A dust-obscured massive maximum-starburst galaxy at a redshift of 6.34.

Massive present-day early-type (elliptical and lenticular) galaxies probably gained the bulk of their stellar mass and heavy elements through intense, dust-enshrouded starbursts--that is, increased rates of star formation--in the most massive dark-matter haloes at early epochs. However, it remains unknown how soon after the Big Bang massive starburst progenitors exist. The measured redshift (z) distribution of dusty, massive starbursts has long been suspected to be biased low in z owing to selection effects, as confirmed by recent findings of systems with redshifts as high as ~5 (refs 2-4). Here we report the identification of a massive starburst galaxy at z = 6.34 through a submillimetre colour-selection technique. We unambiguously determined the redshift from a suite of molecular and atomic fine-structure cooling lines. These measurements reveal a hundred billion solar masses of highly excited, chemically evolved interstellar medium in this galaxy, which constitutes at least 40 per cent of the baryonic mass. A 'maximum starburst' converts the gas into stars at a rate more than 2,000 times that of the Milky Way, a rate among the highest observed at any epoch. Despite the overall downturn in cosmic star formation towards the highest redshifts, it seems that environments mature enough to form the most massive, intense starbursts existed at least as early as 880 million years after the Big Bang.

Subperiosteal abscess of the orbit: duration of intravenous antibiotic therapy in nonsurgical cases.

PURPOSE: To report the duration of intravenous (IV) antibiotic administration and outcomes in a cohort of patients with subperiosteal abscess (SPA) of the orbit triaged to nonsurgical management. METHODS: A retrospective cohort study based on records of patients younger than 9 years admitted to a regional pediatric hospital with a diagnosis of orbital cellulitis from 1999 through 2008. Patients with computed tomography (CT)-confirmed SPA and associated sinusitis were included. Patients who underwent surgical drainage of sinuses and/or orbits during that admission were excluded. Patients discharged with a peripherally inserted central catheter for a predetermined treatment interval were excluded. Dates and times of first and last doses of inpatient IV antibiotics were recorded. Records were reviewed for evidence of hospital readmission for relevant diagnoses. Outcome measures included duration of IV antibiotic administration and hospital readmission. RESULTS: Forty-two patients met study criteria. Duration of IV treatment ranged from 2 to 8 days (mean and median, each 4 days). Forty-one patients were not readmitted with a relevant diagnosis from the time of hospital discharge to completion of data acquisition in April 2011. One patient was readmitted for recurrent acute infection 10 weeks after discharge and underwent urgent SPA and sinus drainage; review of the initial CT revealed an ethmoidal mucocoele. CONCLUSIONS: The duration of IV therapy associated with successful nonsurgical management of appropriately selected children with SPA is considerably shorter than that recommended in current pediatric infectious disease literature. The findings suggest that clinical judgment, based on each patient's initial CT findings and evolving signs, symptoms, and laboratory profile, should be a major determinant of IV intervals.

Visual improvement after optic nerve sheath decompression in a case of congenital hydrocephalus and persistent visual loss despite intracranial pressure correction via shunting.

Among the sequelae of persistent raised intracranial pressure (ICP) are ophthalmologic signs and symptoms, including cranial nerve palsies, visual field deficits, papilledema, and vision loss. Elevated pressure within the optic nerve sheath may not be relieved by shunt procedures, which can decrease generalized ICP. The authors present a case of acute visual loss in the setting of chronic hydrocephalus and multiple shunt revisions. Despite shunt correction resolving systemic symptoms of raised ICP, this child had persistent visual loss. Bilateral optic nerve sheath decompression was performed, and the visual acuity improved over the next 3 days. This case highlights the importance of routine ophthalmologic examination in patients with hydrocephalus and shunts and demonstrates the utility of optic nerve sheath decompression as a surgical intervention when shunting alone does not resolve visual loss.

Out-of-school time activity participation profiles of children with physical disabilities: a cluster analysis.

