Gamma-ray bursts: huge explosion in the early Universe.

Long gamma-ray bursts (GRBs) are bright flashes of high-energy photons that can last for tens of minutes; they are generally associated with galaxies that have a high rate of star formation and probably arise from the collapsing cores of massive stars, which produce highly relativistic jets (collapsar model). Here we describe gamma- and X-ray observations of the most distant GRB ever observed (GRB 050904): its redshift (z) of 6.29 means that this explosion happened 12.8 billion years ago, corresponding to a time when the Universe was just 890 million years old, close to the reionization era. This means that not only did stars form in this short period of time after the Big Bang, but also that enough time had elapsed for them to evolve and collapse into black holes.

An unexpectedly rapid decline in the X-ray afterglow emission of long gamma-ray bursts.

'Long' gamma-ray bursts (GRBs) are commonly accepted to originate in the explosion of particularly massive stars, which give rise to highly relativistic jets. Inhomogeneities in the expanding flow result in internal shock waves that are believed to produce the gamma-rays we see. As the jet travels further outward into the surrounding circumstellar medium, 'external' shocks create the afterglow emission seen in the X-ray, optical and radio bands. Here we report observations of the early phases of the X-ray emission of five GRBs. Their X-ray light curves are characterised by a surprisingly rapid fall-off for the first few hundred seconds, followed by a less rapid decline lasting several hours. This steep decline, together with detailed spectral properties of two particular bursts, shows that violent shock interactions take place in the early jet outflows.

An origin for short gamma-ray bursts unassociated with current star formation.

Two short (< 2 s) gamma-ray bursts (GRBs) have recently been localized and fading afterglow counterparts detected. The combination of these two results left unclear the nature of the host galaxies of the bursts, because one was a star-forming dwarf, while the other was probably an elliptical galaxy. Here we report the X-ray localization of a short burst (GRB 050724) with unusual gamma-ray and X-ray properties. The X-ray afterglow lies off the centre of an elliptical galaxy at a redshift of z = 0.258 (ref. 5), coincident with the position determined by ground-based optical and radio observations. The low level of star formation typical for elliptical galaxies makes it unlikely that the burst originated in a supernova explosion. A supernova origin was also ruled out for GRB 050709 (refs 3, 31), even though that burst took place in a galaxy with current star formation. The isotropic energy for the short bursts is 2-3 orders of magnitude lower than that for the long bursts. Our results therefore suggest that an alternative source of bursts--the coalescence of binary systems of neutron stars or a neutron star-black hole pair--are the progenitors of short bursts.

A short gamma-ray burst apparently associated with an elliptical galaxy at redshift z = 0.225.

Gamma-ray bursts (GRBs) come in two classes: long (> 2 s), soft-spectrum bursts and short, hard events. Most progress has been made on understanding the long GRBs, which are typically observed at high redshift (z approximately 1) and found in subluminous star-forming host galaxies. They are likely to be produced in core-collapse explosions of massive stars. In contrast, no short GRB had been accurately (< 10'') and rapidly (minutes) located. Here we report the detection of the X-ray afterglow from--and the localization of--the short burst GRB 050509B. Its position on the sky is near a luminous, non-star-forming elliptical galaxy at a redshift of 0.225, which is the location one would expect if the origin of this GRB is through the merger of neutron-star or black-hole binaries. The X-ray afterglow was weak and faded below the detection limit within a few hours; no optical afterglow was detected to stringent limits, explaining the past difficulty in localizing short GRBs.

An experimental model of acute and subacute viral myocarditis in the pig.

Twenty-six young pigs were infected with encephalomyocarditis virus, observed clinically, studied at intervals by noninvasive and invasive methods to assess cardiac function and eventually examined pathologically. All infected animals appeared ill, usually manifesting diminished appetite, lethargy and fever. Spontaneous mortality occurred either 1 to 4 or 20 to 21 days after infection. Electrocardiographic abnormalities, seen in the majority of animals, comprised ST-T wave changes, conduction disturbances or ventricular ectopic rhythm. The majority of animals manifested echocardiographic evidence of left ventricular dilation and decreased systolic function, which improved with time in some animals. Hemodynamic studies revealed elevation of biventricular filling pressures in 3 of 10 animals; as a group, infected animals manifested significantly elevated right ventricular filling pressures. In selected animals, the feasibility of gallium scans as well as left ventriculography and coronary angiography was demonstrated. At autopsy, heart weight/body weight ratio was significantly elevated in infected animals. The heart of all but two animals showed active myocarditis associated with fibrosis and focal calcification in the later stages. In general, the cardiovascular manifestations were parallel with those seen in acute and subacute myocarditis in humans. It is concluded that encephalomyocarditis infection in the pig is a large animal model of viral myocarditis suitable for assessing alterations in the structure and function of the cardiovascular system and the effects of interventions.

