An X-ray chimney extending hundreds of parsecs above and below the Galactic Centre.

Evidence has mounted in recent decades that outflows of matter and energy from the central few parsecs of our Galaxy have shaped the observed structure of the Milky Way on a variety of larger scales1. On scales of 15 parsecs, the Galactic Centre has bipolar lobes that can be seen in both the X-ray and radio parts of the spectrum2,3, indicating broadly collimated outflows from the centre, directed perpendicular to the Galactic plane. On larger scales, approaching the size of the Galaxy itself, γ-ray observations have revealed the so-called 'Fermi bubble' features4, implying that our Galactic Centre has had a period of active energy release leading to the production of relativistic particles that now populate huge cavities on both sides of the Galactic plane. The X-ray maps from the ROSAT all-sky survey show that the edges of these cavities close to the Galactic plane are bright in X-rays4-6. At intermediate scales (about 150 parsecs), radio astronomers have observed the Galactic Centre lobe, an apparent bubble of emission seen only at positive Galactic latitudes7,8, but again indicative of energy injection from near the Galactic Centre. Here we report prominent X-ray structures on these intermediate scales (hundreds of parsecs) above and below the plane, which appear to connect the Galactic Centre region to the Fermi bubbles. We propose that these structures, which we term the Galactic Centre 'chimneys', constitute exhaust channels through which energy and mass, injected by a quasi-continuous train of episodic events at the Galactic Centre, are transported from the central few parsecs to the base of the Fermi bubbles4.

Testing General Relativity with Stellar Orbits around the Supermassive Black Hole in Our Galactic Center.

We demonstrate that short-period stars orbiting around the supermassive black hole in our Galactic center can successfully be used to probe the gravitational theory in a strong regime. We use 19 years of observations of the two best measured short-period stars orbiting our Galactic center to constrain a hypothetical fifth force that arises in various scenarios motivated by the development of a unification theory or in some models of dark matter and dark energy. No deviation from general relativity is reported and the fifth force strength is restricted to an upper 95% confidence limit of |α|<0.016 at a length scale of λ=150 astronomical units. We also derive a 95% confidence upper limit on a linear drift of the argument of periastron of the short-period star S0-2 of |ω[over ˙]_{S0-2}|<1.6×10^{-3} rad/yr, which can be used to constrain various gravitational and astrophysical theories. This analysis provides the first fully self-consistent test of the gravitational theory using orbital dynamic in a strong gravitational regime, that of a supermassive black hole. A sensitivity analysis for future measurements is also presented.

Exploring Jordan's rule in Pacific three-spined stickleback Gasterosteus aculeatus.

Coastal marine Gasterosteus aculeatus were captured from seven locations along the Pacific coast of North America, ranging across 21·8° latitude to test Jordan's rule, i.e. that vertebral number should increase with increasing latitude for related populations of fish. Vertebral number significantly increased with increasing latitude for both total and caudal vertebral number. Increasing length with latitude (sensu Bergmann's rule) was also supported, but the predictions for Jordan's rule held when controlling for standard length. Pleomerism was weakly evidenced. Gasterosteus aculeatus exhibited sexual dimorphism for Jordan's rule, with both sexes having more vertebrae at higher latitudes, but only males showing a positive association between latitude and the ratio of caudal to abdominal vertebrae. The number of dorsal- and anal-fin rays and basals increased with increasing latitude, while pectoral-fin ray number decreased. This study reinforces the association between phenotypic variation and environmental variation in marine populations of G. aculeatus.

The relative DNA-shedding propensity of the palm and finger surfaces.

