[The subanalysis of Rheuma-VOR demonstrates a considerable need for rheumatological care]. / Die Subanalyse von Rheuma-VOR zeigt den erheblichen Bedarf der rheumatologischen Versorgung auf.

BACKGROUND: Early diagnosis and treatment of inflammatory rheumatic diseases can prevent consequential damage such as permanently limited mobility and joint or organ damage. Simultaneously, there is an increasing deficit in medical care owing to the lack of rheumatological capacity. Rural regions are particularly affected. OBJECTIVES: The available unconfirmed diagnoses of the study Rheuma-VOR were analysed regarding another definitive inflammatory rheumatic disease. MATERIALS AND METHODS: The returned questionnaires of the rheumatologists participating in Rheuma-VOR were screened for definitive inflammatory rheumatic diseases other than the required diagnosis of rheumatoid arthritis, psoriatic arthritis or spondyloarthritis. RESULTS: Of 910 unconfirmed diagnoses, in 245 patients another definitive diagnosis could be confirmed. A total of 29.8% of the diagnoses corresponded to degenerative joint changes or chronic pain syndrome, whereas 26.1% involved different forms of inflammatory arthritis. The majority of diagnoses (40.5%) were collagenosis or vasculitis, DISCUSSION: The available data show that a rheumatological presentation was indicated for the majority of patients. Owing to the increasing deficits in medical care a prior selection of the patients is crucial to make optimal use of restricted rheumatological capacities.

Selenium deficiency is associated with polyneuropathy in primary Sjögren's syndrome.

BACKGROUND: Selenium plays an important role in the regulation of the immune system. Selenium deficiency is associated with Hashimoto's thyroiditis, a common comorbidity in primary Sjögren's syndrome (pSS). Therefore we aimed to identify whether or not selenium deficiency is also associated with pSS. METHODS: 107 consecutive female patients with pSS and, as a control, 59 female patients with axial spondyloarthritis were recruited. Later, 11 male pSS patients, 5 of these suffering from polyneuropathy, and 15 male axSpA patients were additionally recruited in order to confirm the results from the female patients. All patients were consulted about their diet and food intolerances and their plasma selenium concentrations were analyzed. Current and previous extraglandular manifestations of pSS were recorded. Patients complaining of misperceptions and tingling paraesthesia underwent measurement of nerve conduction velocity. The proportion of patients and controls with a selenium deficiency was compared using Fisher's exact test. RESULTS: The proportion of female pSS patients with a low selenium concentration <0.63 µmol/L (22.4%) was significantly higher than of the controls (1.7%) (p < 0.001). Within the group of female patients with pSS, selenium deficiency was significantly associated with the presence of polyneuropathy (45.8% with vs 14.5% without polyneuropathy, p = 0.003) and particularly polyneuropathy with motor nerve involvement measured by nerve conduction velocity (41.7% with vs 10.8% without motor neuropathy, p = 0.001). The mean selenium concentrations of the 5 male pSS patients with polyneuropathy were significantly lower compared to the 6 pSS patients without polyneuropathy and to the 15 male axSpA controls. CONCLUSIONS: PSS and in particular its complication polyneuropathy is associated with selenium deficiency. Measurement of the selenium concentration in blood is advisable in patients with pSS and in particular in the subset of patients with polyneuropathy. Substitution of selenium may be a possible therapy of polyneuropathy associated with pSS.

[Severe polyneuropathy in primary Sjögren's syndrome : Sjögren's syndrome should be considered in patients with motor neuropathy]. / Schwere Polyneuropathie bei primärem Sjögren-Syndrom : Bei Patienten mit motorischen Neuropathien auch an Sjögren-Syndrom denken!

A 64-year-old male patient developed over a period of 20 years a peripheral neuropathy symmetrically affecting the upper and lower limbs. The histological examination of a sural nerve biopsy revealed a severe axonal neuropathy. Despite extensive laboratory investigations including immunological and metabolic tests the origin could not be identified. Finally, a Schirmer test revealed xerophthalmia. A subsequent salivary gland biopsy from the lower lip revealed a grade III lymphocytic inflammation according to Chisholm and Mason and confirmed the diagnosis of Sjögren's syndrome.

