Lack of an Association or an Inverse Association Between Low-Density-Lipoprotein Cholesterol and Mortality in the Elderly: A Systematic Review

OBJECTIVE: It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue. SETTING, PARTICIPANTS AND OUTCOME MEASURES: We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60 years from the general population. RESULTS: We identified 19 cohort studies including 30 cohorts with a total of 68 094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found. CONCLUSIONS: High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies

The Kago low-sulfidation gold and silver deposit: a peripheral mineralisation to the Nansatsu high-sulfidation system, southern Kyushu, Japan

The Kago deposit is a small deposit located at the southern tip of the Satsuma Peninsula of Southern Kyushu, Japan. It lies proximal to the well-known Nansatsu-type mineralisation province dominated by high-sulfidation type epithermal deposits. The deposit was heavily mined in the 18 th Century, largely for its relatively higher gold compared to that of surrounding and regional deposits. The Kago deposit is a typical low-sulfidation deposit, characterised by adularia-quartz veins, composed of electrum, Ag-tetrahedrite, polybasite, chalcopyrite and pyrite. Based on mine records, the grade ranged from 4.1 to 13.3 g/t Au and 2.6–6.6 g/t Ag. Alteration grades from low to high temperature argillic into a propylitic zone at the extremes of the vein exposures. Carbonate is absent. Fluid inclusion microthermometry reveals a typical temperature range of 220–240 °C with salinity of 0.7–2.6 NaCl eq. wt%. Electrum from high-grade ore ranges from 66 to 69 wt% Au. 40Ar/39Ar age dating of adularia bearing colloform/crustiform and brecciated veins, suggests a mineralisation event from 4.23 to 4.0 Ma. δ18O of veined and silicified quartz ranges from +4.0 to +18.4‰. δ18OH2O of fluids in equilibrium with quartz, in the dominant range of measured fluid inclusion temperatures, ranges from −6.5‰ to −0.2‰. δ34S of pyrite has a narrow range from −1.8 to 2.7‰. The deposit lies at the northern extent of the classic Nansatsu high-sulfidation epithermal area, in which a number of silicified bodies punctuate the region in a roughly semi-circular shape. The Kago deposit lies within the principle mineralisation age range of the high-sulfidation deposits, which range from 5.5 to 3.7 Ma. The structural displacement of the Kago deposit from the Nansatsu mineralisation and the differing host rocks has greatly influenced alteration, ore and rock-water interaction of the ore depositing fluids. Here we seek to establish the relationship that this extended mineral province has between the differing styles of mineralisation

Rapid tests and urine sampling techniques for the diagnosis of urinary tract infection (UTI) in children under five years: a systematic review

Background: Urinary tract infection (UTI) is one of the most common sources of infection in children under five. Prompt diagnosis and treatment is important to reduce the risk of renal scarring. Rapid, cost-effective, methods of UTI diagnosis are required as an alternative to culture. Methods: We conducted a systematic review to determine the diagnostic accuracy of rapid tests for detecting UTI in children under five years of age. Results: The evidence supports the use of dipstick positive for both leukocyte esterase and nitrite (pooled LR+ = 28.2, 95% CI: 17.3, 46.0) or microscopy positive for both pyuria and bacteriuria (pooled LR+ = 37.0, 95% CI: 11.0, 125.9) to rule in UTI. Similarly dipstick negative for both LE and nitrite (Pooled LR- = 0.20, 95% CI: 0.16, 0.26) or microscopy negative for both pyuria and bacteriuria (Pooled LR- = 0.11, 95% CI: 0.05, 0.23) can be used to rule out UTI. A test for glucose showed promise in potty-trained children. However, all studies were over 30 years old. Further evaluation of this test may be useful. Conclusion: Dipstick negative for both LE and nitrite or microscopic analysis negative for both pyuria and bacteriuria of a clean voided urine, bag, or nappy/pad specimen may reasonably be used to rule out UTI. These patients can then reasonably be excluded from further investigation, without the need for confirmatory culture. Similarly, combinations of positive tests could be used to rule in UTI, and trigger further investigation

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

The Regulation of Skeletal Muscle Protein Turnover during the Progression of Cancer Cachexia in the ApcMin/+ Mouse