OBJECTIVE: To determine out-of-school activity participation profiles of school-aged children with physical disabilities. METHODS: Activity participation profiles were determined by cluster analysing 427 children's responses on multiple dimensions of participation (intensity, location, companionship, enjoyment, preference) in five activity types (recreational, active physical, social, skill-based, self-improvement). Socio-demographic, child, parent, family and environmental predictors of group membership were determined, along with child functioning, socio-demographic, self-concept and social support variables significantly associated with group membership. RESULTS: The cluster analysis revealed four groups, labelled Social Participators (a highly social and neighbourhood-focused group), Broad Participators (a group of high participators who enjoy participation), Low Participators (a group with low enjoyment and weak preferences) and Recreational Participators (a group of younger children who participate in recreational activities with family members). The groups showed meaningful differences across a range of socio-demographic, child, parent, family and environmental variables. CONCLUSIONS: The findings support an affective and contextual view of participation, indicating the importance of motivational theory and a person-environment approach in understanding the complexity of children's out-of-school activity participation.

Rubidium-strontium relations in tranquillity base samples.

Preliminary total rock analyses disclosed a greatly different rubidium depletion between two groups of these igneous rocks, and ratios of strontium-87 to strontium-86 indicate that the rubidium depletion in these materials must have occurred during or shortly after the accretion of the terrestrial planets.

Rubidium-strontium age of the bosumtwi crater area, ghana, compared with the age of the ivory coast tektites.

Rocks from the vicinity of Bosumtwi crater, Ghana, and a repre-sentative collection of Ivory Coast tektites have been analyzed mass spectrometrically for rubidium, strontium, and strontium isotopic composition. The data from the rocks of the crater area yield an age of 1.97 x 10(9) years (lambda(gb) = 1.47 chi 10(-11) year(-1)). The data for the Ivory Coast tektites fall on this isochron. This identity of age values for the Ivory Coast tektites and the Birrimian basement rocks of West Africa strongly supports the hypothesis of terrestrial formation for these tektites. The evidence available at present suggests that the Ivory Coast tektites are most probably the fusion products of meteoritic impact at the Bosumtwi crater site.

Test of Continental Drift by Comparison of Radiometric Ages: A pre-drift reconstruction shows matching geologic age provinces in West Africa and Northern Brazil.

1) The distribution of age values obtained by potassium-argon determinations and whole-rock rubidium-strontium determinations appears to be almost identical for West African rocks of the pervasive Eburnean Orogenic Cycle and basement rocks at opposite locations in South America. 2) There is also a close correlation, with respect to potassium-argon age determinations on micas, rubidium-strontium determinations on total-rock samples, and the extent to which these two sets of values differ, between rocks of the Pan-African Orogenic Cycle and rocks of the Caririan Orogenic Cycle in Brazil, where these two groups of rocks lie opposite each other in the two continents. 3) When Africa and South America are "fitted together," the sharply defined boundary between the Eburnean and the Pan-African age provinces in West Africa strikes directly toward the corresponding age boundary in northeast Brazil. 4) The transition from the 550-million-year Pan-African age province to the 2000-million-year age province in the Congo Craton in Cameroun-Gabon is matched in the rocks near the corresponding part of the east coast of Brazil. However the geological and age data are insufficient to do more than suggest the possibility of another age-boundary correlation here. 5) The evidence reported here supports the hypothesis of continental drift.

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation.

The vast majority of cancer cells have defective checkpoints that permit the cell cycle to progress in the presence of double-strand DNA breaks (DSBs) caused by ionizing radiation (IR) and radiomimetic drugs. ATR (ataxia telangiectasia-mutated and Rad3-related) has recently been shown to be activated by DSBs, although the consequences of this activity are largely unknown. In this report, we use advanced gene targeting methods to generate biallelic hypomorphic ATR mutations in human colorectal cancer cells and demonstrate that progression of the cancer cell cycle after IR treatment requires ATR. Cells with mutant ATR accumulated at a defined point at the beginning of the S phase after IR treatment and were unable to progress beyond that point, whereas cells at later stages of the S phase during the time of irradiation progressed and completed DNA replication. The prolonged arrest of ATR mutant cancer cells did not involve the ataxia telangiectasia mutated-dependent S-phase checkpoint, but rather closely resembled a previously characterized form of cell cycle arrest termed S-phase stasis. As ATR strongly contributed to clonogenic survival after IR treatment, these data suggest that blocking ATR activity might be a useful strategy for inducing S-phase stasis and promoting the radiosensitization of checkpoint-deficient cancer cells.

