for hereditary eye diseases was used. Between 1999 and 2009 a total of 798 ocular examinations were carried out in 285 EMD. 20.4 % had cataracts and 69 % of these were of the posterior polar type. PRA was diagnosed in 6.3 % of the dogs. Cataracts were diagnosed at 5.24 ± 2.71 years (mean ± standard error), while PRA was diagnosed at 4.93 ± 1.32 years of age. The incidence of PRA and cataract showed a decreasing trend (p-value > 0.2) without being significant.

Equine recurrent uveitis: the European viewpoint.

Equine recurrent uveitis (ERU) has always been and still is an important disease with a significant impact on the horse industry in Europe, with a prevalence of 8-10%. The need to understand and manage the disease has spurred the development of veterinary ophthalmology in general, although the aetiology of the disease remains the subject of intense discussion. It is most probably an autoimmune disease triggered, at least in Europe, in the majority of cases by Leptospira spp. The therapy of ERU has evolved over the centuries from various methods of bloodletting to rational medical therapy using mydriatics and steroidal and nonsteroidal anti-inflammatory drugs, to surgical therapies, such as vitrectomy or implantation of cyclosporin-releasing devices. In Europe, pars plana vitrectomy in horses testing positive for Leptospira spp. appears to be the most successful form of therapy at the present time.