Suppression of myocardial glucose metabolism in FDG PET/CT: impact of dose variation in heparin bolus pre-administration.

INTRODUCTION: Adequate suppression of physiologic myocardial glucose uptake is important to ensure the interpretability and diagnostic reliability of [18F]fluorodeoxyglucose (FDG) PET/CT studies performed in the context of cardiac inflammation and infection. This study describes our experience with 4 preparatory protocols used in our institution. METHODS: FDG PET/CT scans were performed according to 4 preparatory protocols (716 scans total), i.e. 6-h fast (group 1), low-carbohydrate diet plus 12-h fast (group 2), low-carbohydrate diet plus 12-h fast plus intravenous heparin pre-administration (15 IU/kg) (group 3), and low-carbohydrate diet plus 12-h fast plus intravenous heparin pre-administration (50 IU/kg) (group 4). Consecutive scans were retrospectively included from time frames during which the particular protocol was used. FDG uptake in normal myocardium was scored on a scale ranging from 0 (uptake less than that in the left ventricular blood pool) to 4 (diffuse uptake greater than that in the liver). Complete suppression was defined as uptake less than or equal to the blood pool (scores 0-1). RESULTS: Complete suppression was accomplished in 27% in group 1, 68% in group 2, 69% in group 3 and 81% in group 4. Complete suppression was significantly lower in group 1 compared with all other groups (P < 0.0001 for all comparisons) and significantly higher in group 4 compared with group 2 (P = 0.005) and group 3 (P = 0.007). Groups 2 and 3 did not differ significantly (P = 0.92). CONCLUSION: A total of 50 IU/kg single-dose heparin administration before FDG PET/CT in addition to a low-carbohydrate diet and prolonged fast significantly outperformed protocols with no or lower dose (15 IU/kg) heparin in completely suppressing myocardial glucose metabolism.

Varying development of femoral and tibial subchondral bone tissue and their interaction with articular cartilage during progressing osteoarthritis.

INTRODUCTION: Differences between tibial and femoral joint surfaces and knee compartments concerning coupled bone and cartilage turnover or bone-cartilage cross talk have not been previously examined, although the mechanical and biological interaction of the mineralized subchondral tissues with articular cartilage is of great importance for advancing osteoarthritis. MATERIALS AND METHODS: Therefore, with the help of immunohistochemistry and real-time polymerase chain reaction (RT-PCR), human knee joint cartilage tissue was investigated for expression of key molecules of the extracellular matrix and cartilage composition (collagen type I and II, aggrecan) plus proteoglycan content (colorimetric analysis). Furthermore, we correlated the results with 3D microcomputed tomography of the underlying subchondral bone (high-resolution micro-CT system). Measurements were performed in dependence of the anatomical site (femoral vs. tibial, medial and lateral each) to identify regional differences during the osteoarthritic process. From an enduring series of 108 patients undergoing implantation of TKA, 34 osteochondral samples with lesions macroscopically classified as ICRS grade 1b (group A) and 34 samples with ICRS grade 3a/3b lesions (group B) were compared with 21 healthy controls. RESULTS: Concerning 3D analysis, the medial femoral condyle and tibia showed the most significant increase in bone volume fraction and a decrease in the trabecular number in group B frequently accompanied by subchondral bone resorption pits and enchondral ossification. Under physiological conditions, tibia plateaus show lower bone volume fraction than the corresponding femoral site and this difference enlarges with advancing OA. Partially even contradictory behavior was observed such as trabecular separation at the lateral tibial and medial plateau in osteochondral OA samples of the same patients. Collagen type II expression levels show faster and varying changes than type I during the OA process, leading to a lower positive or negative correlation with bone microstructural analysis, especially on the tibia plateau. CONCLUSIONS: Structural bone and cartilage parameter changes showed varying developments and correlations among each other in the different compartments of the knee. As a clinical conclusion, therapies to postpone or prevent cartilage degeneration by influencing the loss of mineralized bone could be site dependent.

The Effect of Early Thyroidectomy on the Course of Active Graves' Orbitopathy (GO): A Retrospective Case Study.

