EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke.

BACKGROUND: Sleep disorders are highly prevalent in the general population and may be linked in a bidirectional fashion to stroke, which is one of the leading causes of morbidity and mortality. AIM: Four major scientific societies established a task force of experts in neurology, stroke, respiratory medicine, sleep medicine and methodology to critically evaluate the evidence regarding potential links and the impact of therapy. MATERIALS AND METHODS: Thirteen research questions were evaluated in a systematic literature search using a stepwise hierarchical approach: first, systematic reviews and meta-analyses; second, primary studies post-dating the systematic reviews/meta-analyses. A total of 445 studies were evaluated and 88 were included. Statements were generated regarding current evidence and clinical practice. RESULTS: Severe obstructive sleep apnoea (OSA) doubles the risk for incident stroke, especially in young to middle-aged patients. Continuous positive airway pressure (CPAP) may reduce stroke risk, especially in treatment-compliant patients. The prevalence of OSA is high in stroke patients and can be assessed by polygraphy. Severe OSA is a risk factor for recurrence of stroke and may be associated with stroke mortality, whilst CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, whilst the pharmacotherapy of insomnia may increase it. Periodic limb movements in sleep (PLMS), but not restless limb syndrome (RLS), may be associated with an increased risk of stroke. Preliminary data suggest a high frequency of post-stroke insomnia and RLS and their association with a less favourable stroke outcome, whilst treatment data are scarce. DISCUSSION/CONCLUSION: Overall, the evidence base is best for OSA relationship with stroke and supports active diagnosis and therapy. Research gaps remain especially regarding insomnia and RLS/PLMS relationships with stroke.

SAS CARE 2 - a randomized study of CPAP in patients with obstructive sleep disordered breathing following ischemic stroke or transient ischemic attack.

OBJECTIVE/BACKGROUND: The benefit of Continuous Positive Airway Pressure (CPAP) treatment following ischemic stroke in patients with obstructive sleep-disordered breathing (SDB) is unclear. We set out to investigate this open question in a randomized controlled trial as part of the SAS-CARE study. PATIENTS/METHODS: Non-sleepy patients (ESS < 10) with ischemic stroke or transient ischemic attack (TIA) and obstructive SDB (AHI ≥ 20) 3 months post-stroke were randomized 1:1 to CPAP treatment (CPAP+) or standard care. Primary outcome was the occurrence of vascular events (TIA/stroke, myocardial infarction/revascularization, hospitalization for heart failure or unstable angina) or death within 24 months post-stroke. Secondary outcomes included Modified Rankin Scale (mRS) and Barthel Index. RESULTS: Among 238 SAS-CARE patients 41 (17%) non-sleepy obstructive SDB patients were randomized to CPAP (n = 19) or standard care (n = 22). Most patients (80%) had stroke and were males (78%), mean age was 64 ± 7 years and mean NIHSS score 0.6 ± 1.0 (range: 0-5). The primary endpoint was met by one patient in the standard care arm (a new stroke). In an intent-to treat analysis disregarding adherence, this corresponds to an absolute risk difference of 4.5% or an NNT = 22. mRS and Barthel Index were stable and similar between arms. CPAP adherence was sufficient in 60% of evaluable patients at month 24. CONCLUSION: No benefit of CPAP started three months post-stroke was found in terms of new cardio- and cerebrovascular events over 2 years. This may be related to the small size of this study, the mild stoke severity, the exclusion of sleepy patients, the delayed start of treatment, and the overall low event rate.

Spotlight on the Association of Radioactive Iodine Treatment With Cancer Mortality in Patients With Hyperthyroidism is Keeping the Highest Risk From Antithyroid Drugs in the Blind Spot.

July 1, 2019, JAMA Internal Medicine released online an article authored by Kitahara et al entitled "Association of radioactive iodine treatment with cancer mortality in patients with hyperthyroidism." The Altmetric Attention Score, a global indicator of interest from lay public and colleagues, skyrocketed to 223 by July 7, placing the article in the top 5% of all scored reports. The overall perception of death from cancer risk associated with I is inflated and not supported by evidence. As co-authors of this article, we offer previously unpublished data and analysis that (1) disputes clinical significance of the associated risk from I and (2) shows, again, that antithyroid drugs carry a statistically significant and a much more obvious cancer death risk.

