[Pain reduction by radiosynoviorthesis in rheumatism-induced synovitis of the elbow : Results of a retrospective multicenter data analysis]. / Schmerzreduktion durch Radiosynoviorthese bei rheumatisch bedingter Synovialitis des Ellenbogens : Ergebnisse einer retrospektiven, multizentrischen Datenanalyse.

BACKGROUND: Radiosynoviorthesis (RSO) is a nuclear medical local treatment modality for inflammatory joint diseases. It is indicated in patients with rheumatoid arthritis (RA) in joints with persistent synovitis despite adequate pharmacotherapy. Arthritis of the elbow joint occurs in up to 2/3 of patients with RA. Intra-articular radiotherapy using the beta emitter [186Re] rhenium sulfide leads to sclerosis of the inflamed synovial membrane with subsequent pain alleviation. The clinical efficacy in cubital arthritis, however, has so far only been described in small monocentric studies. OBJECTIVE: The degree of pain alleviation by RSO was analyzed in patients with rheumatoid cubital arthritis, treated in several nuclear medical practices specialized in RSO. MATERIAL AND METHODS: The subjective pain intensity before and after RSO was documented in a total of 107 patients with rheumatic cubital arthritis using a 10-step numeric rating scale (NRS). A difference of ≥ -2 is rated as a significant improvement. Follow-up examinations were done after a mean interval of 14 months after RSO (at least 3 months, maximum 50 months). RESULTS: The mean NRS value was 7.3 ± 2.1 before RSO and 2.8 ± 2.2 after RSO. A significant pain alleviation was seen in 78.5% of all patients treated. The subgroup analysis also showed a significant improvement in the pain symptoms in all groups depending on the time interval between the RSO and the control examination. A significant pain progression was not observed. The degree of pain relief was independent of the time of follow-up. CONCLUSION: Using RSO for local treatment of rheumatoid cubital arthritis leads to a significant and long-lasting pain relief in more than ¾ of the treated patients.

Intra-articular Treatment of Digital Osteoarthritis by Radiosynoviorthesis-Clinical Outcome in Long-term Follow-up.

PURPOSE: This retrospective study analyzed the long-term effects of radiosynoviorthesis (RSO) with special emphasis to local joint pain in patients from 4 different RSO centers in Germany and Austria. METHODS: A total of 168 finger joints in 147 patients with digital joint OA were investigated. The indication for RSO was based on both clinical complaints and a proven synovitis, despite anti-inflammatory pharmacotherapy and previous intra-articular corticosteroid injections. Radiosynoviorthesis was performed according to international guidelines. A numeric visual analog scale (VAS) before and after treatment was used to measure the outcome. Follow-up was done for at least 2 years after treatment, in some patients even over 10 years. RESULTS: Radiosynoviorthesis resulted in a significant reduction of VAS values in most of the patients, lasting for the whole period of follow-up. Two-thirds of the treated joints showed clinically relevant improvement, if a reduction of 30% in VAS values was defined as a reasonable cutoff. The best results were achieved in thumb base joints. CONCLUSIONS: This article confirms that RSO is a suitable treatment option for digital joint OA with a proven synovitis. The analgesic effect is long-lasting and comparable to the success of RSO in patients with rheumatoid arthritis.

[The Baker's cyst - a blunt sword of Damokles in radiosynoviorthesis (RSO)?] / Die Bakerzyste ­ das stumpfe Damoklesschwert bei der Radiosynoviorthese (RSO)?

