Reduction of GPSM3 expression akin to the arthritis-protective SNP rs204989 differentially affects migration in a neutrophil model.

G Protein Signaling Modulator-3 (GPSM3) is a leukocyte-specific regulator of G protein-coupled receptors (GPCRs), which binds inactivated Gαi·GDP subunits and precludes their reassociation with Gßγ subunits. GPSM3 deficiency protects mice from inflammatory arthritis and, in humans, GPSM3 single-nucleotide polymorphisms (SNPs) are inversely associated with the risk of rheumatoid arthritis development; recently, these polymorphisms were linked to one particular SNP (rs204989) that decreases GPSM3 transcript abundance. However, the precise role of GPSM3 in leukocyte biology is unknown. Here, we show that GPSM3 is induced in the human promyelocytic leukemia NB4 cell line following retinoic acid treatment, which differentiates this cell line into a model of neutrophil physiology (NB4*). Reducing GPSM3 expression in NB4* cells, akin to the effect ascribed to the rs204989 C>T transition, disrupts cellular migration toward leukotriene B4 (LTB4) and (to a lesser extent) interleukin-8 (a.k.a. IL-8 or CXCL8), but not migration toward formylated peptides (fMLP). As the chemoattractants LTB4 and CXCL8 are involved in recruitment of neutrophils to the arthritic joint, our results suggest that the arthritis-protective GPSM3 SNP rs204989 may act to decrease neutrophil chemoattractant responsiveness.

Genetic variations in GPSM3 associated with protection from rheumatoid arthritis affect its transcript abundance.

G protein signaling modulator 3 (GPSM3) is a regulator of G protein-coupled receptor signaling, with expression restricted to leukocytes and lymphoid organs. Previous genome-wide association studies have highlighted single-nucleotide polymorphisms (SNPs; rs204989 and rs204991) in a region upstream of the GPSM3 transcription start site as being inversely correlated to the prevalence of rheumatoid arthritis (RA)-this association is supported by the protection afforded to Gpsm3-deficient mice in models of inflammatory arthritis. Here, we assessed the functional consequences of these polymorphisms. We collected biospecimens from 50 volunteers with RA diagnoses, 50 RA-free volunteers matched to the aforementioned group and 100 unmatched healthy young volunteers. We genotyped these individuals for GPSM3 (rs204989, rs204991), CCL21 (rs2812378) and HLA gene region (rs6457620) polymorphisms, and found no significant differences in minor allele frequencies between the RA and disease-free cohorts. However, we identified that individuals homozygous for SNPs rs204989 and rs204991 had decreased GPSM3 transcript abundance relative to individuals homozygous for the major allele. In vitro promoter activity studies suggest that SNP rs204989 is the primary cause of this decrease in transcript levels. Knockdown of GPSM3 in THP-1 cells, a human monocytic cell line, was found to disrupt ex vivo migration to the chemokine MCP-1.

Fission barrier of superheavy nuclei and persistence of shell effects at high spin: cases of 254No and 220Th.

We report on the first measurement of the fission barrier height in a heavy shell-stabilized nucleus. The fission barrier height of 254No is measured to be Bf=6.0±0.5 MeV at spin 15ℏ and, by extrapolation, Bf=6.6±0.9 MeV at spin 0ℏ. This information is deduced from the measured distribution of entry points in the excitation energy versus spin plane. The same measurement is performed for 220Th and only a lower limit of the fission barrier height can be determined: Bf(I)>8 MeV. Comparisons with theoretical fission barriers test theories that predict properties of superheavy elements.

Shell-structure and pairing interaction in superheavy nuclei: rotational properties of the z=104 nucleus (256)rf.

The rotational band structure of the Z=104 nucleus (256)Rf has been observed up to a tentative spin of 20ℏ using state-of-the-art γ-ray spectroscopic techniques. This represents the first such measurement in a superheavy nucleus whose stability is entirely derived from the shell-correction energy. The observed rotational properties are compared to those of neighboring nuclei and it is shown that the kinematic and dynamic moments of inertia are sensitive to the underlying single-particle shell structure and the specific location of high-j orbitals. The moments of inertia therefore provide a sensitive test of shell structure and pairing in superheavy nuclei which is essential to ensure the validity of contemporary nuclear models in this mass region. The data obtained show that there is no deformed shell gap at Z=104, which is predicted in a number of current self-consistent mean-field models.

