[Ocular and non-ocular squamous cell carcinomas in the Haflinger: Eight cases at the Institut Suisse de Médecine Equine (2015-2022)]. / Okuläre und nicht-okuläre Platten­-epithel­karzinome beim Haflinger: Acht Fälle am Institut Suisse de Médecine Equine (2015­2022).

INTRODUCTION: This case series describes the clinical course of ocular and non-ocular squamous cell carinoma (SCC) in the Haflinger horse and is intended to raise awareness of the high recurrence rate and tendency to metastasize. Eight Haflingers with histologically confirmed SCC were included, five ocular and three non-ocular, who were presented at the Institut Suisse de Médecine Équine (ISME) Bern between July 2015 and January 2022. The ocular SCC cases were all presented because of an apparent mass, which in most cases was post-treatment recurrence. The occurrence of recurrences was observed between 3 weeks and 16 years after initial therapy. Four of five Haflingers with ocular SCC had an enucleation, three of which were clinically normal at the time of the completion of this study, one case was euthanized due to confirmed metastases and one due to lameness. The result of enucleations for therapy of ocular SCC was good if no metastases occurred. Of the three non-ocular SCC cases, only one case, a penile SCC, had an apparent mass. Therapy was initiated in this case, while the other two cases were euthanized shortly after diagnosis due to the poor prognosis of SCC in the appropriate locations (maxillary sinus, mandible). Metastases occurred three and two years after removal of the primary tumor in ocular SCC in the scapula, liver and lungs and in non-ocular SCC from the penis to the nostrils. Since a postmortem pathological examination was not carried out on all Haflingers, further metastases cannot be ruled out. Haflingers with SCC should be monitored by a veterinarian over the long term, as recurrences and/or metastases can still occur years later.

INTRODUCTION: Cette série de cas décrit l'évolution clinique des carcinomes épidermoïdes (CE) oculaires et non oculaires chez le cheval Haflinger et vise à faire prendre conscience du taux de récidive élevé et de la tendance à la formation de métastases. Huit Haflinger avec un CE confirmé histologiquement, cinq oculaires et trois non-oculaires, qui ont été présentés à l'Institut Suisse de Médecine Équine (ISME) Berne entre juillet 2015 et janvier 2022, ont été inclus. Les cas de CE oculaires ont tous été présentés en raison d'une masse apparente, qui dans la plupart des cas était une récidive post-traitement. La survenue des récidives a été observée entre 3 semaines et 16 ans après le traitement initial. Quatre des cinq Haflinger atteints de CE oculaire ont subi une énucléation, dont trois étaient cliniquement normaux au moment de l'achèvement de l'étude, un cas ayant été euthanasié en raison de métastases confirmées et un autre en raison d'une boiterie. Le résultat des énucléations pour la thérapie du CE oculaire était bon s'il n'y avait pas de métastases. Sur les trois cas de CE non oculaires, seul un cas, un CE pénien, présentait une masse apparente. Le traitement a été initié dans ce cas, tandis que les deux autres cas ont été euthanasiés peu de temps après le diagnostic en raison du mauvais pronostic des CE dans les localisations constatées (sinus maxillaire, mandibule). Des métastases sont apparues trois et deux ans après l'ablation de la tumeur primaire dans le cas du CE oculaire, au niveau de l'omoplate, du foie et des poumons et, dans un cas de CE non oculaire, celui du pénis, aux narines. Étant donné que tous les Haflinger n'ont pas fait l'objet d'un examen pathologique post-mortem, on ne peut exclure la possibilité d'autres métastases. Les Haflinger atteints de CE doivent être suivis à long terme par un vétérinaire, car des récidives et/ou des métastases peuvent encore survenir des années plus tard.

[DDB2-associated incidence of squamous cell carcinoma in Haflingers: risk minimization by genotyping]. / DDB2-assoziiertes Vorkommen von Plattenepithelkarzinomen beim Haflinger: Risikominimierung durch Genotypisierung.

