Natural history and outcome in systemic AA amyloidosis

BACKGROUND:Deposition of amyloid fibrils derived from circulating acute-phase reactant serum amyloid A protein (SAA) causes systemic AA amyloidosis, a serious complication of many chronic inflammatory disorders. Little is known about the natural history of AA amyloidosis or its response to treatment.METHODS:We evaluated clinical features, organ function, and survival among 374 patients with AA amyloidosis who were followed for a median of 86 months. The SAA concentration was measured serially, and the amyloid burden was estimated with the use of whole-body serum amyloid P component scintigraphy. Therapy for inflammatory diseases was administered to suppress the production of SAA.RESULTS:Median survival after diagnosis was 133 months; renal dysfunction was the predominant disease manifestation. Mortality, amyloid burden, and renal prognosis all significantly correlated with the SAA concentration during follow-up. The risk of death was 17.7 times as high among patients with SAA concentrations in the highest eighth, or octile, (greater/equal 155 mg per liter) as among those with concentrations in the lowest octile (< 4 mg per liter); and the risk of death was four times as high in the next-to-lowest octile (4 to 9 mg per liter). The median SAA concentration during follow-up was 6 mg per liter in patients in whom renal function improved and 28 mg per liter in those in whom it deteriorated (P < 0.001). Amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than 10 mg per liter, and survival among these patients was superior to survival among those in whom amyloid deposits did not regress (P=0.04).CONCLUSIONS:The effects of renal dysfunction dominate the course of AA amyloidosis, which is associated with a relatively favorable outcome in patients with SAA concentrations that remain in the low-normal range (< 4 mg per liter)

Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modeling approach.

Finasteride taken for 7 years in the Prostate Cancer Prevention Trial (PCPT) reduced the risk of prostate cancer by 25%, but with an apparent increased risk of high-grade disease. Subsequent analyses found that finasteride biases toward improved prostate cancer detection and accuracy in prostate cancer grading at biopsy. In our first analysis of the present study, we accounted for these biases in estimating the effect of finasteride on the risk of overall and high-grade prostate cancer. This analysis used PCPT data that included 3-month longer collection of endpoints than in the original report with observed prostate cancer rates of 22.9% (4.8% with high grade; placebo) versus 16.6% (5.8% with high grade; finasteride). Based on these updated results, the bias-adjusted prostate cancer rates are estimated to be 21.1% (4.2% high grade; placebo) and 14.7% (4.8% high grade; finasteride), a 30% risk reduction in prostate cancer [relative risk (RR), 0.70; 95% confidence interval (95% CI), 0.64-0.76; P < 0.0001] and a nonsignificant 14% increase in high-grade cancer (RR, 1.14; 95% CI, 0.96-1.35; P = 0.12) with finasteride. We then estimated rates of high-grade prostate cancer based on an analysis that incorporated grading information from radical prostatectomies in 500 subjects diagnosed with cancer. The resulting estimates were high-grade cancer rates of 8.2% (placebo) versus 6.0% (finasteride), a 27% risk reduction (RR, 0.73; 95% CI, 0.56-0.96; P = 0.02) with finasteride. Our third analysis examined the impact of biopsy sensitivity on the relative risk of high-grade prostate cancer and found that differential sensitivity of biopsy between the treatment arms can have a significant impact on risk ratio estimates. These collective results suggest that the observed, unadjusted higher risk of high-grade disease with finasteride seems to have been due to facilitated diagnosis resulting primarily from increased biopsy sensitivity with finasteride. Therefore, men undergoing regular prostate cancer screening or who express an interest in cancer prevention should be informed of the opportunity to take finasteride for preventing prostate cancer

In vitro mutation artifacts after formalin fixation and error prone translesion synthesis during PCR

BACKGROUND: Clinical specimens are routinely fixed in 10% buffered formalin and paraffin embedded. Although DNA is commonly extracted from fixed tissues and amplified by PCR, the effects of formalin fixation are relatively unknown. Formalin fixation is known to impair PCR, presumably through damage that blocks polymerase elongation, but an insidious possibility is error prone translesion synthesis across sites of damage, producing in vitro artifactual mutations during PCR. METHODS: To better understand the consequences of fixation, DNA specimens extracted from fresh or fixed tissues were amplified with Taq DNA polymerase, and their PCR products were cloned and sequenced. RESULTS: Significantly more (3- to 4-fold) mutations were observed with fixed DNA specimens. The majority of mutations were transitions, predominantly at A:T base pairs, randomly distributed along the template. CONCLUSIONS: Formalin fixation appears to cause random base damage, which can be bridged during PCR by Taq DNA polymerase through error prone translesion synthesis. Fixed DNA is a damaged but "readable" template