Gamma-ray spectroscopy at the limits: first observation of rotational bands in 255Lr.

The rotational band structure of 255Lr has been investigated using advanced in-beam gamma-ray spectroscopic techniques. To date, 255Lr is the heaviest nucleus to be studied in this manner. One rotational band has been unambiguously observed and strong evidence for a second rotational structure was found. The structures are tentatively assigned to be based on the 1/2-[521] and 7/2-[514] Nilsson states, consistent with assignments from recently obtained alpha decay data. The experimental rotational band dynamic moment of inertia is used to test self-consistent mean-field calculations using the Skyrme SLy4 interaction and a density-dependent pairing force.

Influence of initial lung deposit on pulmonary clearance after plutonium oxide inhalation in rat.

Alveolar macrophages are a key element in the clearance of inhaled particles after phagocytosis, and thus participate actively in lung dose distribution and in the risk of tumour formation. We studied the influence of initial lung deposit (ILD) on lung clearance and distribution of activity from 3 d to 3 months after inhalation of two forms of PuO2 (97% 239Pu and 70% 239Pu) in rats. ILDs ranging from 2.1 to 17 kBq were used. The total activity measured using X-ray spectrometry 3 months post-inhalation, relative to the ILD, showed a similar decrease in all groups, with the remaining activity representing approximately 30% of the ILD. The total activity recovered in bronchoalveolar lavages represented approximately 60% of the total lung activity. This ratio remained stable over time for the lowest ILD tested but decreased for higher ILD. In addition, the percentage of macrophages associated with particles decreased faster with time in rats with the highest ILD. Under our experimental conditions, there were no marked differences in lung clearance between groups. However, the distribution of the activity seems to vary with the time post-exposure between low and high ILD.

Observation of a rotational band in the odd-Z transfermium nucleus 101251Md.

A rotational band has been unambiguously observed in an odd-proton transfermium nucleus for the first time. An in-beam gamma-ray spectroscopic study of 101/251Md has been performed using the gamma-ray array JUROGAM combined with the gas-filled separator RITU and the focal plane device GREAT. The experimental results, compared to Hartree-Fock-Bogolyubov calculations, lead to the interpretation that the rotational band is built on the [521]1/2(-) Nilsson state.

Direct lung delivery of a dry powder formulation of DTPA with improved aerosolization properties: effect on lung and systemic decorporation of plutonium.

DTPA, an actinide chelating agent, has demonstrated its ability to complex plutonium (Pu) and to facilitate its urinary excretion after internal contamination. This process, known as decorporation is crucial to diminish the burden of Pu in the body. The ability to deliver a chelating agent directly to the alveolar region may increase its local concentration as compared to systemic delivery and therefore increase the extent of decorporation. Second, inhalation offers the potential for needle-free, systemic delivery of small molecules and would be convenient in case of nuclear accident as a first pass emergency treatment. To benefit from the improvement of inhalation technology, we have formulated DTPA into porous particles by spray-drying with dl-Leucine, DPPC and ammonium bicarbonate. The optimized particles possess a volume mean geometric diameter around 4.5 mum and crumpled paper morphology. The in vitro aerodynamic evaluation shows that about 56% of the powder should deposits in the lungs, with about 27% in the alveolar region, an improvement as compared with the micronized powder available with the Spinhaler. After pulmonary administration to rats contaminated with PuO(2), a 3-fold increase of the Pu urinary excretion was observed, but the dissolution of PuO(2) in the lungs was not enhanced.

Comparison of Prussian blue and apple-pectin efficacy on 137Cs decorporation in rats.

