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An expanding radio nebula produced by a giant flare from the magnetar SGR 1806-20.

Soft gamma-ray repeaters (SGRs) are 'magnetars', a small class of slowly spinning neutron stars with extreme surface magnetic fields, B approximately 10(15) gauss (refs 1 , 2 -3). On 27 December 2004, a giant flare was detected from the magnetar SGR 1806-20 (ref. 2), only the third such event recorded. This burst of energy was detected by a variety of instruments and even caused an ionospheric disturbance in the Earth's upper atmosphere that was recorded around the globe. Here we report the detection of a fading radio afterglow produced by this outburst, with a luminosity 500 times larger than the only other detection of a similar source. From day 6 to day 19 after the flare from SGR 1806-20, a resolved, linearly polarized, radio nebula was seen, expanding at approximately a quarter of the speed of light. To create this nebula, at least 4 x 10(43) ergs of energy must have been emitted by the giant flare in the form of magnetic fields and relativistic particles.

Journal Article↗

A neonate with severe thrombocytopenia and radio-ulnar synostosis.

Bone marrow failure syndromes can be associated with abnormalities of the forearms. We observed a neonate with congenital thrombocytopenia who had bilateral radio-ulnar synostosis and fifth finger clinodactly. We performed an evaluation of the mechanism causing the thrombocytopenia using a combination of direct and indirect measures of thrombopoiesis. These tests indicated decreased platelet production. This entity of congenital hyporegenerative thrombocytopenia with bilateral radio-ulnar synostosis and fifth-finger clinodactly is an uncommon but easily recognizable form of congenital amegakaryocytic thrombocytopenia (CAMT). This entity can be distinguished from the TAR syndrome (thrombocytopenia and absent radii) by the distinctive orthopedic issues, different underlying genetic mutations, and a more worrisome prognosis for CAMT than for TAR.

Diagnosis, Differential↗

Caspase independence of radio-induced cell death.

Colon carcinoma cells subjected to gamma-irradiation (4 Gy) manifest signs of apoptosis (caspase activation, chromatin condensation, phosphatidylserine (PS) exposure on the cell surface, sub-diploid DNA content), correlating with their radiosensitivity, which is increased in cells lacking the 14-3-3sigma protein as compared to wild-type controls. Inhibition of caspases by addition of Z-Val-Ala-DL-Asp (OMe)-fluoromethylketone, by stable transfection with the Baculovirus gene coding for p35, or by Bax knockout reduced all signs of apoptosis, yet failed to suppress radio-induced micro- and multinucleation. Moreover, pharmacological caspase inhibition, p35 expression or Bax knockout had no effect on the clonogenic survival that was reduced by gamma-irradiation and caspase inhibition failed to abolish the increased radiosensitivity of 14-3-3sigma-deficient cells. Micro- and multinucleation was detectable among non-apoptotic cells lacking PS exposure, as well as among cells undergoing apoptosis. Moreover, a fraction of micro- or multinucleated cells manifested caspase activation, and videomicroscopic analyses revealed that such cells could succumb to caspase-dependent apoptosis. Altogether, these results suggest that genomic instability induced by gamma-irradiation can trigger apoptosis, although apoptosis is dispensable for radio-induced clonogenic death.

Amino Acid Chloromethyl Ketones↗

Utility of isolated hepatocytes and radio-HPLC-MSn for the analysis of the metabolic fate of 19-nortestosterone laurate in cattle.