INTRODUCTION: SCC (squamous cell carinomas) are among the most common eye neoplasms in horses. In recent studies Haflinger horses with a homozygous genotype for a missense variant in the DDB2 gene (damage specific DNA binding protein 2) had a significant increased risk of developing ocular SCC. The aims of this study were to determine the frequency of the SCC-associated risk allele in the DDB2 gene in Swiss and Austrian Haflinger populations and to validate the previously described phenotypic correlation. For this purpose, Haflingers presented at various horse clinics in Switzerland (n = 21, including 11 SCC cases), privately kept Haflingers (n = 52, including 1 SCC case), and Haflingers from a stud farm in the Austrian Tyrol (n = 53) were recruited. The individual DDB2 genotype of the animals was determined using a polymerase chain ceaction (PCR) test using hair follicle or whole blood samples. Of the 12 horses suffering from SCC, nine had ocular SCC and three had non-ocular SCC. Six of the nine Haflingers with ocular SCC and one of the three Haflingers with non-ocular SCC were homozygous for the DDB2 variant. Of the 113 clinically normal animals, 7/113 were homozygous (6 %) and 42/113 were heterozygous (37 %), which corresponds to an allele frequency of 24,8 % in the control cohort. The risk of ocular SCC occurring in Haflingers is significantly increased with the homozygous DDB2 genotype. However, not all animals with SCC carry this gene variant and not all DDB2 homozygous animals develop SCC, which can be explained by the multifactorial genesis of the disease. Due to the high frequency of the undesirable allele, we recommend taking the individual DDB2 genotype of breeding animals into account in order to avoid homozygous offspring with a greatly increased SCC risk by excluding high-risk matings.

INTRODUCTION: Les carcinomes épidermoïdes (CE) sont parmi les néoplasmes oculaires les plus fréquents chez les chevaux. Des études récentes ont montré que les chevaux Haflinger présentant un génotype homozygote pour un variant faux-sens dans le gène DDB2 (damage specific DNA binding protein 2) avaient un risque significativement plus élevé de développer un CE oculaire. Les objectifs de cette étude étaient de déterminer la fréquence de l'allèle à risque associé au CE dans le gène DDB2 dans les populations suisses et autrichiennes de Haflinger et de valider la corrélation phénotypique décrite précédemment. Pour ce faire, des Haflingers présentés dans différentes cliniques équines en Suisse (n = 21, dont 11 cas de CE), des Haflingers privés (n = 52, dont 1 cas de CE) et des Haflingers d'un haras du Tyrol autrichien (n = 53) ont été recrutés. Le génotype DDB2 individuel des animaux a été déterminé à l'aide d'un test de réaction en chaîne par polymérase (PCR) utilisant des échantillons de follicules pileux ou de sang total. Sur les 12 chevaux souffrant de CE, neuf avaient un CE oculaire et trois un CE non oculaire. Six des neuf Haflingers atteints de CE oculaire et un des trois Haflingers atteints de CE non oculaire étaient homozygotes pour la variante DDB2. Sur les 113 animaux cliniquement normaux, 7/113 étaient homozygotes (6 %) et 42/113 étaient hétérozygotes (37 %), ce qui correspond à une fréquence d'allèle de 24,8 % dans la cohorte de contrôle. Le risque de CE oculaire chez les Haflingers augmente de manière significative avec le génotype DDB2 homozygote. Cependant, tous les animaux atteints de CE ne sont pas porteurs de cette variante génétique et tous les animaux homozygotes DDB2 ne développent pas de CE, ce qui peut s'expliquer par la genèse multifactorielle de la maladie. En raison de la fréquence élevée de l'allèle indésirable, nous recommandons de tenir compte du génotype DDB2 individuel des animaux reproducteurs afin d'éviter une progéniture homozygote présentant un risque fortement accru de CE en excluant les accouplements à haut risque.

The potential of three whole blood microRNAs to predict outcome and monitor treatment response in sarcoid-bearing equids.