Cesium-137 (137Cs) is one of the most important nuclear fission elements that contaminated the environment after the explosion of the Chernobyl nuclear power plant in Ukraine (1986). The aim of the study was to compare the efficacy of two chelating agent, Prussian blue and apple-pectin on 137cesium decorporation in rats. Rats were intravenously injected with a solution of 137cesium (5 kBq per rat). Chelating agents, Prussian blue or apple-pectin were given immediately after Cs contamination and during 11 days by addition of each chelating agent in drinking water at a concentration corresponding to 400 mg kg(-1) day(-1). Efficiency was evaluated 11 days after contamination (at the end of treatment) through their ability to promote Cs excretion and to reduce the radionuclide accumulation in some retention compartments (blood, liver, kidneys, spleen, skeleton and in the remaining carcass). In these conditions after treatment with Prussian blue a fivefold increase in fecal excretion of Cs was observed and was associated with a reduction in the radionuclide retention in the main organs measured. In contrast, no significant differences were observed between untreated rats and rats treated with apple-pectin. These observations were discussed in terms of ability of pectins to bind Cs and compared to recently published results obtained after treatment of Cs-contaminated children with this chelate.

Enhanced decorporation of plutonium by DTPA encapsulated in small PEG-coated liposomes.

The aim of the study was to demonstrate that decorporation of 238Pu is achieved more efficiently by an optimized liposomal formulation of diethylene triamine pentaacetic acid (DTPA) than by the usual free DTPA treatment. The optimized formulation consisted of polyethylene glycol-coated stealth liposomes with a mean diameter of 100 nm (SL-100 nm). Rats were intravenously injected with various Pu-phytate salt solutions in order to test different contamination conditions (activity and salt concentration) impacting liver kinetics and skeletal uptake of Pu. All treatments were given intravenously 1 h after contamination. Efficiency was evaluated 24 h, 7, 16 or 30 days later through their ability to promote Pu elimination and to reduce Pu burden in the skeleton and liver, the main organs of Pu deposition and radiotoxicological effects. Whatever the conditions of contaminations, a single injection of SL-100 nm (3.2 micromol kg(-1) DTPA) boosted urinary elimination of Pu to above 90% of the injected dose. In addition, liposomes strongly and significantly reduced the Pu burden of the liver and skeleton even 30 days after a single treatment: a dose of 0.3 micromol kg(-1) induced the same skeletal Pu reduction as four injections of free DTPA (30 micromol kg(-1)). A log dose-effect relation was found with SL-100 nm DTPA and Pu excretion in urine or Pu burden in the studied organs (liver, femurs, spleen and kidneys). This efficacy was attributed to an optimized targeting of DTPA to the main Pu retention organs and especially the liver.

Radionuclide biokinetics database (RBDATA-EULEP): an update.

The main activity of the RBDATA-EULEP project is the development of an electronic database of information on the biokinetics of radionuclides after intake by inhalation, ingestion or injection. It consists of linked tables of publications and experiments, with details and comments on the materials, procedures and results. By March 2004 it contained information on more than 1600 experiments from 600 publications. It will be extended and Internet access will also be provided.

Comparative tissue uptake and cellular deposition of three different plutonium chemical forms in rats.

PURPOSE: To evaluate the influence of the chemical form of plutonium (Pu) on its distribution in tissues and within liver cells populations. MATERIALS AND METHODS: Groups of male Sprague-Dawley rats were contaminated by intravenous injection of either Pu citrate, Pu nitrate or Pu phytate. Pu content was determined in various tissues at different times after injection. Pu liver distribution was analysed by autoradiography and after cellular separation. RESULTS: Biokinetic studies indicate that Pu citrate and Pu nitrate predominantly retained in the skeleton within the first hours after injection, whereas most of the Pu was in the liver after injection of Pu phytate. Autoradiographs showed that Pu citrate was homogeneously distributed in the liver, while Pu nitrate accumulated into 'hot points'. Pu phytate showed an intermediate distribution pattern. Hepatic cell separation revealed a difference of uptake between the two cell types depending on the chemical form of injected Pu, and on the time after contamination. CONCLUSIONS: Distinct Pu behaviour was observed for biokinetics, retention and liver distribution. The large differences noted between citrate, nitrate and phytate might be explained by differences in systemic and hepatic transport.

Exercise following a sport induced concussion.

