Carbonic Anhydrase Interaction With Lipothioars Enites: A Novel Class of Isozymes I and II Inhibitors

The interaction of carbonic anhydrase (CA) isozymes I and II with a series of As(III) derivatives, dialkyl and diaryl rac-2,3-dimyristoyloxypropyldithioarsonites, was investigated kinetically and spectrophotometrically, utilizing the native and Co(II)-substituted enzymes. Depending on the substitution pattern at the -As(SR)2 moiety of the investigated derivatives, inactive compounds were found for R = phenyl or naphthyl, and active ones for derivatives containing carboxyl groups (R = CH2COOH, cysteinyl and glutathionyl). Together with the arsonolipids previously investigated, the active compounds of this series - the "lipothioarsenites"- constitute a novel class of CA inhibitors that bind to the metal ion within the enzyme active site, as proved by changes in the electronic spectra of adducts of such inhibitors with Co(II)CA

Muon Spin Relaxation Study of (La, Ca)MnO3

We report predominantly zero field muon spin relaxation measurements in a series of Ca-doped LaMnO_3 compounds which includes the colossal magnetoresistive manganites. Our principal result is a systematic study of the spin-lattice relaxation rates 1/T_1 and magnetic order parameters in the series La_{1-x}Ca_xMnO_3, x = 0.0, 0.06, 0.18, 0.33, 0.67 and 1.0. In LaMnO_3 and CaMnO_3 we find very narrow critical regions near the Neel temperatures T_N and temperature independent 1/T_1 values above T_N. From the 1/T_1 in LaMnO_3 we derive an exchange integral J = 0.83 meV which is consistent with the mean field expression for T_N. All of the doped manganites except CaMnO_3 display anomalously slow, spatially inhomogeneous spin-lattice relaxation below their ordering temperatures. In the ferromagnetic (FM) insulating La_{0.82}Ca_{0.18}MnO_3 and ferromagnetic conducting La_{0.67}Ca_{0.33}MnO_3 systems we show that there exists a bi-modal distribution of \muSR rates \lambda_f and \lambda_s associated with relatively 'fast' and 'slow' Mn fluctuation rates, respectively. A physical picture is hypothesized for these FM phases in which the fast Mn rates are due to overdamped spin waves characteristic of a disordered FM, and the slower Mn relaxation rates derive from distinct, relatively insulating regions in the sample. Finally, likely muon sites are identified, and evidence for muon diffusion in these materials is discussed.Comment: 21 pages, 17 figure

Hydrocarbon pneumonitis following liquid paraffin aspiration during a fire-eating performance: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hydrocarbon pneumonitis is an acute, intense pneumonitis resulting from aspiration of volatile hydrocarbon compounds with low viscosity and surface tension, most of which are members of the paraffin, naphthene and aromatic classes.</p> <p>Case presentation</p> <p>Six hours after participating in a party for teenagers, a 16-year-old boy developed dyspnea, cough, a fever (39°C) and chest pain. A chest radiograph showed infiltration in the right middle lobe. The patient reported alcohol abuse during the party and an episode of vomiting a few hours thereafter. He also reported practicing a fire-eating performance at the party using liquid paraffin, but was unaware of inhaling any of it. The radiographic infiltration was diagnosed as an aspiration pneumonia and he was treated at the local health center with antibiotics. Five days later, because of clinical deterioration, he was referred to a pulmonary clinic. A chest computed tomography scan was performed which showed consolidation with an air bronchogram in the right middle lobe and areas of atelectasis and ground glass opacities in the middle and lower right lobes. Spirometry revealed severe restriction of lung function. A bronchoscopy revealed inflamed, hyperemic mucosa. Bronchoalveolar lavage fluid revealed lipid-laden alveolar macrophages, which were detected by lipid staining, and neutrophilia. The patient was finally diagnosed with hydrocarbon pneumonitis and he was treated with systemic steroids and antibiotics. After 6 days of treatment there was complete clinical and significant radiologic regression.</p> <p>Conclusion</p> <p>Hydrocarbon pneumonitis should be included in the differential diagnosis of pneumonias. Recent exposure to volatile hydrocarbons provides a basis for clinical diagnosis, as symptoms and radiologic findings are not specific.</p

