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HIV can infect non-dividing cells because the viral capsid can overcome the selective barrier of the nuclear pore complex and deliver the genome directly into the nucleus1,2. Remarkably, the intact HIV capsid is more than 1,000 times larger than the size limit prescribed by the diffusion barrier of the nuclear pore3. This barrier in the central channel of the nuclear pore is composed of intrinsically disordered nucleoporin domains enriched in phenylalanine-glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins and their bound cargoes solubilize in this phase to drive nucleocytoplasmic transport4. By performing an in vitro dissection of the nuclear pore complex, we show that a pocket on the surface of the HIV capsid similarly interacts with FG motifs from multiple nucleoporins and that this interaction licences capsids to penetrate FG-nucleoporin condensates. This karyopherin mimicry model addresses a key conceptual challenge for the role of the HIV capsid in nuclear entry and offers an explanation as to how an exogenous entity much larger than any known cellular cargo may be able to non-destructively breach the nuclear envelope.
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Proteínas de la Cápside , Glicina , VIH , Carioferinas , Imitación Molecular , Proteínas de Complejo Poro Nuclear , Poro Nuclear , Fenilalanina , Humanos , Transporte Activo de Núcleo Celular , Proteínas de la Cápside/química , Proteínas de la Cápside/metabolismo , Difusión , Dipéptidos/química , Dipéptidos/metabolismo , Glicina/metabolismo , VIH/química , VIH/metabolismo , Técnicas In Vitro , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/metabolismo , Carioferinas/metabolismo , Poro Nuclear/química , Poro Nuclear/metabolismo , Poro Nuclear/virología , Proteínas de Complejo Poro Nuclear/química , Proteínas de Complejo Poro Nuclear/metabolismo , Permeabilidad , Fenilalanina/metabolismo , Solubilidad , Internalización del Virus , Cápside/química , Cápside/metabolismoRESUMEN
The scattering of dark matter (DM) particles with sub-GeV masses off nuclei is difficult to detect using liquid xenon-based DM search instruments because the energy transfer during nuclear recoils is smaller than the typical detector threshold. However, the tree-level DM-nucleus scattering diagram can be accompanied by simultaneous emission of a bremsstrahlung photon or a so-called "Migdal" electron. These provide an electron recoil component to the experimental signature at higher energies than the corresponding nuclear recoil. The presence of this signature allows liquid xenon detectors to use both the scintillation and the ionization signals in the analysis where the nuclear recoil signal would not be otherwise visible. We report constraints on spin-independent DM-nucleon scattering for DM particles with masses of 0.4-5 GeV/c^{2} using 1.4×10^{4} kg day of search exposure from the 2013 data from the Large Underground Xenon (LUX) experiment for four different classes of mediators. This analysis extends the reach of liquid xenon-based DM search instruments to lower DM masses than has been achieved previously.
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The first searches for axions and axionlike particles with the Large Underground Xenon experiment are presented. Under the assumption of an axioelectric interaction in xenon, the coupling constant between axions and electrons g_{Ae} is tested using data collected in 2013 with an exposure totaling 95 live days ×118 kg. A double-sided, profile likelihood ratio statistic test excludes g_{Ae} larger than 3.5×10^{-12} (90% C.L.) for solar axions. Assuming the Dine-Fischler-Srednicki-Zhitnitsky theoretical description, the upper limit in coupling corresponds to an upper limit on axion mass of 0.12 eV/c^{2}, while for the Kim-Shifman-Vainshtein-Zhakharov description masses above 36.6 eV/c^{2} are excluded. For galactic axionlike particles, values of g_{Ae} larger than 4.2×10^{-13} are excluded for particle masses in the range 1-16 keV/c^{2}. These are the most stringent constraints to date for these interactions.
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We present experimental constraints on the spin-dependent WIMP-nucleon elastic cross sections from the total 129.5 kg yr exposure acquired by the Large Underground Xenon experiment (LUX), operating at the Sanford Underground Research Facility in Lead, South Dakota (USA). A profile likelihood ratio analysis allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σ_{n}=1.6×10^{-41} cm^{2} (σ_{p}=5×10^{-40} cm^{2}) at 35 GeV c^{-2}, almost a sixfold improvement over the previous LUX spin-dependent results. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date.