The existence of a popliteal Baker's cyst was regarded as a contraindication for radiosynoviorthesis of the knee joint since decades. A so-called "ventile mechanism" was discussed leading to a significant concentration of the intraarticularly applied, high energy beta emitting radiopharmaceutical yttrium-90-colloid in the cyst. This cyst arises from a bursa beneath the tendon of the medial head of the gastrocnemius muscle, normally communicating with the knee joint space. Since the cyst wall is much thinner than the knee joint capsule, a radiogenic rupture of the cyst was feared, leading to severe radiogenic necroses of the surrounding soft tissue. Due to this potential hazard, knee joint ultrasound is mandatory prior to radiosynoviorthesis to check for any popliteal cysts. New studies however decline the risk of a radiogenic cyst rupture after an appropriately performed radiosynoviorthesis of the knee joint.In case of a preexistent cyst rupture, the risk of a radiogenic tissue damage remains an issue and magnetic resonance imaging (MRI) is the method of choice to exclude this potential hazard. However, MRI sometimes leads to equivocal results. Scintigraphy of the knee joint after intraarticular application of Tc-99m-nanocolloid offers the possibility to check for the integrity of the Baker's cyst in these patients to be sure that radiosynoviorthesis will not lead to a relevant extraarticular leakage with soft tissue necroses. This study describes the procedure of intracavitary distribution scintigraphy by means of representative case reports.

Changes in the global impact of COVID-19 on nuclear medicine departments during 2020: an international follow-up survey.

AIM: As a follow-up to the international survey conducted by the International Atomic Energy Agency (IAEA) in April 2020, this survey aims to provide a situational snapshot of the COVID-19 impact on nuclear medicine services worldwide, 1 year later. The survey was designed to determine the impact of the pandemic at two specific time points: June and October 2020, and compare them to the previously collected data. MATERIALS AND METHODS: A web-based questionnaire, in the same format as the April 2020 survey was disseminated to nuclear medicine facilities worldwide. Survey data was collected using a secure software platform hosted by the IAEA; it was made available for 6 weeks, from November 23 to December 31, 2020. RESULTS: From 505 replies received from 96 countries, data was extracted from 355 questionnaires (of which 338 were fully completed). The responses came from centres across varying regions of the world and with heterogeneous income distributions. Regional differences and challenges across the world were identified and analysed. Globally, the volume of nuclear medicine procedures decreased by 73.3% in June 2020 and 56.9% in October 2020. Among the nuclear medicine procedures, oncological PET studies showed less of a decline in utilization compared to conventional nuclear medicine, particularly nuclear cardiology. The negative impact was also significantly less pronounced in high-income countries. A trend towards a gradual return to the pre-COVID-19 situation of the supply chains of radioisotopes, generators, and other essential materials was evident. CONCLUSION: The year 2020 has a significant decrease in nuclear medicine diagnostic and therapeutic procedures as a result of the pandemic-related challenges. In June, the global decline recorded in the survey was greater than in October when the situation began to show improvement. However, the total number of procedures remained below those recorded in April 2020 and fell to less than half of the volumes normally carried out pre-pandemic.

[Joint DGN, OGNMB and SGNM S1 guideline for radiosynoviorthesis]. / Gemeinsame Handlungsempfehlung (S1-Leitlinie) von DGN, OGNMB und SGNM ­ Radiosynoviorthese ­ Stand: 9/2019 ­ AWMF-Registernummer: 031-023.

This recommendation is intended to provide a guideline for radiosynoviorthesis (RSO) in the effective local treatment of chronic inflammatory (non-infectious) joint diseases. It was developed in an interdisciplinary manner and describes the general objectives, definitions, clinical background information, indication and contraindications of this radionuclide therapy. The requirements to be met by a treatment center, the results of pretherapeutic examinations as well as recommendations on how the treatment should be carried out. Here, organizational and technical issues have been considered. Furthermore, information on the surveillance and follow-up of the treated patients can be found. In general, treatment and follow-up should be done in in close cooperation of the participating disciplines.

[Impact of COVID-19 on Nuclear Medicine Procedures in Germany 2020 - Results of a National Survey]. / Auswirkungen von COVID-19 auf nuklearmedizinische Untersuchungen und Therapien im Verlauf von 2020 ­ Ergebnisse einer nationalen Umfrage.