Self-Calibrating Vector Atomic Magnetometry through Microwave Polarization Reconstruction.

Atomic magnetometry is one of the most sensitive ways to measure magnetic fields. We present a method for converting a naturally scalar atomic magnetometer into a vector magnetometer by exploiting the polarization dependence of hyperfine transitions in rubidium atoms. First, we fully determine the polarization ellipse of an applied microwave field using a self-calibrating method, i.e., a method in which the light-atom interaction provides everything required to know the field in an orthogonal laboratory frame. We then measure the direction of an applied static field using the polarization ellipse as a three-dimensional reference defined by Maxwell's equations. Although demonstrated with trapped atoms, this technique could be applied to atomic vapors, or a variety of atomlike systems.

Preoperative platelet transfusions to reverse antiplatelet therapy for urgent non-cardiac surgery: an observational cohort study.

Essentials An increasing number of patients requiring surgery receive antiplatelet therapy (APT). We analyzed 181 patients receiving presurgery platelet transfusions to reverse APT. No coronary thrombosis occurred after platelet transfusion. This justifies a prospective trial to test preoperative platelet transfusions to reverse APT. SUMMARY: Background Patients receiving antiplatelet therapy (APT) have an increased risk of perioperative bleeding and cardiac adverse events (CAE). Preoperative platelet transfusions may reduce the bleeding risk but may also increase the risk of CAE, particularly coronary thrombosis in patients after recent stent implantation. Objectives To analyze the incidence of perioperative CAE and bleeding in patients undergoing non-cardiac surgery using a standardized management of transfusing two platelet concentrates preoperatively and restart of APT within 24-72 h after surgery. Methods A cohort of consecutive patients on APT treated with two platelet concentrates before non-cardiac surgery between January 2012 and December 2014 was retrospectively identified. Patients were stratified by the risk of major adverse cardiac and cerebrovascular events (MACCE). The primary objective was the incidence of CAE (myocardial infarction, acute heart failure and cardiac troponine T increase). Secondary objectives were incidences of other thromboembolic events, bleedings, transfusions and mortality. Results Among 181 patients, 88 received aspirin, 21 clopidogrel and 72 dual APT. MACCE risk was high in 63, moderate in 103 and low in 15 patients; 67 had cardiac stents. Ten patients (5.5%; 95% CI, 3.0-9.9%) developed a CAE (three myocardial infarctions, four cardiac failures and three troponin T increases). None was caused by coronary thrombosis. Surgery-related bleeding occurred in 22 patients (12.2%; 95% CI, 8.2-17.7%), making 12 re-interventions necessary (6.6%; 95% CI, 3.8-11.2%). Conclusion Preoperative platelet transfusions and early restart of APT allowed urgent surgery and did not cause coronary thromboses, but non-thrombotic CAEs and re-bleeding occurred. Randomized trials are warranted to test platelet transfusion against other management strategies.

Platelet transfusion to reverse antiplatelet therapy before decompressive surgery in patients with intracranial haemorrhage.

BACKGROUND: Platelet concentrates (PC) are transfused to improve primary haemostasis before urgent neurosurgery in patients with intracranial haemorrhage (ICH) receiving antiplatelet therapy (APT). It is unresolved, whether PCs increase the risk for major cardio- and cerebrovascular adverse events. We evaluated a standardized transfusion regimen to reverse APT in patients with ICH who required decompressive neurosurgery. METHODS: Analysed were consecutive patients between 2012 and 2014. The primary outcome was the frequency of new arterial thrombotic complications. The secondary outcome was the frequency of recurrent ICH. RESULTS: Of 72 patients, 14 received acetylsalicylic acid and a P2Y12 inhibitor, 53 received acetylsalicylic acid and five clopidogrel. No acute coronary syndrome (95% CI: 0-5·07) and one ischaemic stroke occurred (1·4%; 95% CI: 0·25-7·46). In contrast, 26·4% of patients developed recurrent ICH (95% CI: 17·59-37·58). The risk of bleeding was significantly higher compared to the risk of arterial thrombosis (P < 0·00001) and was increased for patients with chronic ICH (OR: 4·78; 95% CI: 1·57-14·55) and those receiving clopidogrel (OR: 2·78; 95% CI: 0·90-8·57). CONCLUSION: Platelet concentrate transfusion before cranial decompressive surgery in patients with ICH complicating APT showed a low risk for cardio-cerebral thrombotic complications. However, the risk of rebleeding remains high, especially in patients with chronic ICH and those pretreated with clopidogrel.