Thymus transplantation for complete DiGeorge syndrome: European experience

Background: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). Methods: Twelve patients with cDGS were transplanted with allogeneic cultured thymus. Objective: To confirm and extend the results previously obtained in a single centre. Results: Two patients died of pre-existing viral infections without developing thymopoeisis and one late death occurred from autoimmune thrombocytopaenia. One infant suffered septic shock shortly after transplant resulting in graft loss and the need for a second transplant. Evidence of thymopoeisis developed from 5-6 months after transplantation in ten patients. The median (range) of circulating naïve CD4 counts (x10663 /L) were 44(11-440) and 200(5-310) at twelve and twenty-four months post-transplant and T-cell receptor excision circles were 2238 (320-8807) and 4184 (1582 -24596) per106 65 T-cells. Counts did not usually reach normal levels for age but patients were able to clear pre-existing and later acquired infections. At a median of 49 months (22-80), eight have ceased prophylactic antimicrobials and five immunoglobulin replacement. Histological confirmation of thymopoeisis was seen in seven of eleven patients undergoing biopsy of transplanted tissue including five showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator (AIRE) expression was also demonstrated. Autoimmune complications were seen in 7/12 patients. In two, early transient autoimmune haemolysis settled after treatment and did not recur. The other five suffered ongoing autoimmune problems including: thyroiditis (3); haemolysis (1), thrombocytopaenia (4) and neutropenia (1). Conclusions: This study confirms the previous reports that thymus transplantation can reconstitute T cells in cDGS but with frequent autoimmune complications in survivors

MMP9 but Not EGFR, MET, ERCC1, P16, and P-53 Is Associated with Response to Concomitant Radiotherapy, Cetuximab, and Weekly Cisplatin in Patients with Locally Advanced Head and Neck Cancer

Concomitant administration of radiotherapy with cisplatin or radiotherapy with cetuximab appear to be the treatment of choice for patients with locally advanced head and neck cancer. In the present retrospective analysis, we investigated the predictive role of several biomarkers in an unselected cohort of patients treated with concomitant radiotherapy, weekly cisplatin, and cetuximab (CCRT). We identified 37 patients treated with this approach, of which 13 (35%) achieved a complete response and 10 (27%) achieved a partial response. Severe side effects were mainly leucopenia, dysphagia, rash, and anemia. Tumor EGFR, MET, ERCC1, and p-53 protein and/or gene expression were not associated with treatment response. In contrast, high MMP9 mRNA expression was found to be significantly associated with objective response. In conclusion, CCRT is feasible and active. MMP9 was the only biomarker tested that appears to be of predictive value in cetuximab treated patients. However, this is a hypothesis generating study and the results should not be viewed as definitive evidence until they are validated in a larger cohort

Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types

Innate drug sensitivity in healthy cells aids identification of lineage specific anti-cancer therapies and reveals off-target effects. To characterize the diversity in drug responses in the major hematopoietic cell types, we simultaneously assessed their sensitivity to 71 small molecules utilizing a multi-parametric flow cytometry assay and mapped their proteomic and basal signaling profiles. Unsupervised hierarchical clustering identified distinct drug responses in healthy cell subsets based on their cellular lineage. Compared to other cell types, CD19+/B and CD56+/NK cells were more sensitive to dexamethasone, venetoclax and midostaurin, while monocytes were more sensitive to trametinib. Venetoclax exhibited dose dependent cell selectivity that inversely correlated to STAT3 phosphorylation. Lineage specific effect of midostaurin was similarly detected in CD19+/B cells from healthy, acute myeloid leukemia and chronic lymphocytic leukemia samples. Comparison of drug responses in healthy and neoplastic cells showed that healthy cell responses are predictive of the corresponding malignant cell response. Taken together, understanding drug sensitivity in the healthy cell-of-origin provides opportunities to obtain a new level of therapy precision and avoid off-target toxicity.Peer reviewe

Converging evidence of impaired brain function in systemic lupus erythematosus: changes in perfusion dynamics and intrinsic functional connectivity.

peer reviewed[en] PURPOSE: Τhe study examined changes in hemodynamics and functional connectivity in patients with systemic lupus erythematosus (SLE) with or without neuropsychiatric manifestations. METHODS: Participants were 44 patients with neuropsychiatric SLE (NPSLE), 20 SLE patients without such manifestations (non-NPSLE), and 35 healthy controls. Resting-state functional MRI (rs-fMRI) was used to obtain whole-brain maps of (a) perfusion dynamics derived through time shift analysis (TSA), (b) regional functional connectivity (intrinsic connectivity contrast (ICC) coefficients), and (c) hemodynamic-connectivity coupling. Group differences were assessed through independent samples t-tests, and correlations of rs-fMRI indices with clinical variables and neuropsychological test scores were, also, computed. RESULTS: Compared to HC, NPSLE patients demonstrated intrinsic hypoconnectivity of anterior Default Mode Network (DMN) and hyperconnectivity of posterior DMN components. These changes were paralleled by elevated hemodynamic lag. In NPSLE, cognitive performance was positively related to higher intrinsic connectivity in these regions, and to higher connectivity-hemodynamic coupling in posterior DMN components. Uncoupling between hemodynamics and connectivity in the posterior DMN was associated with worse task performance. Non-NPSLE patients displayed hyperconnectivity in posterior DMN and sensorimotor regions paralleled by relatively increased hemodynamic lag. CONCLUSION: Adaptation of regional brain function to hemodynamic changes in NPSLE may involve locally decreased or locally increased intrinsic connectivity (which can be beneficial for cognitive function). This process may also involve elevated coupling of hemodynamics with functional connectivity (beneficial for cognitive performance) or uncoupling, which may be detrimental for the cognitive skills of NPSLE patients