The metabolic fate of 19-nortestosterone laurate in cattle was investigated to evaluate target analyte(s) appropriate to surveillance for illicit use as a growth promoting agent. Bovine hepatocytes were incubated with either [3H]19-nortestosterone laurate (19-NTL; 4-estren-17 beta-laurate-3-one) or [3H]19-nortestosterone (19-NT; 4-estren-17 beta-ol-3-one; nandrolone). Hepatocyte medium was extracted with solid phase C18 media and analysed by narrow bore radio-HPLC-MSn (LCQ, Finnigan) to evaluate the structure of metabolites of 19-NTL and 19-NT. Radio-HPLC of hepatocyte medium extracts following incubation with [3H]19-NTL confirmed that the first step of biotransformation in liver was hydrolysis of the fatty acid ester to release [3H]19-NT, which, in turn, was converted into a range of metabolites of diverse polarity. Hydrolysis of hepatocyte medium extracts with beta-glucuronidase (Helix pomatia) indicated that some of these metabolites were glucuronide or sulfate conjugates. Structural analysis of unconjugated metabolities by positive-ion atmospheric pressure chemical ionisation MS2 and comparison with available reference preparations indicated biotransformation of 19-NT to 4-estren-17 alpha-ol-3-one, 4-estren-3, 17-dione (major metabolite after 1 h), n-hydroxy-4-estren-3, 17-dione, n-hydroxy-4-estren-17-ol-3-one, 5 beta-estran-3 alpha-ol-17-one (noretiocholanolone) and 5 beta-estran-3 alpha, 17 beta-ol (major metabolite after 4 h). Conjugated metabolites were analysed by electrospray ionization, which revealed the presence of glucuronide conjugates of alpha-(trace) and beta-epimers of 19-NT, n-hydroxy-4-estren-3, 17-dione, n-hydroxy-4-estren-17-ol-3-one and 5 beta-estran-3 alpha, 17 beta-diol. These studies provide a clear indication of the route of hepatic metabolism in the bovine, which may now be readily substantiated by reference to samples, such as urine or bile, derived from animals treated with unlabelled 19-NTL.

Anabolic Agents↗

Fit of some analytical functions to insulin radio-immunoassay standard curves.

Some analytical functions were tested for goodness of fit to standard curves in radio-immunoassays of insulin (Hales & Randle, 1963). Letting a, b and c be parameters, and y the radioactivity measured at an insulin concentration of x, excellent fit was obtained with the function 1/(y+c)=ax+b. This function was associated with a smaller variance around y and a greater number of sign changes for the residuals (calculated radioactivity minus observed radioactivity) than any of the following: 1/y=ax(c)+b; y=ae(bx)+c; y=a+bx+cx(2)+dx(3). The mean number of sign changes of the residuals in 50 separate assays of mouse insulin was within the 95% confidence interval expected for a correct model. The function that was found to be applicable to assays of mouse, human and ox insulins should be useful in routines for computer processing of insulin assay data and may also prove applicable to other radio-immunoassays.

Animals↗

Downregulation of BRCA1 in A375 melanoma cell line increases radio-sensitivity and modifies metastatic and angiogenic gene expression.

The participation of BRCA1 (breast cancer 1) in DNA repair is well established, especially in mammary and ovarian cells. Our purpose was to develop a new in vivo radio-sensitizing therapy for melanoma. We therefore investigated the effect of downregulation of BRCA1 on irradiated melanoma cells using an anti-BRCA1 ribozyme. Our results show that BRCA1 downregulation increased radio-sensitivity of the A375 cell line, suggesting that BRCA1 could act as a caretaker in melanoma; however, as BRCA1 functions are not limited to maintaining genomic integrity but also regulate transcription and the cell cycle, we confirmed that the proliferative rate of BRCA1 downregulated clones did not change. We also demonstrate that: (1) among the major pro-angiogenic genes, FGF-2 was not increased before or after irradiation and vascular endothelial growth factor strongly inhibited after irradiation; (2) expression of two important metalloproteinases, matrix metalloproteinase 2 and 9, involved in melanoma metastasis were decreased before and after irradiation; (3) expression of their major inhibitor, tissue inhibitor of metalloproteinase, was mainly upregulated; and (4) that invasion of BRCA1 downregulated cells was modified. Together these data suggest that BRCA1 downregulation in melanoma cells did not make them more aggressive and could lead to new therapeutic strategies for this tumor, which is so difficult to control once metastasized.

Benzothiazoles↗

Radio-frequency ablation for symptom control in a patient with metastatic pancreatic insulinoma.

Malignant insulinomas are very rare endocrine tumours with a variable clinical course. We describe a 51-year-old man who had two large insulinomas resected from the body of the pancreas and 19 years later, having again become symptomatic, was found to have hepatic metastases. Medical treatment with diazoxide and octreotide failed to control his symptoms, but repeated hepatic embolization effected both symptomatic and biochemical improvements for a further 5 years. When symptoms recurred but further embolization failed to control his symptoms the hepatic metastases were treated by outpatient percutaneous radio-frequency ablation. He remains symptom-free 18 months later and levels of insulin and pro-insulin have nearly normalized. The survival, with liver metastases, for 27 years in a man with a malignant insulinoma has not been described previously. Malignant insulinoma may follow a rather indolent course and symptoms respond well to locally destructive therapies. Hepatic embolization is less traumatic than hepatic lobe resection and radio-frequency ablation offers an alternative if vascular access to the tumour is no longer possible.

