Very-high-energy particle acceleration powered by the jets of the microquasar SS 433.

SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star)1-3. Two jets of ionized matter with a bulk velocity of approximately 0.26c (where c is the speed of light in vacuum) extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets2,4-8. SS 433 differs from other microquasars (small-scale versions of quasars that are present within our own Galaxy) in that the accretion is believed to be super-Eddington9-11, and the luminosity of the system is about 1040 ergs per second2,9,12,13. The lobes of W50 in which the jets terminate, about 40 parsecs from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed14-16. At higher energies (greater than 100 gigaelectronvolts), the particle fluxes of γ-rays from X-ray hotspots around SS 433 have been reported as flux upper limits6,17-20. In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons that are interacting with the ambient gas. Here we report teraelectronvolt γ-ray observations of the SS 433/W50 system that spatially resolve the lobes. The teraelectronvolt emission is localized to structures in the lobes, far from the centre of the system where the jets are formed. We have measured photon energies of at least 25 teraelectronvolts, and these are certainly not Doppler-boosted, because of the viewing geometry. We conclude that the emission-from radio to teraelectronvolt energies-is consistent with a single population of electrons with energies extending to at least hundreds of teraelectronvolts in a magnetic field of about 16 microgauss.

Publisher Correction: Very-high-energy particle acceleration powered by the jets of the microquasar SS 433.

In this Letter, owing to a production error, the penultimate version of the PDF was published. The HTML version was always correct. The PDF has been corrected online.

Discovery of Gamma Rays from the Quiescent Sun with HAWC.

We report the first detection of a TeV γ-ray flux from the solar disk (6.3σ), based on 6.1 years of data from the High Altitude Water Cherenkov (HAWC) observatory. The 0.5-2.6 TeV spectrum is well fit by a power law, dN/dE=A(E/1 TeV)^{-γ}, with A=(1.6±0.3)×10^{-12} TeV^{-1} cm^{-2} s^{-1} and γ=3.62±0.14. The flux shows a strong indication of anticorrelation with solar activity. These results extend the bright, hard GeV emission from the disk observed with Fermi-LAT, seemingly due to hadronic Galactic cosmic rays showering on nuclei in the solar atmosphere. However, current theoretical models are unable to explain the details of how solar magnetic fields shape these interactions. HAWC's TeV detection thus deepens the mysteries of the solar-disk emission.

Constraints on Lorentz Invariance Violation from HAWC Observations of Gamma Rays above 100 TeV.

Because of the high energies and long distances to the sources, astrophysical observations provide a unique opportunity to test possible signatures of Lorentz invariance violation (LIV). Superluminal LIV enables the decay of photons at high energy. The high altitude water Cherenkov (HAWC) observatory is among the most sensitive gamma-ray instruments currently operating above 10 TeV. HAWC finds evidence of 100 TeV photon emission from at least four astrophysical sources. These observations exclude, for the strongest of the limits set, the LIV energy scale to 2.2×10^{31} eV, over 1800 times the Planck energy and an improvement of 1 to 2 orders of magnitude over previous limits.

Multiple Galactic Sources with Emission Above 56 TeV Detected by HAWC.

We present the first catalog of gamma-ray sources emitting above 56 and 100 TeV with data from the High Altitude Water Cherenkov Observatory, a wide field-of-view observatory capable of detecting gamma rays up to a few hundred TeV. Nine sources are observed above 56 TeV, all of which are likely galactic in origin. Three sources continue emitting past 100 TeV, making this the highest-energy gamma-ray source catalog to date. We report the integral flux of each of these objects. We also report spectra for three highest-energy sources and discuss the possibility that they are PeVatrons.

Grey matter structural differences in alcohol-dependent individuals with and without comorbid depression/anxiety-an MRI study.