Diagnosing peri-implant disease using the tongue as a 24/7 detector.

Our ability of screening broad communities for clinically asymptomatic diseases critically drives population health. Sensory chewing gums are presented targeting the tongue as 24/7 detector allowing diagnosis by "anyone, anywhere, anytime". The chewing gum contains peptide sensors consisting of a protease cleavable linker in between a bitter substance and a microparticle. Matrix metalloproteinases in the oral cavity, as upregulated in peri-implant disease, specifically target the protease cleavable linker while chewing the gum, thereby generating bitterness for detection by the tongue. The peptide sensors prove significant success in discriminating saliva collected from patients with peri-implant disease versus clinically asymptomatic volunteers. Superior outcome is demonstrated over commercially available protease-based tests in saliva. "Anyone, anywhere, anytime" diagnostics are within reach for oral inflammation. Expanding this platform technology to other diseases in the future features this diagnostic as a massive screening tool potentially maximizing impact on population health.Early detection of gum inflammation caused by dental implants helps prevent tissue damage. Here, the authors present a peptide sensor that generates a bitter taste when cleaved by proteases present in peri-implant disease, embed it in a chewing gum, and compare the probe to existing sensors using patient saliva.

Transfusion-transmitted CMV infection - current knowledge and future perspectives.

Transmission of human cytomegalovirus (CMV) via transfusion (TT-CMV) may still occur and remains a challenge in the treatment of immunocompromised CMV-seronegative patients, e.g. after stem cell transplantation, and for low birthweight infants. Measures to reduce the risk of TT-CMV have been evaluated in clinical studies, including leucocyte depletion of cellular blood products and/or the selection of CMV-IgG-negative donations. Studies in large blood donor cohorts indicate that donations from newly CMV-IgG-positive donors should bear the highest risk for transmitting CMV infections because they contain the highest levels of CMV-DNA, and early CMV antibodies cannot neutralise CMV. Based on this knowledge, rational strategies to reduce the residual risk of TT-CMV using leucoreduced blood products could be designed. However, there is a lack of evidence that CMV is still transmitted by transfusion of leucoreduced units. In low birthweight infants, most (if not all) CMV infections are caused by breast milk feeding or congenital transmission rather than by transfusion of leucoreduced blood products. For other patients at risk, no definitive data exist about the relative importance of alternative transmission routes of CMV compared to blood transfusion. As a result, only the conduction of well-designed studies addressing strategies to prevent TT-CMV and the thorough examination of presumed cases of TT-CMV will achieve guidance for the best transfusion regimen in patients at risk.

Very low rates of Helicobacter pylori infection in organ transplant recipients presenting with peptic ulcer disease.

BACKGROUND: Leading causative factors of peptic ulcer disease (PUD) in the general population are infection with Helicobacter pylori (HP) and exposure to non-steroidal anti-inflammatory drugs (NSAID). We hypothesized that this may be different in transplant recipients given increased exposure of immunosuppressive and anti-microbial drugs. METHODS: We performed a retrospective single center analysis of all patients presenting with PUD to the endoscopy unit at a tertiary care and transplant center in Germany between 2006 and 2013. PUD was diagnosed by upper endoscopy. HP was identified by biopsy and histology. Organ transplant recipients were compared to non-transplant recipients (control group). RESULTS: 66 patients with PUD were identified in the study period. 12% (44/366) had previously received an organ transplant. 7% (3/44) of transplant recipients were found to be positive for HP compared to 25% (81/322) in the control group (p=0.007). Even when excluding patients taking proton-pump-inhibitors (PPI) from the analysis rates were similar with 30% (65/214) of the ulcers being HP positive in the control group compared to 14% (1/7) in transplant recipients (p=0.006). Furthermore, in the transplant recipient group rates of being in intensive care, concurrent PPI and concurrent antibiotic medication were significantly higher than in the control group. CONCLUSION: Organ transplant recipients with PUD have lower rates of Helicobacter pylori positivity compared to the general population.