The aim of the work was to investigate the effect of early thyroidectomy on the course of active Graves' orbitopathy (GO) in patients with low probability of remission [high TSH receptor antibody (TRAb) serum levels, severe GO] compared to that of continued therapy with antithyroid drugs. Two cohorts were evaluated retrospectively (total n=92 patients with active GO, CAS≥4). Forty-six patients underwent early thyroidectomy (Tx-group) 6±2 months after initiation of antithyroid drug (ATD) therapy, while ATD was continued for another 6±2 months in the ATD-group (n=46). These controls were consecutively chosen from a database and matched to the Tx-group. GO was evaluated (activity, severity, TRAb) at baseline and at 6 month follow-up. At baseline, both cohorts were virtually identical as to disease severity, activity and duration, as well as prior anti-inflammatory treatment, age, gender, and smoking behavior. At 6 month follow-up, NOSPECS severity score was significantly decreased within each group, but did not differ between both groups. However, significantly more patients of the Tx-group presented with inactive GO (89.1 vs. 67.4%, * p=0.02), and mean CAS score was significantly lower in Tx-group (2.1) than in ADT-group (2.8; * p=0.02) at the end of follow-up. TRAb levels declined in both groups (Tx-group: from 18.6 to 5.2 vs. ATD-group: 12.8-3.2 IU/l, p0=0.07, p6months=0.32). Residual GO activity was lower in Tx-group, associated with a higher rate of inactivation of GO. This allows an earlier initiation of ophthalmosurgical rehabilitation in patients with severe GO, which may positively influence quality of life of the patients.

[Tumours and metastases of the spine : cavity/coblation surgery and vertebroplasty/kyphoplasty]. / Tumoren und Metastasen an der Wirbelsäule : Cavity/Coblation-Operation und Vertebro-/Kyphoplastie.

BACKGROUND: Radical surgery for metastases in the spine is in many cases not possible, includingthe higher risk of surgery in older patients with co-morbidities. The aims of treatment are: minimally invasive and maximally effective tumour removal, fracture position, stabilization, pain reduction, and improved quality of life. The specific features and problems of diagnosis and treatment using the cavity/coblation method, , the surgical technique, and the results of the treatment of 250 patients with spinal tumours/metastases are presented. MATERIALS AND METHODS: Tumour resection is carried out by plasma field, via percutaneous trans-/extrapedicular access, followed by kyphoplasty. Clinical and radiological follow-up was carried out postoperatively, including data on pain reduction and improvement of quality of life. RESULTS: Within 6 years (March 2008t February 2014) a total of 250 patients, or 812 spines were treated. In 59 cases dorsal percutaneous instrumentation and straightening were carried out. Minimal blood loss and a very low complication rate were recorded. After surgery, significant pain reduction, satisfaction, early mobilization, and improvement in quality of life were demonstrated in all patients. Immediate radio- and chemotherapy could be carried out. In 38 cases cement escaped laterally into the intervertebral space, but this had no clinical relevance. 188 patients have since died because of tumour manifestations. CONCLUSIONS: The cavity/coblation method has been demonstrated to be a safe, minimally invasive procedure, with good short- and long-term results and lower complication rates. A comprehensive diagnostic, including tumour staging, the correct indication, and prognosis estimation, is important.

[Contralateral Recession of the Inferior Oblique Muscle in Grave's Disease Patients with Mild M. rectus inferior fibrosis]. / Prinzip Gegenparese: M.-obliquus-inferior-Rücklagerung bei Patienten mit endokriner Orbitopathie.

INTRODUCTION: The aim of this study was to evaluate the dose effect and the resulting binocular single vision for inferior oblique muscle recession in patients with Grave's orbitopathy. METHODS AND PATIENTS: The evaluation covered all patients (n = 13) between 2010-2013 treated with recession of the inferior oblique muscle for vertical deviation caused by inferior fibrosis of the contralateral eye. The inclusion criterion was a small vertical squint angle with excyclotorsion. The corrected vertical squint angle was 3.75° [7 pdpt] (median, min 1.5° [3 pdpt], max 8° [16 pdpt]) in primary position and 5.5° in adduction [11pdpt] (median, min 3°[6 pdpt], max 9°[18pdpt]). Excyclotorsion was 4° [8 pdpt] (median, min 1° [2 pdpt], max 9° [18 pdpt]). Elevation was only slightly impaired and the side difference was 5° (median). The recession distance was preoperatively determined: 0.5° squint angle reduction per mm recession distance (calculation from patients who received surgery before 2010). RESULTS: Inferior oblique recession generated a good field of binocular single vision (BSV) for all patients. All patients reached BSV in the central area (20°) and within 30° of downgaze. Sixty nine percent of the patients were completely diplopia free in downgaze. Diplopia persisted in more than half of the patients in up gaze outside 15°. Squint reduction was 0.5° [1 pdpt] [0.45-0.67]/per mm recession distance in primary position and 0.65° [1.3 pdpt] [0.55-0.76]/per mm for the vertical deviation in adduction. Excyclotorsion was reduced to ≤ 2° in 77 % of the patients. CONCLUSION: Inferior oblique muscle recession can be very successfully performed on the contralateral eye in patients with mild inferior rectus muscle fibrosis. Surgery at the contralateral yoke muscle prevents the risk of overeffect with resulting diplopia in downgaze, which could occur if small distance recession had been performed at the inferior rectus muscle. An overeffect in relation to inferior oblique recession will only cause diplopia in upgaze, which is much less troublesome in daily routine.

Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Bronchoalveolar lavage fluid exosomes contribute to cytokine and leukotriene production in allergic asthma.

BACKGROUND: Leukotrienes (LTs) are potent pro-inflammatory mediators involved in asthma. Exosomes, nanosized vesicles released from various cells, can stimulate or down-regulate immune responses, depending on the state and nature of the originating cell. We have recently shown an altered exosome profile in bronchoalveolar lavage fluid (BALF) of patients with sarcoidosis, but their role in asthma is unknown. Our aims were to investigate whether exosomes from BALF have LT biosynthetic capacity and to explore phenotypic and functional characteristics of BALF exosomes in asthma. METHODS: Bronchoalveolar lavage fluid exosomes were collected from healthy individuals (n = 13) and patients with mild allergic asthma to birch pollen (n = 12) before and after birch allergen provocation. Exosomes were characterized by flow cytometry and Western blot. Their capacity to induce IL-8 and LT production in the human bronchial epithelial cell (BEC) line 16HB14o- was measured by ELISA and reverse-phase HPLC, respectively. RESULTS: Compared to BALF exosomes from healthy individuals, BALF exosomes from asthmatics displayed higher levels of exosome-associated markers, such as the tetraspanins CD63 and CD81 and the scavenger receptor CD36. No major differences were observed between BALF exosomes from before and after allergen provocation. Furthermore, we show that BALF exosomes contain enzymes for LT biosynthesis. The effect of exosomes to promote LTC(4) and IL-8 release in BEC was significantly increased for exosomes from asthmatics, and the CysLT(1) receptor antagonist Montelukast reduced exosome-induced IL-8 secretion. CONCLUSIONS: Bronchoalveolar lavage fluid exosomes from asthmatic and healthy individuals exhibit distinct phenotypes and functions. BALF exosomes from asthmatics might contribute to subclinical inflammation by increasing cytokine and LTC(4) generation in airway epithelium.

[Graves' orbitopathy]. / Endokrine Orbitopathie.

Graves' orbitopathy (GO) is part of an autoimmune systemic disease (prevalence of 0.5 - 2%) which is composed of hyperthyroidism, orbitopathy, dermopathy and acropachy. Stimulating antibodies against the TSH receptor plays the central pathogenetic role and high levels indicate the risk of a severe course of the disease. The main symproms of GO comprise soft tissue inflammation, proptosis impairment of ocular motility and lid retraction. Inflammatory reactions of orbital fibroblasts are responsible for the symptoms. To restrict damage, anti-inflammatory therapy (mainly i. v. systemic steroids, orbital irradiation) is indicated in moderate to severe active disease stages, and surgical orbital decompression is indicated in sight-threatening states. In mild GO selenium administration and otherwise a wait and see strategy is sufficient. In inactive disease stages surgery (orbital decompression, eye muscle surgery and lid surgery) is performed to improve appearance and function. Smoking increases the prevalence and severity of GO and reduces the efficiency of therapy. Restoring euthyroidism leads to an improvement of GO in about 60% of the patients.

[A temporal tarsorrhaphy increases the effect of lower lid lengthening in patients with Graves' orbitopathy]. / Durch eine kleine temporale Tarsorrhaphie lässt sich der Effekt der Unterlidverlängerung mit Implantat bei Patienten einer Endokrinen Orbitopathie signifikant steigern.