INTRODUCTION: The COVID-19 pandemic imposed an unimaginable challenge to the healthcare systems worldwide. This online survey captured the impact of the COVID-19 pandemic on nuclear medicine services in Germany comparing 2020 to 2019. MATERIALS AND METHODS: A web-based questionnaire was developed to record the 2020 numbers of nuclear medicine procedures and, in particular, the change compared with 2019. The changes in nuclear medicine diagnostics and therapy were queried, as well as the extent to which "Coronavirus SARS-CoV-2" recommendations provided by the DGN were implemented. RESULTS: 91 complete responses were recorded and evaluated. This corresponds to about 20 % of all German nuclear medicine facilities. Nuclear medicine diagnostic tests showed a decrease in scintigraphies for thyroid (15.9 %), bone (8.8 %), lung (7.6 %), sentinel lymph nodes (5.5 %), and myocardium (1.4 %) with small increases in PET/CT examinations (1.2 %) compared with 2019. Among nuclear medicine therapies, reductions were highest for benign indications (benign thyroid 13.3 %, RSO 7.7 %), while changes from 2019 were less pronounced for malignant indications (PRRT: + 2.2 %, PSMA: + 7.4 %, SIRT: -5.9 %, and RJT for thyroid carcinoma -2.4 %). The DGN recommendations for action were fully or partially applied in 90 %. CONCLUSIONS: The initial significant reduction in nuclear medicine procedures in the first three weeks of the COVID-19 pandemic did not continue, but there was no compensation of the previously not performed services. The decrease in diagnostics and therapy procedures of benign diseases was particularly severe.

Impact of COVID-19 on Nuclear Medicine in Germany, Austria and Switzerland: An International Survey in April 2020.

INTRODUCTION: Preparations of health systems to accommodate large number of severely ill COVID-19 patients in March/April 2020 has a significant impact on nuclear medicine departments. MATERIALS AND METHODS: A web-based questionnaire was designed to differentiate the impact of the pandemic on inpatient and outpatient nuclear medicine operations and on public versus private health systems, respectively. Questions were addressing the following issues: impact on nuclear medicine diagnostics and therapy, use of recommendations, personal protective equipment, and organizational adaptations. The survey was available for 6 days and closed on April 20, 2020. RESULTS: 113 complete responses were recorded. Nearly all participants (97 %) report a decline of nuclear medicine diagnostic procedures. The mean reduction in the last three weeks for PET/CT, scintigraphies of bone, myocardium, lung thyroid, sentinel lymph-node are -14.4 %, -47.2 %, -47.5 %, -40.7 %, -58.4 %, and -25.2 % respectively. Furthermore, 76 % of the participants report a reduction in therapies especially for benign thyroid disease (-41.8 %) and radiosynoviorthesis (-53.8 %) while tumor therapies remained mainly stable. 48 % of the participants report a shortage of personal protective equipment. CONCLUSIONS: Nuclear medicine services are notably reduced 3 weeks after the SARS-CoV-2 pandemic reached Germany, Austria and Switzerland on a large scale. We must be aware that the current crisis will also have a significant economic impact on the healthcare system. As the survey cannot adapt to daily dynamic changes in priorities, it serves as a first snapshot requiring follow-up studies and comparisons with other countries and regions.

Dosimetric comparison of mono-isocentric and multi-isocentric plans for oligobrain metastases: A single institutional experience.