The relative DNA shedding propensity of palmar and finger surfaces has not previously been examined. In the study presented here, palm and fingermarks of six volunteers were analysed for DNA recovery, after deposition at a pressure of approximately 4900 Pa onto glass plates or slides, respectively. The marks were swabbed; DNA extracted using a modified Chelex® method, and then quantified using qPCR, followed by genotype analysis. To assess the availability of DNA-containing material on the skin surface, DNA was analysed by directly swabbing the palm and fingerprint areas of the skin. A further set of palm and fingermarks was subjected to microscopic examination. The results demonstrated that the quantity of DNA shed from the palmar surface is significantly less than from two fingers. Single donor DNA profiles were obtained from deposited fingermarks by applying a low copy number protocol (32 cycles). DNA retrieved from palm and fingers may be degraded, as suggested by reduced peak intensity and allelic dropout amongst the larger STR loci. These findings suggest that, owing to the low levels of DNA deposition, when palmar marks are found at crime scenes, every effort should be made to recover friction ridge detail to use as an identification metric, with collection for DNA analysis performed afterwards.

Maternal effects are long-lasting and influence female offspring's reproductive strategy in the swordtail fish Xiphophorus multilineatus.

The adaptive benefits of maternal investment into individual offspring (inherited environmental effects) will be shaped by selection on mothers as well as their offspring, often across variable environments. We examined how a mother's nutritional environment interacted with her offspring's nutritional and social environment in Xiphophorus multilineatus, a live-bearing fish. Fry from mothers reared on two different nutritional diets (HQ=high quality and LQ=low quality) were all reared on a LQ diet in addition to being split between two social treatments: exposed to a large adult male during development and not exposed. Mothers raised on a HQ diet produce offspring that were not only initially larger (at 14 days of age), but grew faster, and were larger at sexual maturity. Male offspring from mothers raised on both diets responded to the exposure to courter males by growing faster; however, the response of their sisters varied with mother's diet; females from HQ diet mothers reduced growth if exposed to a courter male, whereas females from LQ diet mothers increased growth. Therefore, we detected variation in maternal investment depending on female size and diet, and the effects of this variation on offspring were long-lasting and sex specific. Our results support the maternal stress hypothesis, with selection on mothers to reduce investment in low-quality environments. In addition, the interaction we detected between the mother's nutritional environment and the female offspring's social environment suggests that female offspring adopted different reproductive strategies depending on maternal investment.

Alternative life histories in Xiphophorus multilineatus: evidence for different ages at sexual maturity and growth responses in the wild.

In order to examine potential trade-offs in alternative life histories of the high-backed pygmy swordtail Xiphophorus multilineatus, otoliths were used from wild-caught males to determine if sneaker males had the advantage of maturing earlier in natural environments. The sneakers matured significantly earlier than courters, but there was no difference among the three courter variants. In addition, analyses suggested that the effect of the pituitary locus on size at sexual maturity and growth rates was a consequence of age at sexual maturity. Finally, one of the courter variants had a significantly different relationship between age and size at sexual maturity than the other variants, suggesting that in this variant, age at sexual maturity may be more closely related to size and therefore may be less plastic in its growth responses.

Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN.

PURPOSE: Familial renal cell carcinoma (RCC) is genetically heterogeneous. The most common histopathologic subtype of sporadic and familial RCC is clear cell (cRCC) and von Hippel-Lindau (VHL) disease is the most common cause of inherited cRCC. Familial cRCC may also be associated with chromosome 3 translocations and has recently been described in patients with Birt-Hogg-Dube (BHD) syndrome, caused by germline FLCN mutation. Fewer than 20 kindreds with familial cRCC without VHL disease or a constitutional translocation have been described. The purpose of this investigation was to define the clinical and genetic features of familial non-VHL cRCC (FcRCC) and to evaluate whether unrecognized BHD syndrome might be present in patients with apparent nonsyndromic RCC susceptibility. EXPERIMENTAL DESIGN: We analyzed the clinical features of, and undertook segregation analysis in, 60 kindreds containing two or more cases of RCC (at least one confirmed case of cRCC) and no evidence of an RCC susceptibility syndrome. We also undertook FLCN analysis to evaluate whether unrecognized BHD syndrome might be present in 69 patients with apparent nonsyndromic RCC susceptibility. RESULTS: FcRCC was characterized by an earlier age at onset than sporadic cases and more frequent occurrence of bilateral or multicentric tumors. Segregation analysis showed autosomal dominant inheritance with sex- and age-dependent penetrance. A germline FLCN mutation was detected in 3 of 69 (4.3%) patients with apparent nonsyndromic RCC susceptibility. CONCLUSIONS: We describe the clinical and genetic features of the largest series of FcRCC and recommend these patients be offered FLCN analysis, in addition to constitutional cytogenetic and VHL analysis.