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We report constraints on spin-independent weakly interacting massive particle (WIMP)-nucleon scattering using a 3.35×10^{4} kg day exposure of the Large Underground Xenon (LUX) experiment. A dual-phase xenon time projection chamber with 250 kg of active mass is operated at the Sanford Underground Research Facility under Lead, South Dakota (USA). With roughly fourfold improvement in sensitivity for high WIMP masses relative to our previous results, this search yields no evidence of WIMP nuclear recoils. At a WIMP mass of 50 GeV c^{-2}, WIMP-nucleon spin-independent cross sections above 2.2×10^{-46} cm^{2} are excluded at the 90% confidence level. When combined with the previously reported LUX exposure, this exclusion strengthens to 1.1×10^{-46} cm^{2} at 50 GeV c^{-2}.
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We present constraints on weakly interacting massive particles (WIMP)-nucleus scattering from the 2013 data of the Large Underground Xenon dark matter experiment, including 1.4×10^{4} kg day of search exposure. This new analysis incorporates several advances: single-photon calibration at the scintillation wavelength, improved event-reconstruction algorithms, a revised background model including events originating on the detector walls in an enlarged fiducial volume, and new calibrations from decays of an injected tritium ß source and from kinematically constrained nuclear recoils down to 1.1 keV. Sensitivity, especially to low-mass WIMPs, is enhanced compared to our previous results which modeled the signal only above a 3 keV minimum energy. Under standard dark matter halo assumptions and in the mass range above 4 GeV c^{-2}, these new results give the most stringent direct limits on the spin-independent WIMP-nucleon cross section. The 90% C.L. upper limit has a minimum of 0.6 zb at 33 GeV c^{-2} WIMP mass.
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We present experimental constraints on the spin-dependent WIMP (weakly interacting massive particle)-nucleon elastic cross sections from LUX data acquired in 2013. LUX is a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota), which is designed to observe the recoil signature of galactic WIMPs scattering from xenon nuclei. A profile likelihood ratio analysis of 1.4×10^{4} kg day of fiducial exposure allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σ_{n}=9.4×10^{-41} cm^{2} (σ_{p}=2.9×10^{-39} cm^{2}) at 33 GeV/c^{2}. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date.
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While the standard model of particle physics does not include free particles with fractional charge, experimental searches have not ruled out their existence. We report results from the Cryogenic Dark Matter Search (CDMS II) experiment that give the first direct-detection limits for cosmogenically produced relativistic particles with electric charge lower than e/6. A search for tracks in the six stacked detectors of each of two of the CDMS II towers finds no candidates, thereby excluding new parameter space for particles with electric charges between e/6 and e/200.
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PURPOSE: To analyse antibiotic use density (AD)--World Health Organization defined daily doses/1,000 patient-days--before and after implementation of a local antimicrobial stewardship programme (ASP) in conjunction with a procalcitonin (PCT)-guided protocol in a surgical intensive care unit (ICU). METHODS: In this retrospective observational study, data on 2,422 ICU patients between 2010 and 2012 were analysed. In 2011, an ASP in conjunction with a PCT protocol had been introduced into clinical practice. In a multivariate analysis, hospital mortality, length of stay (LOS) in hospital and ICU LOS were adjusted for effects from effective cost weight, gender, and age. AD and changes in the use of antibiotic classes were analysed. RESULTS: AD decreased from 1,005.0 in 2010 to 791.9 in 2012 which is a total reduction of 21.2%. Consumption of aminoglycosides, cephalosporins and quinolones showed a marked reduction, whereas the use of penicillins did not change significantly. The multivariate models revealed no relevant changes in mortality rate, ICU LOS and hospital LOS. CONCLUSIONS: Implementation of an ASP in conjunction with a PCT protocol in 2011 was associated with a marked decrease in total AD and led to a significant change in the spectrum of antibiotics. Clinical outcomes appeared to remain unchanged over the study period.
