Quantifying the Ripple Effects of Civil War: How Armed Conflict Is Associated with More Severe Violence in the Home

Both the fields of public health and that of human rights seek to improve human well-being, including through reducing and preventing all forms of violence, to help individuals attain the highest quality of life. In both fields, mathematical methods can help “visibilize” the hidden architecture of violence, bringing new methods to bear to understand the scope and nuance of how violence affects populations. An increasing number of studies have examined how residing in a conflict-affected place may impact one of the most pervasive forms of violence—intimate partner violence (IPV)—during and after conflict. This paper contributes to this effort by examining whether severe forms of IPV are associated with previous experience of political violence in one conflict-affected country: Liberia. Our findings indicate that living in a district with conflict fatalities increased the risk of IPV among women by roughly 60%. Additionally, living in a district with conflict fatalities increased the risk of a past-year injury from IPV by 50%. This analysis brings to light links between two of the most pervasive forms of violence—political violence and violence against women. The findings suggest that women residing in a district that is more highly affected by conflict, not only people experiencing direct trauma during conflict, may be at risk of increased violence long after peace is declared. These findings point to the need for targeted programs that address IPV postconflict.     

The effect of ara-C-induced inhibition of DNA synthesis on its cellular pharmacology

Summary The cytotoxicity of ara-C is believed to result from incorporation of ara-CTP into DNA and inhibition of DNA synthesis. Since complete inhibition of DNA synthesis would prevent further incorporation of ara-CTP, ara-C may have a self-limiting effect on its own cytotoxicity, particularly at the high concentrations typical of highdose ara-C clinical protocols. In this study, the incorporation of [³H]-dThd and [³H]-ara-C into DNA were compared. Within 1 h of exposure of L5178Y cells to ara-C, the rate of [³H]-dThd incorporation into the acid-insoluble fraction was reduced by 98%. Despite this nearly complete block in [³H]-dThd incorpration, DNA synthesis was not completely inhibited since [³H]-ara-C continued to be incorporated for up to 6 h, although a plateau in ara-CDNA synthesis was observed between 2 and 3 h exposure when ara-CTP levels were maximal. The effect of ara-C on [³H]-dThd incorporation into DNA was due in part to an indirect effect of ara-C on the metabolism of intracellular [³H]-dThd to [³H]-dTTP. Within 30 min exposure to 10 M ara-C, the rate of cellular [³H]-dTTP synthesis was slowed to only 15% of the control rate. This was not due to inhibition of [³H]-dThd transport, since the intracellular and extracellular concentrations of the nucleoside were equal. The effect of ara-C on [³H]-dTTP synthesis resulted from significant changes in deoxynucleoside 5-triphosphate (dNTP) pools. dTTP, dATP, and dGTP levels were increased, whereas the dCTP concentration was decreased. When dThd kinase from L5178Y cells was assayed with increased dTTP levels induced by ara-C vs the dTTP level in control cells, its activity was reduced by 72%. Thus, the [³H]-dThd incorporation experiment overestimated the extent of inhibition of DNA synthesis by ara-C due to increased feedback inhibition of dThd kinase and increased competition for DNA polymerase between the elevated unlabeled dTTP pool and the decreased levels of [³H]-dTTP. In vitro assay of DNA polymerase in the presence of the ara-CTP concentration achieved after 0.5 or 3 h exposure to 10 M ara-C (60 M and 200 M, respectively), plus the mixture of dNTPs found intracellularly at these times, resulted in 57% and 80% inhibition of the polymerase, respectively. This inhibition may account for the plateau in the accumulation of ara-CDNA that was observed at 3 h and suggests that ara-C incorporation may be self-limiting at high cellular concentrations of ara-CTP. The ara-C-induced decline in dCTP noted above was apparently a secondary effect resulting from the inhibition of ribonucleotide reductase by the elevated dTTP and dATP. CDP reductase activity in the presence of dATP and dTTP at the concentrations found in ara-C-treated cells was 58% of the activity observed in the presence of nucleotide levels found in control cells. The decrease in dCTP levels was associated with a reciprocal increase in the rate of [³H]-ara-C phosphorylation following subsequent exposure to unlabeled ara-C. Thus, ara-C self-potentiated its own uptake in these cells. These observations of the self-limiting and self-potentiating effects of high concentrations of ara-C may be relevant to the selection of the optimal dose and the duration of exposure in the clinical use of high-dose ara-C infusions.Abbreviations ara-C I--d-arabinofuranosyl, cytosine (cytosine arabinoside) - ara-CTP ara-C triphosphate - NTP unspecified nucleoside 5-triphosphate - dNTP deoxynucleoside 5-triphosphate - PBS phosphate-buffered saline This research was supported by grants from the American Cancer Society (CH35J), the National Institutes of Health (CA 12197), the Gaston County Cancer Society, and Dr. George Royer of the Upjohn Company     