Although depression and anxiety disorders are common comorbid conditions in alcohol dependence, few structural brain imaging studies have compared alcohol-dependent subjects with and without such comorbidity. In the current study, brain scans of 35 alcohol-dependent with and 40 individuals without diagnosis of a comorbid ICD-10 depressive or anxiety disorder receiving detoxification inpatient treatment were evaluated. Thickness and volumes of automatically segmented neuroanatomical structures were measured in FreeSurfer. Furthermore, associations of brain structure with biological markers and clinical severity markers of alcohol dependence were assessed. Despite comparable addiction severity, the non-comorbid group had evidence of higher cytotoxic effects of alcohol use on hepatic and haematological markers, and showed significantly smaller volumes of total cerebral, and cerebellar grey matter. Similarly, they showed unexpected smaller hippocampal and nucleus accumbens volumes, and thinner frontal, temporal and occipital cortices. Smaller brain volumes correlated with increased markers of hepatic and haematological dysfunction, and with longer duration of alcohol dependence in the non-comorbid group. Evidence of higher biomarkers of alcohol use may be indicative of more severe alcohol dependence or higher vulnerability to ethanol toxicity in this group. Furthermore, psychopathology-related drug treatment, which occurred in 53% of the comorbid group over the recent years, or tissue inflammation may have a moderate effect on the grade of cerebral atrophy in alcohol-dependent patients. Longitudinal studies are needed to investigate this issue more fully.

Functional MRI activation in response to panic-specific, non-panic aversive, and neutral pictures in patients with panic disorder and healthy controls.

There is evidence that besides limbic brain structures, prefrontal and insular cortical activations and deactivations are involved in the pathophysiology of panic disorder. This study investigated activation response patterns to stimulation with individually selected panic-specific pictures in patients with panic disorder with agoraphobia (PDA) and healthy control subjects using functional magnetic resonance imaging (fMRI). Structures of interest were the prefrontal, cingulate, and insular cortex, and the amygdalo-hippocampal complex. Nineteen PDA subjects (10 females, 9 males) and 21 healthy matched controls were investigated using a Siemens 3-Tesla scanner. First, PDA subjects gave Self-Assessment Manikin (SAM) ratings on 120 pictures showing characteristic panic/agoraphobia situations, of which 20 pictures with the individually highest SAM ratings were selected. Twenty matched pictures showing aversive but not panic-specific stimuli and 80 neutral pictures from the International Affective Picture System were chosen for each subject as controls. Each picture was shown twice in each of four subsequent blocks. Anxiety and depression ratings were recorded before and after the experiment. Group comparisons revealed a significantly greater activation in PDA patients than control subjects in the insular cortices, left inferior frontal gyrus, dorsomedial prefrontal cortex, the left hippocampal formation, and left caudatum, when PA and N responses were compared. Comparisons for stimulation with unspecific aversive pictures showed activation of similar brain regions in both groups. Results indicate region-specific activations to panic-specific picture stimulation in PDA patients. They also imply dysfunctionality in the processing of interoceptive cues in PDA and the regulation of negative emotionality. Therefore, differences in the functional networks between PDA patients and control subjects should be further investigated.

Tibia segment deformation in response to simulated muscle forces: a cadaveric study with a novel optical segment tracking (OST) approach.

OBJECTIVES: A novel optical segment tracking (OST) approach reliant upon motion capturing was previously proposed to assess human tibia segment deformation. The purposes of the present study were to validate the OST approach and assess the contribution of muscular forces to the bone deformation in a well-defined ex vivo human model. METHODS: A custom-made Lower Extremity Loading Device (LELD) was developed to simulate physiological muscle contractions in six human cadaveric lower extremities. Tibia segment deformation was measured by tracking the relative movement between two marker clusters which were affixed into the proximal and distal tibia, respectively. RESULTS: Compared to the physiological norms, the simulated muscle forces remained at a low level. When quadriceps muscle was loaded with forces from 198 N to 505 N, posterior bending (0.12°-0.25°) and lateral bending (0.06°-0.21°) of the tibia segment were found. Large tibia bending angles were found when simulating the co-contraction of upper leg muscles and plantar flexors, and of all leg muscles, respectively. The standard deviations of the deformation angles between the repetitions remained at a low level. CONCLUSIONS: We conclude that the OST approach has the potential to be applied in vivo and quantify muscle-induced bone deformations.