MicroRNAs (miRNAs) have been proposed as biomarkers for equine sarcoid (ES) disease. In this study, the suitability of three whole blood miRNAs to diagnose ES and to predict and monitor the outcome of therapy was explored. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), expression levels of eca-miR-127, eca-miR-379, and eca-miR-432 in whole blood of ES-affected equids before and at least one year after therapy were compared to those of unaffected control equids. Associations of age, sex, species, diagnosis, and therapy outcome with miRNA expression levels were examined using general linear models. In total, 48 ES-affected equids and 47 control equids were recruited. From the affected animals, 31 responded favorably to treatment, and 17 demonstrated a failure of therapy. None of the tested miRNAs were influenced by age. Male equids showed increased expression of eca-miR-127 compared to females and horses showed higher expression levels of eca-miR-379 and eca-miR-432 than donkeys. Eca-miR-127 was confirmed as a diagnostic discriminator between ES-affected and control equids. No difference in miRNA profiles before therapy was found when comparing ES-affected equids with success vs. failure of therapy. Eca-miR-379 and eca-miR-432 decreased over time in horses where therapy was successful, but not in those cases where it failed. Biological variables influence equine whole blood miRNA expression, which may complicate biomarker validation. While none of the tested miRNAs could predict the response to therapy in ES-affected equids and eca-miR-127 showed poor diagnostic accuracy for ES, eca-miR-379 and eca-miR-432 miRNAs might allow refinement of monitoring of success of ES therapy.

Characterization of an outbreak of equine coronavirus infection in adult horses in Switzerland.

INTRODUCTION: Outbreaks of equine coronavirus (ECoV) infections have been described in different parts of the world including Europe. The aim of this report was to describe clinical signs, diagnostic work-up and outcome of the first documented outbreak of ECoV in Switzerland in order to raise the awareness for the disease and its various clinical presentations. The outbreak occurred on a farm with 26 horses. Of these, seven horses developed clinical disease ranging from mild signs such as fever and anorexia to severe signs of acute colitis. One horse died due to severe endotoxemia and circulatory shock secondary to severe acute necrotizing enteritis and colitis. Out of the 26 horses, five horses tested positive for ECoV, including two ponies without any clinical signs of infection. The low number of positive cases should nevertheless be interpreted with caution as testing was only performed on one occasion, over a month after the onset of clinical signs in the first suspected case. This report highlights the importance of diagnostic testing and early implementation of biosecurity measures on a farm with an ECoV outbreak. It should furthermore raise the awareness for unspecific and mild clinical signs such as fever and anorexia in affected animals that are potentially able to spread the disease.

INTRODUCTION: Des foyers d'infection à coronavirus équin (ECoV) ont été décrits dans différentes parties du monde, y compris en Europe. L'objectif de ce rapport est de décrire les signes cliniques, le diagnostic et les conséquences du premier foyer d'ECoV documenté en Suisse, afin de sensibiliser le public à cette maladie et à ses différents aspects cliniques. L'épidémie s'est produite dans une écurie comptant 26 chevaux. Parmi ceux-ci, sept chevaux ont développé une forme clinique allant de signes légers tels que la fièvre et l'anorexie à des signes sévères de colite aiguë. Un cheval est mort en raison d'une endotoxémie sévère et d>un choc circulatoire secondaire à une entérite nécrosante aiguë sévère et à une colite. Sur les 26 chevaux, cinq ont été testés positifs à l>ECoV, dont deux poneys sans aucun signe clinique d'infection. Le faible nombre de cas positifs doit néanmoins être interprété avec prudence car les tests n'ont été effectués qu'à une seule occasion, plus d'un mois après l'apparition des signes cliniques chez le premier cas suspect. Ce rapport souligne l'importance des tests de diagnostic et de la mise en œuvre rapide de mesures de biosécurité dans une exploitation où un foyer d'ECoV est détecté. Il devrait en outre sensibiliser à la présence de signes cliniques peu spécifiques et bénins tels que la fièvre et l'anorexie chez les animaux atteints qui sont potentiellement capables de propager la maladie.