PUPOSE: To compare dosimetric plans for the treatments of oligobrains metastases (2-6) using mono-isocentric arc therapy and multi-isocentric volumetric modulated arc therapy (VMAT). MATERIAL AND METHODS: A total of sixteen patients with multiple brain metastases were selected. Prescription dose was between 24 and 15Gy depending on the tumor size. For every patient,arctherapy and VMAT plans were generated respectively, with Elements Multiple Brain Mets SRS version 2.0 (BrainLab) and Eclipse SRS Treatment Planning Systeme version 15.5. The conformity index (CI), homogeinity index (HI), gradient index (GI), dose volume histogram for each organs at risk, total Monitor Units were evaluated. RESULTS: For coverage of the PTV, mono-isocentric plans showed a better CI and a better GI than multi-isocentric plans, respectively CI of 1.18±0.11 vs 1.41±0.20 (P<0.01), and GI of 3.55±0.59 vs 4.03±1.20 (P<0.01). Homogeneity index was not better with mono-isocentric plans, with respectively HI 24.32±3.87 vs 14.05±4.46 (P=1). For organs at risk, there were no statistical differences between mono and multi-isocentric plans for both eyes, both lenses, both optic nerves, chiasma, brainstem, and hippocampi.V12Gy and V10Gy of normal brain were statistically lower with mono-isocentric plans than with multi-isocentric plans, respectivellyV12Gy of 3.06Gy 95%CI [2.25;3.86]vs 5.18Gy 95%CI [3.43;6.93] (P<0,01) and V10Gy 4.66Gy 95%CI [3.33;5.98] vs7.30Gy 95%CI [4.73;9.87] (P<0.03). Total number of MU was significantly lower with mono-isocentric plans than with multi-isocentric plans, respectively 6668±1463 vs 12403±4941 (P<0.01), then treatment time was lower with mono-isocentric plans. CONCLUSION: Mono-isocentric plans had a better conformity index and gradient index than multi-isocentric plans for the treatment of multiple brain metastases. Moreover, mono-isocentric techniques gave fewer doses to normal brain and used less monitor units than multi-isocentric techniques.

Immunomodulatory asthma therapy in the equine animal model: A dose-response study and evaluation of a long-term effect.

INTRODUCTION: Equine asthma represents a naturally occurring animal model for human allergic neutrophilic asthma. Inhalative nanoparticle-bound cytosine-phosphate-guanosine (CpG-GNP) immunotherapy, independent of specific allergens, has already shown promising clinical and immunological results in previous studies and offers the possibility to treat the underlying cause of the disease. This study analyses the relationship between dose and response, and evaluates a possible long-term effect. METHODS: In the prospective, randomised, double-blind clinical field study, 29 horses suffering from equine asthma received 10 inhalation treatments with either 187.5 µg CpG-GNP (CpG single dose [CpGsd]; n = 11), 375 µg CpG-GNP double dose (CpG double dose [CpGdd]; n = 9) (q48h for 20 days) or 1600 µg beclomethasone (n = 9) (q24h for 10 days). Each horse was examined three times: before the treatment (I), immediately after the 10 inhalations (II), and 8 weeks after the final inhalation (III). The three groups were compared according to clinical and laboratory parameters. The study examined the sustainability of the long-term effect of the treatment after 8 weeks, as well as the tolerability of the formula as a double dose. RESULTS: The CpGsd resulted in a significant improvement in 82% of the parameters, the CpGdd in 72%. In the long-term evaluation, the CpGsd showed a significant improvement in 100% of the parameters in comparison to the initial values, the CpGdd in 67%. On the immunological level, the bronchoalveolar lavage revealed a significant reduction of IL-4, IL-8, and interferon-γ. CONCLUSION: Both CpG groups displayed significant improvements in clinical and laboratory parameters, especially regarding the long-term effect of CpGsd. Doubling the CpG dose did not result in any improvement in comparison to the original single dose. On the immunological level, an anti-inflammatory, as well as an immunomodulatory effect, apart from a Th2-dominated immune response, could be observed. This immunomodulatory inhalation treatment could indicate a new possibility for human allergic asthma therapy.

An International Survey on Clinical Reporting of PET/CT Examinations: A Starting Point for Cross-Specialty Engagement.