Tissue inflammation without bacteria produces increased oxygen consumption and distant organ lipid peroxidation.

An inflammatory focus was produced by implantation of gauze below the hide in the flanks of six sheep with flank lymph fistulas. Physiologic and metabolic parameters were monitored in the unanesthetized animals for 7 days, after which the gauze was removed and monitoring continued for another 5 days. Animals were then killed. Lung and liver tissue was inspected and analyzed for lipid peroxide content. Data were compared with those of six controls in which gauze was not implanted. We noted a transient significant increase (on day 1 only) in wound lymph, thromboxane B2, and 6-keto-PGF1 alpha from baseline values of 190 +/- 70 and 20 +/- 10 pg/ml to 1000 +/- 240 and 420 +/- 70 pg/ml, respectively. Plasma values were also significantly increased on day 1. Body temperature increased by 1 degree C and cardiac index increased by 30% during this period, whereas oxygen consumption, VO2, was not significantly increased. The VO2 and cardiac index increased by 50% over baseline, beginning on day 5, whereas systemic vascular resistance decreased. Body temperature was not increased. These changes corresponded with an increase in wound lymph monocyte count from 0% to 15% of total. The VO2 and cardiac index remained increased after gauze removal. No bacteria were found in the wound. Postmortem analysis revealed a marked monocyte-macrophage infiltration in both lung and liver. Lung water, represented as water content over dry weight, was normal. Lung and liver lipid peroxidation, measured by the by-product malondialdehyde content, increased 300% and 90% over control values, respectively. We conclude that a local, nonbacteria-induced wound inflammation increases VO2, with the increase not corresponding to increase in body temperature. Distant organ changes, namely, changes in lung and liver, were also evident 5 days after gauze removal.

Effect of ibuprofen on the pulmonary and systemic response to repeated doses of endotoxin.

We infused 10 doses of Escherichia coli endotoxin, 1 microgram/kg, during a 5-day period, into eight unanesthetized sheep with lung and systemic lymph fistulas. The animals were then monitored for an additional 5 days. We noted an attenuation of the lung microvascular permeability changes with the later endotoxin doses. However, a 50% increase in cardiac index and oxygen consumption and a leukocytosis were seen beginning with the ninth endotoxin injection; these persisted throughout the 15-day postendotoxin period, as did an increase in pulmonary artery pressure. The hyperdynamic state was present when plasma prostanoids were only modestly increased, and there was no evidence of increased lung or systemic vascular permeability. Postmortem lung findings, 5 days after endotoxin administration, showed a marked interstitial inflammatory response, with infiltration of macrophages, neutrophils, and some lymphocytes and an increase in interstitial fibrous tissue. Six sheep were then given ibuprofen, 12.5 mg/kg, intravenously before the ninth and tenth doses and on the subsequent day. Ibuprofen significantly attenuated the hyperdynamic state and the pulmonary hypertension. In addition, the lung inflammation and fibrous tissue deposition was markedly attenuated. We conclude that a systemic hyperdynamic state develops that corresponds in time with lung inflammation but not with increased permeability. The lung and systemic changes may be blocked by ibuprofen. The ibuprofen effect may be due to a response other than prostanoid production.

The effects of dietary butylated hydroxytoluene on liver and colon tumor development in mice.

Male and female C3H mice were fed a diet containing 0.5% or 0.05% of the antioxidant butylated hydroxytoluene (BHT). After 10 months, male but not female animals had a significantly increased incidence of liver tumors compared to animals kept on a BHT-free control diet. In a second experiment, male BALB/c mice were treated subcutaneously with the carcinogens dimethylhydrazine (DMH) or intrarectally with methylnitrosourea (MNU). A diet containing 0.5% BHT significantly increased the incidence of colon tumors in DMH treated animals but had no effect in mice given MNU. It is concluded that the effect of BHT on tumor development depends on strain and target organ examined and possibly also on the chemical carcinogen used.

Surfactant alterations following acute bleomycin and hyperoxia-induced lung damage.

Hamsters treated with 0.5 U/kg intratracheal bleomycin and exposed for 24 h to 80% O2 develop acute respiratory failure 72 h after treatment. To examine indirectly the lung epithelial type II cell changes, alterations in pulmonary surfactant was measured. Presence and amount of dipalmitoyl phosphatidyl choline (DDPC) and sphingomyelin (SM) were measured, and the DPPC/SM ratio was determined in brochoalveolar lavage samples from treated and control animals 24, 48, 72, and 96 h after treatment. Hamsters treated with bleomycin and O2 had a significantly decreased DPPC/SM ratio at 72 h, which is the time of onset of respiratory failure. The decreased DPPC/SM ratio may reflect type II cell damage and inhibition of surfactant function by the edema fluid.

Osteoarticular sporotrichosis in a dog.