[Outpatient specialist medical care : Regulations and practical example of rheumatology]. / Ambulante spezialfachärztliche Versorgung : Regularien und Praxisbeispiel Rheumatologie.

Outpatient specialist medical care targets the intersectoral and interdisciplinary cooperation between hospital physicians and panel physician structures in the diagnostics and treatment of certain disease symptoms under the same framework conditions. The administrative coordination bundled through one person has contributed to an effective placement of applications. In this way the daunting effect of bureaucratic hurdles for potential team members could be intercepted. A close and constructive collaboration of all participants is helpful to come to terms with the new treatment structure and to achieve the anticipated targets for patients, panel physicians and hospitals.

Mesenteric granulomas independently predict long-term risk of surgical recurrence in Crohn's disease.

AIM: The risk factors that predict surgical recurrence in Crohn's disease (CD) remain controversial. Postoperative anti-tumour necrosis factor (anti-TNF) therapy might lower recurrence rates whilst the presence of mesenteric granulomas has been postulated to increase the risk. We hypothesized that mesenteric granulomas indicate disease severity and might predict the risk of surgical recurrence, irrespective of immunosuppressive therapy. METHOD: We performed a retrospective review of all consecutive patients undergoing operations for CD between January 2000 and December 2014 at a single tertiary referral centre and assessed the perioperative factors and histological findings at the time of surgery. Surgical recurrence rates and the immunosuppressive regimen were assessed through retrospective chart review and telephone interviews. RESULTS: A total of 274 patients were eligible for analysis. Median follow-up was 8.54 (5.48-14.42) years. A total of 63 patients (23.0%) underwent surgery for recurrent CD after a median of 4.75 (2.10-7.96) years. In final histology, 35 (12.8%) patients had mesenteric granulomas. TNF inhibitors were administered postoperatively in 104 (38.0%) and thiopurines in 137 (50.0%) patients. In univariate analysis, only the presence of mesenteric granulomas [hazard ratio (HR) 1.95; 95% CI 1.05-3.62; P = 0.035] significantly increased the risk for recurrent surgery while postoperative anti-TNF (HR 0.85; 95% CI 0.49-1.50; P = 0.581) or thiopurine therapy (HR 1.03; 95% CI 0.61-1.73; P = 0.916) did not. In multivariate analysis, only the presence of mesenteric granulomas significantly influenced the risk of surgical recurrence (HR 1.94, 95% CI 1.04-3.60; P = 0.037). CONCLUSION: Intestinal and mesenteric granulomas should be differentiated in pathology reports, because mesenteric, but not intestinal, granulomas may be associated with an increased risk of surgical recurrence.

[Future of rheumatologists: what are the perspectives? : Survey of resident physicians in rheumatology in middle Germany]. / Rheumatologin/Rheumatologe in spe: Wie geht es weiter? : Befragung der rheumatologischen Assistenzärzte und -ärztinnen in Mitteldeutschland.

BACKGROUND AND OBJECTIVE: The work environment for rheumatologists has significantly changed over the last years. The healthcare of patients with rheumatic diseases is at risk due to the age structure of specialized rheumatologists in middle Germany and the limited availability of training positions for rheumatologists. In this context, it is important to have detailed information on the resident physicians in rheumatology concerning their own visions regarding their future professional career. MATERIAL AND METHODS: A questionnaire was sent to resident physicians in 25 rheumatology training hospitals in the middle of Germany (Saxony, Saxony-Anhalt and Thuringia). The questionnaire was completed and returned by 27 participants (17 women and 10 men). RESULTS: Most of the participants (60%) aimed to qualify as a specialist in internal medicine followed by a specialization in rheumatology (altogether training for a minimum of 8 years). After finishing training 44% would prefer to work in an outpatient setting while 30% planned to work in a combined outpatient and clinical setting. Of the participants 48% would prefer to work as part-time rheumatologists and 74% (women 94% and men 40%) were interested in employment in an outpatient medical healthcare center. The compatibility of family and work as well as the work-life balance was considered to be highly relevant for the future professional life. CONCLUSION: Less than half of the participants intended to work exclusively in an outpatient setting after completing the training in rheumatology. In addition, the participants preferred a part-time employment with compatibility of professional and private life. Consequently, alternative models of employment should be created in rheumatology to be attractive for future physicians. On the other hand, the study revealed that the independent rheumatological practice has a lower priority for the young rheumatologists taking part in this survey.