Combined PET/CT imaging has become an integral part of patient management, particularly in oncology. After the imaging examination, a report of the findings is created by expert readers and sent to the referrers as a basis for subsequent decisions. In view of the known wide variation in operational models for PET/CT imaging, we surveyed PET/CT users on their approaches toward PET/CT reporting. Methods: The electronic survey comprised 28 questions on the demographics and professional background of the responders, as well as questions on the structure and quality of PET/CT reports, including the type of reported information, the use of reporting standards, and the mix of reporting standards and expert opinions. The survey was active for 6 wk in early 2018. In total, 242 responses were collected worldwide. Results: The responders were mainly from Europe (78%), with 22% being nuclear medicine specialists, 42% radiologists, 22% dual board-certified, 10% residents in either nuclear medicine or radiology, and 5% medical physicists, radiographers, or oncologists. A slim majority (55%) of responses indicated reports being done according to the European Association of Nuclear Medicine 2015 guidelines for 18F-FDG PET/CT imaging, but 30% of responders were unaware of these guidelines. Report structures varied across sites, with most sites (38%) reporting the PET findings with supplementary localization information from CT, whereas 27% of sites reported along the lines of a CT report with supplementary PET information. One third of the sites included information on the TNM stage of the oncology patient in all reports, whereas 34% and 12% of sites included this information occasionally or only for selected tumors, respectively. For therapy response assessment, various well-established criteria were used. The number of sites utilizing these criteria ranged from 15% (European Organisation for Research and Treatment of Cancer criteria) to 57% (Deauville criteria). Conclusion: Broad variation in the PET/CT reporting strategies adopted for oncology studies and widespread lack of awareness of existing guidelines for PET/CT reporting are evident from responses to this survey, raising concerns as to whether reporting clinicians are optimally using the complementary information from each modality. Greater efforts are needed to ensure harmonization of reporting practices.

[Development of a national competency-based learning objective catalogue for undergraduate medical education in Germany]. / Entwicklung eines kompetenzbasierten Lernzielkatalogs Nuklearmedizin für das Studium der Humanmedizin in Deutschland.

AIMS: Implementation of the guidelines on the Competency-based Learning Objective Catalogue for Undergraduate Medical Education for a Nuclear Medicine curriculum on behalf of the committee on professional training and continuing education of the German Association of Nuclear Medicine (DGN) METHODS:: In 7 domains 100 learning objectives (LOs) were subject to a prioritization in 3 categories (A, B and C) by means of a questionnaire as part of a Delphi method, in collaboration with all members of the DGN holding a "venia legendi" as experts. Category A defined the essential LOs for each medical practitioner. The prioritization was made by ranking the frequency of the A-classifications. In the 2nd step of the Delphi method, a list of LOs with the ranking positions 1-5 in each domain was presented to the first round's experts as a core curriculum, asking either for acceptance or modifications. RESULTS: The results of the 1st step of the Delphi method deliver a return rate of 29% of the questionnaires (55 out of 184). The 2nd round shows a return rate of 30.9% (57 out of 184) and full approval of the proposed LOs in all LO domains by in median 72 % of the experts consulted (61%-81%). The present final version contains 37 competency-based LOs in the LO domains "legal basis and radiation protection", "basic science", indications and contra-indications for "PET/CT", "scintigraphy and SPECT", "patient preparation", "image interpretation" as well as "therapy". CONCLUSION: The Competency-based Learning Objective Catalogue for Nuclear Medicine describes the knowledge and competencies, every physician should have at the end of his medical studies. The LO catalogue is a living document, which needs to be adapted continuously to the progress of the medical and technological development.

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence.

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 × 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

CD20-Specific Immunoligands Engaging NKG2D Enhance γδ T Cell-Mediated Lysis of Lymphoma Cells.