Modelling and simulation of flow and agglomeration in deep veins valves using discrete multi physics.

The hemodynamics in flexible deep veins valves is modelled by means of discrete multi-physics and an agglomeration algorithm is implemented to account for blood accrual in the flow. Computer simulations of a number of valves typologies are carried out. The results show that the rigidity and the length of the valve leaflets play a crucial role on both mechanical stress and stagnation in the flow. Rigid and short membranes may be inefficient in preventing blood reflux, but reduce the volume of stagnant blood potentially lowering the chances of thrombosis. Additionally, we also show that in venous valves, cell agglomeration is driven by stagnation rather than mechanical stress.

MIRD Pamphlet No. 26: Joint EANM/MIRD Guidelines for Quantitative 177Lu SPECT Applied for Dosimetry of Radiopharmaceutical Therapy.

The accuracy of absorbed dose calculations in personalized internal radionuclide therapy is directly related to the accuracy of the activity (or activity concentration) estimates obtained at each of the imaging time points. MIRD Pamphlet no. 23 presented a general overview of methods that are required for quantitative SPECT imaging. The present document is next in a series of isotope-specific guidelines and recommendations that follow the general information that was provided in MIRD 23. This paper focuses on (177)Lu (lutetium) and its application in radiopharmaceutical therapy.

Influenza vaccination is safe and effective in patients suffering from fibromyalgia syndrome.

The fibromyalgia syndrome (FMS) is considered to result from the exposure of a genetically susceptible individual to various triggers, such as physical trauma, stress, viral infections etc. A possible role of vaccination in FMS etiology has been suspected. Our objective was to evaluate the efficacy and safety of influenza vaccination in FMS patients. Nineteen FMS patients underwent physical and dolorimetric examinations and answered the fibromyalgia impact questionnaire (FIQ), the widespread pain index (WPI) checklist and the symptoms severity scale (SSS), which are part of the 2010 diagnostic criteria. Thirty-eight healthy subjects were recruited as controls. All participants were vaccinated with the inactivated split virion influenza vaccine. Serum was collected for antibody titration. Six weeks after vaccination, sera were tested by hemagglutination (HI) against A/California (H1N1), A/Perth (H3N2) and B/Brisbane. Humoral response was defined as either a fourfold or greater increase in titer, or an increase from a non-protective baseline level of <1/40 to a level of 1/40. No severe vaccination reactions were observed. No significant change was observed between WPI, SSS and FIQ values before and after vaccination, indicating no worsening of FMS symptoms. Vaccine immunogenicity: Six weeks after vaccination, FMS patients showed a significant increase in geometric mean titers of HI antibody. The rates of sero-protection increased from 22.9% for H1N1 to 89.5% post-vaccination. A significant increase in HI antibody titers was also demonstrated among healthy controls. Influenza vaccination was both safe and effective in FMS patients. In view of these results, FMS patients should be encouraged to undergo influenza vaccination according to the standard WHO recommendations.

Tissue factor expressed by circulating cancer cell-derived microparticles drastically increases the incidence of deep vein thrombosis in mice.

BACKGROUND: The risk of thrombotic complications such as deep vein thrombosis (DVT) during tumor development is well known. Tumors release into the circulation procoagulant microparticles (MPs) that can participate in thrombus formation following vessel injury. The importance of this MP tissue factor (TF) in the initiation of cancer-associated DVT remains uncertain. OBJECTIVE: To investigate how pancreatic cancer MPs promote DVT in vivo. METHODS: We combined a DVT mouse model in which thrombosis is induced by flow restriction in the inferior vena cava with one of subcutaneous pancreatic cancer in C57BL/6J mice. We infused high-TF and low-TF tumor MPs to determine the importance of TF in experimental cancer-associated DVT. RESULTS: Both tumor-bearing mice and mice infused with tumor MPs subjected to 3 h of partial flow restriction developed an occlusive thrombus; fewer than one-third of the control mice did. We observed that MPs adhered to neutrophil extracellular traps (NETs), which are functionally important players during DVT, whereas neither P-selectin nor glycoprotein Ib were required for MP recruitment in DVT. The thrombotic phenotype induced by MP infusion was suppressed by hirudin, suggesting the importance of thrombin generation. TF carried by tumor MPs was essential to promote DVT, as mice infused with low-TF tumor MPs had less thrombosis than mice infused with high-TF tumor MPs. CONCLUSIONS: TF expressed on tumor MPs contributes to the increased incidence of cancer-associated venous thrombosis in mice in vivo. These MPs may adhere to NETs formed at the site of thrombosis.