Catheter Ablation↗

Neoadjuvant radio-chemotherapy in advanced primarilynon-resectable carcinomas of the pancreas.

AIM: To investigate the feasibility of neoadjuvant radio-chemotherapy (RCT) in the treatment of primarily non-resectable pancreas carcinoma the parameters tumour regression, possibility of subsequent resection and tolerability were examined. METHOD: Between 1995 and 1997, 27 patients with locally inoperable (assessed by CT criteria) pancreatic carcinoma received radio-chemotherapy for 5 weeks comprising irradiation (55.8 Gy) and chemotherapy with 5-fluorouracil (5-FU, 1000 mg/m(2)/day; 120 h continuous infusion) and mitomycin C (10 mg/m(2)i.v.-bolus, day 2 and day 30) during the first and fifth week of radiotherapy. Two target volumes were irradiated with fractionated doses of 1.8 Gy up to a total of 50.4 Gy. Radiation was applied once a day five times a week and target volume 1 was irradiated with the same fractionated dose, and an additional boost of 5.4 Gy to make an overall total of 55.8 Gy. RESULTS: Sixteen patients underwent explorative laparotomy, 10 of these were resected (eight Whipple's procedures, two distal pancreatic resections), while six could not be resected due to peritoneal carcinosis (n=3), local irresectability (n=2) and liver cirrhosis (n=1). A further nine patients were found to have unresectable tumours on CT and did not undergo surgery after restaging (five of these patients were staged as < >, three patients had distant metastases and one patient refused surgery). In two patients RCT was abandoned because of progression of disease. CONCLUSIONS: The study protocol described is feasible without significant acute toxicity and when used the resectability rate was improved; the survival rate, however, was not improved. Additional intra-arterial or intraportal application of such drugs as mitomycin C or cisplatin may be necessary.

Adenocarcinoma↗

Radio-labeled receptor-binding peptides: a new class of radiopharmaceuticals.

Radio-labeled receptor-binding peptides have emerged as an important class of radiopharmaceuticals. In vertebrates, these peptides transmit their biological function by binding to their specific receptor on the target cell surface. This specific receptor-binding property is exploited when the radio-labeled peptide is used as a radiopharmaceutical. The high-binding affinity for its receptor facilitates retention of the peptide in receptor-expressing tissues, whereas its relatively small size facilitates rapid clearance from the blood and other nontarget tissues. Receptor-binding peptides labeled with gamma-emitters can be used to visualize receptor-positive cells in vivo. In addition, when labeled with beta- or alpha-emitters, these peptides can be used for peptide-receptor radionuclide therapy. Various receptors are overexpressed on particular tumor types, and peptides binding to these receptors can be used to visualize tumor lesions scintigraphically. Furthermore, peptides binding receptors on granulocytes can be used to image infectious and inflammatory foci, whereas peptides binding receptors on activated thrombocytes can be used for thrombus imaging. Here, the peptide analogs that are under development for these applications are reviewed.

Animals↗

[Radio-radial external fixation for correction of malunited distal radius fracture].

For correction of malunited distal radius fractures, the use of the external fixator in radio-radial application was assessed. The device has been used for one-stage correction with corticocancellous bone blocks as well as with hemicallotasis for correction of dorsal angulation. The technical application is described and the use of the external fixator defined. Fourteen patients were treated with radio-radial application, seven of those were corrected with callus distraction. The mechanical possibilities of the fixator allowed complete correction of the malunion.

Adolescent↗

In vivo and in vitro study of radio-frequency application with a new long linear probe: implication for the maze operation.