Existing technologies to reduce specific toxicant emissions in cigarette smoke.

BACKGROUND: The World Health Organization Tobacco Product Regulation (TobReg) study group has proposed emissions level performance standards for nine toxicants (NNN, NNK, acetaldehyde, acrolein, 1,3-butadiene, CO, BaP, benzene and formaldehyde, all expressed as micrograms per milligram nicotine as measured under the Canadian intensive method) in cigarette smoke for parties to the FCTC in conjunction with regular monitoring of emissions of nine other toxicants of interest, nicotine and nicotine-free dry particulate matter (NFDPM, or "tar"). METHODS: We examined the published literature and publicly available tobacco industry documents to determine the extent to which existing available technologies can be applied to reduce the emissions of the specified toxicants in cigarette smoke. RESULTS: Agricultural practices (for example, fertilisers, curing), plant characteristics (for example, protein content, nicotine content), tobacco blending (for example, American blend vs Virginia blend) and cigarette design (for example, additives, filters, paper) issues all have roles in the generation and reduction of specific smoke toxicants. The tobacco industry has explored a number of technologies, including selective filtration, changes to curing practices and rod additives to reduce specific toxicants. CONCLUSIONS: Technologies exist to reduce the toxicants identified by TobReg. The extent to which the industry is able to simultaneously reduce toxicants, however, is unknown.

Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis.

BACKGROUND: B7-H3 (CD276), part of the B7 superfamily of immune checkpoint molecules, has been shown to have an immunomodulatory role. Its regulation, receptor and mechanism of action remain unclear. B7-H3 protein expression correlates with prostate cancer outcomes, and humanized monoclonal antibodies (that is, enoblituzumab) are currently being investigated for therapeutic use. Here we used genomic expression data to examine the relationship between B7-H3 mRNA expression and prostate cancer. METHODS: Prostatectomy tissue from 2781 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Pairwise comparisons were used to identify significant associations between B7-H3 expression and clinicopathologic variables, and survival analyses were used to evaluate the prognostic significance of B7-H3. Pearson's correlation analyses were performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy at the B7-H3 locus was determined using chromatin immunoprecipitation (ChIP), and androgen-dependent expression changes in B7-H3 was evaluated by quantitative reverse transcription PCR in LNCaP cell lines. Oncomine was queried to evaluate B7-H3 expression in metastatic disease. RESULTS: B7-H3 mRNA expression was positively associated with higher Gleason score (P<0.001), tumor stage (P<0.001), and castrate resistant metastatic disease (P<0.0001). High B7-H3 expression correlated with the development of metastasis and prostate cancer specific mortality, but this was not significant on multi-variable analysis. B7-H3 expression correlated with ERG-positive disease (r=0.99) and AR expression (r=0.36). ChIP revealed an AR-binding site upstream of B7-H3, and the presence of androgens decreased B7-H3 expression in LNCaP suggesting potential direct AR regulation. Gene set enrichment analysis demonstrated an association of B7-H3 with androgen signaling as well as immune regulatory pathways. CONCLUSIONS: Higher B7-H3 expression correlates with Gleason grade, prostate cancer stage and poor oncologic outcomes in prostatectomy cohorts. B7-H3 expression appears to be related to androgen signaling as well as the immune reactome.

A similar pattern of chromosomal alterations in prostate cancers from African-Americans and Caucasian Americans.