Recovering from failure by asking for help

Robots inevitably fail, often without the ability to recover autonomously. We demonstrate an approach for enabling a robot to recover from failures by communicating its need for specific help to a human partner using natural language. Our approach automatically detects failures, then generates targeted spoken-language requests for help such as “Please give me the white table leg that is on the black table.” Once the human partner has repaired the failure condition, the system resumes full autonomy. We present a novel inverse semantics algorithm for generating effective help requests. In contrast to forward semantic models that interpret natural language in terms of robot actions and perception, our inverse semantics algorithm generates requests by emulating the human’s ability to interpret a request using the Generalized Grounding Graph (G[superscript 3]) framework. To assess the effectiveness of our approach, we present a corpus-based online evaluation, as well as an end-to-end user study, demonstrating that our approach increases the effectiveness of human interventions compared to static requests for help.Boeing CompanyU.S. Army Research Laboratory (Robotics Collaborative Technology Alliance

Muscle Fiber Type-Dependent Differences in the Regulation of Protein Synthesis

This study examined fiber type-dependent differences in the regulation of protein synthesis in individual muscle fibers found within the same whole muscle. Specifically, the in vivo SUrface SEnsing of Translation (SUnSET) methodology was used to measure protein synthesis in type 1, 2A, 2X and 2B fibers of the mouse plantaris muscle, in response to food deprivation (FD), and mechanical overload induced by synergist ablation (SA). The results show that 48 h of FD induced a greater decrease in protein synthesis in type 2X and 2B fibers compared to type 1 and 2A fibers. Type 2X and 2B fibers also had the largest FD-induced decrease in total S6 protein and Ser240/244 S6 phosphorylation, respectively. Moreover, only type 2X and 2B fibers displayed a FD-induced decrease in cross-sectional area (CSA). Ten days of SA also induced fiber type-dependent responses, with type 2B fibers having the smallest SA-induced increases in protein synthesis, CSA and Ser240/244 S6 phosphorylation, but the largest increase in total S6 protein. Embryonic myosin heavy chain (MHCEmb) positive fibers were also found in SA muscles and the protein synthesis rates, levels of S6 Ser240/244 phosphorylation, and total S6 protein content, were 3.6-, 6.1- and 2.9-fold greater than that found in fibers from control muscles, respectively. Overall, these results reveal differential responses in the regulation of protein synthesis and fiber size between fiber types found within the same whole muscle. Moreover, these findings demonstrate that changes found at the whole muscle level do not necessarily reflect changes in individual fiber types

Reductions in cardiovascular, cerebrovascular, and respiratory mortality following the national Irish smoking ban: Interrupted time-series analysis

Copyright @ 2013 Stallings-Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Background: Previous studies have shown decreases in cardiovascular mortality following the implementation of comprehensive smoking bans. It is not known whether cerebrovascular or respiratory mortality decreases post-ban. On March 29, 2004, the Republic of Ireland became the first country in the world to implement a national workplace smoking ban. The aim of this study was to assess the effect of this policy on all-cause and cause-specific, non-trauma mortality. Methods: A time-series epidemiologic assessment was conducted, utilizing Poisson regression to examine weekly age and gender-standardized rates for 215,878 non-trauma deaths in the Irish population, ages ≥35 years. The study period was from January 1, 2000, to December 31, 2007, with a post-ban follow-up of 3.75 years. All models were adjusted for time trend, season, influenza, and smoking prevalence. Results: Following ban implementation, an immediate 13% decrease in all-cause mortality (RR: 0.87; 95% CI: 0.76-0.99), a 26% reduction in ischemic heart disease (IHD) (RR: 0.74; 95% CI: 0.63-0.88), a 32% reduction in stroke (RR: 0.68; 95% CI: 0.54-0.85), and a 38% reduction in chronic obstructive pulmonary disease (COPD) (RR: 0.62; 95% CI: 0.46-0.83) mortality was observed. Post-ban reductions in IHD, stroke, and COPD mortalities were seen in ages ≥65 years, but not in ages 35-64 years. COPD mortality reductions were found only in females (RR: 0.47; 95% CI: 0.32-0.70). Post-ban annual trend reductions were not detected for any smoking-related causes of death. Unadjusted estimates indicate that 3,726 (95% CI: 2,305-4,629) smoking-related deaths were likely prevented post-ban. Mortality decreases were primarily due to reductions in passive smoking. Conclusions: The national Irish smoking ban was associated with immediate reductions in early mortality. Importantly, post-ban risk differences did not change with a longer follow-up period. This study corroborates previous evidence for cardiovascular causes, and is the first to demonstrate reductions in cerebrovascular and respiratory causes