Spatio-temporal Analysis of Multichannel Atrial Electrograms Based on a Concept of Active Areas.

Atrial tachycardia and atrial flutter are frequent arrhythmia that occur spontaneously and after ablation of atrial fibrillation. Depolarization waves that differ significantly from sinus rhythm propagate across the atria with high frequency (typically 140 to 220 beats per minute). A detailed and personalized analysis of the spread of depolarization is imperative for a successful ablation therapy. Thus, catheters with several electrodes are employed to measure multichannel electrograms inside the atria. Here we propose a new concept for spatio-temporal analysis of multichannel electrograms during atrial tachycardia and atrial flutter. It is based on the calculation of simultaneously active areas. The method allows to identify atrial tachycardia and to automatically distinguish between subtypes of focal activity, micro-reentry and macro-reentry.

Genetic risk for squamous cell carcinoma of the nictitating membrane parallels that of the limbus in Haflinger horses.

Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye, with a higher incidence documented in Haflinger horses. Recently, a missense variant in the gene damage specific DNA binding protein 2 (DDB2, p.Thr338Met) on ECA12 was identified as a risk factor for the development of limbal SCC in Haflinger horses. SCC also occurs on the nictitating membrane; therefore, investigating the role of this missense variant in nictitating membrane SCC is warranted. In this study, a common ancestor was identified among Haflinger horses affected with limbal SCC or with nictitating membrane SCC, thus supporting a recessive risk factor for the development of cancer at both ocular locations. Analysis of genotype data from Haflinger horses with and without nictitating membrane SCC revealed that the same region on ECA12 associated with limbal SCC was also associated with nictitating membrane SCC (P < 2.04 × 10-5 ). Fine mapping of this locus using 25 cases and 49 controls supported the hypothesis that DDB2:c.1013C>T, p.Thr338Met, is a risk factor for nictitating membrane SCC, as 88% of our cases were homozygous for this variant and no other polymorphism was more strongly associated (P = 4.13 × 10-14 ). These data indicate that the genetic risk is the same for the development of both limbal and nictitating membrane SCC in Haflinger horses and validates utilization of genetic testing of the DDB2 variant for both clinical management and the guidance of mating decisions.

Effect of pathologist's dedication on lymph node detection rate and postoperative survival in colorectal cancer.

AIM: As adjuvant chemotherapy in colorectal cancer relies on the identification of lymph node metastases, the pathologist's dedication may have a considerable influence on postoperative survival. METHOD: The aim of this retrospective study was to assess the impact of the pathologist's dedication on lymph node detection rate and postoperative survival in patients operated on by a single experienced colorectal surgeon within a 5-year period. We assessed 229 patients undergoing total mesorectal excision or complete mesocolic excision by the senior author between 1 January 2009 and 31 December 2013. Pathologists were grouped as 'general pathologist' or 'dedicated pathologist' depending on their dedication/specialization. RESULTS: Dedicated pathologists found statistically significantly more lymph nodes in colorectal specimens than general pathologists [23 (interquartile range 24) vs 14 (interquartile range 11), respectively; P < 0.001]. The detection rate of ≥ 12 lymph nodes per specimen was significantly higher in the dedicated pathologist group [65/74 (87.8%) vs 105/155 (67.7%); P = 0.016]. However, postoperative survival did not differ in the respective subgroups. In the multivariable analysis by Cox proportional hazard model, International Union against Cancer Stage IV was the only factor associated with decreased disease-specific survival (hazard ratio 28.257; 95% CI 3.850-207.386; P = 0.001). CONCLUSION: In our centre, the pathologist's dedication has an impact on lymph node detection rate but does not influence postoperative disease-specific survival.