OBJECTIVE: To determine if an athlete's capacity to perform exercise is impaired following concussion and whether this would be reflected by an altered heart rate response. METHODS: Of the 14 concussed athletes, nine missed playing time as a direct result of their concussion and five did not. The concussed athletes performed an exercise protocol on a cycle ergometer within 72 hours of being asymptomatic at rest and a second test at 5 days following the previous assessment. Matched controls (n = 14) were tested using the same time line. The exercise protocol consisted of a 2 minute warm up, 10 minute, low-moderate intensity, steady state exercise session, and a high intensity interval protocol. The interval protocol consisted of a 40 second high intensity bout, followed by a 40 second rest period. This protocol continued until the participant had reached volitional fatigue. RESULTS: The number of exercise bouts completed was not significantly different from their matched controls. However, concussed athletes who missed playing time had a significantly higher heart rate during the steady state exercise session. During this same period, they also exhibited a greater rise in heart rate over time. CONCLUSION: These findings indicate that exercise capacity is unaffected in concussed athletes who are asymptomatic at rest. However, their heart rate response to submaximal exercise is increased.

Choledochal cyst: a case report and review of literature.

BACKGROUND: We present our first experience in managing a case of choledochal cyst in a two and half year old girl highlighting the difficulties in the management together with a review of literature. METHOD: A two and half year old girl presented to the University of Maiduguri Teaching Hospital. A pertinent clinical evaluation with abdominal ultrasound allowed accurate pre-operative diagnosis. RESULTS: A young girl with a right hypochondrial mass confirmed as choledochal cyst by ultrasound scans. Haematological parameters were normal but deranged clotting profiles were corrected with vitamin-K injection before surgical drainage. CONCLUSION: High index of suspicion with abdominal ultrasound scan allowed accurate pre-operative diagnosis of choledochal cyst that was successfully managed by surgical drainage, when attempted dissection of cyst wall for excision failed.

Targeting of diethylene triamine pentaacetic acid encapsulated in liposomes to rat liver: an effective strategy to prevent bone deposition and increase urine elimination of plutonium in rats.

PURPOSE: To modify the distribution of the chelating agent diethylene triamine pentaacetic acid (DTPA) by using a formulation approach with liposomes in order to match the in vivo distribution of plutonium (Pu) and, as a consequence, to improve actinide decorporation. MATERIALS AND METHODS: DTPA was encapsulated in conventional and stealth liposomes. Their pharmacokinetics and ability to remove Pu were evaluated in rats 2 and 16 days after a single intravenous treatment given 2 h after contamination with colloidal Pu (239Pu phytate) or with soluble Pu (238Pu citrate). RESULTS: Both formulations induced major pharmacokinetic modifications in rats, allowing an accumulation of [14C]-DTPA mainly in the liver and secondarily (for stealth liposomes) in bone and spleen. These modifications were associated with major increases in urine elimination and with a decrease in skeletal Pu deposition, depending of the nature of the Pu contaminant. After contamination by Pu phytate, conventional liposomes of DTPA (6 micromol kg(-1)) were as efficient as free DTPA (30 micromol kg(-1)) in maintaining the Pu content in the femur below 4.3% of the injected dose after 16 days, a 3.6-fold reduction compared with free DTPA (4 micromol kg(-1)) treatment or without treatment. CONCLUSIONS: A formulation approach with liposomes appears to be a powerful tool to improve the efficiency of Pu chelating agents in vivo.

In vivo measurement of Pu dissolution parameters of MOX aerosols and related uncertainties in the values of the dose per unit intake.

The aim of this study was to compare dissolution parameter values for Pu from industrial MOX with different Pu contents. For this purpose, preliminary results obtained after inhalation exposure of rats to MOX containing 2.5% Pu are reported and compared to those obtained previously with MOX containing 5% Pu. Dissolution parameter values appear to increase when the amount of Pu decreases. Rapid fractions, f(r), of 4 x 10(-3) (s.d. = 2 x 10(-3)) and 1 x 10(-3) (s.d. = 6 x 10(-4)) and slow dissolution rates, s(s) of 2 x 10(-4) d(-1) (standard deviation, sigma = 5 x 10(-5)) and 5 x 10(-5) d(-1) (sigma = 1 x 10(-5)) were derived for MOX containing 2.5 and 5% of Pu, respectively. Simulations were performed to assess uncertainties on dose due to experimental errors. The relative standard deviations of the dose per unit intake (DPUI) due to f(r) (4-8%), are far less than those due to s(s) (about 20%), which is the main parameter altering the dose. Although quite different dissolution parameter values were derived, similar DPUIs were obtained for MOX aerosols containing 2.5 and 5% Pu which appear close to that for default Type S values.