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Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Calcitonina/sangre , Unidades de Cuidados Intensivos , Precursores de Proteínas/sangre , Antibacterianos/economía , Infecciones Bacterianas/mortalidad , Infecciones Bacterianas/prevención & control , Péptido Relacionado con Gen de Calcitonina , Cuidados Críticos , Costos de los Medicamentos , Utilización de Medicamentos/estadística & datos numéricos , Mortalidad Hospitalaria , Humanos , Tiempo de Internación/estadística & datos numéricos , Análisis Multivariante , Estudios RetrospectivosRESUMEN
We present a technique to pattern the charge density of a large-area epitaxial graphene sheet locally without using metallic gates. Instead, local intercalation of the graphene-substrate interface can selectively be established in the vicinity of graphene edges or predefined voids. It provides changes of the work function of several hundred meV, corresponding to a conversion from n-type to p-type charge carriers. This assignment is supported by photoelectron spectroscopy, scanning tunneling microscopy, scanning electron microscopy and Hall effect measurements. The technique introduces materials contrast to a graphene sheet in a variety of geometries and thus allows for novel experiments and novel functionalities.
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BACKGROUND AND PURPOSE: To evaluate the long-term efficacy of pain reduction by two dose fractionation schedules used for low-dose radiotherapy of painful elbow syndrome. PATIENTS AND METHODS: Between February 2006 and February 2010, 199 evaluable patients were recruited for this prospective trial. All patients received low-dose orthovoltage radiotherapy. One course consisted of 6 fractions in 3 weeks. In the case of insufficient pain remission after 6 weeks, a second course was administered. Patients were randomly assigned to one of two groups to receive single doses of either 0.5 or 1.0 Gy. Endpoint was pain reduction. Pain was measured before radiotherapy, as well as immediately after (early response), 6 weeks after (delayed response) and approximately 3 years after (long-term response) completion of radiotherapy using a questionnaire-based visual analogue scale (VAS) and a comprehensive pain score (CPS). RESULTS: Median follow-up was 35 months (range 9-57 months). The overall early, delayed and long-term response rates for all patients were 80, 90 and 94 %, respectively. The mean VAS scores before treatment and those for early, delayed and long-term response in the 0.5- and 1.0-Gy groups were 59.6 ± 20.2 and 55.7 ± 18.0 (p = 0.46); 32.1 ± 24.5 and 34.4 ± 22.5 (p = 0.26); 27.0 ± 27.7 and 23.5 ± 21.6 (p = 0.82) and 10.7 ± 15.0 and 21.5 ± 26.9 (p = 0.12), respectively. The mean CPS values before treatment and those for early, delayed and long-term response were 8.7 ± 2.9 and 8.1 ± 3.1 (p = 0.21); 4.5 ± 3.2 and 5.0 ± 3.4 (p = 0.51); 3.9 ± 3.6 and 2.8 ± 2.8 (p = 0.19) and 1.5 ± 2.3 and 2.4 ± 3.5 (p = 0.27), respectively. No significant differences in the quality of the long-term response were found between the 0.5- and 1.0-Gy arms (p = 0.28). CONCLUSION: Low-dose radiotherapy is an effective treatment for the management of benign painful elbow syndrome. For radiation protection reasons, the dose for a radiotherapy series should not exceed 3.0 Gy.