Osteoarticular sporotrichosis was diagnosed in a dog referred for evaluation of hindlimb lameness. There was radiographic evidence of osteopenia of the fourth tarsal and proximal aspects of the metatarsal bones. The diagnosis was based on histologic findings and results of physical examination, radiography, fungal culturing, and serologic tests. The dog was treated successfully with ketoconazole for 3 1/2 months.

Hyperadrenocorticism in a ferret.

A 7-year-old adult male ferret had progressive hair loss that was bilaterally symmetric. Also clinically evident were severe dehydration, polydipsia, muffled heart sounds, weak femoral pulses, hepatomegaly, lethargy, weakness, temporal muscular atrophy, dyspnea, and weakness. The blood profile of the ferret indicated profound leukopenia, eosinopenia, and high phosphorus, BUN, creatinine, and potassium concentrations, as well as high aspartate transaminase activity; the albumin concentration was low. The serum cortisol concentration was 8.1 micrograms/dl. Necropsy and histologic findings confirmed a diagnosis of hyperadrenocorticism, complicated by dilatative cardiomyopathy, chronic active hepatitis, and renal disease.

Bright x-ray flares in gamma-ray burst afterglows.

Gamma-ray burst (GRB) afterglows have provided important clues to the nature of these massive explosive events, providing direct information on the nearby environment and indirect information on the central engine that powers the burst. We report the discovery of two bright x-ray flares in GRB afterglows, including a giant flare comparable in total energy to the burst itself, each peaking minutes after the burst. These strong, rapid x-ray flares imply that the central engines of the bursts have long periods of activity, with strong internal shocks continuing for hundreds of seconds after the gamma-ray emission has ended.

Idiopathic cardiomyopathy in C3Hf/Bd mice.

Male and female 16 to 18 month old C3Hf/Bd mice in a dermal carcinogenicity study were moribund or died at earlier time points than the expected 24 to 30 months. Clinical signs observed in both treated and control animals included dyspnea, lethargy, and death. Lesions seen in treated as well as control mice were cardiomegaly with myocardial degeneration and necrosis, hydrothorax and pulmonary edema, and ascites and chronic passive congestion of the liver. Mice were negative for serologic, bacteriologic and microscopic evidence of viruses, bacteria and protozoa which can induce heart lesions. Possible causes of the cardiomyopathy include metabolic, degenerative, genetic or undetermined infectious disease.

Acute respiratory failure induced by bleomycin and hyperoxia: pulmonary edema, cell kinetics, and morphology.

The acute manifestations of experimental bleomycin- and hyperoxia-induced lung damage were examined. Hamsters were treated with 5 U/kg bleomycin intratracheally followed by exposure to 80% oxygen (O2). As little as 12 hr of O2 exposure potentiated the bleomycin injury; however, the onset of mortality was 72 hr after treatment. The onset of pulmonary edema, measured by radiolabeled tracers, also occurred 72 hr after treatment. Cell kinetics studies showed that 24 hr exposure to 80% O2 did not alter early alveolar cell proliferation. Treatment with bleomycin alone did result in an early increase in alveolar macrophage and type II pneumocyte labeling. Animals treated with both bleomycin and hyperoxia had an increase in macrophage labeling, but not in type II pneumocyte labeling. We conclude that increased macrophage numbers associated with suppressed type II pneumocyte proliferation may play key roles in the potentiation and development of lung damage caused by bleomycin and hyperoxia treatment.

Tissue specific toxicities of the anticancer drug 6-thioguanine is dependent on the Hprt status in transgenic mice.

6-Thioguanine (6TG) a cytostatic antimetabolite is currently used to treat patients with cancer, in particular leukemias. However, one drawback of such use is the development of 6TG resistance. Hypoxanthine-guanine phosphoribosyl transferase (Hprt) plays a crucial role in the bioactivation of 6TG. Loss of Hprt has been associated with the resistance of leukemias to 6TG chemotherapy, however, nothing has been known about the effect of Hprt status on tissue specific toxicity of 6TG in vivo. We determined the effect of Hprt status on the tissue-specific toxicity of 6TG in vivo in transgenic Hprt-deficient mice. The approximate lethal dose for Hprt-deficient mice was 23-fold higher than for the wild-type. Serum biochemical analyses of 6TG-treated wild-type mice showed elevated serum enzyme levels characteristic of liver damage whereas the levels in Hprt-deficient 6TG-treated mice were within normal physiological limits. Histopathological examination of tissues from wild-type and from Hprt-deficient mice showed contrasting spectrums of microscopic lesions. Wild-type mice had loss of hematopoietic cells from bone marrow starting at the lowest dose of 25 mg/kg 6TG whereas Hprt-deficient mice had normal bone marrow and spleen even at doses of 720 mg/kg 6TG. Wild-type mice also experienced severe loss of epithelial cells from the gastrointestinal tract starting at 50 mg/kg; however, the gastrointestinal tract of Hprt -/- mice remained unaffected. Wild-type livers revealed atrophy and necrosis at doses of 25 mg/kg 6TG although Hprt -/- livers displayed no effect until 507 mg/kg. In this study we show that Hprt-deficient mice had 6TG-resistant bone marrow and there are several other factors contributing to 6TG resistance in patients. Because variations among people exist in terms of their 6TG sensitivity, determining 6TG sensitivity of lymphocytes prior to 6TG chemotherapy and restricting treatment to 6TG-sensitive patients may improve the efficacy.