Multiwavelength Light Curves of Two Remarkable Sagittarius A* Flares.

Sgr A*, the supermassive black hole (SMBH) at the center of our Milky Way Galaxy, is known to be a variable source of X-ray, near-infrared (NIR), and submillimeter radiation and therefore a prime candidate to study the electromagnetic radiation generated by mass accretion flow onto a black hole and/or a related jet. Disentangling the power source and emission mechanisms of this variability is a central challenge to our understanding of accretion flows around SMBHs. Simultaneous multiwavelength observations of the flux variations and their time correlations can play an important role in obtaining a better understanding of possible emission mechanisms and their origin. This paper presents observations of two flares that both apparently violate the previously established patterns in the relative timing of submillimeter/NIR/X-ray flares from Sgr A*. One of these events provides the first evidence of coeval structure between NIR and submillimeter flux increases, while the second event is the first example of the sequence of submillimeter/X-ray/NIR flux increases all occurring within ~1 hr. Each of these two events appears to upend assumptions that have been the basis of some analytic models of flaring in Sgr A*. However, it cannot be ruled out that these events, even though unusual, were just coincidental. These observations demonstrate that we do not fully understand the origin of the multiwavelength variability of Sgr A* and show that there is a continued and important need for long-term, coordinated, and precise multiwavelength observations of Sgr A* to characterize the full range of variability behavior.

Simultaneous X-Ray and Infrared Observations of Sagittarius A*'s Variability.

Emission from Saggitarius A* is highly variable at both X-ray and infrared (IR) wavelengths. Observations over the last ~20 yr have revealed X-ray flares that rise above a quiescent thermal background about once per day, while faint X-ray flares from Sgr A* are undetectable below the constant thermal emission. In contrast, the IR emission of Sgr A* is observed to be continuously variable. Recently, simultaneous observations have indicated a rise in IR flux density around the same time as every distinct X-ray flare, while the opposite is not always true (peaks in the IR emission may not be coincident with an X-ray flare). Characterizing the behavior of these simultaneous X-ray/IR events and measuring any time lag between them can constrain models of Sgr A*'s accretion flow and the flare emission mechanism. Using 100+ hours of data from a coordinated campaign between the Spitzer Space Telescope and the Chandra X-ray Observatory, we present results of the longest simultaneous IR and X-ray observations of Sgr A* taken to date. The cross-correlation between the IR and X-ray light curves in this unprecedented data set, which includes four modest X-ray/IR flares, indicates that flaring in the X-ray may lead the IR by approximately 10-20 min with 68% confidence. However, the 99.7% confidence interval on the time-lag also includes zero, i.e., the flaring remains statistically consistent with simultaneity. Long-duration and simultaneous multi-wavelength observations of additional bright flares will improve our ability to constrain the flare timing characteristics and emission mechanisms, and must be a priority for Galactic Center observing campaigns.

Identification of novel VHL targets that are associated with the development of renal cell carcinoma.