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Artralgia/radioterapia , Fraccionamiento de la Dosis de Radiación , Codo/efectos de la radiación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Alemania , Humanos , Masculino , Persona de Mediana Edad , Manejo del Dolor , Dimensión del Dolor/efectos de la radiación , Satisfacción del Paciente , Estudios Prospectivos , Protección Radiológica , Dosificación Radioterapéutica , Recurrencia , Retratamiento , Encuestas y Cuestionarios , SíndromeRESUMEN
BACKGROUND AND PURPOSE: To evaluate the long-term efficacy of pain reduction by two dose-fractionation schedules for radiotherapy of painful shoulder syndrome. PATIENTS AND METHODS: Between February 2006 and February 2010, 312 evaluable patients were recruited for this prospective trial. All patients received low-dose orthovoltage radiotherapy. One course consisted of 6 fractions in 3 weeks. In the case of insufficient pain remission after 6 weeks, a second course was administered. Patients were randomly assigned to one of two groups to receive single doses of either 0.5 or 1.0 Gy. Endpoint was pain reduction. Pain was measured before radiotherapy, as well as immediately after (early response), 6 weeks after (delayed response) and approximately 3 years after (long-term response) completion of radiotherapy using a questionnaire-based visual analogue scale (VAS) and a comprehensive pain score (CPS). RESULTS: Median follow-up was 35 months (range 11-57). The overall early, delayed and long-term response rates for all patients were 83, 85 and 82 %, respectively. The mean VAS scores before treatment and those for early, delayed and long-term response in the 0.5- and 1.0-Gy groups were 56.8 ± 23.7 and 53.2 ± 21.8 (p = 0.16); 38.2 ± 36.1 and 34.0 ± 24.5 (p = 0.19); 33.0 ± 27.2 and 23.7 ± 22.7 (p = 0.04) and 27.9 ± 25.8 and 32.1 ± 26.9 (p = 0.25), respectively. The mean CPS values before treatment and those for early, delayed and long-term response were 9.7 ± 3.0 and 9.5 ± 2.7 (p = 0.31); 6.1 ± 3.6 and 5.4 ± 3.6 (p = 0.10); 5.3 ± 3.7 and 4.1 ± 3.7 (p = 0.05) and 4.0 ± 3.9 and 5.3 ± 4.4 (p = 0.05), respectively. No significant differences in the quality of the long-term response were found between the 0.5- and 1.0-Gy arms (p = 0.28). CONCLUSION: Radiotherapy is an effective treatment for the management of benign painful shoulder syndrome. For radiation protection reasons, the dose for a radiotherapy series should not exceed 3.0 Gy.
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Bursitis/epidemiología , Bursitis/radioterapia , Fraccionamiento de la Dosis de Radiación , Dimensión del Dolor/efectos de la radiación , Radioterapia Conformacional/estadística & datos numéricos , Dolor de Hombro/epidemiología , Dolor de Hombro/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Bursitis/diagnóstico , Femenino , Alemania/epidemiología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Dimensión del Dolor/estadística & datos numéricos , Prevalencia , Dosificación Radioterapéutica , Medición de Riesgo , Dolor de Hombro/diagnóstico , Resultado del TratamientoRESUMEN
SuperCDMS is an experiment designed to directly detect weakly interacting massive particles (WIMPs), a favored candidate for dark matter ubiquitous in the Universe. In this Letter, we present WIMP-search results using a calorimetric technique we call CDMSlite, which relies on voltage-assisted Luke-Neganov amplification of the ionization energy deposited by particle interactions. The data were collected with a single 0.6 kg germanium detector running for ten live days at the Soudan Underground Laboratory. A low energy threshold of 170 eVee (electron equivalent) was obtained, which allows us to constrain new WIMP-nucleon spin-independent parameter space for WIMP masses below 6 GeV/c2.
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The Large Underground Xenon (LUX) experiment is a dual-phase xenon time-projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota). The LUX cryostat was filled for the first time in the underground laboratory in February 2013. We report results of the first WIMP search data set, taken during the period from April to August 2013, presenting the analysis of 85.3 live days of data with a fiducial volume of 118 kg. A profile-likelihood analysis technique shows our data to be consistent with the background-only hypothesis, allowing 90% confidence limits to be set on spin-independent WIMP-nucleon elastic scattering with a minimum upper limit on the cross section of 7.6 × 10(-46) cm(2) at a WIMP mass of 33 GeV/c(2). We find that the LUX data are in disagreement with low-mass WIMP signal interpretations of the results from several recent direct detection experiments.