MIRD pamphlet No. 24: Guidelines for quantitative 131I SPECT in dosimetry applications.

The reliability of radiation dose estimates in internal radionuclide therapy is directly related to the accuracy of activity estimates obtained at each imaging time point. The recently published MIRD pamphlet no. 23 provided a general overview of quantitative SPECT imaging for dosimetry. The present document is the first in a series of isotope-specific guidelines that will follow MIRD 23 and focuses on one of the most commonly used therapeutic radionuclides, (131)I. The purpose of this document is to provide guidance on the development of protocols for quantitative (131)I SPECT in radionuclide therapy applications that require regional (normal organs, lesions) and 3-dimensional dosimetry.

Uncertainties in estimating health risks associated with exposure to ionising radiation.

The information for the present discussion on the uncertainties associated with estimation of radiation risks and probability of disease causation was assembled for the recently published NCRP Report No. 171 on this topic. This memorandum provides a timely overview of the topic, given that quantitative uncertainty analysis is the state of the art in health risk assessment and given its potential importance to developments in radiation protection. Over the past decade the increasing volume of epidemiology data and the supporting radiobiology findings have aided in the reduction of uncertainty in the risk estimates derived. However, it is equally apparent that there remain significant uncertainties related to dose assessment, low dose and low dose-rate extrapolation approaches (e.g. the selection of an appropriate dose and dose-rate effectiveness factor), the biological effectiveness where considerations of the health effects of high-LET and lower-energy low-LET radiations are required and the transfer of risks from a population for which health effects data are available to one for which such data are not available. The impact of radiation on human health has focused in recent years on cancer, although there has been a decided increase in the data for noncancer effects together with more reliable estimates of the risk following radiation exposure, even at relatively low doses (notably for cataracts and cardiovascular disease). New approaches for the estimation of hereditary risk have been developed with the use of human data whenever feasible, although the current estimates of heritable radiation effects still are based on mouse data because of an absence of effects in human studies. Uncertainties associated with estimation of these different types of health effects are discussed in a qualitative and semi-quantitative manner as appropriate. The way forward would seem to require additional epidemiological studies, especially studies of low dose and low dose-rate occupational and perhaps environmental exposures and for exposures to x rays and high-LET radiations used in medicine. The development of models for more reliably combining the epidemiology data with experimental laboratory animal and cellular data can enhance the overall risk assessment approach by providing biologically refined data to strengthen the estimation of effects at low doses as opposed to the sole use of mathematical models of epidemiological data that are primarily driven by medium/high doses. NASA's approach to radiation protection for astronauts, although a unique occupational group, indicates the possible applicability of estimates of risk and their uncertainty in a broader context for developing recommendations on: (1) dose limits for occupational exposure and exposure of members of the public; (2) criteria to limit exposures of workers and members of the public to radon and its short-lived decay products; and (3) the dosimetric quantity (effective dose) used in radiation protection.

[28-year-old patient with iron deficiency anemia]. / 28-jährige Patientin mit Eisenmangelanämie.

We report the case of a 28-years-old woman with Turner's syndrome and iron deficiency anaemia. The faecal occult blood test was intermittently positive whereas earlier upper and lower endoscopy revealed no source of bleeding. Capsule endoscopy showed multiple vascular malformations on the jejunum and ileum. Our case report emphasizes the importance of capsule endoscopy in the localising occult bleedings in the small bowel. We discuss the different diagnostic modalities and possible treatments.

MIRD pamphlet No. 23: quantitative SPECT for patient-specific 3-dimensional dosimetry in internal radionuclide therapy.