Intermittent PTH administration and mechanical loading are anabolic for periprosthetic cancellous bone

The purpose of this study was to determine the individual and combined effects on periprosthetic cancellous bone of intermittent parathyroid hormone administration (iPTH) and mechanical loading at the cellular, molecular, and tissue levels. Porous titanium implants were inserted bilaterally on the cancellous bone of adult rabbits beneath a loading device attached to the distal lateral femur. The left femur received a sham loading device. The right femur was loaded daily, and half of the rabbits received daily PTH. Periprosthetic bone was evaluated up to 28 days for gene expression, histology, and µCT analysis. Loading and iPTH increased bone mass by a combination of two mechanisms: (1) Altering cell populations in a pro‐osteoblastic/anti‐adipocytic direction, and (2) controlling bone turnover by modulating the RANKL‐OPG ratio. At the tissue level, BV/TV increased with both loading (+53%, p < 0.05) and iPTH (+54%, p < 0.05). Combined treatment showed only small additional effects at the cellular and molecular levels that corresponded to a small additive effect on bone volume (+13% compared to iPTH alone, p > 0.05). This study suggests that iPTH and loading are potential therapies for enhancing periprosthetic bone formation. The elucidation of the cellular and molecular response may help further enhance the combined therapy and related targeted treatment strategies. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:163–173, 2015.

     

Exercise in the Management of Patients with Chronic Heart Failure

Despite the establishment of feasibility and physiologic benefits, questions remained about the safety and clinical effectiveness of physical exercise in patients with heart failure. In 2002, however, the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training trial showed that physical exercise is safe, improves health status, increases cardiorespiratory capacity, and yields a modest reduction in clinical events among patients with HF. The magnitude of these benefits may relate to the volume of exercise completed.     

Elevated serum IGF‐1 levels synergize PTH action on the skeleton only when the tissue IGF‐1 axis is intact

There is growing evidence that insulin‐like growth factor 1 (IGF‐1) and parathyroid hormone (PTH) have synergistic actions on bone and that part of the anabolic effects of PTH is mediated by local production of IGF‐1. In this study we analyzed the skeletal response to PTH in mouse models with manipulated endocrine or autocrine/paracrine IGF‐1. We used mice carrying a hepatic IGF‐1 transgene (HIT), which results in a threefold increase in serum IGF‐1 levels and normal tissue IGF‐1 expression, and Igf1 null mice with blunted IGF‐1 expression in tissues but threefold increases in serum IGF‐1 levels (KO‐HIT). Evaluation of skeletal growth showed that elevations in serum IGF‐1 in mice with Igf1 gene ablation in all tissues except the liver (KO‐HIT) resulted in a restoration of skeletal morphology and mechanical properties by adulthood. Intermittent PTH treatment of adult HIT mice resulted in increases in serum osteocalcin levels, femoral total cross‐sectional area, cortical bone area and cortical bone thickness, as well as bone mechanical properties. We found that the skeletal response of HIT mice to PTH was significantly higher than that of control mice, suggesting synergy between IGF‐1 and PTH on bone. In sharp contrast, although PTH‐treated KO‐HIT mice demonstrated an anabolic response in cortical and trabecular bone compartments compared with vehicle‐treated KO‐HIT mice, their response was identical to that of PTH‐treated control mice. We conclude that (1) in the presence of elevated serum IGF‐1 levels, PTH can exert an anabolic response in bone even in the total absence of tissue IGF‐1, and (2) elevations in serum IGF‐1 levels synergize PTH action on bone only if the tissue IGF‐1 axis is intact. Thus enhancement of PTH anabolic actions depends on tissue IGF‐1. © 2010 American Society for Bone and Mineral Research.