Realistic three-dimensional imaging of injuries in forensic medicine - Survey-based method comparison of CRT and VRT.

OBJECTIVE: A comparison between Cinematic Rendering Technique (CRT) and Volume Rendering Technique (VRT) in cases with postmortem CT-angiography (PMCTA) was carried out. METHODS: For different injuries seen in PMCTA, a VRT and a CRT image of exactly the same pathological section was generated. Two questionnaires were created, one with CRT and one with VRT reconstructions, with the same questions per 3D-image. The questionnaires were sent to forensic pathologists, lawyers and police officers. In total eleven different injuries had to be analyzed. RESULTS: In total 109 questionnaires were answered fully. Of these returnees, 36 stated that they were forensic pathologists. Seventy-three people were assigned to the group of medical laypersons, in the study this group consists mainly of police officers, judges and lawyers. Between the two software programs CRT and VRT that were compared, no significant difference could be identified in any of the participating groups with regard to the assessment of the life-threatening nature of the injury images shown. When asked about the comprehensibility of pathology, there was a significant difference in favour of CRT. This advantage was apparent to named medical laypersons and to forensic pathologists. CONCLUSIONS: The study showed a positive trend that CRT may be more understandable than VRT. Not only the medical laypersons, but also the forensic physicians found CRT to be beneficial.

BIoecology of Oncideres cervina Thomson (Coleoptera: Cerambycidae) on Persea americana Mill. (Lauraceae).

Cerambycidae beetles limit production and establishment of forest and fruit trees. Oncideres cervina Thomson, 1868 (Coleoptera: Cerambycidae) is one of the most important species. The objective was to record O. cervina girdling branches of Persea americana Mill. (Lauraceae) for the first time, check the number of oviposition incisions (Noi) as a function of the diameter of branch sections, period of emergence, and describe the larval-pupal chamber. Individuals of O. cervina were observed, for the first time, in P. americana orchards in Santa Maria, Rio Grande do Sul, Brazil. The middle section of branches (40-60 cm interval) had higher number of incisions. Girdled branches with a diameter of 40-50 mm had higher number of them. Adults emerged from November through January. Larval-pupal boreholes had diameters between 9 and 11 mm, and average tunnel length was 28 mm, with a mean volume of consumed wood of 4.3 mL. This information is useful for establishing integrated pest management practices against O. cervina in P. americana since this crop has a high added value and can be significantly compromised by attack by Cerambycidae beetles.

Multidimensional Analysis of the Adult Human Heart in Health and Disease using Hierarchical Phase-Contrast Tomography (HiP-CT).

Cardiovascular diseases (CVDs) are a leading cause of death worldwide. Current clinical imaging modalities provide resolution adequate for diagnosis but are unable to provide detail of structural changes in the heart, across length-scales, necessary for understanding underlying pathophysiology of disease. Hierarchical Phase-Contrast Tomography (HiP-CT), using new (4th) generation synchrotron sources, potentially overcomes this limitation, allowing micron resolution imaging of intact adult organs with unprecedented detail. In this proof of principle study (n=2), we show the utility of HiP-CT to image whole adult human hearts ex-vivo: one 'control' without known cardiac disease and one with multiple known cardiopulmonary pathologies. The resulting multiscale imaging was able to demonstrate exemplars of anatomy in each cardiac segment along with novel findings in the cardiac conduction system, from gross (20 um/voxel) to cellular scale (2.2 um/voxel), non-destructively, thereby bridging the gap between macroscopic and microscopic investigations. We propose that the technique represents a significant step in virtual autopsy methods for studying structural heart disease, facilitating research into abnormalities across scales and age-groups. It opens up possibilities for understanding and treating disease; and provides a cardiac 'blueprint' with potential for in-silico simulation, device design, virtual surgical training, and bioengineered heart in the future.

[Palliative care guidelines in uro-oncology]. / Leitliniengerechte palliativmedizinische Therapie in der Uroonkologie.

