Moderate Hyponatremia Is Associated with Increased Risk of Mortality: Evidence from a Meta-Analysis

Background

Hyponatremia is the most common electrolyte disorder in clinical practice, and evidence to date indicates that severe hyponatremia is associated with increased morbidity and mortality. The aim of our study was to perform a meta-analysis that included the published studies that compared mortality rates in subjects with or without hyponatremia of any degree.

Methods and Findings

An extensive Medline, Embase and Cochrane search was performed to retrieve the studies published up to October 1^st 2012, using the following words: “hyponatremia” and “mortality”. Eighty-one studies satisfied inclusion criteria encompassing a total of 850222 patients, of whom 17.4% were hyponatremic. The identification of relevant abstracts, the selection of studies and the subsequent data extraction were performed independently by two of the authors, and conflicts resolved by a third investigator. Across all 81 studies, hyponatremia was significantly associated with an increased risk of overall mortality (RR = 2.60[2.31–2.93]). Hyponatremia was also associated with an increased risk of mortality in patients with myocardial infarction (RR = 2.83[2.23–3.58]), heart failure (RR = 2.47[2.09–2.92]), cirrhosis (RR = 3.34[1.91–5.83]), pulmonary infections (RR = 2.49[1.44–4.30]), mixed diseases (RR = 2.59[1.97–3.40]), and in hospitalized patients (RR = 2.48[2.09–2.95]). A mean difference of serum [Na⁺] of 4.8 mmol/L was found in subjects who died compared to survivors (130.1±5.6 vs 134.9±5.1 mmol/L). A meta-regression analysis showed that the hyponatremia-related risk of overall mortality was inversely correlated with serum [Na⁺]. This association was confirmed in a multiple regression model after adjusting for age, gender, and diabetes mellitus as an associated morbidity.

Conclusions

This meta-analysis shows for the first time that even a moderate serum [Na⁺] decrease is associated with an increased risk of mortality in commonly observed clinical conditions across large numbers of patients.     

Stem annual increments as ecobiological indicators in Turkey oak (Quercus cerris L.)

In recent decades, the biostatistical analysis of relationships among tree growth and macroclimatic factors has developed remarkably. In this discipline, the parametrisation of tree growth is generally based on the records of annual ring widths measured on breast height transverse sections of tree stems (ARI). The present research enables the stem volume annual increment (AVI) to be evaluated as a dendroclimatic indicator in comparison with ARI. The research is a part of a broader investigation into the ecobiological characteristics of Turkey oak in the Gargano region (southern Italy). The results indicate that AVI is no better than ARI as a means of highlighting expressive relationships among the examined macroclimatic factors (monthly precipitation and monthly averages of temperature daily maxima and minima) and the Turkey oak annual stem growth. In the examined stands, the most growthinfluencing factors are the autumn and spring rainfalls. Regarding the stem breast height radial increment, the most effective temperature factors are the June averages of daily minima and maxima.     

Urinary 3-methoxy-4-hydroxyphenylglycol determination using reversed-phase chromatography with amperometric detection

A reversed-phase liquid chromatographic method with amperometric detection has been developed for the determination of urinary 3-methoxy-4-hydroxyphenylglycol. Before and after enzymatic deconjugation, it was purified by an extraction procedure and rapidly quantified under isocratic conditions. The 24-h excretion profile in normal human subjects (eight males and seven females) was determined; our results are consistent with those arrived at in a number of other studies. The present method is highly sensitive and selective; in addition, a good degree of precision is assured by use of 4-methoxy-3-hydroxyphenylglycol as internal standard.     

pH microelectrode: modified Thomas recessed-tip configuration

Through the use of a glass-membrane pH electrode and a water-tight seal a modified Thomas pH microelectrode has been developed. The modified Thomas electrode has a relatively low electrical resistance (10(11) omega), a small sensing chamber (10 microns3), and a rapid response time (10 s) and can be manufactured in both single- and double-barreled configurations. The modified Thomas electrode is designed to measure the intracellular pH of small cells such as those found in the mammalian kidney tubule.     

A multi-layer method to study genome-scale positions of nucleosomes

The basic unit of eukaryotic chromatin is the nucleosome, consisting of about 150 bp of DNA wrapped around a protein core made of histone proteins. Nucleosomes position is modulated in vivo to regulate fundamental nuclear processes. To measure nucleosome positions on a genomic scale both theoretical and experimental approaches have been recently reported. We have developed a new method, Multi-Layer Model (MLM), for the analysis of nucleosome position data obtained with microarray-based approach. The MLM is a feature extraction method in which the input data is processed by a classifier to distinguish between several kinds of patterns. We applied our method to simulated-synthetic and experimental nucleosome position data and found that besides a high nucleosome recognition and a strong agreement with standard statistical methods, the MLM can identify distinct classes of nucleosomes, making it an important tool for the genome wide analysis of nucleosome position and function. In conclusion, the MLM allows a better representation of nucleosome position data and a significant reduction in computational time.     

