Radiation down-regulates replication origin activity throughout the S phase in mammalian cells

An asynchronous culture of mammalian cells responds acutely to ionizing radiation by inhibiting the overall rate of DNA replication by approximately 50% for a period of several hours, presumably to allow time to repair DNA damage. At low and moderate doses, this S phase damage-sensing (SDS) pathway appears to function primarily at the level of individual origins of replication, with only a modest inhibition of chain elongation per se. We have shown previously that the majority of the inhibition observed in an asynchronous culture can be accounted for by late G1cells that were within 2-3 h of entering the S period at the time of irradiation and which then fail to do so. A much smaller effect was observed on the overall rate of replication in cells that had already entered the S phase. This raised the question whether origins of replication that are activated within S phase per se are inhibited in response to ionizing radiation. Here we have used a two-dimensional gel replicon mapping strategy to show that cells with an intact SDS pathway completely down-regulate initiation in both early- and late-firing rDNA origins in human cells. We also show that initiation in mid- or late-firing rDNA origins is not inhibited in cells from patients with ataxia telangiectasia, confirming the suggestion that these individuals lack the SDS pathway.     

Normal lung function in subjects heterozygous for surfactant protein-B deficiency

OBJECTIVE AND IMPORTANCE: We present a case report of a patient with a left frontal brain abscess. Cultures obtained from the abscess at the time of surgery were identified as dental flora known to establish a synergistic relationship in polymicrobial infections. This type of synergistic relationship makes the clearance of an infection more difficult for an intact immune system. A serum immunoglobulin (Ig) Type A deficiency was identified postoperatively. This immunodeficiency may have contributed to the development of the abscess. CLINICAL PRESENTATION: The patient presented with headaches and photophobia. Computed tomography of the head performed with intravenously administered contrast demonstrated a left frontal brain abscess. INTERVENTION: The patient was operated on through a left frontal approach, carefully avoiding the frontal sinus. The abscess was aspirated, and the patient was treated with intravenous antibiotics for several weeks. Postoperatively, the patient did well. There were no signs of enhancement on follow-up computed tomographic scans at 7 and 12 months postoperatively. CONCLUSION: Through a comprehensive immunological workup, an IgA deficiency was identified postoperatively. Although the deficiency of a single type of Ig may be asymptomatic, complications from recurrent or chronic bacterial infections may occur. The deficiency of IgA, combined with a synergistic polymicrobial infection, contributed to the development of an intracranial abscess. A patient presenting with a brain abscess without any predisposing medical history should be evaluated for an underlying immune deficiency.     

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Assessing the sustainability of the UK society using thermodynamic concepts: Part 1

This paper provides a concise overview of the influence of human activity within the UK society on resource consumption and the subsequent effects on the environment. The concept of the Multi Scale Integrated Analysis of Societal Metabolism (MSIASM) is applied in order to elucidate the evolution of the UK economy for the period between 1981 and 2004. Our findings highlight the transition to a service-based economy and the disproportionate increase of energy demand when compared to the overall population increase. Emergy synthesis is applied in order to understand the production and consumption patterns and the environmental support required to sustain human activity within the UK for the year 2004. Generally speaking the UK society greatly benefits from its significant natural resources with 44.3% of the total emergy used coming from home sources and 29.1% from locally renewable sources. Interestingly enough, despite its significant natural resources, the UK economy, seems to be a net emergy importer by 638.5 × 10²¹ seJ. Furthermore, the current economic activity is believed to have a significant impact in the environment despite the relatively low environmental load ratio of 2.44.     

Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals

The pharmacokinetic and pharmacodynamic properties of nonpeptide angiotensin antagonists in humans are reviewed in this paper. Representatives of this new therapeutic class share common features: lipophilia, intermediate bioavailability, high affinity for plasma proteins and liver metabolism; some have active metabolites. Angiotensin II antagonists block the blood pressure response to exogenous angiotensin II in healthy volunteers, decrease baseline blood pressure in both normal and hypertensive patients, produce a marked rise in plasma renin activity and endogenous angiotensin II and increase renal blood flow without altering glomerular filtration rate. These effects are dose-dependent, but their time course varies between the drugs owing to pharmacokinetic and pharmacodynamic differences. Additionally, the extent of blood pressure reduction is dependent on physiological factors such as sodium and water balance. The characterisation of their pharmacokinetic-pharmacodynamic relationships deserves further refinement for designing optimal therapeutic regimens and proposing dosage adaptations in specific conditions.     

Pharmacokinetics of rocuronium during the three stages of liver transplantation

BACKGROUND: Little is known about the influence of liver transplantation on the pharmacokinetics of most anesthetic drugs. The authors determined the pharmacokinetics of rocuronium during liver transplantation and examined whether variability in pharmacokinetics could explain variability in recovery of neuromuscular function. METHODS: Twenty patients undergoing liver transplantation were given rocuronium, 600 microg/kg, after induction of anesthesia and again after perfusion of the transplanted liver. Plasma was sampled to determine rocuronium concentrations. Pharmacokinetic models were fit to rocuronium concentrations versus time data using a mixed-effects population approach. Various models permitted changes in clearance (Cl) or central compartment volume to account for changes in hepatic function and circulatory status during the paleohepatic, anhepatic, and neohepatic periods. Time to initial recovery of four twitches of the orbicularis oculi was determined. RESULTS: During the paleohepatic and anhepatic periods, the typical value of Cl was 2.47 ml x kg(-1) x min(-1) and was not influenced by the magnitude of preexisting liver disease (as evidenced by prothrombin time, bilirubin, serum albumin, alanine transaminase [ALT], and aspartate transaminase [AST]). During the neohepatic period, the typical value of Cl varied as a function of the duration of warm ischemia of the hepatic allograft and was 2.72 ml x kg(-1) x min(-1) for a patient with an average 60-min period of warm ischemia; time to neuromuscular recovery varied as a function of Cl. CONCLUSIONS: Despite prolonged hypothermic ischemia, the newly transplanted liver eliminates rocuronium as well as the diseased native liver (and comparably with historical control values). However, some patients had decreased rocuronium Cl during the neohepatic period, apparently a result of prolonged graft warm ischemia. The authors' finding of preservation of hepatic drug elimination in the hepatic allograft is consistent with limited data for other drugs evaluated during anesthesia.