Public Medical Malpractice Insurance: An Analysis of State-Operated Patient Compensation Funds

Compared to major tort and insurance reforms, PCFs have received virtually no attention by scholars. With an exception or two, they are not a major focus of public policy debate either. Because they are small organizations and there have been lengthy periods in which medical malpractice markets are quiescent, they have not attracted much scrutiny. Given a lack of quantitative evidence, our evaluation depended on qualitative evidence. Yet PCFs address the fundamental issues of medical malpractice that have led to reoccurring crises in the availability of medical malpractice insurance coverage and in its premiums for such coverage. As such, PCFs represent a potentially effective policy instrument when designed correctly

Trace amounts of 8-oxo-dGTP in mitochondrial dNTP pools reduce DNA polymerase γ replication fidelity

Replication of the mitochondrial genome by DNA polymerase γ requires dNTP precursors that are subject to oxidation by reactive oxygen species generated by the mitochondrial respiratory chain. One such oxidation product is 8-oxo-dGTP, which can compete with dTTP for incorporation opposite template adenine to yield A-T to C-G transversions. Recent reports indicate that the ratio of undamaged dGTP to dTTP in mitochondrial dNTP pools from rodent tissues varies from ∼1:1 to >100:1. Within this wide range, we report here the proportion of 8-oxo-dGTP in the dNTP pool that would be needed to reduce the replication fidelity of human DNA polymerase γ. When various in vivo mitochondrial dNTP pools reported previously were used here in reactions performed in vitro, 8-oxo-dGTP was readily incorporated opposite template A and the resulting 8-oxo-G-A mismatch was not proofread efficiently by the intrinsic 3′ exonuclease activity of pol γ. At the dNTP ratios reported in rodent tissues, whether highly imbalanced or relatively balanced, the amount of 8-oxo-dGTP needed to reduce fidelity was <1% of dGTP. Moreover, direct measurements reveal that 8-oxo-dGTP is present at such concentrations in the mitochondrial dNTP pools of several rat tissues. The results suggest that oxidized dNTP precursors may contribute to mitochondrial mutagenesis in vivo, which could contribute to mitochondrial dysfunction and disease

Yeast POS5 NADH Kinase: Effects of a Mitochondrial Mutator Mutation on Mitochondrial Nucleotides

Saccharomyces cerevisiae contains three NAD⁺/NADH kinases, one of which is localized in mitochondria and phosphorylates NADH in preference to NAD⁺. Strand et al (Euk. Cell 2:809 (2003)) reported that a yeast mutation in POS5, which encodes the mitochondrial NADH kinase, is a mutator, specific for mitochondrial genes. Because of the involvement of NADPH in deoxyribonucleotide biosynthesis, we asked whether mitochondria in a pos5 deletion mutant contain abnormal deoxyribonucleoside triphosphate pools. We found pools of the four dNTPs² to be more than doubled in mutant mitochondrial extracts relative to wild-type. This might partly explain the mitochondrial mutator phenotype. However, the loss of antioxidant protection is also likely to be significant. To this end, we measured pyridine nucleotide pools in mutant and wild-type mitochondrial extracts and found levels of NADPH to be diminished about fourfold in Δpos5 mitochondrial extracts, with NADP⁺ diminished to a lesser degree. Our data suggest that both dNTP abnormalities and lack of antioxidant protection contribute to elevated mitochondrial gene mutagenesis in cells lacking the mitochondrial NADH kinase. The data also confirm previous reports of the specific function of POS5p in mitochondrial NADP⁺ and NADPH biosynthesis.Keywords: NADH kinase, Deoxyribonucleoside triphosphates, Mitochondria, Mutator, Pyridine nucleotidesKeywords: NADH kinase, Deoxyribonucleoside triphosphates, Mitochondria, Mutator, Pyridine nucleotide

Oxidation of primary amines to ketones

A simple method for the oxidn. of primary amines to the corresponding ketones in the presence of both moisture and air is described. Treatment of an amine with benzoyl peroxide in the presence of Cs2CO3, followed by warming of the hydroxylamine product to 50-70° leads directly to the ketone. The method is shown to be effective for both benzylic and aliph. substrates. [on SciFinder(R)

An Illustration of Inverse Probability Weighting to Estimate Policy-Relevant Causal Effects

Traditional epidemiologic approaches allow us to compare counterfactual outcomes under 2 exposure distributions, usually 100% exposed and 100% unexposed. However, to estimate the population health effect of a proposed intervention, one may wish to compare factual outcomes under the observed exposure distribution to counterfactual outcomes under the exposure distribution produced by an intervention. Here, we used inverse probability weights to compare the 5-year mortality risk under observed antiretroviral therapy treatment plans to the 5-year mortality risk that would had been observed under an intervention in which all patients initiated therapy immediately upon entry into care among patients positive for human immunodeficiency virus in the US Centers for AIDS Research Network of Integrated Clinical Systems multisite cohort study between 1998 and 2013. Therapy-naïve patients (n = 14,700) were followed from entry into care until death, loss to follow-up, or censoring at 5 years or on December 31, 2013. The 5-year cumulative incidence of mortality was 11.65% under observed treatment plans and 10.10% under the intervention, yielding a risk difference of −1.57% (95% confidence interval: −3.08, −0.06). Comparing outcomes under the intervention with outcomes under observed treatment plans provides meaningful information about the potential consequences of new US guidelines to treat all patients with human immunodeficiency virus regardless of CD4 cell count under actual clinical conditions

Ribonucleotide Reductase Association with Mammalian Liver Mitochondria

Deoxyribonucleoside triphosphate pools in mammalian mitochondria are highly asymmetric, and this asymmetry probably contributes toward the elevated mutation rate for the mitochondrial genome as compared with the nuclear genome. To understand this asymmetry, we must identify pathways for synthesis and accumulation of dNTPs within mitochondria. We have identified ribonucleotide reductase activity specifically associated with mammalian tissue mitochondria. Examination of immunoprecipitated proteins by mass spectrometry revealed R1, the large RNR subunit, in purified mitochondria. Significant enzymatic and immunological activity was seen in rat liver mitochondrial nucleoids, isolated as described by Wang, Y., and Bogenhagen, D. F. (2006) J. Biol. Chem. 281, 25791–25802. Moreover, incubation of respiring rat liver mitochondria with [¹⁴C]cytidine diphosphate leads to acccumulation of radiolabeled deoxycytidine and thymidine nucleotides within the mitochondria. Comparable results were seen with [¹⁴C]guanosine diphosphate. Ribonucleotide reduction within the mitochondrion, as well as outside the organelle, needs to be considered as a possibly significant contributor to mitochondrial dNTP pools.This research was originally published in the Journal of Biological Chemistry. Chimploy, K., Song, S., Wheeler, L. J., & Mathews, C. K. Ribonucleotide reductase association with mammalian liver mitochondria. 2013. 288(18), 13145-13155. © the American Society for Biochemistry and Molecular Biology. This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Society for Biochemistry and Molecular Biology and can be found at: http://www.jbc.org/.Keywords: deoxyribonucleotide metabolism, ribonucleotide reductase, mitochondria, nucleotide pool asymmetryKeywords: deoxyribonucleotide metabolism, ribonucleotide reductase, mitochondria, nucleotide pool asymmetr