Implications of a switch to a 100% apheresis platelet supply for patients and for blood donors: a risk benefit analysis.

BACKGROUND: A 100% apheresis platelet supply is considered to increase transfusion safety by lowering donor exposures for transfusion recipients. We performed a risk benefit analysis to contrast the reduction of donor exposures and the risk of contaminated blood products in the nation-wide inventory with the donor risks associated with a switch to a 100% apheresis platelet supply in Germany. METHODS: Donor exposures and the number of contaminated blood products resulting from HIV-like, HBV-like, HCV-like pathogens and two theoretical agents with infection rates of 10 and 1000 in 100 000, respectively, were calculated for a 100% apheresis platelet supply in Germany based on the 2006-2012 hemovigilance reports. These numbers were compared with the current mixed platelet supply of pooled and apheresis platelets. Moreover, additional donation time and apheresis donor complications resulting from a 100% apheresis platelet supply were estimated. RESULTS: Per million total blood products (red cells, platelets, fresh frozen plasma), a 100% apheresis platelet supply would reduce donor exposures by 87 100 and the number of contaminated blood products ranging from 0·8 to 871·1. On the other hand, this requires additional 29 478 apheresis donations, 3·4 years additional donor time, and would be associated with 58 additional donor complications, respectively. CONCLUSIONS: A 100% apheresis platelet supply would reduce donor exposures and the number of contaminated blood products in the inventory, but would increase apheresis complications in donors. Potential risks for patients must be carefully weighed against the risks for donors, dependent on the specific pathogen scenario.

[Hemostatic management of patients undergoing ear-nose-throat-surgery]. / Perioperatives Hämostasemanagement bei HNO-Eingriffen.

Perioperative hemostatic management is increasingly important in Otolaryngology. This review summarizes the key elements of perioperative risk stratification, thromboprophylaxis, and therapies for bridging of antithrombotic treatment. It gives a practical advise based on the current literature with an emphasis for patients undergoing ear-nose-throat surgery.

Tolerance of platelet concentrates treated with UVC-light only for pathogen reduction--a phase I clinical trial.

BACKGROUND: The THERAFLEX UV-Platelets pathogen reduction system for platelet concentrates (PCs) operates with ultraviolet C light (UVC; 254 nm) only without addition of photosensitizers. This phase I study evaluated safety and tolerability of autologous UVC-irradiated PCs in healthy volunteers. METHODS: Eleven volunteers underwent two single (series 1 and 2) and one double apheresis (series 3). PCs were treated with UVC, stored for 48 h and retransfused in a dose-escalation scheme: 12·5, 25% and 50% of a PC (series 1); one complete PC (series 2); two PCs (series 3). Platelet counts, fibrinogen, activated partial thromboplastin time, prothrombin time, D-dimer, standard haematology, temperature, heart rate, blood pressure and clinical chemistry parameters were measured. One- and 24-h corrected count increments were determined in series 2 and 3. Platelet-specific antibodies were assessed before and at the end of the study. RESULTS: Neither adverse reactions related to transfusions nor antibodies against UVC-treated platelets were observed. Corrected count increments did not differ between series 2 and 3. CONCLUSIONS: Repeated transfusions of autologous UVC-treated PCs were well tolerated and did not induce antibody responses in all volunteers studied. EudraCT No. 2010-023404-26.

Novel calibration tools and validation concepts for microarray-based platforms used in molecular diagnostics and food safety control.