Muscle wasting that occurs with cancer cachexia is caused by an imbalance in the rates of muscle protein synthesis and degradation. The ApcMin/+ mouse is a model of colorectal cancer that develops cachexia that is dependent on circulating IL-6. However, the IL-6 regulation of muscle protein turnover during the initiation and progression of cachexia in the ApcMin/+ mouse is not known. Cachexia progression was studied in ApcMin/+ mice that were either weight stable (WS) or had initial (≤5%), intermediate (6–19%), or extreme (≥20%) body weight loss. The initiation of cachexia reduced %MPS 19% and a further ∼50% with additional weight loss. Muscle IGF-1 mRNA expression and mTOR targets were suppressed with the progression of body weight loss, while muscle AMPK phosphorylation (Thr 172), AMPK activity, and raptor phosphorylation (Ser 792) were not increased with the initiation of weight loss, but were induced as cachexia progressed. ATP dependent protein degradation increased during the initiation and progression of cachexia. However, ATP independent protein degradation was not increased until cachexia had progressed beyond the initial phase. IL-6 receptor antibody administration prevented body weight loss and suppressed muscle protein degradation, without any effect on muscle %MPS or IGF-1 associated signaling. In summary, the %MPS reduction during the initiation of cachexia is associated with IGF-1/mTOR signaling repression, while muscle AMPK activation and activation of ATP independent protein degradation occur later in the progression of cachexia. IL-6 receptor antibody treatment blocked cachexia progression through the suppression of muscle protein degradation, while not rescuing the suppression of muscle protein synthesis. Attenuation of IL-6 signaling was effective in blocking the progression of cachexia, but not sufficient to reverse the process

Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia can findings from animal models be translated to humans?

Background: Cachexia is a multi-factorial, systemic syndrome that especially affects patients with cancer of the gastrointestinal tract, and leads to reduced treatment response, survival and quality of life. The most important clinical feature of cachexia is the excessive wasting of skeletal muscle mass. Currently, an effective treatment is still lacking and the search for therapeutic targets continues. Even though a substantial number of animal studies have contributed to a better understanding of the underlying mechanisms of the loss of skeletal muscle mass, subsequent clinical trials of potential new drugs have not yet yielded any effective treatment for cancer cachexia. Therefore, we questioned to which degree findings from animal studies can be translated to humans in clinical practice and research. Discussion: A substantial amount of animal studies on the molecular mechanisms of muscle wasting in cancer cachexia has been conducted in recent years. This extensive review of the literature showed that most of their observations could not be consistently reproduced in studies on human skeletal muscle samples. However, studies on human material are scarce and limited in patient numbers and homogeneity. Therefore, their results have to be interpreted critically. Summary: More research is needed on human tissue samples to clarify the signaling pathways that lead to skeletal muscle loss, and to confirm pre-selected drug targets from animal models in clinical trials. In addition, improved diagnostic tools and standardized clinical criteria for cancer cachexia are needed to conduct standardized, randomized controlled trials of potential drug candidates in the future

Hf-W evidence for rapid differentiation of iron meteorite parent bodies

New, high-precision W isotope data on iron meteorites are presented that provide important constraints on the timing of silicate-metal segregation in planetesimals. Magmatic iron meteorites all have

Archaean andesite petrogenesis: Insights from the Graedefjord Supracrustal Belt, southern West Greenland

We present new whole-rock major, trace and platinum-group element data, as well as Sm-Nd and Lu-Hf isotope data for meta-volcanic rocks from the Mesoarchaean Graedefjord Supracrustal Belt (GSB), located within the Tasiusarsuaq terrane, southern West Greenland. We also present new in situ zircon U-Pb isotope data (by LA-ICP-MS) for associated felsic rocks. This region has experienced amphibolite to lower granulite fades metamorphism, causing re-equilibration of most mineral phases (including zircon). An intrusive tonalite sheet with a zircon U-Pb age of 2888 +/- 6.8 Ma, yields a minimum age for the GSB. The Sm-Nd and Lu-Hf isotope data do not provide meaningful isochron ages, but the isotope compositions of the mafic rocks are consistent with the ca. 2970 Ma regional volcanic event, which is documented in previous studies of the Tasiusarsuaq terrane. The major and trace element data suggest a significant crustal contribution in the petrogenesis of andesitic volcanic rocks in the GSB. The trace element variation of these andesitic leucoamphibolites cannot be explained by bulk assimilation-fractional-crystallisation (AFC) processes involving local basement. Rather, the observed patterns require binary mixing between basaltic and felsic end-member magmas with between 50% and 80% contributions from the latter (depending on the assumed felsic composition). Hf-isotope constraints point to contamination with pre-existing continental crust with an age of ca. 3250 Ma. Basement gneisses of this age were previously described at two localities in the Tasiusarsuaq terrane, which supports the mixing hypothesis. Thus the felsic end-member likely represents melts derived from the local basement. Ultramafic rocks (18.35-22.80 wt.% MgO) in GSB have platinum-group element (PGE) patterns that are similar to magmas derived from high-degree melting of mantle, but they have relatively enriched trace element patterns. We propose that the ultramafic rocks represent arc-related picrites or alternatively were derived by melting of metasomatised sub-continental lithospheric mantle. Overall these new geochemical data from the Mesoarchaean Graedefjord Supracrustal Belt and the petrogenetic mixing model in particular, are similar to observations from modern continental subduction zone environments, which also require large degrees of mixing with felsic basement melts. Therefore, we propose that the metavolcanic rocks formed in a modern-style subduction zone geodynamic setting, which due to the hotter Archaean mantle conditions allowed for substantial amounts of partial melting and magma mixing, rather than assimilating pre-existing continental crust. (C) 2013 Elsevier B.V. All rights reserved