Human γδ T cells are innate-like T cells which are able to kill a broad range of tumour cells and thus may have potential for cancer immunotherapy. The activating receptor natural killer group 2 member D (NKG2D) plays a key role in regulating immune responses driven by γδ T cells. Here, we explored whether recombinant immunoligands consisting of a CD20 single-chain fragment variable (scFv) linked to a NKG2D ligand, either MHC class I chain-related protein A (MICA) or UL16 binding protein 2 (ULBP2), could be employed to engage γδ T cells for tumour cell killing. The two immunoligands, designated MICA:7D8 and ULBP2:7D8, respectively, enhanced cytotoxicity of ex vivo-expanded γδ T cells against CD20-positive lymphoma cells. Both Vδ1 and Vδ2 γδ T cells were triggered by MICA:7D8 or ULBP2:7D8. Killing of CD20-negative tumour cells was not induced by the immunoligands, indicating their antigen specificity. MICA:7D8 and ULBP2:7D8 acted in a dose-dependent manner and induced cytotoxicity at nanomolar concentrations. Importantly, chronic lymphocytic leukaemia (CLL) cells isolated from patients were sensitized by the two immunoligands for γδ T cell cytotoxicity. In a combination approach, the immunoligands were combined with bromohydrin pyrophosphate (BrHPP), an agonist for Vδ2 γδ T cells, which further enhanced the efficacy in target cell killing. Thus, employing tumour-directed recombinant immunoligands which engage NKG2D may represent an attractive strategy to enhance antitumour cytotoxicity of γδ T cells.

Microenvironmental interactions between endothelial and lymphoma cells: a role for the canonical WNT pathway in Hodgkin lymphoma.

The interaction between vascular endothelial cells (ECs) and cancer cells is of vital importance to understand tumor dissemination. A paradigmatic cancer to study cell-cell interactions is classical Hodgkin Lymphoma (cHL) owing to its complex microenvironment. The role of the interplay between cHL and ECs remains poorly understood. Here we identify canonical WNT pathway activity as important for the mutual interactions between cHL cells and ECs. We demonstrate that local canonical WNT signaling activates cHL cell chemotaxis toward ECs, adhesion to EC layers and cell invasion using not only the Wnt-inhibitor Dickkopf, tankyrases and casein kinase 1 inhibitors but also knockdown of the lymphocyte enhancer binding-factor 1 (LEF-1) and ß-catenin in cHL cells. Furthermore, LEF-1- and ß-catenin-regulated cHL secretome promoted EC migration, sprouting and vascular tube formation involving vascular endothelial growth factor A (VEGF-A). Importantly, high VEGFA expression is associated with a worse overall survival of cHL patients. These findings strongly support the concept that WNTs might function as a regulator of lymphoma dissemination by affecting cHL cell chemotaxis and promoting EC behavior and thus angiogenesis through paracrine interactions.

WNT5A: a motility-promoting factor in Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) has a typical clinical manifestation, with dissemination involving functionally neighboring lymph nodes. The factors involved in the spread of lymphoma cells are poorly understood. Here we show that cHL cell lines migrate with higher rates compared with non-Hodgkin lymphoma cell lines. cHL cell migration, invasion and adhesion depend on autocrine WNT signaling as revealed by the inhibition of WNT secretion with the porcupine inhibitors Wnt-C59/IWP-2, but did not affect cell proliferation. While application of recombinant WNT5A or WNT5A overexpression stimulates HL cell migration, neither WNT10A, WNT10B nor WNT16 did so. Time-lapse studies revealed an amoeboid type of cell migration modulated by WNT5A. Reduced migration distances and velocity of cHL cells, as well as altered movement patterns, were observed using porcupine inhibitor or WNT5A antagonist. Knockdown of Frizzled5 and Dishevelled3 disrupted the WNT5A-mediated RHOA activation and cell migration. Overexpression of DVL3-K435M or inhibition of ROCK (Rho-associated protein kinase) by Y-27632/H1152P disrupted cHL cell migration. In addition to these mechanistic insights into the role of WNT5A in vitro, global gene expression data revealed an increased WNT5A expression in primary HL cells in comparison with normal B-cell subsets and other lymphomas. Furthermore, the activity of both porcupine and WNT5A in cHL cells had an impact on lymphoma development in the chick chorionallantoic membrane assay. Massive bleeding of these lymphomas was significantly reduced after inhibition of WNT secretion by Wnt-C59. Therefore, a model is proposed where WNT signaling has an important role in regulating tumor-promoting processes.

