Kidney function and retinol status in type 2 diabetes mellitus patients

Kidneys play an important role in retinol turnover. We postulated that retinol homeostasis is disturbed in diabetic nephropathy. The aim of this research was to study the effect of kidney impairment on urinary excretion and on serum concentrations of retinol in type 2 diabetes mellitus patients. For this purpose, 41 type 2 diabetes patients and 9 sex -and age-matched healthy subjects were enrolled. Serum and urinary retinol and retinol-binding protein (RBP) were assessed by high-pressure liquid chromatography and enzyme-linked immunosorbent assay, respectively. The study showed that 17 out of 41 diabetic patients (41.5%) and none of the controls excreted retinol in urine (P < 0.02). Retinol excretion in the urine in these patients was 1.5-fold more prevalent than hypercreatininemia. Urinary retinol significantly correlated with clinically diagnosed nephropathy (P = 0.02). All but one of the patients with hypercreatininemia excreted retinol in the urine. Serum retinol and RBP in patients with hypercreatininemia were higher than in controls (P < 0.002). Values of urinary retinol, unlike urinary RBP, albumin and total protein, did not overlap between patients and controls. Our results indicate that (i) urinary retinol is a specific sign of tubular damage in type 2 diabetic patients and (ii) urinary retinol enables a more clear-cut identification of proximal tubule dysfunction in type 2 diabetes patients than urinary RBP or albumin.     

Influence of Intra- and Extracellular Acidification on Free Radical Formation and Mitochondria Membrane Potential in Rat Brain Synaptosomes

Brain ischemia is accompanied by lowering of intra- and extracellular pH. Stroke often leads to irreversible damage of synaptic transmission by unknown mechanism. We investigated an influence of lowering of pH_i and pH_o on free radical formation in synaptosomes. Three models of acidosis were used: (1) pH_o 6.0 corresponding to pH_i decrease down to 6.04; (2) pH_o 7.0 corresponding to the lowering of pH_i down to 6.92: (3) 1 mM amiloride corresponding to pH_i decrease down to 6.65. We have shown that both types of extracellular acidification, but not intracellular acidification, increase 2′,7′-dichlorodihydrofluorescein diacetate fluorescence that reflects free radical formation. These three treatments induce the rise of the dihydroethidium fluorescence that reports synthesis of superoxide anion. However, the impact of amiloride on superoxide anion synthesis was less than that induced by moderate extracellular acidification. Superoxide anion synthesis at pH_o 7.0 was almost completely eliminated by mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone. Furthermore, using fluorescent dyes JC-1 and rhodamine-123, we confirmed that pH_o lowering, but not intracellular acidification, led to depolarization of intrasynaptosomal mitochondria. We have shown that pH_o but not pH_i lowering led to oxidative stress in neuronal presynaptic endings that might underlie the long-term irreversible changing in synaptic transmission.     

The association of registered nurse staffing levels and patient outcomes: systematic review and meta-analysis

OBJECTIVE: To examine the association between registered nurse (RN) staffing and patient outcomes in acute care hospitals. STUDY SELECTION: Twenty-eight studies reported adjusted odds ratios of patient outcomes in categories of RN-to-patient ratio, and met inclusion criteria. Information was abstracted using a standardized protocol. DATA SYNTHESIS: Random effects models assessed heterogeneity and pooled data from individual studies. Increased RN staffing was associated with lower hospital related mortality in intensive care units (ICUs) [odds ratios (OR), 0.91; 95% confidence interval (CI), 0.86-0.96], in surgical (OR, 0.84; 95% CI, 0.80-0.89), and in medical patients (OR, 0.94; 95% CI, 0.94-0.95) per additional full time equivalent per patient day. An increase by 1 RN per patient day was associated with a decreased odds ratio of hospital acquired pneumonia (OR, 0.70; 95% CI, 0.56-0.88), unplanned extubation (OR, 0.49; 95% CI, 0.36-0.67), respiratory failure (OR, 0.40; 95% CI, 0.27-0.59), and cardiac arrest (OR, 0.72; 95% CI, 0.62-0.84) in ICUs, with a lower risk of failure to rescue (OR, 0.84; 95% CI, 0.79-0.90) in surgical patients. Length of stay was shorter by 24% in ICUs (OR, 0.76; 95% CI, 0.62-0.94) and by 31% in surgical patients (OR, 0.69; 95% CI, 0.55-0.86). CONCLUSIONS: Studies with different design show associations between increased RN staffing and lower odds of hospital related mortality and adverse patient events. Patient and hospital characteristics, including hospitals' commitment to quality of medical care, likely contribute to the actual causal pathway.     

Molecular pathways of liver regeneration: A comprehensive review

The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70% of its volume. Although knowledge of this phenomenon dates back to Greek mythology(the story of Prometheus), many aspects of liver regeneration are still not understood. A variety of different factors, including inflammatory cytokines, growth factors, and bile acids, promote liver regeneration and control the final size of the organ during typical regeneration, which is performed by mature hepatocytes, and during alternative regeneration, which is performed by recently identified resident stem cells called "hepatic progenitor cells". Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass, such as in cases of chronic injury or excessive acute injury. In liver maintenance, the body mass ratio is essential for homeostasis because the liver has numerous functions; therefore, a greater understanding of this process will lead to better control of liver injuries, improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases. The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries. Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.     

Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons

Dopamine is believed to contribute to the degeneration of dopamine-containing neurons in the brain. However, whether dopamine affects the survival of other neuronal populations has remained unclear. Here we document that mice with persistently elevated extracellular dopamine, resulting from inactivation of the dopamine transporter gene, sporadically develop severe symptoms of dyskinesia concomitant with apoptotic death of striatal dopamine-responsive gamma-aminobutyric acidergic neurons. Chronic inhibition of dopamine synthesis prevents the appearance of motor dysfunction. The neuronal death is associated with overactivation of dopaminergic signaling as evidenced by the robust up-regulation of striatal DeltaFosB, cyclin-dependent kinase 5, and p35. Moreover, hyperphosphorylation of the tau protein, a phenomenon associated with the activation of cyclin-dependent kinase 5 in several neurodegenerative disorders, is observed in symptomatic mice. These findings provide in vivo evidence that, in addition to its proposed role in the degeneration of dopamine neurons, dopamine can also contribute to the selective death of its target neurons via a previously unappreciated mechanism.     

Intraspecific phylogenetic analysis of Siberian woolly mammoths using complete mitochondrial genomes

We report five new complete mitochondrial DNA (mtDNA) genomes of Siberian woolly mammoth (Mammuthus primigenius), sequenced with up to 73-fold coverage from DNA extracted from hair shaft material. Three of the sequences present the first complete mtDNA genomes of mammoth clade II. Analysis of these and 13 recently published mtDNA genomes demonstrates the existence of two apparently sympatric mtDNA clades that exhibit high interclade divergence. The analytical power afforded by the analysis of the complete mtDNA genomes reveals a surprisingly ancient coalescence age of the two clades, approximately 1-2 million years, depending on the calibration technique. Furthermore, statistical analysis of the temporal distribution of the (14)C ages of these and previously identified members of the two mammoth clades suggests that clade II went extinct before clade I. Modeling of protein structures failed to indicate any important functional difference between genomes belonging to the two clades, suggesting that the loss of clade II more likely is due to genetic drift than a selective sweep.     

Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis

Type 2 diabetes (T2DM) is characterized by insulin resistance, defective insulin secretion, loss of beta-cell mass with increased beta-cell apoptosis and islet amyloid. The islet amyloid is derived from islet amyloid polypeptide (IAPP, amylin), a protein coexpressed and cosecreted with insulin by pancreatic beta-cells. In common with other amyloidogenic proteins, IAPP has the propensity to form membrane permeant toxic oligomers. Accumulating evidence suggests that these toxic oligomers, rather than the extracellular amyloid form of these proteins, are responsible for loss of neurons in neurodegenerative diseases. In this review we discuss emerging evidence to suggest that formation of intracellular IAPP oligomers may contribute to beta-cell loss in T2DM. The accumulated evidence permits the amyloid hypothesis originally developed for neurodegenerative diseases to be reformulated as the toxic oligomer hypothesis. However, as in neurodegenerative diseases, it remains unclear exactly why amyloidogenic proteins form oligomers in vivo, what their exact structure is, and to what extent these oligomers play a primary or secondary role in the cytotoxicity in what are now often called unfolded protein diseases.     

Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis

Obesity is a principal risk factor for type 2 diabetes, and elevated fatty acids reduce beta-cell function and survival. An unbiased proteomic screen was used to identify targets of palmitate in beta-cell death. The most significantly altered protein in both human islets and MIN6 beta-cells treated with palmitate was carboxypeptidase E (CPE). Palmitate reduced CPE protein levels within 2 h, preceding endoplasmic reticulum (ER) stress and cell death, by a mechanism involving CPE translocation to Golgi and lysosomal degradation. Palmitate metabolism and Ca(2+) flux were also required for CPE proteolysis and beta-cell death. Chronic palmitate exposure increased the ratio of proinsulin to insulin. CPE null islets had increased apoptosis in vivo and in vitro. Reducing CPE by approximately 30% using shRNA also increased ER stress and apoptosis. Conversely, overexpression of CPE partially rescued beta-cells from palmitate-induced ER stress and apoptosis. Thus, carboxypeptidase E degradation contributes to palmitate-induced beta-cell ER stress and apoptosis. CPE is a major link between hyperlipidemia and beta-cell death pathways in diabetes.     

Nano-architecture of silica nanoparticles as a tool to tune both electrochemical and catalytic behavior of NiII@SiO2

The present work introduces a facile synthetic route for efficient doping of [Ni^II(bpy)_x] into silica nanoparticles with various sizes and architectures. Variation of the latter results in different concentrations of the Ni^II complexes at the interface of the composite nanoparticles. The UV-Vis analysis of the nanoparticles reveals changes in the inner-sphere environment of the Ni^II complexes when embedded into the nanoparticles, while the inner-sphere of Ni^II is invariant for the nanoparticles with different architecture. Comparative analysis of the electrochemically generated redox transformations of the Ni^II complexes embedded in the nanoparticles of various architectures reveals the latter as the main factor controlling the accessibility of Ni^II complexes to the redox transitions which, in turn, controls the electrochemical behavior of the nanoparticles. The work also highlights an impact of the nanoparticulate architecture in catalytic activity of the Ni^II complexes within the different nanoparticles in oxidative C–H fluoroalkylation of caffeine. Both low leakage and high concentration of the Ni^II complexes at the interface of the composite nanoparticles enables fluoroalkylated caffeine to be obtained in high yields under recycling of the nanocatalyst five times at least.

The present work introduces a facile synthetic route for efficient doping of [Ni^II(bpy)_x] into silica nanoparticles with various sizes and architectures.