OBJECTIVE: The aim of this study was to compare outcomes of lower lid lengthening with and without an additional temporal tarsorrhaphy. METHODS: Lower lid lengthening was performed in 39 patients (16 without tarsorrhaphy [group 1], 23 with tarsorrhaphy [group 2]) via a posterior subtarsal transconjunctival ac-ess. A bovine pericardial transplant (Tutopatch, length = amount of retraction + 4 mm) was placed between the recessed retractors and the tarsus. RESULTS: Mean preoperative lower lid retraction was 2.3 mm in group 1 and 2.6 mm in group 2 (n. s.). Lower lid lengthening and simultaneous tarsorrhaphy resulted in significantly increased reduction of lower lid retraction: 2.3 mm (1.5 - 4.5) (p = 0.003) compared to patients without tarsorrhaphy: 1.4 mm (0 - 3.0). Patients with tarsorrhaphy presented a higher success rate concerning the elimination of lagophthalmos (success = lagophthalmos ≤ 0.5 mm: 21 / 23 (91.3 %) as opposed to patients without tarsorrhaphy: 8 / 16 (50 %); (p = 0.004). Scleral show was eliminated in 78 % of group 2 in comparison to only 50 % in group 1 (p = 0.06). CONCLUSIONS: Lower lid lengthening should be combined with simultaneous temporal tarsorrhaphy in patients with lower lid retraction exceeding 1.5 mm. The tarsorrhaphy increases the effect of lower lid lengthening by about 1 mm.

[Graves' orbitopaty: inferior rectus tendon elongation for large vertical squint angles that cannot be corrected by simple muscle recession]. / Endokrine Orbitopathie: M.-rectus-inferior-Sehnenverlängerung bei großen vertikalen Schielwinkeln, die nicht durch eine einfache Muskelrücklagerung korrigiert werden können.

BACKGROUND: In motility disorders related to Graves' orbitopathy, recession of fibrotic eye muscles is the treatment of choice. Correction of very large squint angles can be difficult, since the distance of recession is limited by the necessity to maintain a sufficient arc of contact. A new technique of tendon elongation has been developed in order to maintain sufficient arcs of contact even in patients with large horizontal squint angles, especially after orbital decompression surgery. The established dose-effect relationship cannot simply be conveyed to inferior rectus muscle surgery, due to a different impact of simple recession on inferior and medial rectus muscles. METHODS: Recession of the inferior rectus muscle was performed in 10 patients with simultaneous suturing of bovine pericardium (Tutopatch). This procedure was performed as primary surgery in 7 patients (2 after orbital decompression) and as secondary procedure in 3 patients. Squint angle (far distance), bulbus excursion movements and field of binocular single vision were evaluated pre- and postoperatively. RESULTS: Alignment (far distance) was achieved in 8 of 10 cases at the final follow-up examination. Two patients required corrective prisms. Visual fields were virtually free of diplopia in all patients. The dose-response effect for tendon elongation of the inferior rectus muscle was identical to that for the simple recession of this muscle. There were no complications. CONCLUSIONS: The new technique of tendon elongation using a bovine pericardium graft is applicable in large vertical squint angles (with or without prior bony orbital decompression) as well as for corrections after insufficient simple recessions (by realignment of the muscle and secondary suturing of the graft). Functional improvement can thus be achieved through surgery of a single muscle, keeping the other muscles in reserve for further interventions (lowering the risk of postoperative anterior segment ischaemia). There is a dose effect analogous to large horizontal squint angles in Graves' orbitopathy (dosing formula: 1 mm inferior rectus recession [including graft] leads to 2.0° vertical angle reduction). This corresponds to simple recessions of the inferior rectus muscle but differs from tendon elongations of the medial rectus muscles.

Clinical value of TSH receptor antibodies measurement in patients with Graves' orbitopathy.

Graves' orbitopathy (GO) is part of an autoimmune disease, in which TSH-receptor antibodies (TRAb) stimulate the target organs. Most of these patients develop hyperthyroidism and about half an orbitopathy. To ensure the diagnosis, TRAb are determined, especially in patients with GO without associated thyroid disease. Because of their significantly improved sensitivity and equal specificity, second generation TRAb-assays should be preferred. Persisting high TRAb levels are associated with a severe course of GO. TRAb cut off levels are available for prognostic statements during the course of GO and can be applied for crucial treatment decisions. Persisting high TRAb levels are also associated with low remission rates of hyperthyroidism. TRAb cut off levels are available for prognostic statements at 6, 12 and 18 months after the beginning of antithyroid drug treatment. Definitive treatment of the thyroid can be decided early on this basis, which is an advantage for ophthalmosurgical rehabilitation.