99mTc-DPD SPECT/CT for localisation of inflammatory and chronic osteoarthritis of the foot and ankle. Comparison with planar imaging and SPECT as a clinical adjunct in radiosynovectomy.

AIM: The precise localisation of osteoarthritic and inflammatory changes is crucial for selective treatment planning of radiosynovectomy (RSV). The present study evaluated the diagnostic accuracy of planar bone imaging and SPECT for the detection of pathological bone metabolism and inflammation in joints of the foot and ankle, compared with SPECT/CT. PATIENTS, METHODS: 39 patients (mean age 65.6 ± 11.1 years) with suspected inflammatory osteoarthritis underwent SPECT/CT of the feet. After injection of approximately 500 MBq 99mTc DPD, all patients had three-phase planar bone imaging and late-phase hybrid SPECT/CT. late-phase SPECT, and CT of the foot. Increased bone metabolism and blood-pool was assigned to the respective joint of the fore-, mid-, and hindfoot, using SPECT/CT as the reference standard. RESULTS: Overall, SPECT had a higher sensitivity than planar imaging (0.80 vs 0.68, n.s.). The advantage of SPECT was most obvious in the anatomically complex midfoot area (0.63 vs 0.26, p < 0.05) and less obvious in the forefoot (0.85 vs 0.79, n.s.) and hindfoot (0.89 vs 0.89, n.s.). The overall concordance (Cohen`s Kappa) between SPECT/CT and planar (late-phase) imaging and SPECT was high for the forefoot and the hindfoot (planar: 0.78/0.81; SPECT 0.86/0.88) and comparatively low for the midfoot (planar: 0.27; SPECT 0.61). CONCLUSION: SPECT was significantly superior to planar bone imaging for the detection of joint lesions in the midfoot. The differences between SPECT and planar imaging in the fore- and hindfoot were not significant, most likely due to the inherently less complex anatomy. Compared with SPECT alone, a benefit from the use of SPECT/CT can be observed in the midfoot region where it facilitates the identification of the correct joint for RSV.

Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.

We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.

PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways.

Recent studies suggest that the signal molecules cAMP and cGMP have antifibrotic effects by negatively regulating pathways associated with fibroblast to myofibroblast (MyoCF) conversion. The phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, which leads to a remarkable increase in cAMP hydrolysis and thus mediates a negative cross-talk between both pathways. PDE2 has been recently investigated in cardiomyocytes; here we specifically addressed its role in fibroblast conversion and cardiac fibrosis. PDE2 is abundantly expressed in both neonatal rat cardiac fibroblasts (CFs) and cardiomyocytes. The overexpression of PDE2 in CFs strongly reduced basal and isoprenaline-induced cAMP synthesis, and this decrease was sufficient to induce MyoCF conversion even in the absence of exogenous profibrotic stimuli. Functional stress-strain experiments with fibroblast-derived engineered connective tissue (ECT) demonstrated higher stiffness in ECTs overexpressing PDE2. In regard to cGMP, neither basal nor atrial natriuretic peptide-induced cGMP levels were affected by PDE2, whereas the response to nitric oxide donor sodium nitroprusside was slightly but significantly reduced. Interestingly, despite persistently depressed cAMP levels, both cGMP-elevating stimuli were able to completely prevent the PDE2-induced MyoCF phenotype, arguing for a double-tracked mechanism. In conclusion, PDE2 accelerates CF to MyoCF conversion, which leads to greater stiffness in ECTs. Atrial natriuretic peptide- and sodium nitroprusside-mediated cGMP synthesis completely reverses PDE2-induced fibroblast conversion. Thus PDE2 may augment cardiac remodeling, but this effect can also be overcome by enhanced cGMP. The redundant role of cAMP and cGMP as antifibrotic meditators may be viewed as a protective mechanism in heart failure.