In internal radionuclide therapy, a growing interest in voxel-level estimates of tissue-absorbed dose has been driven by the desire to report radiobiologic quantities that account for the biologic consequences of both spatial and temporal nonuniformities in these dose estimates. This report presents an overview of 3-dimensional SPECT methods and requirements for internal dosimetry at both regional and voxel levels. Combined SPECT/CT image-based methods are emphasized, because the CT-derived anatomic information allows one to address multiple technical factors that affect SPECT quantification while facilitating the patient-specific voxel-level dosimetry calculation itself. SPECT imaging and reconstruction techniques for quantification in radionuclide therapy are not necessarily the same as those designed to optimize diagnostic imaging quality. The current overview is intended as an introduction to an upcoming series of MIRD pamphlets with detailed radionuclide-specific recommendations intended to provide best-practice SPECT quantification-based guidance for radionuclide dosimetry.

[Consequences of an accidental aspiration of petroleum in a case of a fire eating man]. / Folgen einer akzidentellen Aspiration von Petroleum bei einem Feuerspucker.

Fire-eater's pneumonitis, caused by aspiration of petroleum, is an infrequent clinical problem in our region. It is an acute inflammatory response of the lungs to the accidental aspiration of hydrocarbons, as shown in our patient. Despite the severe initial clinical und radiological presentation, fire-eater's pneumonitis usually shows a favourable evolution with "restitutio ad integrum". Acute mortality rate is less than 1%. Fire-eater's lung is a medical emergency and needs medical support and surveillance. There is no good evidence that systemic cortico-steroids and antibiotics are effective in the treatment of hydrocarbon aspiration. Concerning chronic lung injury after fire-eater's pneumonitis, there are favorable results from short observational series.

Neutrophil extracellular traps promote deep vein thrombosis in mice.

BACKGROUND: Upon activation, neutrophils can release nuclear material known as neutrophil extracellular traps (NETs), which were initially described as a part of antimicrobial defense. Extracellular chromatin was recently reported to be prothrombotic in vitro and to accumulate in plasma and thrombi of baboons with experimental deep vein thrombosis (DVT). OBJECTIVE: To explore the source and role of extracellular chromatin in DVT. METHODS: We used an established murine model of DVT induced by flow restriction (stenosis) in the inferior vena cava (IVC). RESULTS: We demonstrate that the levels of extracellular DNA increase in plasma after 6 h IVC stenosis, compared with sham-operated mice. Immunohistochemical staining revealed the presence of Gr-1-positive neutrophils in both red (RBC-rich) and white (platelet-rich) parts of thrombi. Citrullinated histone H3 (CitH3), an element of NETs' structure, was present only in the red part of thrombi and was frequently associated with the Gr-1 antigen. Immunofluorescent staining of thrombi showed proximity of extracellular CitH3 and von Willebrand factor (VWF), a platelet adhesion molecule crucial for thrombus development in this model. Infusion of Deoxyribonuclease 1 (DNase 1) protected mice from DVT after 6 h and also 48 h IVC stenosis. Infusion of an unfractionated mixture of calf thymus histones increased plasma VWF and promoted DVT early after stenosis application. CONCLUSIONS: Extracellular chromatin, likely originating from neutrophils, is a structural part of a venous thrombus and both the DNA scaffold and histones appear to contribute to the pathogenesis of DVT in mice. NETs may provide new targets for DVT drug development.

Updated mortality analysis of radiation workers at Rocketdyne (Atomics International), 1948-2008.

