Multisystem combined uranium resistance mechanisms and bioremediation potential of Stenotrophomonas bentonitica BII-R7: Transcriptomics and microscopic study.

The potential use of microorganisms in the bioremediation of U pollution has been extensively described. However, a lack of knowledge on molecular resistance mechanisms has become a challenge for the use of these technologies. We reported on the transcriptomic and microscopic response of Stenotrophomonas bentonitica BII-R7 exposed to 100 and 250 µM of U. Results showed that exposure to 100 µM displayed up-regulation of 185 and 148 genes during the lag and exponential phases, respectively, whereas 143 and 194 were down-regulated, out of 3786 genes (>1.5-fold change). Exposure to 250 µM of U showed up-regulation of 68 genes and down-regulation of 290 during the lag phase. Genes involved in cell wall and membrane protein synthesis, efflux systems and phosphatases were up-regulated under all conditions tested. Microscopic observations evidenced the formation of U-phosphate minerals at membrane and extracellular levels. Thus, a biphasic process is likely to occur: the increased cell wall would promote the biosorption of U to the cell surface and its precipitation as U-phosphate minerals enhanced by phosphatases. Transport systems would prevent U accumulation in the cytoplasm. These findings contribute to an understanding of how microbes cope with U toxicity, thus allowing for the development of efficient bioremediation strategies.

Exploring the molecular reorientations in amorphous rosuvastatin calcium.

Molecular reorientations in rosuvastatin calcium, a drug that is widely used to prevent cardiovascular disease, were explored thoroughly by means of solid state nuclear magnetic resonance (1H and 13C NMR) combined with calculations of steric hindrances. The experimental results reveal rich internal reorientational dynamics. All relaxation processes were tested in a broad range of temperatures and described in terms of their type and the associated energy barriers. The internal molecular mobility of rosuvastatin calcium can be associated with the reorientational dynamics of four methyl groups, accompanied by reorientation of the isopropyl group. The energy barriers of methyl and isopropyl group reorientation depended on the type of E/Z isomers, while the water content also had a strong influence on the dynamics of the isopropyl group. In the paper, a consistent picture of the molecular dynamics is provided, facilitating our understanding of molecular mobility in this important pharmaceutical solid.

Molecular Dynamics Study of Polystyrene-b-poly(ethylene oxide) Asymmetric Diblock Copolymer Systems.

Two polystyrene-b-poly(ethylene oxide) (PS-b-PEO) diblock copolymers differing in molecular mass (49 and 78 kDa) but possessing the same PEO cylindrical morphology are examined to elucidate their molecular dynamics. Of particular interest here is the molecular motion of the PEO blocks involved in the rigid amorphous fraction (RAF). An analysis of complementary thermal calorimetry and X-ray scattering data confirms the presence of microphase-separated morphology as well as semicrystalline structure in each copolymer. Molecular motion within the copolymer systems is monitored by dielectric and nuclear magnetic resonance spectroscopies. The results reported herein reveal the existence of two local Arrhenius-type processes attributed to the noncooperative local motion of PEO segments involved in fully amorphous and rigid amorphous PEO microphases. In both systems, two structural relaxations governed by glass-transition phenomena are identified and assigned to cooperative segmental motion in the fully amorphous phase (the α process) and the RAF (the αc process). We measure the temperature dependence of the dynamics associated with all of the processes mentioned above and propose that these local processes are associated with corresponding cooperative segmental motion in both copolymer systems. In marked contrast to the thermal activation of the α process as discerned in both copolymers, the αc process appears to be a sensitive probe of the copolymer nanostructure. That is, the copolymer with shorter PEO blocks exhibits more highly restricted cooperative dynamics of PEO segments in the RAF, which can be explained in terms of the greater constraint imposed by the glassy PS matrix on the PEO blocks comprising smaller cylindrical microdomains.

Analysis of the Distribution of Energy Barriers in Amorphous Diazepam on the Basis of Computationally Supported NMR Relaxation Data.