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We report a first search for weakly interacting massive particles (WIMPs) using the background rejection capabilities of SuperCDMS. An exposure of 577 kg days was analyzed for WIMPs with mass <30 GeV/c(2), with the signal region blinded. Eleven events were observed after unblinding. We set an upper limit on the spin-independent WIMP-nucleon cross section of 1.2×10(-42) cm(2) at 8 GeV/c(2). This result is in tension with WIMP interpretations of recent experiments and probes new parameter space for WIMP-nucleon scattering for WIMP masses <6 GeV/c(2).
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BACKGROUND: Further characterization of the post-cardiac arrest syndrome (PCAS) is essential to better understand the mechanisms resulting in injury and death. We investigated serial serum concentrations of the stress hormone c-terminal provasopressin (CT-proAVP or copeptin), the cardiac biomarker MR-proANP and a biomarker of oxidation injury, Peroxiredoxin 4 (Prx4) in patients treated with mild hypothermia (MHT) after cardiac arrest, and studied their association to the PCAS and long-term outcome. METHODS: Serum samples from cardiac arrest patients were collected serially: at admission, 2, 6, 12, 24, 36, 48 and 72 h after cardiac arrest. CT-proAVP, MR-proANP and Prx4 concentrations were determined and tested for association with two surrogate markers of PCAS (time to return of spontaneous circulation and circulation-SOFA score) and with cerebral performance category (CPC) at 6 months. Good outcome was defined as CPC 1 to 2. RESULTS: Eighty-four patients were included. CT-proAVP, MR-proANP and Prx4 were early biomarkers with maximum concentrations soon after cardiac arrest and with a significant discriminatory ability between good and poor long-term outcome at most time points. CT-proAVP predicted a poor outcome with the highest accuracy, followed by MR-proANP and Prx4 (area under the receiving operating characteristics curve at 12 h of 0.85, 0.77 and 0.76 respectively). CT-proAVP and MR-proANP showed best correlation to the PCAS. CONCLUSION: In 84 resuscitated patients receiving MHT after cardiac arrest, there is a significant difference in concentrations of CT-proAVP, MR-proANP and Prx4 between patients with good and poor outcome. CT-proAVP and MR-proANP have a significant correlation to surrogate markers of the PCAS.
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Factor Natriurético Atrial/sangre , Biomarcadores/sangre , Glicopéptidos/sangre , Paro Cardíaco/metabolismo , Paro Cardíaco/terapia , Peroxirredoxinas/sangre , Anciano , Femenino , Humanos , Hipotermia Inducida , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Resultado del TratamientoRESUMEN
This study evaluates the ideal pH for anti-erosion and anti-adherent efficacy of fluoride and stannous solutions (sodium fluoride (SF), amine fluoride (AF), sodium monofluorophosphate (SMFP), stannous fluoride (SnF2) with 500 ppm fluoride concentration each and stannous chloride (SnCl2, 1563 ppm stannous)). In vitro, solutions were tested at pH 4.5 and 5.5. The main in situ experiments were carried out at the pH of 4.5: For pellicle formation 6 volunteers wore bovine enamel slabs intraorally for 1 min, rinsed with 8 ml solution for 1 min and continued for up to 30 min/8 h. Physiological pellicle samples served as controls. After incubation in HCl (2.0, 2.3) for 2 min mineral release was determined photometrically. Bacterial counts on 8 h biofilms were determined by fluorescence microscopy (BacLight™ and DAPI with Concanavalin A). Modification of the pellicle ultrastructure was examined by TEM. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney-U tests with Bonferroni-correction (p < 0.05). SnF2 showed a significant erosion protection. AF, SnF2, and SnCl2 were most anti-adherent. SnF2 and SnCl2 caused a pronounced basal pellicle with stannous precipitates. Compared to other fluoride monosubstances, stannous ions offer greater protection against erosive acidic attacks. Stannous ions act as crucial co-factor in this process.