Commercial platforms consisting of ready-to-use microarrays printed with target-specific DNA probes, a microarray scanner, and software for data analysis are available for different applications in medical diagnostics and food analysis, detecting, e.g., viral and bacteriological DNA sequences. The transfer of these tools from basic research to routine analysis, their broad acceptance in regulated areas, and their use in medical practice requires suitable calibration tools for regular control of instrument performance in addition to internal assay controls. Here, we present the development of a novel assay-adapted calibration slide for a commercialized DNA-based assay platform, consisting of precisely arranged fluorescent areas of various intensities obtained by incorporating different concentrations of a "green" dye and a "red" dye in a polymer matrix. These dyes present "Cy3" and "Cy5" analogues with improved photostability, chosen based upon their spectroscopic properties closely matching those of common labels for the green and red channel of microarray scanners. This simple tool allows to efficiently and regularly assess and control the performance of the microarray scanner provided with the biochip platform and to compare different scanners. It will be eventually used as fluorescence intensity scale for referencing of assays results and to enhance the overall comparability of diagnostic tests.

The protective effects of the melanocortin receptor (MCR) agonist, melanotan-II (MTII), against binge-like ethanol drinking are facilitated by deletion of the MC3 receptor in mice.

Recent data have implicated the melanocortin (MC) system in modulating voluntary ethanol consumption. Administration of melanotan-II (MTII), a nonselective melanocortin receptor (MCR) agonist, reduces voluntary ethanol consumption in C57BL/6J mice. Previous studies have demonstrated that central infusion of MTII effectively reduced voluntary ethanol drinking in mutant mice lacking normal expression of MC3R (MC3R-/- mice) but failed to alter ethanol drinking in mice lacking expression of MC4R, demonstrating that central MTII administration reduces voluntary ethanol drinking by signaling through the MC4R. However, evidence shows that the neurocircuitry recruited during excessive binge-like ethanol drinking versus moderate ethanol drinking are not identical. Thus the present study sought to investigate the potential role of the MC3R in binge-like ethanol intake. To this end, the "drinking in the dark" (DID) procedure, a commonly used animal model of binge-like ethanol drinking, was employed. Wild-type MC3R+/+ and MC3R-/- mice were given intracerebroventricular (i.c.v.) infusion of MTII (0.0, 0.25, 0.50, or 1.0 µg) prior to the onset of a 4-h testing period in which mice were given access to 20% (v/v) ethanol. Immediately after the 4-h testing period, tail blood samples were collected from each animal in order to assess blood ethanol concentrations (BECs). Consistent with previous findings, central administration of MTII blunted binge-like ethanol drinking in both MC3R+/+ and MC3R-/- mice. Interestingly, all doses of MTII blunted binge-like ethanol drinking in MC3R-/- mice during the first hour of testing, while only the 1.0 µg dose reduced binge-like drinking in MC3R+/+ mice. Thus, MC3R-/- mice were more sensitive to the protective effects of MTII. These data suggest that MC3Rs oppose the protective effects of MTII against binge-like ethanol drinking, and thus selective MC3R antagonists may have potential therapeutic roles in treating excessive ethanol drinking.

Demonstration of a state-insensitive, compensated nanofiber trap.

We report the experimental realization of an optical trap that localizes single Cs atoms ≃215 nm from the surface of a dielectric nanofiber. By operating at magic wavelengths for pairs of counterpropagating red- and blue-detuned trapping beams, differential scalar light shifts are eliminated, and vector shifts are suppressed by ≈250. We thereby measure an absorption linewidth Γ/2π=5.7±0.1 MHz for the Cs 6S(1/2), F=4→6P(3/2), F'=5 transition, where Γ0/2π=5.2 MHz in free space. An optical depth d≃66 is observed, corresponding to an optical depth per atom d1≃0.08. These advances provide an important capability for the implementation of functional quantum optical networks and precision atomic spectroscopy near dielectric surfaces.

Driving Rydberg-Rydberg transitions from a coplanar microwave waveguide.