Serum thyroxine and triiodothyronine radioimmunoassay values in the normal ferret.

The European ferret, Mustela putorius furo, has become increasingly popular as an animal model in biomedical research. However, certain important normal clinical data have not been established for the ferret. In this study, serum thyroxine (T4) and 3,3',5-triiodothyronine (T3) values were obtained from ferrets by the use of commercial radioimmunoassays. Sera from 44 animals, 31 males (27 intact and 4 castrated) and 13 females (10 intact and 3 spayed) were assayed. Serum T4 values ranged from 1.01-8.29 micrograms/dl for males (mean = 3.24 +/- 1.65 micrograms/dl), and 0.71-3.43 micrograms/dl for females (mean = 1.87 +/- 0.79 micrograms/dl). Serum T4 values of adult female ferrets, juvenile ferrets (less than 1 year old) of either sex, and castrated males were similar to the normal T4 values of the cat, 1.20-3.80 micrograms/dl. Intact adult male ferrets had higher serum T4 values which were more comparable to those of the normal dog 1.52-3.60 micrograms/dl. Serum T3 values ranged from 0.45-0.78 ng/ml for males (mean = 0.58 +/- 0.09 ng/ml), and 0.29-0.73 ng/ml for females (mean = 0.53 +/- 0.13 ng/ml). These values are comparable to those of dogs and cats which are 0.50-1.50 ng/ml.

Methyl prednisolone acetate modulation of infection and subsequent pulmonary pathology in hamsters exposed to parainfluenza-1 virus (Sendai).

Parainfluenza-1 virus (PI-1) has a wide host range; the disease process observed varies with the age, previous exposure, and species. This study was performed to determine possible effects of the corticosteroid methyl prednisolone acetate (MPA) on PI-1 infection in hamsters. Hamsters serologically negative for PI-1 were exposed to virus alone or were exposed to virus the day after pretreatment with a single subcutaneous injection of MPA. Serum antibodies to PI-1 were present in virus-only exposed hamsters by Day 8 and increased up to Day 20. PI-1 was recovered from lungs of virus-only exposed hamsters on Day 2 to 8. Virus antigen was detected by immunocytochemistry on Days 2 to 10 in lungs of virus-only exposed hamsters. Virus-associated lesions in these hamsters began as acute bronchiolar epithelium degeneration and necrosis on Day 4 and were foci of fibrosis by Days 12 to 20. Hamsters exposed to virus after MPA treatment developed no antibodies to virus, had no virus detectable by plaque assays or immunocytochemistry, and had no pulmonary lesions. Hamsters treated with MPA had decreased total lymphocyte counts up to Day 20 after treatment. Treatment of hamsters with MPA one day prior to PI-1 virus exposure is associated with no detectable evidence of viral infection. Humoral and cellular immunity mediated by MPA-sensitive lymphocytes may mediate some of the manifestations of PI-1 pulmonary disease.

Expression of hygR in transgenic mice causes resistance to toxic effects of hygromycin B in vivo.

Aminoglycoside antibiotics are indispensable for treatment of serious bacterial infections, and despite careful attention to dosage regimens, nephrotoxicity and ototoxicity still cause concern. In the present study, we tested whether side effects of aminoglycoside therapy could be limited by expression of prokaryotic genes of antibiotic resistance in vivo. We characterized the acute and tissue-specific toxicity of hygromycin B in transgenic mice bearing the hygromycin B phosphotransferase (hygR) gene under control of a constitutive promoter. We characterized the tissue-specific expression of hygR mRNA and also investigated the acute toxicity of hygromycin B in hygR and wild-type mice. The hygR mRNA reached its highest levels in brain and reached intermediate levels in spleen, muscle, kidney, liver and testis. The lowest levels were detected in heart and lungs. The hygR expression in transgenic animals caused an 89-fold increase in the approximate lethal dose of hygromycin B compared with wild-type mice. Serum biochemical analysis of hygR and wild-type mice treated with lethal doses of hygromycin B indicated liver and kidney damage measured as ALT, AST and BUN. On the morphological level, these changes led to acute tubular nephrosis in wild-type mice and acute liver damage in hygR mice. Our results show that constitutive expression of the bacterial hygR gene in transgenic mice in vivo confers resistance to hygromycin B.