The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype

neurogenetics - Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. Here, we report three Turkish siblings from...     

Efficiency of Soil Amendments for Copper Removal and Brassica Juncea (L.) Growth in Wastewater Irrigated Agricultural Soil

Wastewater irrigation is becoming a massive challenge for sustainable agriculture. Particularly, copper (Cu) presence in wastewater poses a great threat to the food chain quality. Thus, scientists need to address this issue by using chemical and organic soil amendments to restore the soil ecosystem. Therefore, this study aims to examine the efficacy of sulphur, compost, acidified animal manure and sesame straw biochar for Cu immobilization, adsorption and Brassica growth in wastewater irrigated soil. The current findings presented that all the soil amendments prominently improved brassica yield and significantly minimized the Cu uptake by Brassica shoots and roots in sesame straw biochar (SB) (64.2% and 50.2%), compost (CP) (48% and 32.5%), acidified manure (AM) (37% and 23.2%) and Sulphur (SP) (16% and 3.1%) respectively relative to untreated soil. In addition, Cu bioavailability was reduced by 51%, 34%, 16.6%, and 7.4% when SB, CP, AM, and SP were incorporated in wastewater irrigated polluted soil. The Cu adsorption isotherm results also revealed that SB treated soil has great potential to increase Cu adsorption capacity by 223 mg g^??1 over control 89 mg g^??1. Among all the treatments, SB and CP were considered suitable candidates for the restoration of Cu polluted alkaline nature soil.

     

β-Cyclodextrin tetradecasulfate/tetrahydrocortisol±minocycline as modulators of cancer therapies in vitro and in vivo against primary and metastatic lewis lung carcinoma

Tetrahydrocortisol, -cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 M, 24 h) and -cyclodextrin tetradecasulfate (100 M, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 M, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studies. Tetrahydrocortisol and -cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14×5mg/kg, days 4–18) and cyclophosphamide (3×150 mg/kg, days, 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.Abbreviations 14(SO₄)ßCD -cyclodextrin tetradecasulfate - THC tetrahydrocortisol - CDDP cis-diamminedichloroplatinum(II) - 4-HC 4-hydroperoxycyclophosphamide - BCNU N,N-bis(2-chloroethyl)-N-nitrosourea - CAM chick embryo chorioallantoic membrane; IC₅₀, concentration of a drug required to kill 50% of the cells This work was supported by NIH grant P01-CA38493 and a grant from Bristol-Myers-Squibb, Inc., Wallingford, Connecticut     

Allosteric effectors of hemoglobin as modulators of chemotherapy and radiation therapy in vitro and in vivo

Introduction: A series of molecules designed to be allosteric effectors of hemoglobin were examined for their potential as radiation sensitizers in vitro and in vivo and for their potential as chemosensitizers in vivo as well as for their antimetastatic effect. Results: At a concentration of 100 μM for 1 h prior to, during and for 1.5 h after radiation exposure, the allosteric effectors decreased the shoulder of the radiation survival curve of normally oxygenated EMT-6 cells and increased the slope of the radiation survival curves of hypoxic EMT-6 cells resulting in dose-modifying factors of 1.8 to 2.1. In vivo the allosteric effectors had antitumor activity against the Lewis lung carcinoma and produced primarily additive tumor growth delay when administered along with fractionated radiation therapy. When administered on days 4 through 18 after tumor implantation, the allosteric effectors, especially JP-7, RSR-13 and RSR-4, were highly effective antimetastatic agents in animals bearing Lewis lung carcinoma. In cell culture, simultaneous exposure to the allosteric effectors (at 100 μM ) effectively sensitized EMT-6 cells to the effects of 4-hydroperoxycyclophosphamide, thiotepa and carboplatin. The allosteric effectors were not very cytotoxic toward EMT-6 tumor cells from tumors treated in vivo with single doses of each molecule nor were these agents very cytotoxic toward bone marrow CFU-GM taken from the same animals. Conclusions: It is likely that the allosteric effectors have a molecular target in addition to hemoglobin. Other possible targets include hydroxymethyl-glutaryl-CoA reductase or microsomal cytochrome b₅. Received: 27 June 1997 / Accepted: 8 October 1997     

Differences in presentation and follow-up between HIV-1 antibody positive teenagers and adults: the need for a more focused approach to care?

Our findings show a high rate of loss to follow-up in HIV-positive teenagers compared with adults. Of concern is the fact that this group also have high rates of sexually transmitted infections, unprotected sex and pregnancy. There is an urgent need to examine the reasons for this and adopt strategies to minimize risk-taking behaviour and to improve access to appropriate healthcare.     

Investigation of rotameric conformations of substituted imidazo-[1,2-a]pyrazine: experimental and theoretical approaches

The different rotameric conformations of imidazo-[1,2-a]pyrazine have been synthesized and characterized by means of different experimental techniques, such as NMR, FTIR, and absorption spectroscopy and quantum chemical calculations. The different conformations were stabilized by hydrogen bonds, such as OH⋯N, ArH⋯N and ArH⋯ArH. The ground state optimizations and potential energy surface (PES) scanning profiles produced using density functional theory (DFT) show two stable rotameric forms for each molecule. The relative population of the conformations is affected by the strength of the hydrogen bonds. The calculated absorption spectra and isotopic shielding constants were acquired by time-dependent density functional theory (TD-DFT) and gauge invariant atomic orbitals (GIAO)-DFT, respectively. The strength of the hydrogen bonding interactions that resulted in the different conformations was studied by quantum theory of atoms in molecules (QTAIM).

The different rotameric conformations of imidazo-[1,2-a]pyrazine have been synthesized and characterized by means of different experimental techniques, such as NMR, FTIR, and absorption spectroscopy and quantum chemical calculations.     

Percutaneous coronary intervention versus coronary bypass graft surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass: The VA AWESOME multicenter registry: comparison with the randomized clinical trial.

OBJECTIVES: This study was designed to compare the three-year survival after percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) in physician-directed and patient-choice registries with the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) randomized trial results. BACKGROUND: The AWESOME multicenter randomized trial and registry compared the long-term survival after PCI and CABG for the treatment of patients with medically refractory myocardial ischemia and at least one additional risk factor for adverse outcome with CABG. The randomized trial demonstrated comparable three-year survival. METHODS: Over a five-year period (1995 to 2000), 2,431 patients with medically refractory myocardial ischemia and at least one of five risk factors (prior heart surgery, myocardial infarction within seven days, left ventricular ejection fraction <0.35, age >70 years, intra-aortic balloon required to stabilize) were identified. By physician consensus, 1,650 patients formed a physician-directed registry assigned to CABG (692), PCI (651) or further medical therapy (307), and 781 were angiographically eligible for random allocation; 454 of these patients constitute the randomized trial, and the remaining 327 constitute a patient choice registry. Survival for CABG and PCI was compared using Kaplan-Meier curves and log-rank tests. RESULTS: The CABG and PCI 36-month survival rates for randomized patients were 79% and 80%, respectively. The CABG and PCI 36-month survival rates were both 76% for the physician-directed subgroup; comparable survival rates for the patient-choice subgroup were 80% and 89%, respectively. None of the global log-rank tests for survival demonstrated significant differences. CONCLUSIONS: Both registries support the randomized trial conclusion: PCI is an alternative to CABG for some medically refractory high-risk patients.