von Hippel-Lindau (VHL) disease is a dominantly inherited family cancer syndrome characterized by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma (RCC) and phaeochromocytoma. Specific germline VHL mutations may predispose to haemangioblastomas, RCC and phaeochromocytoma to a varying extent. Although dysregulation of the hypoxia-inducible transcription factor-2 and JunB have been linked to the development of RCC and phaeochromocytoma, respectively, the precise basis for genotype-phenotype correlations in VHL disease have not been defined. To gain insights into the pathogenesis of RCC in VHL disease we compared gene expression microarray profiles in a RCC cell line expressing a Type 1 or Type 2B mutant pVHL (RCC-associated) to those of a Type 2A or 2C mutant (not associated with RCC). We identified 19 differentially expressed novel VHL target genes linked to RCC development. Eight targets were studied in detail by quantitative real-time polymerase chain reaction (three downregulated and five upregulated by wild-type VHL) and for six genes the effect of VHL inactivation was mimicked by hypoxia (but hypoxic-induction of smooth muscle alpha-actin 2 was specific for a RCC cell line). The potential role of four RCC-associated VHL target genes was assessed in vitro. NB thymosin beta (TMSNB) and proteinase-activated receptor 2 (PAR2) (both downregulated by wt pVHL) increased cell growth and motility in a RCC cell line, but aldehyde dehydrogenase (ALDH)1 and ALDH7 had no effect. These findings implicate TMSNB and PAR2 candidate oncogenes in the pathogenesis of VHL-associated RCC.

Variability Timescale and Spectral Index of Sgr A* in the Near Infrared: Approximate Bayesian Computation Analysis of the Variability of the Closest Supermassive Black Hole.

Sagittarius A* (Sgr A*) is the variable radio, near-infrared (NIR), and X-ray source associated with accretion onto the Galactic center black hole. We present an analysis of the most comprehensive NIR variability data set of Sgr A* to date: eight 24 hr epochs of continuous monitoring of Sgr A* at 4.5 µm with the IRAC instrument on the Spitzer Space Telescope, 93 epochs of 2.18 µm data from Naos Conica at the Very Large Telescope, and 30 epochs of 2.12 µm data from the NIRC2 camera at the Keck Observatory, in total 94,929 measurements. A new approximate Bayesian computation method for fitting the first-order structure function extracts information beyond current fast Fourier transformation (FFT) methods of power spectral density (PSD) estimation. With a combined fit of the data of all three observatories, the characteristic coherence timescale of Sgr A* is τ b = 243 - 57 + 82 minutes (90% credible interval). The PSD has no detectable features on timescales down to 8.5 minutes (95% credible level), which is the ISCO orbital frequency for a dimensionless spin parameter a = 0.92. One light curve measured simultaneously at 2.12 and 4.5 µm during a low flux-density phase gave a spectral index α s = 1.6 ± 0.1 ( F ν ∝ ν - α s ) . This value implies that the Sgr A* NIR color becomes bluer during higher flux-density phases. The probability densities of flux densities of the combined data sets are best fit by log-normal distributions. Based on these distributions, the Sgr A* spectral energy distribution is consistent with synchrotron radiation from a non-thermal electron population from below 20 GHz through the NIR.

Osmotically induced cytosolic free Ca(2+) changes in human neutrophils.

Cytosolic free Ca(2+) concentration in neutrophils was measured by ratiometric fluorometry of intracellular fura2. Increasing the extracellular osmolarity, by either NaCl (300-600 mM) or sucrose (600-1200 mM), caused a rise in cytosolic free Ca(2+) (Delta(max) approximately equal to 600 nM). This was not due to cell lysis as the cytosolic free Ca(2+) concentration was reversed by restoration of isotonicity and a second rise in cytosolic free Ca(2+) could be provoked by repeating the change in extracellular osmolarity. Furthermore, the rise in cytosolic free Ca(2+) concentration occurred in the absence of extracellular Ca(2+), demonstrating that release of intracellular fura2 into the external medium did not occur. The osmotically-induced rise in cytosolic free Ca(2+) was not inhibited by either the phospholipase C-inhibitor U73122, or the microfilament inhibitor cytochalasin B, suggesting that neither signalling via inositol tris-phosphate or the cytoskeletal system were involved. However, the rise in cytosolic free Ca(2+) may have resulted from a reduction in neutrophil water volume in hyperosmotic conditions. As these rises in cytosolic Ca(2+) (Delta(max) approximately equal to 600 nM) were large enough to provoke changes in neutrophil activity, we propose that conditions which removes cell water may similarly elevate cytosolic free Ca(2+) to physiologically important levels.