Palliative care is an integral part in the treatment of patients in uro-oncology. The German S3 guideline palliative care for patients with incurable cancer is an essential working basis for physicians and healthcare workers. In addition to basic recommendations in palliative care, the guideline provides evidence-based advice in a symptom-oriented approach. Basic knowledge in palliative care is recommended for every urologist who is treating uro-oncologic patients.

Molecular characterisation of group A streptococcus isolates recovered from the north-west of Pretoria, South Africa.

BACKGROUND: Group A streptococcus (GAS) is a human pathogen responsible for a wide range of invasive and non-invasive infections. Pharyngitis caused by GAS may have complications such as acute rheumatic fever subsequently leading to rheumatic heart disease (RHD). RHD continues to have high morbidity and mortality and affects millions of children and young adults, mostly in developing countries. An effective preventive vaccine against GAS may reduce the morbidity and mortality. A 30-valent M-protein-based vaccine is currently at the clinical trials stage of development. Potential vaccine coverage will depend on the geographical distribution of GAS emm (M protein) types. OBJECTIVES: To determine the emm types of GAS isolates circulating in the north-west of Pretoria, South Africa. METHODS: Throat swabs were collected from patients aged 3 - 20 years presenting with pharyngitis at one local clinic. In addition, GAS clinical isolates were collected from the National Health Laboratory Service diagnostic laboratory. Emm genotyping was done on the GAS isolates by amplification of the emm gene followed by sequencing of the 5' portion of the gene. The emm types were correlated with the types in the vaccine. RESULTS: A total of 54 GAS isolates were collected, comprising 19 pharyngitis and 35 clinical isolates. We found 15 different emm types among the 43 GAS isolates that were successfully sequenced. Eleven isolates (20%) could not be typed. The most prevalent emm type was 92 (26%), which is part of the 30-valent vaccine. This was followed by emm 25 and 75, each accounting for 12% of the isolates. Up to 67% of the emm types are not covered in the 30-valent vaccine. CONCLUSIONS: Fifteen emm types were identified, of which 92 was the most prevalent. It is concerning that 67% of the emm types are not covered in the vaccine currently under development. It is recommended that surveillance studies be extended to include other parts of the country in order to expand knowledge of the circulating emm types.

Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria.

Twenty-three patients with late onset argininosuccinate lyase deficiency (ASLD) were identified during a 27-year period of newborn screening in Austria (1:95,600, 95% CI=1:68,036-1:162,531). One additional patient was identified outside the newborn screening with neonatal hyperammonemia. Long-term outcome data were available in 17 patients (median age 13 years) ascertained by newborn screening. Patients were treated with protein restricted diet and oral arginine supplementation during infancy and childhood. IQ was average/above average in 11 (65%), low average in 5 (29%), and in the mild intellectual disability range in 1 (6%) patients. Four patients had an abnormal EEG without evidence of clinical seizures and three had abnormal liver function tests and/or evidence of hepatic steatosis. Plasma citrulline levels were elevated in four patients. Plasma ammonia levels were within normal range prior and after a protein load in all patients. Seven different mutations were identified in the 16 alleles investigated. Four mutations were novel (p.E189G, p.R168C, p.R126P, and p.D423H). All mutations were associated with low argininosuccinate lyase activities (0-15%) in red blood cells. Newborn screening might be beneficial in the prevention of chronic neurologic and intellectual sequelae in late onset ASLD, but a proportion of benign variants might have contributed to the overall favorable outcome as well.

In vitro to in vivo comparison of the substrate characteristics of sorafenib tosylate toward P-glycoprotein.

