Functional analysis of a novel POLγA mutation associated with a severe perinatal mitochondrial encephalomyopathy

Mutations in the mitochondrial DNA polymerase gamma catalytic subunit (POLγA) compromise the stability of mitochondrial DNA (mtDNA) by leading to mutations, deletions and depletions in mtDNA. Patients with mutations in POLγA often differ remarkably in disease severity and age of onset. In this work we have studied the functional consequence of POLγA mutations in a patient with an uncommon and a very severe disease phenotype characterized by prenatal onset with intrauterine growth restriction, lactic acidosis from birth, encephalopathy, hepatopathy, myopathy, and early death. Muscle biopsy identified scattered COX-deficient muscle fibers, respiratory chain dysfunction and mtDNA depletion. We identified a novel POLγA mutation (p.His1134Tyr) in trans with the previously identified p.Thr251Ile/Pro587Leu double mutant. Biochemical characterization of the purified recombinant POLγA variants showed that the p.His1134Tyr mutation caused severe polymerase dysfunction. The p.Thr251Ile/Pro587Leu mutation caused reduced polymerase function in conditions of low dNTP concentration that mimic postmitotic tissues. Critically, when p.His1134Tyr and p.Thr251Ile/Pro587Leu were combined under these conditions, mtDNA replication was severely diminished and featured prominent stalling. Our data provide a molecular explanation for the patient´s mtDNA depletion and clinical features, particularly in tissues such as brain and muscle that have low dNTP concentration.     

Pentoxifylline Increases Antiadhesion Effect of Streptokinase on Postoperative Adhesion Formation: Involvement of Fibrinolytic Pathway

Pentoxifylline reduces peritoneal adhesions and increases peritoneal fibrinolysis in rodents. Furthermore, the activation of the fibrinolytic system by streptokinase leading to degradation of fibrin is effective in the prevention of adhesion formation. We have investigated the effects of pentoxifylline and streptokinase alone and/or coadministration on postoperative intra-abdominal adhesion formation in adult female NMRI mice. Drugs were administered from the day of surgery until 10 days after surgery. At relaparotomy 11 days after surgery, the abdomen was opened, and the adhesions were graded in a blinded fashion utilizing the classification system described. Oral gavage administration of lower doses of pentoxifylline (3.125, 6.25, and 12.5 mg/kg) had no significant effect on postsurgical adhesion formation, while the higher doses of pentoxifylline (25 and 50 mg/kg) significantly decreased postsurgical adhesion formation. Moreover, intraperitoneal injection of lower doses of streptokinase (9.375, 18.75, and 37.5 unit/kg, i.p.) had no significant effect on postsurgical adhesion formation, while the higher doses of streptokinase (75 and 150 unit/kg) significantly decreased postsurgical adhesion formation. In other series of experiments, coadministration of lower doses of pentoxifylline and streptokinase doses, which were ineffective when given alone, significantly decreased postsurgical intra-abdominal adhesion formation compared with streptokinase control group. The results suggest that pentoxifylline may interfere with streptokinase in the reduction of postoperative intra-abdominal adhesion formation by enhancing local fibrinolytic activity.     

Locator® versus ceramic/electroplated double-crown attachments: a prospective study on the intraindividual comparison of implant-supported mandibular prostheses

Clinical Oral Investigations - Implant-supported overdentures are an established dental treatment mode. The aim of this prospective study was and interindividual comparison of patient satisfaction...     

Aluminum concentration in deciduous teeth is dependent on tooth type and dental status

Aluminum (Al) concentration was assessed in deciduous teeth in relation to sex, year of birth, tooth type, and the presence of caries and roots. Three hundred and twenty-three deciduous teeth from children born during the period 1952-93 in a county in southeast Sweden were sampled, and the Al content determined by graphite furnace atomic absorption spectrophotometry. The arithmetic mean of the Al concentration was 0.58 &#45 0.64 ppm dry weight (mean &#45 standard deviation) and differed significantly between incisors (1.05 &#45 1.04 ppm) and canines (0.48 &#45 0.50 ppm) and between incisors and molars (0.53 &#45 0.55 ppm). A significant difference was found between teeth with and without caries. No significant differences were found between sexes. The Al concentration correlated significantly with tooth weight for incisors (r =-0.47)and canines (r =-0.45) but not for molars (r = 0.03). No significant change in Al concentration was found over time. Caries-free deciduous molars are suggested as the most useful teeth for biological monitoring of aluminum.     