Supernovae. Old supernova dust factory revealed at the Galactic center.

Dust formation in supernova ejecta is currently the leading candidate to explain the large quantities of dust observed in the distant, early universe. However, it is unclear whether the ejecta-formed dust can survive the hot interior of the supernova remnant (SNR). We present infrared observations of ~0.02 solar masses of warm (~100 kelvin) dust seen near the center of the ~10,000-year-old Sagittarius A East SNR at the Galactic center. Our findings indicate the detection of dust within an older SNR that is expanding into a relatively dense surrounding medium (electron density ~10(3) centimeters(-3)) and has survived the passage of the reverse shock. The results suggest that supernovae may be the dominant dust-production mechanism in the dense environment of galaxies of the early universe.

Efficacy of gadoteridol for contrast-enhanced magnetic resonance imaging in children.

RATIONALE AND OBJECTIVES: This study assesses the efficacy of gadoteridol for contrast-enhanced magnetic resonance imaging (MRI) in children. METHODS: Patients were examined by MRI before and after receiving 0.10 mmol/kg gadoteridol. Blinded and unblinded readers analyzed brain and spine MRI studies from a multicenter clinical trial involving 101 patients at 11 sites. Ninety-two cases (76 brain, 16 spine) were evaluated by unblinded investigators, and 91 cases (76 brain, 15 spine) were evaluated by three neuroradiologists unaffiliated with any investigational site and blinded to clinical information. RESULTS: Unblinded readers noted enhancement of brain pathology in 70% of cases versus 50% to 67% among blinded readers. Unblinded readers determined that additional diagnostic information was available after contrast in 82% of brain studies (average, 64% for blinded readers) and would have changed patient diagnoses in 48% of these studies (average, 46% for blinded readers). In spine cases, enhancement of pathology was noted in 38% (unblinded) and 33% to 40% (blinded). Additional diagnostic information was available after contrast in 63% of spine studies (unblinded), or an average of 58% (blinded), and patient diagnoses would have changed in 20% (unblinded), or an average of 59% (blinded). CONCLUSIONS: Gadoteridol is suitable for enhanced MRI detection, localization, and characterization of central nervous system pathology in children.

Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma.

BACKGROUND: Overexpression of the hypoxia inducible factor 1 (HIF-1) and HIF-2 transcription factors and the consequent upregulation of hypoxia inducible mRNAs is a feature of many human cancers and may be unrelated to tissue hypoxia. Thus, the VHL (von Hippel-Lindau) tumour suppressor gene (TSG) regulates HIF-1 and HIF-2 expression in normoxia by targeting the alpha subunits for ubiquitination and proteolysis. Inactivation of the VHL TSG in VHL tumours and in sporadic clear cell renal cell carcinoma (RCC) results in overexpression of HIF-1 and HIF-2. However, RCC without VHL inactivation may demonstrate HIF upregulation, suggesting that VHL independent pathways for HIF activation also exist. In RCC, three candidate HIF activating genes exist-FIH-1 (factor inhibiting HIF), SDHB, and FH-which may be dependent or independent of VHL inactivation. AIMS: To investigate FIH-1, SDHB, and FH for somatic mutations in sporadic RCC. METHODS: Gene mutation was analysed in primary RCCs (clear cell RCCs, papillary RCCs, and oncocytomas) and RCC cell lines. SDHB mutation analysis was performed by denaturing high performance liquid chromatography followed by direct sequencing of aberrant PCR products. FH and FIH-1 mutation analysis were performed by single stranded conformational polymorphism and direct sequencing of PCR products. RESULTS: No mutations were identified in the three genes investigated. CONCLUSIONS: There was no evidence to suggest that somatic mutations occur in the FH, FIH-1, or SDHB TSGs in sporadic RCCs.

Chondrosarcoma of the temporomandibular joint: case report.