Sorafenib (Nexavar) is a novel oral Raf kinase and vascular endothelial growth factor receptor inhibitor. Most anticancer drugs are substrates for ATP-binding cassette efflux pumps especially for P-glycoprotein (P-gp). To evaluate the influence of P-gp on the pharmacokinetics of sorafenib substrate properties for this transporter were investigated. Therefore, permeability of sorafenib across Caco-2 and P-gp-overexpressing cells was determined. To determine the in vivo relevance of these in vitro findings, pharmacokinetics of sorafenib in mdr1a/1b(-/-) and wild-type (WT) mice was studied. Sorafenib is highly permeable and exhibits a slight efflux across Caco-2 cells. In P-gp-overexpressing cells, a small concentration-dependent efflux was observed, which was completely blocked by the addition of ivermectin. In mdr1a/1b(-/-) and WT mice, unchanged compound represented by far the majority of radioactivity in plasma. After intravenous and oral administration, brain/plasma concentration ratios in mdr1a/1b(-/-) mice were 1.3- to 1.5-fold higher than those in WT mice. However, after intravenous or oral administration, plasma concentrations were similar in both mouse strains. In conclusion, sorafenib is highly permeable and a weak P-gp substrate in vitro. These findings were confirmed by the small factor of 1.3 to 1.5 observed for the brain/plasma ratios in mdr1a/1b(-/-) versus WT mice in vivo. Based on these in vitro and in vivo results, it is unlikely that P-gp has a major effect on the plasma concentrations of sorafenib in humans. Because of the high permeability and low P-gp-mediated transport, sorafenib might be able to cross the blood-brain barrier and target tumors within the brain.

Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression?

Deficiency of the urea cycle enzyme carbamylphosphate synthetase 1 (CPS1) causes hyperammonemia with a vast range of clinical severity from neonatal onset with early lethality to onset after age 40 with rare episodes of hyperammonemic confusion. The cause for this variability is not understood. We report two patients from one family with highly divergent clinical course, one presenting neonatally with a fatal form and the other at age 45 with benign diet-responsive disease. The patients are compound heterozygous for two mutations of the CPS1 gene, c.3558 + 1G > C and c.4101 + 2T > C. The haplotypes containing each mutation are identical between the two patients, as are the sequences of CPS1 exons and flanking introns. Transcriptional experiments show that the abnormal CPS1 transcripts generated by both mutations are identical in these two patients. We characterize promoter and enhancer sequences of the CPS1 gene and find also in these regions no sequence differences between patients. Finally, we perform cloning experiments and find that in the neonatal-onset case, clones of messenger RNA (mRNA) expressed from the allele carrying the c.4101 + 2T > C mutation are threefold more than clones of mRNA from the allele with the c.3558 + 1G > C mutation, whereas in the adult-onset case the two types of clones are equal, indicating skewed expression towards the c.4101 + 2T > C allele in the neonatal case. Although we are yet to understand the mechanism of this differential expression, our work suggests that allelic imbalance may explain clinical variability in CPS1 deficiency in some families.

Three different actin filament assemblies occur in every hair cell: each contains a specific actin crosslinking protein.

The apex of hair cells of the chicken auditory organ contains three different kinds of assemblies of actin filaments in close spatial proximity. These are (a) paracrystals of actin filaments with identical polarity in stereocilia, (b) a dense gellike meshwork of actin filaments forming the cuticular plate, and (c) a bundle of parallel actin filaments with mixed polarities that constitute the circumferential filament belt attached to the cytoplasmic aspect of the zonula adhaerens (ZA). Each different supramolecular assembly of actin filaments contains a specific actin filament cross-linking protein which is unique to that particular assembly. Thus fimbrin appears to be responsible for paracrystallin packing of actin filaments in stereocillia; an isoform of spectrin resides in the cuticular plate where it forms the whisker-like crossbridges, and alpha actinin is the actin crosslinking protein of the circumferential ZA bundle. Tropomyosin, which stabilizes actin filaments, is present in all the actin filament assemblies except for the stereocilia. Another striking finding was that myosin appears to be absent from the ZA ring and cuticular plate of hair cells although present in the ZA ring of supporting cells. The abundance of myosin in the ZA ring of the surrounding supporting cells means that it may be important in forming a supporting tensile cellular framework in which the hair cells are inserted.

Optical properties of the South pole ice at depths between 0.8 and 1 kilometer.