[Off-label biologic therapy of ANCA-associated and non-ANCA-associated small-vessel vasculitis : Efficacy and safety analysis of a national registry (GRAID2)]. / Off-label-Biologikatherapie von ANCA-assoziierten und nicht-ANCA-assoziierten Kleingefäßvaskulitiden : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the clinical efficacy and safety of off-label biological therapies in patients with ANCA-associated vasculitis (AAV) and non-ANCA-associated small-vessel vasculitis (nAAV) in clinical practice. METHODS: The German Registry in Autoimmune Diseases 2 (GRAID2) is a national, retrospective, non-interventional, multicentre observational study (August 2006 until December 2013) on patients with autoimmune diseases refractory to standard immunosuppressive therapy treated with off-label biologicals. RESULTS: Data from 64 patients (20.6% of all GRAID2 patients) were collected: 54 patients (84.4%) had ANCA-associated vasculitis (AAV) and 10 patients (15.6%) had non-ANCA-associated small-vessel vasculitis (nAAV). Of the AAV patients, 96.3% were treated off-label with rituximab (RTX) and 3.7% with tumor necrosis factor alpha (TNFα)-inhibitors. Of patients with nAAV, 30% were treated with RTX, 60% with TNFα-inhibitors, and 10% with tocilizumab. The main reasons for off-label biological treatment in AAV patients were pulmonary, renal, or ear, nose, and throat involvement. These manifestations clearly improved in most patients after off-label biological therapy was initiated. Daily glucocorticoid dosage could be reduced. The off-label biological therapy was generally well tolerated. In AAV patients, 4.18 severe infections per 100 patient years were observed. There was one death in the nAAV group caused by fungal infection and ileus. A correlation between this fatality and RTX treatment was regarded as possible. CONCLUSION: Safety and efficacy of off-label RTX-treatment in AAV-patients could be assessed in the GRAID2 data. Results point to good efficacy and safety of RTX in this special patient cohort and support the approval of RTX for AAV induction therapy.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

[Rituximab for the treatment of poly- and dermatomyositis : Results from the GRAID-2 registry]. / Rituximab zur Behandlung von Poly- und Dermatomyositis : Die Ergebnisse des GRAID-2-Registers.

INTRODUCTION: In the treatment of poly- and dermatomyositis, only a limited number of treatment modalities are established. OBJECTIVE: The goal of the GRAID-2 registry was to study off-label use of biologic drugs for this indication in Germany. PATIENTS AND METHODS: Analysis of the data of the GRAID-2 registry for poly- and dermatomyositis. RESULTS: In 22 of the 23 patients in the GRAID-2 registry, rituximab (RIX) was administered, while 1 patient was given tocilizumab as off-label therapy. The 22 patients who received RIX treatment were analyzed. At the start of treatment, the following active manifestations were present: myositis (n = 18), lung involvement (mainly interstitial lung disease; n = 10), arthritis (n = 10), skin manifestation (n = 9), and Raynaud syndrome (n = 5). Nine of the patients were Jo-1-antibody positive. All patients had previous treatments with multiple conventional immunosuppressive drugs. Treatment with RIX was given as infusions of 1 g i. v., which were repeated after 2 weeks. Patients received a mean of 3.09 ± 2.27 infusions (equivalent to 1.5 cycles of 2 × 1 g, max. 5 cycles). Tolerability of RIX treatment was rated as very good in 16 of 22 patients (72%), good in 5 (23%), and moderate in 1 (5%). In all, 27 adverse events were documented, with the majority being infections, whereby 2 severe infections occurred (6.59 per 100 patient-years). Eighty six percent of the patients showed complete remission of their myositis and 79% of their arthritis. The mean value of creatinine kinase in plasma fell from 1505 ± 2534 U/l before the start of treatment to 39 ± 134 U/l at the last visit. Regarding lung involvement, 1 of 10 of the patients showed complete and 6 of 10 partial remissions. In 2 of 10 patients, lung disease was stable during treatment. CONCLUSION: RIX is the preferred off-label biologic drug for poly- and dermatomyositis in Germany. In spite of a strongly pretreated group of patients, the tolerability is acceptable, although the patient number in this investigation is small. Moreover, the results lead to the assumption that the majority of the patients had a good or even very good therapeutic response to RIX.