Frequency of fall-related injuries of female patients referred to the trauma center in the city of Kashan from years 2005 to 2008

Objective:Falls are one of the life events leading to injury and in serious cases cause high morbidity and mortality.This research was conducted to determine the fall incidence among female population ...     

Dosimetric and radiobiological investigation of permanent implant prostate brachytherapy based on Monte Carlo calculations

PurposePermanent implant prostate brachytherapy plays an important role in prostate cancer treatment, but dose evaluations typically follow the water-based TG-43 formalism, ignoring patient anatomy and interseed attenuation. The purpose of this study is to investigate advanced TG-186 model-based dose calculations via retrospective dosimetric and radiobiological analysis for a new patient cohort.Methods and MaterialsA cohort of 155 patients treated with permanent implant prostate brachytherapy from The Ottawa Hospital Cancer Centre is considered. Monte Carlo (MC) dose calculations are performed using tissue-based virtual patient models. Dose–volume histogram (DVH) metrics (target, organs at risk) are extracted from 3D dose distributions and compared with those from calculations under TG-43 assumptions (TG43). Equivalent uniform biologically effective dose and tumor control probability are calculated.ResultsFor the target, D₉₀ (V₁₀₀) is 136.7 ± 20.6 Gy (85.8% ± 7.8%) for TG43 and 132.8 ± 20.1 Gy (84.1% ± 8.2%) for MC; D₉₀ is 3.0% ± 1.1% lower for MC than TG43. For organs at risk, MC D_1cc = 104.4 ± 27.4 Gy (TG43: 106.3 ± 28.3 Gy) for rectum and 80.8 ± 29.7 Gy (TG43: 78.4 ± 28.4 Gy) for bladder; D_1cc = 185.9 ± 30.2 Gy (TG43: 191.1 ± 32.0 Gy) for urethra. Equivalent uniform biologically effective dose and tumor control probability are generally lower when evaluated using MC doses. The largest dosimetric and radiobiological discrepancies between TG43 and MC are for patients with intraprostatic calcifications, for whom there are low doses (cold spots) in the vicinity of calcifications within the target, identified with MC but not TG43.ConclusionsDVH metrics and radiobiological indices evaluated with TG43 are systematically inaccurate by upward of several percent compared with MC patient-specific models. Mean cohort DVH metrics and their MC:TG43 variances are sensitive to patient cohort and clinical practice, underlining the importance of further retrospective MC studies toward widespread clinical adoption of advanced model-based dose calculations.     

Anti-epileptogenic effect of beta-carotene and vitamin A in pentylenetetrazole-kindling model of epilepsy in mice

Vitamin A (Vit A) and its derivatives have recently been reported to be implicated in synaptic plasticity. In this study, the possible effect of Vit A and its precursor, beta-carotene on acute seizure and kindling, induced by pentylenetetrazole (PTZ) was assessed. Vit A and beta-carotene were evaluated for their ability to: (1) elevate the threshold of clonic seizures induced by i.v. infusion of PTZ; (2) suppress the seizures (clonic and tonic) and lethality induced by i.p. PTZ in PTZ-kindled mice (anticonvulsant effect); (3) attenuate the development of sensitization to convulsive and lethal effects of i.p. PTZ in kindled mice (anti-epileptogenic effect). Diazepam was employed as positive control. All the drugs showed anti-epileptogenic effect against PTZ-induced tonic seizures and lethality. Vit A and beta-carotene had no effect on clonic seizures threshold and also on tonic seizures and lethality induced by PTZ in kindled mice. Non-genomic and genomic mechanisms could be involved in the anti-epileptogenic effect of Vit A and beta-carotene.