The coherent interaction between ensembles of helium Rydberg atoms and microwave fields in the vicinity of a solid-state coplanar waveguide is reported. Rydberg-Rydberg transitions, at frequencies between 25 and 38 GHz, have been studied for states with principal quantum numbers in the range 30-35 by selective electric-field ionization. An experimental apparatus cooled to 100 K was used to reduce effects of blackbody radiation. Inhomogeneous, stray electric fields emanating from the surface of the waveguide have been characterized in frequency- and time-resolved measurements and coherence times of the Rydberg atoms on the order of 250 ns have been determined. These results represent a key element in the development of an experimental architecture to interface Rydberg atoms with solid-state devices.

[Heparin-induced thrombocytopenia]. / Heparininduzierte Thrombozytopenie.

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction that carries an increased risk of thromboembolic complications. HIT is caused by platelet-activating antibodies directed against a complex of platelet factor 4 (PF4) and heparin. HIT typically manifests in the second week after initiation of heparin therapy with a platelet count reduction of more than 50% of the highest level after the start of heparin administration as well as thromboembolic events. The clinical probability can be calculated by the 4 T's score. The laboratory diagnosis of HIT is based on confirmation of PF4/heparin antibodies or on functional tests that provide evidence of heparin-dependent platelet-activating antibodies. A low 4 T's score and negative HIT test virtually rule out the presence of HIT. Patients with acute HIT require anticoagulation with a compatible anticoagulant in a therapeutic dose. The drugs currently available for this include the direct thrombin inhibitors argatroban, lepirudin, bivalirudin, and desirudin and the indirect factor Xa inhibitors danaparoid and fondaparinux.

Deletion of agouti-related protein blunts ethanol self-administration and binge-like drinking in mice.

The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). Recent pharmacological and genetic evidence suggests that melanocortin receptor (MCR) signaling modulates neurobiological responses to ethanol and ethanol intake. Agouti-related protein (AgRP) is synthesized by neurons in the arcuate nucleus of the hypothalamus and is a natural antagonist of MCRs. Because central administration of the functionally active AgRP fragment AgRP-(83-132) increases ethanol intake by C57BL/6 J mice, we determined if mutant mice lacking normal production of AgRP (AgRP(-/-)) and maintained on a C57BL/6 J genetic background would show reduced self-administration of ethanol relative to littermate wild-type (AgRP(+/+)) mice. AgRP(-/-) mice showed reduced 8% (v/v) ethanol-reinforced lever-pressing behavior relative to AgRP(+/+) mice in daily 2-h sessions, but normal sucrose-, saccharin- and water-reinforced lever-pressing. Similarly, AgRP(-/-) mice showed reduced consumption of 8% ethanol in a two-bottle limited access test (2 h/day), although this effect was largely sex-dependent. Using drinking-in-the-dark (DID) procedures, AgRP(-/-) mice showed blunted binge-like drinking of 20% (v/v) ethanol which was associated with lower blood ethanol levels (85 mg/dl) relative to AgRP(+/+) mice (133 mg/dl) after 4 h of intake. AgRP(-/-) mice showed normal ethanol metabolism and did not show altered sensitivity to the sedative effects of ethanol. These observations with genetically altered mice are consistent with previous pharmacological data and suggest that endogenous AgRP signaling modulates the reinforcing properties of ethanol and binge-like ethanol drinking.

Artificial dirt: microfluidic substrates for nematode neurobiology and behavior.

With a nervous system of only 302 neurons, the free-living nematode Caenorhabditis elegans is a powerful experimental organism for neurobiology. However, the laboratory substrate commonly used in C. elegans research, a planar agarose surface, fails to reflect the complexity of this organism's natural environment, complicates stimulus delivery, and is incompatible with high-resolution optophysiology experiments. Here we present a new class of microfluidic devices for C. elegans neurobiology and behavior: agarose-free, micron-scale chambers and channels that allow the animals to crawl as they would on agarose. One such device mimics a moist soil matrix and facilitates rapid delivery of fluid-borne stimuli. A second device consists of sinusoidal channels that can be used to regulate the waveform and trajectory of crawling worms. Both devices are thin and transparent, rendering them compatible with high-resolution microscope objectives for neuronal imaging and optical recording. Together, the new devices are likely to accelerate studies of the neuronal basis of behavior in C. elegans.