[Graves' ophthalmopathy]. / Endokrine Orbitopathie.

Graves' orbitopathy is part of an autoimmune systemic disease which compiles hyperthyroidism, orbitopathy, dermopathy and acropachy. Stimulating antibodies against the TSH receptor play the central pathogenetic role. Main symptoms of Graves' orbitopathy comprise soft tissue inflammation, proptosis impairment of ocular motility and lid retraction. Inflammatory reactions of orbital fibroblasts are responsible for the symptoms. To restrict damage anti-inflammatory therapy (mainly systemic steroids, orbital irradiation) is indicated in moderate to severe active disease stages, and surgical orbital decompression in sight threatening states. In mild cases expectant strategy and selenium administration is sufficient. In inactive disease stages surgery is performed to improve appearance and function. Restoring euthyroidism leads to improvement of Graves' orbitopathy in about 60% of the patients. Radioiodine therapy without glucocorticoids is associated with a small but significant risk (15%) of deterioration or relapse. Thyroidectomy is neutral in later stages but may improve Graves' orbitopathy in early active stages.

Current insights into the pathogenesis of Graves' orbitopathy.

Graves' orbitopathy (GO) is part of an autoimmune disease constellation comprising hyperthyroidism, orbitopathy, pretibial myxedema, and acropachy. Signs and symptoms of GO occur due to inflammation of the orbital connective tissue, inflammation and fibrosis of the extraocular muscles, and adipogenesis. Stimulatory TSH receptor (TSHR) antibodies (TRAb) cause hyperthyroidism, but pathogenetic mechanisms in the orbit are less clear. The TSHR is one of the favoured candidate antigens; others such as the IGF1R might also play a role. Compared with other anatomical locations, orbital fibroblasts are extremely reactive to inflammatory stimuli, especially via CD40 activation. Orbital fibroblasts also differentiate into adipocytes, in response to the prevailing inflammatory cytokine milieu. Consequently TSHR gene expression increases together with expression of adipogenesis related genes. The same genes that confer susceptibility to Graves' disease (GD), both thyroid specific and immunoregulatory, also influence GO, although an increasing number of candidate genes with higher impact on orbitopathy are being identified. Smoking is the only environmental factor known to increase the likelihood and severity of GO developing in GD patients. A robust animal model of GO would facilitate the evaluation of new treatments. To date most models have centered on provoking autoimmune responses to the TSHR, but other antigens, alone or in combination with this receptor, hopefully will succeed in inducing the full spectrum of GD.

The T393C polymorphism of the Galphas gene (GNAS1) is associated with the course of Graves' disease.

Genotypes of the T393C SNP of GNAS1, a gene that encodes for the Galphas subunit of G proteins have been significantly associated with the clinical course in a variety of cancers. Since this SNP may also influence the course of Graves' disease (GD) and, especially, Graves' ophthalmopathy (GO), we determined genotype and allele frequency in a series of 359 patients, which were referred to our clinic within 6 months of the onset of GO. Among them, 336 patients also suffered from associated hyperthyroidism. Data on relapse and remission rates 12 months after termination of a 1 year antithyroid drug therapy was available for 276 patients. As controls, 820 healthy individuals were recruited. Our data suggest that the T393C SNP does not represent a risk factor for the development of both GD and GO. It was, however, significantly associated with the course of hyperthyroidism (p=0.013) and a similar trend was evident for the course of GO (p=0.093). Homozygous TT carriers showed a significantly increased risk (p=0.03) for hyperthyroidism to relapse (OR 2.4; 95% CI 1.1-5.4). Also, the TT genotype was associated with significantly increased serum TRAb levels (CC+CT: 5.4 IU/l vs. TT: 9.3 IU/l). This is probably caused by increased G-Protein susceptibility to TSHR-mediated stimulation through TRAb. Genotyping of the T393C SNP of GNAS1 may become a useful additional tool to predict the clinical course of GD and GO. This may allow the clinician to identify patients at risk for more severe courses of disease and to come to more timely decisions for treatment.