BACKGROUND: The maze operation for atrial fibrillation is effective but highly invasive. We tested, both in vitro and in vivo, a new technique for creating long linear atrial lesions with a custom-made, 25-mm long, stainless-steel, linear probe and a corresponding 500-kHz generator for assistance in the maze operation. METHODS: In the in vitro study with the isolated canine atria, the power of the delivered radio-frequency energy and the saline irrigating flow rate were changed independently, and the sizes of the lesions were measured. In the in vivo study radio-frequency energy was delivered to 4 portions (ie, the smooth and trabeculated portions of the right and left atria). The sizes of the lesions were measured, and the histologic features of the lesions were examined. Electrical isolation of the right atrial appendage from the remaining right atrium was attempted by using this linear probe. RESULTS: In the in vitro study the size of the lesion became larger as the delivered power was increased, although the lesion was limited when the flow rate was high. In the in vivo study the size of the lesion was equal at the 4 different sites. Histologic examinations demonstrated linear and transmural lesions, and electrophysiologic examinations revealed conduction block between the right atrial appendage and the remaining right atrium. CONCLUSIONS: The new original long linear probe was effective for creating transmural linear atrial lesions with the irrigation method, presenting the possibility of an intraoperative technique that mimics the maze procedure.

Animals↗

Observational model of the ionized gas in Seyfert and radio-galaxy nuclei.

Equivalent widths of the total emission-line Hbeta in Seyfert 1, Seyfert 2, and intermediate-type Seyfert galaxies, expressed in terms of the featureless continuum, all have approximately the same frequency distribution. This suggests that the energy-input mechanism to both the narrow-line, low-density gas and the broad-line, high-density gas is photoionization by the featureless continuum. The reason for the weakness of the narrow emission lines in extreme Seyfert 1 galaxies is then the absorption of most of the ionizing photons in the dense gas near the central source. The statistics of line widths can be fitted by a model in which the dense gas has typical rotational velocity 5000 km/sec and typical turbulent velocity 2000 km/sec. A model is proposed in which the dense gas forms a rotating, turbulent disk with dimension approximately 0.1 pc and height/diameter approximately 2/5. Seyfert 2 galaxies are objects with little dense gas, and intermediate-type Seyfert galaxies are objects in which the dense gas is optically thin to ionizing radiation at least along the poles. Most radio galaxies have strong narrow emission lines, suggesting that escape of radio plasma can only occur where some ionizing photons can also escape from the dense gas. Other predictions, implications, and tests of this model are discussed.

Journal Article↗

Evolution of powerful extragalactic radio sources.

Observations of complete flux density limited samples of powerful extragalactic radio sources by very-long-baseline interferometry enable us to study the evolution of these objects over the range of linear scales from 1 parsec to 15 kiloparsees (1 parsec = 3.09 x 10(18) cm). The observations are consistent with the unifying hypothesis that compact symmetric objects evolve into compact steep-spectrum doubles, which in turn evolve into large-scale Fanaroff-Riley class II objects. It is suggested that this is the primary evolutionary track of powerful extragalactic radio sources. In this case there must be significant luminosity evolution in these objects, but little velocity evolution, as they expand from 1 parsec to several hundred kiloparsecs in overall size.

Journal Article↗

Biodegradable X-ray markers of controlled radio-opacity. Temporary position measurements in bone.

In order to analyze X-ray markers for potential use in biodegradable implants or radiostereogrammatic analysis (RSA), we combined iopromide contrast fluid with biodegradable calcium phosphate cement. The radio-opacity of 10 x 10 mm markers containing different iodine concentrations (0, 120, 240, 360 and 720 mg per gram cement) was compared to an aluminium wedge of increasing (1-10 mm) thickness. The addition of iopromide increased the radio-opacity in a dose-dependent manner, which was comparable to 9-mm aluminium at concentrations of 240-720 mg/g. Radiographs of markers placed in explanted rabbit and in human femora were made to investigate the clinical accuracy for position determination. Markers of 1 x 1 mm (120 mg/g) were clearly discernable in all femora, and could be used to adequately measure distances of 5-45 mm (accuracy 0.10-2.19 mm). These markers might be embedded in biodegradable implants or used as temporary markers in the bone to analyze postoperative position on radiographs.

Absorbable Implants↗

125I-(Thr34, Nle37)- CCK31-39 a non oxidizable tracer for the characterization of CCK receptor on pancreatic acini and radio-immunoassay of C-terminal CCK peptides.

A derivative of the C-terminal nonapeptide of CCK, namely (Thr34, Nle37) - CCK31-39 was radio-iodinated by conjugation with 125I-Bolton-Hunter reagent. The labelled peptide was purified by RP-HPLC on a C-18 column. Validation of the iodinated peptide was performed by measuring its biological integrity and by studying its binding characteristics on pancreatic acini. 125I-(Thr, Nle)-CCK-9 present the same ability to stimulates amylase release than (Thr, Nle)- CCK-9 and CCK-8. Binding of the radio-ligand to CCK receptors is specific, reversible, saturable. Inhibition of the binding by CCK-related peptides correlates well their biological potencies. 125I-(Thr, Nle)-CCK-9 is able to interact with high affinity CCK receptors. Furthermore, 125I-(Thr, Nle)-CCK-9 is recognized by C-terminal CCK directed antibodies. This reliable tracer could be used as a replacement of CCK-8 since it is protected from risks of oxidation.