Updated analyses of mortality data are presented on 46,970 workers employed 1948-1999 at Rocketdyne (Atomics International). Overall, 5,801 workers were involved in radiation activities, including 2,232 who were monitored for intakes of radionuclides, and 41,169 workers were engaged in rocket testing or other non-radiation activities. The worker population is unique in that lifetime occupational doses from all places of employment were sought, updated and incorporated into the analyses. Further, radiation doses from intakes of 14 different radionuclides were calculated for 16 organs or tissues using biokinetic models of the International Commission on Radiation Protection (ICRP). Because only negligible exposures were received by the 247 workers monitored for radiation activities after 1999, the mean dose from external radiation remained essentially the same at 13.5 mSv (maximum 1 Sv) as reported previously, as did the mean lung dose from external and internal radiation combined at 19.0 mSv (maximum 3.6 Sv). An additional 9 years of follow-up, from December 31,1999 through 2008, increased the person-years of observation for the radiation workers by 21.7% to 196,674 (mean 33.9 years) and the number of cancer deaths by 50% to 684. Analyses included external comparisons with the general population and the computation of standardized mortality ratios (SMRs) and internal comparisons using proportional hazards models and the computation of relative risks (RRs). A low SMR for all causes of death (SMR 0.82; 95% CI 0.78-0.85) continued to indicate that the Rocketdyne radiation workers were healthier than the general population and were less likely to die. The SMRs for all cancers taken together (SMR 0.88; 95% CI 0.81-0.95), lung cancer (SMR 0.87; 95% CI 0.76-1.00) and leukemia other than chronic lymphocytic leukemia (CLL) (SMR 1.04; 95% 0.67-1.53) were not significantly elevated. Cox regression analyses revealed no significant dose-response trends for any cancer. For all cancers excluding leukemia, the RR at 100 mSv was estimated as 0.98 (95% CI 0.82-1.17), and for all leukemia other than CLL it was 1.06 (95% CI 0.50-2.23). Uranium was the primary radionuclide contributing to internal exposures, but no significant increases in lung and kidney disease were seen. The extended follow-up reinforces the findings in the previous study in failing to observe a detectable increase in cancer deaths associated with radiation, but strong conclusions still cannot be drawn because of small numbers and relatively low career doses. Larger combined studies of early workers in the United States using similar methodologies are warranted to refine and clarify radiation risks after protracted exposures.

MIRD Pamphlet No. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy.

The potential of alpha-particle emitters to treat cancer has been recognized since the early 1900s. Advances in the targeted delivery of radionuclides and radionuclide conjugation chemistry, and the increased availability of alpha-emitters appropriate for clinical use, have recently led to patient trials of radiopharmaceuticals labeled with alpha-particle emitters. Although alpha-emitters have been studied for many decades, their current use in humans for targeted therapy is an important milestone. The objective of this work is to review those aspects of the field that are pertinent to targeted alpha-particle emitter therapy and to provide guidance and recommendations for human alpha-particle emitter dosimetry.

Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17).

BACKGROUND: Peripheral serotonin (5-hydroxytryptamine, 5-HT) is transported by platelets and released upon stimulation. In the platelet cytoplasm, 5-HT is transamidated to small GTPases, promoting alpha-granule release and primary hemostasis. OBJECTIVE: We hypothesized that 5-HT could also stimulate platelet receptor shedding after binding to the membrane 5-HT receptor (5-HT2AR). METHODS: Western blot and flow cytometry were used to determine levels of the adhesion receptor glycoprotein (GP)Ibalpha on platelets or its shed fragment glycocalicin in plasma and serum from wild-type mice, Tph1(-/-) mice lacking peripheral 5-HT, and mice lacking functional tumor necrosis factor-alpha-converting enzyme (TACE, ADAM17). Flow chamber experiments and intravital microscopy were used to examine the adhesive properties of platelets after stimulation of 5-HT2AR. RESULTS: Glycocalicin was significantly reduced in Tph1(-/-) plasma and serum. In isolated platelets, 5-HT induced shedding of GPIbalpha, which was increased to 60% when 5-HT uptake was inhibited by the selective serotonin reuptake inhibitor fluoxetine. Specific 5-HT2AR agonism and antagonism suggested activation of this receptor. The shedding could not be induced in TACE(DeltaZn/DeltaZn) platelets, suggesting that activated TACE mediated the shedding of GPIbalpha. Intracellular signaling involved phosphorylation of p38 mitogen-activated protein kinase rather than G-protein signaling. 5-HT2AR stimulation decreased platelet adhesion to collagen-bound von Willebrand factor under arterial shear (1500 s(-1)) and incorporation into FeCl3-induced thrombi in mesenteric arterioles. CONCLUSIONS: Stimulation of 5-HT2AR on platelets induces TACE-mediated shedding of GPIbalpha, the key adhesion molecule under high shear conditions. Our observations demonstrate a new pathway through which 5-HT could modulate cardiovascular disease.