Comparative decorporation efficacy of 3,4,3-LIHOPO, 4,4,4-LIHOPO and DTPA after contamination of rats with soluble forms of 238Pu and 233U.

The aim of this study was to compare the efficacies of DTPA, 3,4,3-LIHOPO and a newly synthesised molecule, 4,4,4-LIHOPO, in removing 233U and 238Pu after internal contamination by soluble forms of those nuclides. For this purpose, intravenous injections of DTPA (30 micromol kg(-1)) or 3,4,3-LIHOPO or 4,4,4-LIHOPO at dosages of 0.3 or 30 micromol kg(-1) were performed 1, 6 and 24 h after contamination of rats by intravenously injected 238Pu citrate and 1 h after intravenous injection of 233U nitrate. Actinide content in the main retention organs and cumulated excretion were measured 48 h after contamination. These experiments show similar decorporation efficacies of 4,4,4-LIHOPO and 3,4,3-LIHOPO for Pu, which are much higher than that of DTPA. At a dosage of 0.3 micromol kg(-1), the two LIHOPO analogues were as efficient as DTPA at a dosage of 30 micromol kg(-1). After U contamination, a 20% decorporation efficacy was obtained for either 3,4,3-LIHOPO or 4,4,4-LIHOPO at a dosage of 30 micromol kg(-1).

RBDATA-EULEP: providing information to improve internal dosimetry.

The overall aim of the concerted action RBDATA-EULEP is to provide information to improve the assessments of intakes of radionuclides and of the resulting doses. This involves a review of the behaviour of radionuclides following intake, and the transfer of expertise on methodology by organising small training workshops. The main activity is the development of an electronic database, effectively an annotated bibliography, but the electronic format used facilitates extension, updating and information retrieval. It consists of linked tables of references and experiments, with details and comments on the materials, procedures and results. By June 2002 it contained information on 524 inhalation, 282 ingestion and 164 injection experiments from 391 references. It will be extended, and Internet access provided. Prospective users include groups developing standards for internal dosimetry, scientists conducting research on radionuclide biokinetics and health physicists assessing the consequences of accidental intakes.

[In vitro uranyle affinity of per (3,6-anhydro-2-O-carboxyméthyle)-alpha-cyclodextrin and conditions required for in vivo application]. / Affinité in vitro de la per (3,6-anhydro-2-O-carboxyméthyle)-alpha-cyclodextrine pour les uranyles et conditions requises en vue d'une application in vivo.

Per (3.6-anhydro-2-O-carboxymethyle)- alpha-cyclodextrin ([1]) is a polydentate analog of EDTA, a well-known cation chelating reagent. [1] exhibits strong affinities in vitro for lanthanids, cobalt and also for uranyl cations. Hence, a 1:1 stoechiometry and a high affinity for uranyle (6

[Specific parameters for the calculation of dose after aerosol inhalation of transuranium elements]. / Mesure de paramètres spécifiques pour le calcul de dose après inhalation d'aérosols renfermant des éléments transuraniens.

A review on specific parameter measurements to calculate doses per unit of incorporation according to recommendations of the International Commission of Radiological Protection has been performed for inhaled actinide oxides. Alpha activity distribution of the particles can be obtained by autoradiography analysis using aerosol sampling filters at the work places. This allows us to characterize granulometric parameters of "pure" actinide oxides, but complementary analysis by scanning electron microscopy is needed for complex aerosols. Dissolution parameters with their standard deviation are obtained after rat inhalation exposure, taking into account both mechanical lung clearance and actinide transfer to the blood estimated from bone retention. In vitro experiments suggest that the slow dissolution rate might decrease as a function of time following exposure. Dose calculation software packages have been developed to take into account granulometry and dissolution parameters as well as specific physiological parameters of exposed individuals. In the case of poorly soluble actinide oxides, granulometry and physiology appear as the main parameters controlling dose value, whereas dissolution only alters dose distribution. Validation of these software packages are in progress.