A combination of genetic and epigenetic factors may explain the disproportionate incidence and mortality of prostate cancer among African-American males (AAMs) as compared with Caucasian American males (CAMs). We wished to determine whether primary prostate cancers from AAMs and CAMs harbor different patterns or frequencies of chromosomal alterations. Comparative genomic hybridization (CGH) was performed on clinically localized, untreated primary prostate cancers from 16 AAMs and 16 CAMs. Detailed statistical analysis was used to delineate gains and deletions with high sensitivity and specificity and to compare the frequency and pattern of alterations between the two groups of tumors. The two groups of patients had indistinguishable preoperative serum prostate-specific antigen levels, and the two groups of tumors had similar pathological stages and grades. Chromosomal gains and deletions occurred in regions known to be frequently altered in prostate cancer. Specifically, the most frequent alterations were deletions of regions on chromosomes 13q, 5q, 16q, and 8p and gains of regions on 8q and 5q. When tumors from AAMs and CAMs were compared, the frequencies of alteration (deletion, gain, or no alteration) were similar across 98.9% of the length of the genome. The patterns of alterations of the most frequently altered chromosomes were also similar between tumors from AAMs and CAMs. We concluded that primary prostate cancers from AAMs and CAMs harbor a similar pattern and frequency of chromosomal alterations. These data support the notion that sporadic prostate cancers from AAMs and CAMs develop by similar chromosomal mechanisms. Biological differences, if present, do not occur on the chromosomal level.

The effects of isoprenaline on epicardial ST-segment elevation, lactate production, and myocardial blood flow following coronary artery ligation.

Isoprenaline was infused at low and high rates into anaesthetized dogs after ligation of the left anterior descending coronary artery, the resultant changes in epicardial ST-segment elevation being compared with lactate production and myocardial blood flow in the infarcting myocardium. Although ST elevation was increased at both infusion rates, there was no change in the arterial-local coronary venous difference of lactate concentration nor in myocardial blood flow at the centre of the infarct. The results suggest that the relationship between epicardial ST-segment elevation and other indices of ischaemic myocardial injury is complex and requires further evaluation.

Development of radioimmunoassays for free tetra-L-aspartyl-L-lysine trypsinogen activation peptides (TAP).

Tetra-L-aspartyl-L-lysine (D4K) containing trypsinogen activation peptides were synthesised on solid-phase supports. Synthetic D4K peptides were N-terminally haptenised and used to generate specific C-terminally directed anti-D4K antibodies. Affinity purification of antisera using Sepharose-immobilised synthetic D4K segregated two highly purified populations of anti-D4K antibodies, one eluting with EDTA recognising the calcium chelate and the other eluting with propionic acid recognising an alternative epitope on the anionic oligopeptide. Both specific anti-D4K antibodies were C-terminally directed and did not bind trypsinogen. Specific antisera and calcium-independent antibodies were used to develop and characterise solution and solid-phase immunoassays specific for free trypsinogen activation peptides (TAP assay), with a detection limit of 10(-11) M and between assay CV of 10.7% for the solution-phase system. The release of D4K peptides by enteropeptidase activation of trypsinogen and dog pancreatic secretion is demonstrated. TAP assays specifically indicate trypsinogen activation and may contribute to the recognition and understanding of disease states such as pancreatitis.

Unusual remission of Pneumocystis carinii pneumonia in a patient with the acquired immune deficiency syndrome.

Pneumocystis carinii is a well-recognized cause of pneumonia in patients with immune deficiency, and when untreated, mortality approaches 100 percent. Although rare cases suggesting spontaneous recovery (usually accompanied by resolving immune deficiency) have been reported, spontaneous resolution of P. carinii pneumonia in patients with the acquired immune deficiency syndrome (AIDS) has not been described. A patient with AIDS in whom Pneumocystis pneumonia developed and remitted without appropriate therapy is described. This case suggests that the immunologic defects of AIDS are not fixed and that fluctuations in the degree of immunocompetence may allow for clinical recovery from opportunistic infections associated with AIDS even without appropriate therapy.

Red cell and plasma volumes in normal adults.

Despite numerous published methods for predicting normal red cell and plasma volumes, little is known of the range of normal in subjects of given body dimensions. In this study, reported results of red cell and plasma volumes in 481 normal men and 303 normal women have been used to calculate mean volumes and standard deviations (s.d.) for any given body surface area (male and female results being kept separate). All of these mean volumes, each plus or minus 2 s.d., have been plotted against body surface area. The resulting graphs of means and 95% confidence limits have tended to be curvilinear. Standard deviations have increased with increasing mean volumes, but coefficients of variation (s.d./mean) have shown considerable constancy at 11-12%. The mean values observed in this series have often differed substantially from those predicted from published formulas. Use of the presently observed means with the 11-12% coefficients of variation allows compilation for any surface area of a range of normal against which a clinically obtained volume can be compared.