Regulatory T Cells Promote Natural Killer Cell Education in Mixed Chimeras.

Therapeutic administration of regulatory T cells (Tregs) leads to engraftment of conventional doses of allogeneic bone marrow (BM) in nonirradiated recipient mice conditioned with costimulation blockade and mammalian target of rapamycin inhibition. The mode of action responsible for this Treg effect is poorly understood but may encompass the control of costimulation blockade-resistant natural killer (NK) cells. We show that transient NK cell depletion at the time of BM transplantation led to BM engraftment and persistent chimerism without Treg transfer but failed to induce skin graft tolerance. In contrast, the permanent absence of anti-donor NK reactivity in mice grafted with F1 BM was associated with both chimerism and tolerance comparable to Treg therapy, implying that NK cell tolerization is a critical mechanism of Treg therapy. Indeed, NK cells of Treg-treated BM recipients reshaped their receptor repertoire in the presence of donor MHC in a manner suggesting attenuated donor reactivity. These results indicate that adoptively transferred Tregs prevent BM rejection, at least in part, by suppressing NK cells and promote tolerance by regulating the appearance of NK cells expressing activating receptors to donor class I MHC.

The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses.

B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.

Interactions between Metopolophium festucae cerealium (Hemiptera: Aphididae) and Barley yellow dwarf virus (BYDV-PAV).

Interactions between an invasive aphid, Metopolophium festucae (Theobald) subsp. cerealium, and Barley yellow dwarf virus (BYDV-PAV) were studied under laboratory conditions. M. festucae cerealium is an economic pest of wheat and barley that has recently been found in high population densities in wheat in the Pacific Northwest of the United States. BYDV-PAV is the most prevalent and injurious species of BYDV worldwide and in the Pacific Northwest. Although M. festucae sensu stricto (Theobald 1917) has been reported previously as a vector of some BYDV isolates, there is no confirmed transmission of BYDV by M. festucae cerealium. Two experiments examined the ability of M. festucae cerealium to transmit BYDV-PAV. The first used single aphids caged to indicator plants of a BYDV-susceptible winter wheat cultivar and the second used multiple aphids on each test plant. M. festucae cerealium did not transmit BYDV-PAV in either experiment, whereas transmission by a known BYDV vector, Rhopalosiphum padi L., was consistently high (≥ 93%). A third experiment compared the intrinsic growth rate, days until first reproduction and daily reproduction by M. festucae cerealium on sham-inoculated and BYDV-PAV-infected wheat, but detected no differences. The findings are reviewed in light published data on M. festucae species, BYDV transmission, and the potential pest status of this new invading aphid.

Tacrolimus, Mycophenolate Mofetil, and Low-Dose Steroids With or Without Interleukin-2 Receptor Antibody Induction Therapy: A Retrospective Cohort Analysis.

