Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency.

Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion, multiple deletions, or both due to loss of TK2 enzyme activity and ensuing unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, we administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2 H126N (Tk2(-/-)) knock-in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Assessment of 13-day-old Tk2(-/-) mice treated with dCMP+dTMP 200 mg/kg/day each (Tk2(-/-200dCMP/) (dTMP)) demonstrated that in mutant animals, the compounds raise dTTP concentrations, increase levels of mtDNA, ameliorate defects of mitochondrial respiratory chain enzymes, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency

Micro Pb filled polymer composites: Theoretical, experimental and simulation results for γ-ray shielding performance

Researches on advanced composites to protect environment health towards radioactive pollution have drawn attention with the rising use of radioactive elements. From this point, polymer micro composites are quite encouraging in terms of multifunctional properties in mechanical, electrical, thermal, as well as nuclear shielding. The present study has explored the efficacy of micro lead (Pb) loaded polymer composites for radio protective applications such as a fabrication of protective enclosures. High energetic photon shielding experiments have been applied through gamma spectrometer equipped with HPGe detector and various radioactive point sources namely 137Cs, 22Na, 152Eu, 133Ba, 241Am and 57,60Co which are widely used in several medical and industrial applications. The results demonstrated that mass attenuation coefficients of the composites at different photon energies are proportional to the filler loading. The validation of FLUKA and GEANT4 Monte Carlo software has been performed in the simulation of transmission experiments as well as WinXCOM software. The tests of the Pb (20%) micro composite for the nuclear radiation shielding reveal that it has high attenuation coefficients for photon radiation

PO-067: The impact of different radiotherapy techniques on treatment outcome of hypopharyngeal carcinomas

Getting an unbiased result is a remarkably long standing problem ofcollective observation/measurement. It is pointed out that quantum coin tossingcan generate unbiased result defeating dishonesty

Response to hypoxia involves smad proteins in human endothelial cells

Smad proteins are the downstream substrates of membrane ser/thr kinase TGF-β receptors, and mediate responses of endothelial cells (EC) to mechanical and metabolic stress. Oxygen deprivation (Hypoxia: Hx) is a consistent component of ischémie vascular disorders and induces an inflammatory response in vascular endothelium. This study, performed in human umbilical vein endothelial cells (HUVEC), examined the effect of Hx on activity of Smads and their target gene TGF-β2, a cytokine regulator of inflammation in EC. RNase protection studies showed that exposure to Hx (1% O2) increased mRNA levels of TGF-β2 by 10-fold in a time-dependent fashion (P \u3c .01). Parallel increases in active and latent TGF-β2 protein were found by measuring the response of a TGF-βresponsive luciferase construct in a bioassay. Hx stimulated TGF-β2 transcription in HUVEC, determined by activity of a TGF-β2 CAT promoter construct, by 3-fold; Hxinduced transcription was increased by a further 4-fold (P \u3c .01) after cotransfection of HUVEC with Smad 3/4 expression vectors. Hx also increased transcription from a known TGF-β-responsive promoter, 3TP-lux, by 10-fold (P \u3c .01); cotransfection of Smad 3/4 vectors increased the activity of 3TP-lux by a further 3-fold ( P \u3c .01). Smad association with DNA was shown with EMSA using a Smad-binding oligonucleotide, SEE, as probe. Binding to SBE occurred only with nuclear extracts from hypoxic but not normoxic HUVEC, was not competed by oligonucleotides corresponding to DNA-binding sites of SP1 or HIF-1, and was supershifted with antibody to Smad 3 and 4 but not to HIF-1 or preimmune sera. To further examine the effects of Hx on EC signal transduction and function, total RNA obtained from HUVEC exposed to Hx for increasing time periods was used for mRNA transcript profiling by cDNA arrays (Clonetech, Atlas 1.2). Results were normalized to β-actin and show that mRNA of TGF-β l, -β2, and their upstream regulators such as TGF-β RI and Ang II Rl were induced at 18h after Hx compared to normoxia. Furthermore, Hx induced mRNAs of Smad co-factors SP1 and -2, which cooperate to inhibit Gl cell cycle progression. mRNA levels of Smads, Jak-Stat proteins, or NF-KB were unchanged, but HIF-1 mRNA was increased. In sum, Hx-induced increases in TGF-β2, TGF-β RI, and Smad 3/4 function in EC suggest that this pathway plays an important role in endothelial response to hypoxic stress

Acute but transient neurological deterioration revealing adult polyglucosan body disease

Adult polyglucosan body disease (APBD) is a metabolic disorder usually caused by glycogen branching enzyme (GBE) deficiency. APBD associates progressive walking difficulties, bladder dysfunction and, in about 50% of the cases, cognitive decline. APBD is characterized by a recognizable leukodystrophy on brain MRI. We report here a novel presentation of this disease in a 35-year old woman who presented with an acute deterioration followed by an unexpected recovery. Enzymatic analysis displayed decreased GBE activity in leukocytes. Molecular analyses revealed that only one mutated allele was expressed, bearing a p.Arg515His mutation. This is the first observation reporting acute and reversible neurological symptoms in APBD. These findings emphasize the importance of searching GBE deficiency in patients presenting with a leukodystrophy and acute neurological symptoms mimicking a stroke, in the absence of cardiovascular risk factors.status: publishe