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Fluoruros , Erosión de los Dientes , Animales , Bovinos , Humanos , Fluoruros/farmacología , Erosión de los Dientes/prevención & control , Compuestos de Estaño , Fluoruro de Sodio/farmacología , Fluoruro de Sodio/química , Concentración de Iones de HidrógenoRESUMEN
We report results of a search for weakly interacting massive particles (WIMPS) with the silicon detectors of the CDMS II experiment. This blind analysis of 140.2 kg day of data taken between July 2007 and September 2008 revealed three WIMP-candidate events with a surface-event background estimate of 0.41(-0.08)(+0.20)(stat)(-0.24)(+0.28)(syst). Other known backgrounds from neutrons and 206Pb are limited to <0.13 and <0.08 events at the 90% confidence level, respectively. The exposure of this analysis is equivalent to 23.4 kg day for a recoil energy range of 7-100 keV for a WIMP of mass 10 GeV/c2. The probability that the known backgrounds would produce three or more events in the signal region is 5.4%. A profile likelihood ratio test of the three events that includes the measured recoil energies gives a 0.19% probability for the known-background-only hypothesis when tested against the alternative WIMP+background hypothesis. The highest likelihood occurs for a WIMP mass of 8.6 GeV/c2 and WIMP-nucleon cross section of 1.9×10(-41) cm2.
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Dental hard tissues from different species are used in dental research, but little is known about their comparability. The aim of this study was to compare the erosive behaviour of dental hard tissues (enamel, dentin) obtained from human, bovine and equine teeth. In addition, the protective effect of the pellicle on each hard tissue under erosive conditions was determined. In situ pellicle formation was performed for 30 min on enamel and dentin samples from all species in four subjects. Calcium and phosphate release was assessed during 120 s of HCl incubation on both native and pellicle-covered enamel and dentin samples. SEM and TEM were used to examine surface changes in native enamel and dentin samples after acid incubation and the ultrastructure of the pellicle before and after erosive exposure. In general, bovine enamel and dentin showed the highest degree of erosion after acid exposure compared to human and equine samples. Erosion of human primary enamel tended to be higher than that of permanent teeth, whereas dentin showed the opposite behaviour. SEM showed that eroded equine dentin appeared more irregular than human or bovine dentin. TEM studies showed that primary enamel appeared to be most susceptible to erosion.
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Erosión de los Dientes , Humanos , Animales , Bovinos , Caballos , Dentina , Calcio/farmacología , Ácido Clorhídrico/farmacología , Fosfatos/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: To compare the efficacy of two different dose-fractionation schedules for radiotherapy of patients with benign painful shoulder syndrome. PATIENTS AND METHODS: Between February 2006 and February 2010, 312 consecutive evaluable patients were recruited for this prospective randomized trial. All patients received radiotherapy with an orthovoltage technique. One radiotherapy course consisted of 6 single fractions in 3 weeks. In case of insufficient remission of pain after 6 weeks, a second radiation series was performed. Patients were randomly assigned to receive either single doses of 0.5 or 1.0 Gy. The endpoint was pain reduction. Pain was measured before, right after, and 6 weeks after radiotherapy using a visual analogue scale (VAS) and a comprehensive pain score (CPS). RESULTS: The overall response rate for all patients was 83% directly after and 85% 6 weeks after radiotherapy. The mean VAS values before, directly after, and 6 weeks after treatment for the 0.5 and 1.0 Gy groups were 56.8 ± 23.7 and 53.2 ± 21.8 (p = 0.158), 38.2 ± 26.1 and 34.0 ± 24.5 (p = 0.189), and 33.0 ± 27.2 and 23.7 ± 22.7 (p = 0.044), respectively. The mean CPS before, directly after, and 6 weeks after treatment was 9.7 ± 3.0 and 9.5 ± 2.7 (p = 0.309), 6.1 ± 3.6 and 5.4 ± 3.6 (p = 0.096), 5.3 ± 3.7 and 4.1 ± 3.7 (p = 0.052), respectively. Despite a slight advantage in the VAS analysis for the 1.0 Gy group for delayed response, the CPS analysis revealed no statistically significant differences between the two single-dose trial arms for early (p = 0.652) and delayed response quality (p = 0.380). CONCLUSION: Radiotherapy is an effective treatment option for the management of benign painful shoulder syndrome. Concerning radiation protection, the dose for a radiotherapy series is recommended not to exceed 3-6 Gy.