Crystalline and amorphous diazepam, a psychoactive drug, were investigated by employing spin-lattice relaxation 1H NMR along with atom-atom calculations of the landscape of energy barriers. The activation barriers for reorientation of the methyl group in amorphous diazepam were found to be in the range of 1.9-12.7 kJ/mol. Atom-atom calculations permitted determination of the distribution of energy barriers for reorientations of methyl groups, which was in a good agreement with that obtained on the basis of experimental data. The NMR relaxation combined with calculations provided a quantitative description of the distribution of energy barriers including intra- and inter-molecular interactions.

Inverse PPARß/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.

Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor ß/δ (PPARß/δ) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPARß/δ in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPARß/δ, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor ß (TGFß)-induced invasion of MDA-MB-231 human breast cancer cells into a three-dimensional matrigel matrix. To elucidate the molecular basis of this finding, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) and microarray analyses, which identified the gene encoding angiopoietin-like 4 (ANGPTL4) as the major transcriptional PPARß/δ target in MDA-MB-231 cells, previously implicated in TGFß-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGFß and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPARß/δ-dependent fashion, resulting in the inhibition of ANGPTL4 secretion. This effect is attributable to these ligands' ability to induce a dominant transcriptional repressor complex at the site of transcription initiation that blocks preinitiation complex formation through an histone deacetylase-independent, non-canonical mechanism. Repression of ANGPTL4 transcription by inverse PPARß/δ agonists is functionally linked to the inhibition of cancer cell invasion into a three-dimensional matrix, as (i) invasion of MDA-MB-231 cells is critically dependent on ANGPTL4 expression, (ii) recombinant ANGPTL4 stimulates invasion, and (iii) reverses the inhibitory effect of ST247 and DG172. These findings indicate that a PPARß/δ-ANGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPARß/δ agonists is feasible.

Prospective use of intramuscular triamcinolone acetonide in pseudogout.

OBJECTIVE: To prospectively assess the efficacy of intramuscular (i.m.) triamcinolone acetonide in the treatment of pseudogout. METHODS: Fourteen patients with crystal proven pseudogout presenting with an acute attack within 5 days of onset were treated with intramuscular triamcinolone acetonide 60 mg and followed for 30 days. Patients with inadequate response were eligible for a 2nd triamcinolone acetonide injection on Day 1-2. RESULTS: Twelve patients had contraindication to nonsteroidal antiinflammatory agents (NSAID). Acute arthritis was monoarticular in 10 patients, and involved 2 or more joints in 4 patients. All patients had good clinical response to triamcinolone acetonide based on restoration of near baseline joint range of motion and joint circumference, and at least 50% improvement in patient and physician global assessment. Major clinical improvement occurred by Day 1-2 (2 patients), Day 3-4 (11 patients), and Day 10-14 (one patient). Six patients required a 2nd triamcinolone acetonide injection on Day 1-2. Toxicities were not observed. CONCLUSION: I.m. triamcinolone acetonide appears to be safe, well tolerated, and effective in the treatment of pseudogout. It may be a reasonable alternative therapy when NSAID are contraindicated, and for polyarticular attacks where intraarticular corticosteroids are impractical.

Pure red cell aplasia in systemic lupus erythematosus.

Pure red cell aplasia (PRCA) is a rare hematologic disorder characterized by a severe progressive anemia and a marked decrease or absence of red cell precursors on bone marrow examination. PRCA can occur in the course of many other diseases of which thymoma is the most common. Rarely, PRCA has occurred in patients with connective tissue disorders, the most common being systemic lupus erythematosus (SLE), with 13 cases reported to date in the English literature. In this subset of patients, PRCA can be difficult to manage, and a high rate of mortality has been reported. Multiple therapeutic modalities have been reported, with no clear consensus on the optimal treatment. To date, splenectomy has not been reported in this subset of patients.We describe a patient with SLE who developed PRCA. Prednisone was the initial treatment, but unacceptably high doses were required to control the disease. Intravenous gamma globulin was given with prompt but temporary improvement. The patient subsequently underwent splenectomy with resolution of the PRCA. The patient continues to have a normal hemoglobin 3 years after splenectomy despite no interim therapy. This case represents the 14th case of PRCA occurring in patients with SLE and is the first case of PRCA in SLE treated with splenectomy. Splenectomy should be considered as a therapeutic modality in the management of corticosteroid-refractory PRCA occurring in patients with SLE.