Chondrosarcoma of the head and neck region is a rarely encountered tumor. Aggressive surgical excision offers the best chance for cure. In our case, combined diagnostic techniques consisting of fine needle aspiration (FNA), computed tomography (CT), and magnetic resonance imaging (MRI) made an accurate preoperative assessment possible and greatly influenced the treatment provided.

Evaluation of a rapid micro-scale assay for tacrolimus by liquid chromatography-tandem mass spectrometry.

BACKGROUND: The immunosuppressive drug tacrolimus has complex and unpredictable pharmacokinetics, therefore regular monitoring is required in patients receiving tacrolimus therapy. We have developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring tacrolimus concentrations in whole blood and have compared it with a microparticle enzyme immunoassay. METHODS: For the LC-MS/MS assay, samples were prepared in a 96-deep well microtitre plate by adding 10 micro L of blood to 40 micro L of 0.1 mol/L zinc sulphate solution. Proteins were precipitated by adding 100 micro L acetonitrile containing ascomycin internal standard. After vigorous mixing and centrifugation, 20 micro L of the supernatant was injected into the LC-MS/MS system. A C18 cartridge (3 mm x 4 mm) was eluted with a step gradient of 50% to 100% methanol containing 2 mmol/L ammonium acetate and 0.1% (v/v) formic acid, at 0.6 mL/min. The column was maintained at 55 degrees C. RESULTS: The retention times were 0.98 min for ascomycin and 0.98 min for tacrolimus. Cycle time was 2.5 min, injection to injection. The analytes were monitored using a Quattro micro trade mark tandem mass spectrometer operated in multiple reaction monitoring mode using the following transitions: m/z821 > 768 (tacrolimus) and m/z809 > 756 (ascomycin). The limit of quantitation was 0.5 micro g/L and the assay was linear up to 30 micro g/L. Precision of the method, over the concentration range 2.5-15.0 micro g/L, was < 7% within-batch and < 6% between-batch. Total time to analyse 24 samples including result generation was 90 min. CONCLUSION: We conclude that the LC-MS/MS method is quick, precise and robust and will provide a fast turn around of results for the transplant physician.

Onlay bone augmentation with an osteoinductive implant.

The repair of contour defects of craniofacial bone can be accomplished by several methods, including autogenous bone grafts, demineralized bone, and alloplastic materials. The objective of this study was to assess a biodegradable, xenogeneic, osteoinductive implant for craniofacial onlay bone augmentation. Twelve New Zealand White rabbits each had craniofacial onlays consisting of three experimental materials: 1) autograft; 2) allogeneic, demineralized block implant; and 3) partially purified osteoinductive protein (osteogenin) with allogeneic collagen and 50:50 poly (DL-lactide-co-glycolide). Implants with host bone were recovered after 20 weeks and assessed by histomorphometric methods. There was no evidence of adverse local reaction to the three treatments. No significant difference in bone replacement or bone density resulting from each of the implant types was demonstrated. In conclusion, the osteoinductive implants were well tolerated, and over the 20-week period they appeared to maintain their contour as onlays.

The temporoparietal fascia flap in head and neck reconstruction.

The temporoparietal-galeal system of flaps provides the head and neck surgeon with a reliable source of pliable, well vascularized local tissue capable of reconstructing auricular, oropharyngeal/base of tongue/lateral floor of mouth, dural, mandibular, and facial defects. This report provides a description of the types of flaps available, methods of dissection, and examples of reconstructive uses with this versatile tissue.

Aggressive paranasal sinus ossifying fibroma.

Sixty-one cases of an aggressive OF involving the paranasal sinus area are reviewed from the literature. We describe another case of this unusual lesion in an 11-year-old girl. These tumors share a similar radiographic appearance, aggressive clinical behavior, and tendency for recurrence after incomplete treatment. Our experiences show that active OF accurately describes this entity and avoids the confusing histologic nomenclature usually encountered. The head and neck surgeon should be aware of this diagnosis so aggressive en bloc resection can be employed whenever possible.