Innate immune responses of airway epithelial cells to infection with equine herpesvirus-1.

Equine herpesvirus-1 (EHV-1) is the cause of respiratory disease, abortion and myelitis in horses worldwide. Protection following infection or vaccination is typically incomplete and this lack of protective immunity is thought to be due to the immunomodulatory properties of EHV-1. EHV-1 immune modulation is likely initiated early in the infection cycle at the respiratory epithelium, but to date, immunity to EHV-1 at the epithelial cell barrier remains poorly characterized. Thus, the purpose of this study was to use a recently established primary equine respiratory epithelial cell culture (EREC) system to characterize innate immunity to EHV-1. Differentiated ERECs were inoculated with a neuropathogenic strain of EHV-1 and cytokine responses were determined using quantitative real-time polymerase chain reaction and ELISA. Major histocompatibility complex (MHC)-I and MHC-II as well as toll-like receptor (TLR)3 and TLR9 protein expression were examined using fluorescence activated cell-sorting analysis and chemotaxis of neutrophils and monocytes were evaluated using chemotaxis assays. Infection with EHV-1 resulted in increased expression of TLR3 and 9 as well as inflammatory cytokines (IL-1, TNF-alpha, IFN-alpha, and IL-6) and chemokines (IL-8, MCP-1). In contrast, EHV-1 infection caused marked decreases of MHC-I and MHC-II expression as well as a reduction in IFN-gamma production. In summary, these results provide an initial characterization of the early immune response to EHV-1 at the epithelial cell barrier and show that, while EHV-1 maintains induction of an inflammatory response, it causes an attenuation of IFN-gamma responses and down-modulates expression of MHC-I and MHC-II, which are important molecules for antigen presentation.

[Evaluation of serum cobalamin concentration in cats with clinical signs of gastrointestinal disease]. / Untersuchungen zur Serumcobalaminkonzentration bei Katzen mit gastrointestinaler Symptomatik.

Medical records of 261 cats presenting with gastrointestinal disease that had a serum cobalamin concentration measured were reviewed. In addition, a reference range for cobalamin (305 - 1.967ng/L) was established using 22 healthy adult cats with undetectable levels of urinary methylmalonic acid. A total of 108 of 261 cats (41.4 %) had hypocobalaminemia; 69 cats (26.4 %) had cobalamin concentrations below the detection limit of the assay (< 150ng/L, group A) and 39 (15 %) had concentrations between 150 - 304ng/L (group B). The remaining 153 (58.6 %) cats had normal cobalamin concentrations (group C). Diarrhea was the most common clinical sign in hypocobalaminemic cats and vomiting or anorexia was the most common sign in normocobalaminemic cats. Only cats with both, vomiting and diarrhea were more likely to have hypocobalaminemia than cats with other clinical signs (odds ratio, 2.879; 95 % CI, 1.313 - 6.310). Serum cobalamin concentration was negatively correlated with age of the patient and positively correlated with body condition score. Cats of group A had a significantly higher neutrophil count (p = 0.0009) and higher MCV (p = 0.0064) and significantly lower hematocrit (p = 0.0018) and albumin concentration (p = 0.0037) than cats in other groups. There was no difference between cats of groups B and C with respect to complete blood cell counts and metabolic profiles. Among the diagnoses made in 125 cats (A 69.6 %, B 59 %, C 35.3 %), lymphoma and inflammatory enteropathy were most common. Lymphoma was diagnosed in 31.2 % (A 53.8 %, B 15.4 %, C 30.8 %) and inflammatory enteropathy in 22.4 % (A 35.7 %, B 7.1 %, C 57.2 %) of cats. Hypocobalaminemia is a frequent problem in cats with gastrointestinal disease. Presenting clinical signs as well as laboratory results may already indicate its probability and severity. However, only values below the detection limit of the assay seem to affect routine bloodwork results. Cobalamin should be routinely measured in feline gastrointestinal disease, as its serum concentration may influence the choice of further diagnostics.