Dynamic subcellular localization of isoforms of the folate pathway enzyme serine hydroxymethyltransferase (SHMT) through the erythrocytic cycle of Plasmodium falciparum

Background

The folate pathway enzyme serine hydroxymethyltransferase (SHMT) converts serine to glycine and 5,10-methylenetetrahydrofolate and is essential for the acquisition of one-carbon units for subsequent transfer reactions. 5,10-methylenetetrahydrofolate is used by thymidylate synthase to convert dUMP to dTMP for DNA synthesis. In Plasmodium falciparum an enzymatically functional SHMT (PfSHMTc) and a related, apparently inactive isoform (PfSHMTm) are found, encoded by different genes. Here, patterns of localization of the two isoforms during the parasite erythrocytic cycle are investigated.

Methods

Polyclonal antibodies were raised to PfSHMTc and PfSHMTm, and, together with specific markers for the mitochondrion and apicoplast, were employed in quantitative confocal fluorescence microscopy of blood-stage parasites.

Results

As well as the expected cytoplasmic occupancy of PfSHMTc during all stages, localization into the mitochondrion and apicoplast occurred in a stage-specific manner. Although early trophozoites lacked visible organellar PfSHMTc, a significant percentage of parasites showed such fluorescence during the mid-to-late trophozoite and schizont stages. In the case of the mitochondrion, the majority of parasites in these stages at any given time showed no marked PfSHMTc fluorescence, suggesting that its occupancy of this organelle is of limited duration. PfSHMTm showed a distinctly more pronounced mitochondrial location through most of the erythrocytic cycle and GFP-tagging of its N-terminal region confirmed the predicted presence of a mitochondrial signal sequence. Within the apicoplast, a majority of mitotic schizonts showed a marked concentration of PfSHMTc, whose localization in this organelle was less restricted than for the mitochondrion and persisted from the late trophozoite to the post-mitotic stages. PfSHMTm showed a broadly similar distribution across the cycle, but with a distinctive punctate accumulation towards the ends of elongating apicoplasts. In very late post-mitotic schizonts, both PfSHMTc and PfSHMTm were concentrated in the central region of the parasite that becomes the residual body on erythrocyte lysis and merozoite release.

Conclusions

Both PfSHMTc and PfSHMTm show dynamic, stage-dependent localization among the different compartments of the parasite and sequence analysis suggests they may also reversibly associate with each other, a factor that may be critical to folate cofactor function, given the apparent lack of enzymic activity of PfSHMTm.     

Hsp60 Is Actively Secreted by Human Tumor Cells

Background

Hsp60, a Group I mitochondrial chaperonin, is classically considered an intracellular chaperone with residence in the mitochondria; nonetheless, in the last few years it has been found extracellularly as well as in the cell membrane. Important questions remain pertaining to extracellular Hsp60 such as how generalized is its occurrence outside cells, what are its extracellular functions and the translocation mechanisms that transport the chaperone outside of the cell. These questions are particularly relevant for cancer biology since it is believed that extracellular chaperones, like Hsp70, may play an active role in tumor growth and dissemination.

Methodology/Principal Findings

Since cancer cells may undergo necrosis and apoptosis, it could be possible that extracellular Hsps are chiefly the result of cell destruction but not the product of an active, physiological process. In this work, we studied three tumor cells lines and found that they all release Hsp60 into the culture media by an active mechanism independently of cell death. Biochemical analyses of one of the cell lines revealed that Hsp60 secretion was significantly reduced, by inhibitors of exosomes and lipid rafts.

Conclusions/Significance

Our data suggest that Hsp60 release is the result of an active secretion mechanism and, since extracellular release of the chaperone was demonstrated in all tumor cell lines investigated, our observations most likely reflect a general physiological phenomenon, occurring in many tumors.     

FKBP12 deficiency reduces strength deficits after eccentric contraction-induced muscle injury.

Strength deficits associated with eccentric contraction-induced muscle injury stem, in part, from excitation-contraction uncoupling. FKBP12 is a 12-kDa binding protein known to bind to the skeletal muscle sarcoplasmic reticulum Ca2+ release channel [ryanodine receptor (RyR1)] and plays an important role in excitation-contraction coupling. To assess the effects of FKBP12 deficiency on muscle injury and recovery, we measured anterior crural muscle (tibialis anterior and extensor digitorum longus muscles) strength in skeletal muscle-specific FKBP12-deficient and wild-type (WT) mice before and after a single bout of 150 eccentric contractions, as well as before and after the performance of six injury bouts. Histological damage of the tibialis anterior muscle was assessed after injury. Body weight and peak isometric and eccentric torques were lower in FKBP12-deficient mice compared with WT mice. There were no differences between FKBP12-deficient and WT mice in preinjury peak isometric and eccentric torques when normalized to body weight, and no differences in the relative decreases in eccentric torque with a single or multiple injury bouts. After a single injury bout, FKBP12-deficient mice had less initial strength deficits and recovered faster (especially females) than WT mice, despite no differences in the degree of histological damage. After multiple injury bouts, FKBP12-deficient mice recovered muscle strength faster than WT mice and exhibited significantly less histological muscle damage than WT mice. In summary, FKBP12 deficiency results in less initial strength deficits and enhanced recovery from single (especially females) and repeated bouts of injury than WT mice.