Amylases↗

Effectiveness of radiolabelled antibodies for radio-immunotherapy in a colorectal xenograft model: a comparative study using the linear--quadratic formulation.

PURPOSE: To develop a model that relates the pattern of dose delivery during radio-immunotherapy to biological effect. This model was used to assess the efficacy of a range of antibodies labelled with 131I, 186Re and 90Y. MATERIALS AND METHODS: Pharmacokinetic data were obtained by injecting tumour-bearing nude mice with radiolabelled antibody. The dose-rate in bone marrow and tumour was then given by a two-compartment model description of the pharmacokinetics combined with the radionuclide properties. Response characteristics of tumour and marrow were defined in terms of radiosensitivity, repair capacity and proliferation, and the biological effect was assessed using the linear quadratic formulation. RESULTS: Tumour-specific antibodies with intermediate molecular weight and clearance from the circulation delivered the most effective doses to tumour due to their rapid uptake and prolonged retention in tumour coupled with efficient clearance from blood. Matching the radionuclide with antibody pharmacokinetics and tumour type further increased this effect. CONCLUSIONS: The model improves conceptual understanding of the relationship of parameters affecting therapy and makes it possible to optimize radio-immunotherapy by selecting the most effective antibody and radionuclide according to tumour biology.

Animals↗

Constitutive mRNA expression of DNA repair-related genes as a biomarker for clinical radio-resistance: A pilot study in prostate cancer patients receiving radiotherapy.

PURPOSE: Repair of radiation-induced DNA damage is believed to play a critical role in the development of adverse reactions in radiotherapy patients. Constitutive mRNA expression of repair genes was investigated in such patients to analyze whether expression patterns are predictive for therapy-related acute side effects. MATERIALS AND METHODS: Prostate cancer patients (n = 406) receiving intensity-modulated radiotherapy were recruited in a prospective epidemiological study. Adverse effects were monitored during therapy using common toxicity criteria. For expression analyses, samples from 58 patients were selected according to their observed grade of clinical side effects to radiotherapy. Expression profiles were generated from peripheral blood lymphocytes using customized cDNA-arrays which carried probes for 143 DNA repair or repair-related genes. In addition, expression of selected genes was confirmed by quantitative real-time reverse transcription PCR (RT-PCR). Constitutive mRNA expression profiles were analyzed for predicting acute clinical radiosensitivity or radio-resistance. RESULTS: Cluster analysis identified 19 differentially expressed genes. Many of these genes are involved in DNA double strand break repair. Expression levels of these genes differed up to 7-fold from the mean of all patients whereas expression levels of housekeeping genes varied only up to 2-fold. High expression of the identified genes was associated with a lack of clinical radiation sensitivity thus indicating radio-resistance. CONCLUSIONS: Constitutive expression of DNA repair-related genes may affect the development of acute side effects in radiotherapy patients, and high expression levels of these genes seem to support protection from adverse reactions.

Biomarkers, Tumor↗

Mechanisms of radio-protection by catecholamines in the hamster (Mesocricetus auratus).

Whole-body exposure to 1000 or 2000 rads in a 60Co source was used to study radio-protection by norepinephrine, isoproterenol, and phenylephrine in normal and splenectomized hamsters. After exposure, the animals were caged individually, and percent survivals were recorded daily. The aortic blood pressure of permanently cannulated, unanaesthetized hamsters was measured to test the vasoconstriction-hypoxia mechanism of radio-protection, and plasma calcium levels were measured to test the hypothesis that isoproterenol protects through a mechanism of hypercalcaemia-stimualted cell proliferation. The data support the vasoconstriction-hypoxia mechanism for agents stimulating the alpha receptors, while beta agonists seem to protect through a hypotensive-hypoxia mechanism similar to that of histamine. All the catecholamines protect against the haematopoietic syndrome, but show no evidence of protection against the gastrointestinal syndrome.

Animals↗