BACKGROUND: Selective interleukin-2 receptor (IL2R) blockade is one option to decrease acute rejection rates in kidney transplant recipients. However, there are little data on the impact of basiliximab in a triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and low-dose steroids). Thus, this analysis aims at investigating the impact of basiliximab induction on rejection rates and immediate graft function following kidney transplantation. METHODS: Basiliximab was introduced in our center according to our center's policy in the beginning of 2011. Patients who received basiliximab (n = 83) were compared with patients without induction therapy (n = 65) transplanted before the introduction of IL2R antibody induction. RESULTS: The use of basiliximab as induction therapy decreased the incidence of biopsy-proven acute rejection (BPAR) within the 1st year after transplantation (21.5% vs 14.5%; P = .283). Overall rejection episodes (including BPAR and borderline rejection) were significantly reduced in patients with basiliximab compared with patients without (41.5% vs 24.1%; P = .033). However, graft function (incidence of delayed graft function, primary nonfunction, slow graft function, and serum creatinine decline) and overall outcome (patient and graft survivals) were similar in both groups. CONCLUSIONS: We found a favorable impact of basiliximab induction therapy on early acute rejection rate. The impact on long-term outcome must be addressed in further randomized controlled trials.

Lung Sealing with the Sandwich-Technique: A New Surgical Method to Deal with the Emphysematous Lung.

UNLABELLED: The persistent air leak is a common and sometimes difficult to manage complication after major pulmonary resections. Especially in cases with lung emphysema spontaneous sealing of the lung surface under conservative therapy can be prolonged or even fail and a reoperation to close the damaged visceral pleura might be necessary. An ideal surgical solution to deal with this problem is not known, all of the techniques have advantages but also limitations and additional operations should be avoided in this group of frail patients. In this paper a new surgical method to seal the lung surface is presented based on two exemplary cases and our clinical experience. Basically, two stripes of fleece bounded fibrin based sealant are put on the visceral pleura parallel to the wound, which will be then closed by multiple stitches of absorbable suture line inserted through the stripes. Afterwards, a second layer of the same sealant will be placed over it to cover the suture with a narrow overlapping in all directions to the adjacent visceral pleura (Sandwich-Technique). In our experience, this technique can be used to successfully prevent or treat persistent air leaks especially in patients with lung emphysema in whom otherwise treatment options are limited. ABBREVIATIONS: VATS = video-assisted thoracoscopic surgery POD = postoperative day LVRS = lung volume reduction surgery FEV1 = forced expiratory volume in the first second DLCO = diffusing capacity of the lung for carbon monoxide.

Outcomes for split-thickness skin transplantation in high-risk patients using octenidine.

Skin transplantation is a commonly used surgical technique; however, the complication rate, including postoperative infection and delayed wound healing due to inefficient perfusion, is significantly higher in patients suffering from comorbidities. Hence, a subsequent repeat procedure is often necessary. In this report, two case studies are presented in which an octenidine-based antiseptic is used with a tie-over dressing (TOD) instead of povidone iodine (PVP-iodine), following a split-thickness skin graft. The two patients selected were deemed to be at high risk of impaired wound healing due to comorbidities. The first patient, a confirmed smoker with diabetes, presented with a nodular melanoma that was resected and covered with a split-thickness skin graft. After 5 days of negative pressure wound therapy as a TOD, in combination with PVP-iodine, the graft became necrotic. A second split-thickness skin graft was performed and an antiseptic regimen with octenidine in combination with the same TOD resulted in a completely healed transplant. The second patient, also a confirmed smoker with diabetes and receiving oral corticosteroid treatment, was diagnosed with a skin necrosis on her leg. Following the split-thickness skin graft, octenidine and TOD were applied. The patient's skin graft completely healed without any adverse events. These two case studies indicate that the combination of octenidine and TOD following split-thickness skin transplantation is safe, well-tolerated and appears to have positive benefits in the reconstruction of defects in patients with impaired wound healing.

Nodular epitheloid sarcoma of the upper limb. A case report and review of the literature.

Epitheloid sarcoma is a rare malignant soft tissue sarcoma. We present a 36-year-old male patient with a primary tumour on his wrist and subcutaneous spread in a sporotrichoid pattern along the upper extremity. Early surgical treatment with micrographic control of all margins provides best long term outcome as long as a solitary lesion is present. In case of cutaneous and internal spread of the disease treatment options are only palliative. Early diagnosis, therefore, is most crucial.