Functional coupling of a recombinant human 5-HT5A receptor to G-proteins in HEK-293 cells.

1. We have cloned, expressed and pharmacologically characterized the Human 5-HT5A receptor. 2. We have shown that ligand activation of the Human 5-HT5A receptor results in functional coupling to G-proteins in HEK-293 cells. 3. Stimulation of the receptor with 5-CT (5-carboxamidotryptamine) resulted in a dose-dependent increase in the % [35S]-GTPgammaS binding over the basal level. This is the first study to describe such G-protein activation for the Human 5-HT5A receptor in any cell. 4. A dose-dependent inhibition of cyclic AMP accumulation was observed in the recombinant Human 5-HT5A receptor cell line, suggesting a functional coupling to a G alpha i, G-protein in the HEK-293 cell line. 5. A ligand-stimulated reduction in the detectable level of the catalytic domain of protein kinase A (PKA) in nuclear extracts isolated from Human 5-HT5A expressing cells was observed. This observation was consistent with the reduction in the level of cyclic AMP accumulation, in response to receptor activation.

Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents.

Of 240 pesticides screened for carcinogenicity by the U.S. Environmental Protection Agency Office of Pesticide Programs, at least 24 (10%) produce thyroid follicular cell tumors in rodents. Thirteen of the thyroid carcinogens also induce liver tumors, mainly in mice, and 9 chemicals produce tumors at other sites. Some mutagenic data are available on all 24 pesticides producing thyroid tumors. Mutagenicity does not seem to be a major determinant in thyroid carcinogenicity, except for possibly acetochlor; evidence is less convincing for ethylene thiourea and etridiazole. Studies on thyroid-pituitary functioning, including indications of thyroid cell growth and/or changes in thyroxine, triiodothyronine, or thyroid-stimulating hormone levels, are available on 19 pesticides. No such antithyroid information is available for etridiazole, N-octyl bicycloheptene dicarboximide, terbutryn, triadimefon, and trifluralin. Of the studied chemicals, only bromacil lacks antithyroid activity under study conditions. Intrathyroidal and extrathyroidal sites of action are found: amitrole, ethylene thiourea, and mancozeb are thyroid peroxidase inhibitors; and acetochlor, clofentezine, fenbuconazole, fipronil, pendimethalin, pentachloronitrobenzene, prodiamine, pyrimethanil, and thiazopyr seem to enhance the hepatic metabolism and excretion of thyroid hormone. Thus, with 12 pesticides that mode of action judgments can be made, 11 disrupt thyroid-pituitary homeostasis only; no chemical is mutagenic only; and acetochlor may have both antithyroid and some mutagenic activity. More information is needed to identify other potential antithyroid modes of thyroid carcinogenic action.

An overview of current efforts in short-term carcinogen testing.

Scientists in the Health and Environmental Review Division (HERD), Office of Toxic Substances of the U.S. Environmental Protection Agency, are examining the feasibility of expanding efforts in short-term carcinogen testing. Three areas for consideration have been defined. These are (1) short-term in vitro tests; (2) short-term in vivo tests; and (3) tumor markers. HERD's current efforts in short-term in vitro testing are exemplified by the Gene-Tox program. Through a comprehensive system of committees and reviews, the published literature on eukaryotic and prokaryotic in vitro and in vivo test systems are being examined and analyzed. The suitability of utilizing the various systems in a test battery to identify potential chemical mutagens and carcinogens will be ascertained. A review of the literature on short-term in vivo tests (limited bioassays) and tumor markers is currently being conducted. Correlations will be made between results obtained from these tests and epidemiological information and long-term animal bioassays. The attributes and deficiencies of each test or marker will be examined. Further testing, development, or validation needs will be outlined. The aim of this review is to attempt to expand the prechronic test battery for carcinogenicity in order to provide sufficient information for regulatory decision-making.