The optical properties of the ice at the geographical South Pole have been investigated at depths between 0.8 and 1 kilometer. The absorption and scattering lengths of visible light ( approximately 515 nanometers) have been measured in situ with the use of the laser calibration setup of the Antarctic Muon and Neutrino Detector Array (AMANDA) neutrino detector. The ice is intrinsically extremely transparent. The measured absorption length is 59 +/- 3 meters, comparable with the quality of the ultrapure water used in the Irvine-Michigan-Brookhaven and Kamiokande proton-decay and neutrino experiments and more than twice as long as the best value reported for laboratory ice. Because of a residual density of air bubbles at these depths, the trajectories of photons in the medium are randomized. If the bubbles are assumed to be smooth and spherical, the average distance between collisions at a depth of 1 kilometer is about 25 centimeters. The measured inverse scattering length on bubbles decreases linearly with increasing depth in the volume of ice investigated.

[Functional diagnostics of mobility control, mobility stabilization and hypermobility. Reliability of clinical tests - results of a multicenter study]. / Funktionelle Diagnostik der Bewegungssteuerung, Bewegungsstabilisation und Hypermobilität. Reliabilität klinischer Tests - Ergebnisse einer Multicenterstudie.

BACKGROUND: Complex forms of musculoskeletal dysfunction are thought to be risk factors for the development of chronic pain syndromes of the locomotor system. Unfortunately there are insufficient data on the reliability and validity of clinical tests for musculoskeletal dysfunctions. METHOD: The intrarater and interrater reliability of clinical tests for hypermobility and for the stabilisation system were examined in a multicentre trial. A total of 68 patients in 6 centres were functionally examined by 2 examiners once (intrarater reliability) and by 1 examiner twice (interrater reliability). RESULTS: The tests for hypermobility showed good to very good reliability. The results for the stabilisation system were more variable whereby 23 tests showed a kappa-coefficient greater than 0.5 and 15 tests good to very good reliability. DISCUSSION: All tests for hypermobility and 23 tests for the stabilisation system are suitable for further evaluation. The broad range in test reliability might be explained by the differences in examiner skills demanded by each test. Therefore, dependent on their validity, some tests will be useful in specialized centres while others might be used in primary care.

Molecular Epidemiology of Noninvasive and Invasive Group A Streptococcal Infections in Cape Town.

Group A streptococcus (GAS) is responsible for a wide range of noninvasive group A streptococcal (non-iGAS) and invasive group A streptococcal (iGAS) infections. Information about the emm type variants of the M protein causing GAS disease is important to assess potential vaccine coverage of a 30-valent vaccine under development, particularly with respect to how they compare and contrast with non-iGAS isolates, especially in regions with a high burden of GAS. We conducted a prospective passive surveillance study of samples from patients attending public health facilities in Cape Town, South Africa. We documented demographic data and clinical presentation. emm typing was conducted using CDC protocols. GAS was commonly isolated from pus swabs, blood, deep tissue, and aspirates. Clinical presentations included wound infections (20%), bacteremia (15%), abscesses (9%), and septic arthritis (8%). Forty-six different emm types were identified, including M76 (16%), M81 (10%), M80 (6%), M43 (6%), and M183 (6%), and the emm types were almost evenly distributed between non-iGAS and iGAS isolates. There was a statistically significant association with M80 in patients presenting with noninvasive abscesses. Compared to the 30-valent vaccine under development, the levels of potential vaccine coverage for non-iGAS and iGAS infection were 60% and 58%, respectively, notably lower than the coverage in developed countries; five of the most prevalent emm types, M76, M81, M80, M43, and M183, were not included. The emm types from GAS isolated from patients with invasive disease did not differ significantly from those from noninvasive disease cases. There is low coverage of the multivalent M protein vaccine in our setting, emphasizing the need to reformulate the vaccine to improve coverage in areas where the burden of disease is high.IMPORTANCE The development of a vaccine for group A streptococcus (GAS) is of paramount importance given that GAS infections cause more than 500,000 deaths annually across the world. This prospective passive surveillance laboratory study evaluated the potential coverage of the M protein-based vaccine currently under development. While a number of GAS strains isolated from this sub-Sahara African study were included in the current vaccine formulation, we nevertheless report that potential vaccine coverage for GAS infection in our setting was approximately 60%, with four of the most prevalent strains not included. This research emphasizes the need to reformulate the vaccine to improve coverage in areas where the burden of disease is high.