The "Ram Effect": A "Non-Classical" Mechanism for Inducing LH Surges in Sheep

During spring sheep do not normally ovulate but exposure to a ram can induce ovulation. In some ewes an LH surge is induced immediately after exposure to a ram thus raising questions about the control of this precocious LH surge. Our first aim was to determine the plasma concentrations of oestradiol (E2) E2 in anoestrous ewes before and after the "ram effect" in ewes that had a "precocious" LH surge (starting within 6 hours), a "normal" surge (between 6 and 28h) and "late» surge (not detected by 56h). In another experiment we tested if a small increase in circulating E2 could induce an LH surge in anoestrus ewes. The concentration of E2 significantly was not different at the time of ram introduction among ewes with the three types of LH surge. "Precocious" LH surges were not preceded by a large increase in E2 unlike "normal" surges and small elevations of circulating E2 alone were unable to induce LH surges. These results show that the "precocious" LH surge was not the result of E2 positive feedback. Our second aim was to test if noradrenaline (NA) is involved in the LH response to the "ram effect". Using double labelling for Fos and tyrosine hydroxylase (TH) we showed that exposure of anoestrous ewes to a ram induced a higher density of cells positive for both in the A1 nucleus and the Locus Coeruleus complex compared to unstimulated controls. Finally, the administration by retrodialysis into the preoptic area, of NA increased the proportion of ewes with an LH response to ram odor whereas treatment with the α1 antagonist Prazosin decreased the LH pulse frequency and amplitude induced by a sexually active ram. Collectively these results suggest that in anoestrous ewes NA is involved in ram-induced LH secretion as observed in other induced ovulators

Combining evidence and values in priority setting: testing the balance sheet method in a low-income country

<p>Abstract</p> <p>Background</p> <p>Procedures for priority setting need to incorporate both scientific evidence and public values. The aim of this study was to test out a model for priority setting which incorporates both scientific evidence and public values, and to explore use of evidence by a selection of stakeholders and to study reasons for the relative ranking of health care interventions in a setting of extreme resource scarcity.</p> <p>Methods</p> <p>Systematic search for and assessment of relevant evidence for priority setting in a low-income country. Development of a balance sheet according to Eddy's explicit method. Eight group interviews (n-85), using a modified nominal group technique for eliciting individual and group rankings of a given set of health interventions.</p> <p>Results</p> <p>The study procedure made it possible to compare the groups' ranking before and after all the evidence was provided to participants. A rank deviation is significant if the rank order of the same intervention differed by two or more points on the ordinal scale. A comparison between the initial rank and the final rank (before deliberation) showed a rank deviation of 67%. The difference between the initial rank and the final rank after discussion and voting gave a rank deviation of 78%.</p> <p>Conclusion</p> <p>Evidence-based and deliberative decision-making does change priorities significantly in an experimental setting. Our use of the balance sheet method was meant as a demonstration project, but could if properly developed be feasible for health planners, experts and health workers, although more work is needed before it can be used for laypersons.</p

The cost of uncomplicated childhood fevers to Kenyan households: implications for reaching international access targets

BACKGROUND: Fever is the clinical hallmark of malaria disease. The Roll Back Malaria (RBM) movement promotes prompt, effective treatment of childhood fevers as a key component to achieving its optimistic mortality reduction goals by 2010. A neglected concern is how communities will access these new medicines promptly and the costs to poor households when they are located in rural areas distant to health services. METHODS: We assemble data developed between 2001 and 2002 in Kenya to describe treatment choices made by rural households to treat a child's fever and the related costs to households. Using a cost-of-illness approach, we estimate the expected cost of a childhood fever to Kenyan households in 2002. We develop two scenarios to explore how expected costs to households would change if more children were treated at a health care facility with an effective antimalarial within 48 hours of fever onset. RESULTS: 30% of uncomplicated fevers were managed at home with modern medicines, 38% were taken to a health care facility (HCF), and 32% were managed at home without the use of modern medicines. Direct household cash expenditures were estimated at $0.44 per fever, while the total expected cost to households (cash and time) of an uncomplicated childhood fever is estimated to be$1.91. An estimated mean of 1.42 days of caretaker time devoted to each fever accounts for the majority of household costs of managing fevers. The aggregate cost to Kenyan households of managing uncomplicated childhood fevers was at least $96 million in 2002, equivalent to 1.00$1.86 because caretakers also save time with prompt treatment if the child has malaria. CONCLUSION: The management of uncomplicated childhood fevers imposes substantial costs on Kenyan households. Achieving substantial improvements in the numbers of fevers treated within 48 hours at a HCF with an effective antimalarial drug (Scenario 1) will not impose additional costs on households. Achieving additional improvements in fevers treated promptly at a HCF (Scenario 2) will impose additional costs on some households roughly equal to average cash expenses for transportation to a HCF. Additional financing mechanisms that further reduce the costs of accessing care at a HCF and/or that make artemisinin-based combination therapies (ACTs) accessible for home management need to be developed and evaluated as a top priority