Periorbital edema and mees' lines in systemic lupus erythematosus.

There are many cutaneous findings that have been described in systemic lupus erythematosus (SLE). These include disease-specific and nonspecific lesions. Periorbital edema in the absence of proteinuria or hypoalbuminemia has been only rarely described. We report three patients who developed marked periorbital edema in association with a flare of SLE. All patients were without proteinuria or significant hypoalbuminemia, and no other etiology for the periorbital swelling was identified. This occurred despite all three taking antimalarial therapy, but the edema resolved promptly and completely with glucocorticoids. One of these patients also had transverse leukonychia, or Mees' lines, present on several fingernails, that appeared to correspond with previous SLE flares.Mees' lines and periorbital edema may represent two additional nonspecific but disease-related dermatologic manifestations of SLE. Whereas periorbital edema usually develops in concert with other clinical evidence of a lupus flare and is easily treated, Mees' lines appear to serve as a time line for previous SLE activity.

Magnetic resonance imaging in systemic lupus erythematosus patients without a history of neuropsychiatric lupus erythematosus.

OBJECTIVE: To determine the prevalence of magnetic resonance imaging (MRI) lesions in systemic lupus erythematosus (SLE) patients without a history of neuropsychiatric symptoms and to correlate any MRI abnormalities with the patient's other disease manifestations or treatment. METHODS: Prospective study of 32 consecutive patients with SLE without a history of neuropsychiatric symptoms, from inpatient and outpatient rheumatology services, who underwent MRI scan during a 3-year period. RESULTS: Five patients had MRI abnormalities consisting of white matter lesions or periventricular hyperintensities; this is similar to the prevalence of these abnormalities in the general population. CONCLUSION: The prevalence of silent brain MRI abnormalities is not increased in SLE patients who do not have a history of neuropsychiatric manifestations.

Endocrine profiles for outcome prediction from the intensive care unit.

OBJECTIVE: To evaluate the discriminating ability of various specific endocrine studies on patient outcome from the intensive care unit (ICU). DESIGN: Prospective cohort study of patients requiring intensive care. SETTING: Adult medical and coronary care units in a military referral hospital. PATIENTS: A total of 61 consecutive patients requiring intensive care over a 5-month period and 20 control subjects. INTERVENTIONS: Patients were evaluated within 24 hrs of ICU admission (day 1) with determination of the following variables: serum triiodothyronine, thyroxine, triiodothyronine resin uptake, thyrotropin, luteinizing hormone, follicle-stimulating hormone, testosterone, basal cortisol, adrenocorticotropic hormone-stimulated cortisol, cortisol increment, and Acute Physiology and Chronic Health Evaluation (APACHE II) score. A total of 24 hrs later (day 2), the same battery of tests was repeated with the exception of the adrenocorticotropic hormone-stimulated cortisol, cortisol increment, and APACHE II score. Individual variables were compared between survivors and nonsurvivors. MEASUREMENTS AND MAIN RESULTS: The best discriminators of patient outcome in descending order were the basal serum cortisol and triiodothyronine concentrations obtained on day 2 and the APACHE II score with predictive abilities of 81%, 74%, and 70%, respectively. No combination of variables was superior to the day 2 basal cortisol concentration for discrimination of outcome. CONCLUSIONS: The basal cortisol and triiodothyronine concentrations obtained from blood samples collected within 48 hrs of ICU admission appear to be better discriminators of patient outcome than the APACHE II score.