Decrease in Urinary Creatinine Excretion in Early Stage Chronic Kidney Disease

Background

Little is known about muscle mass loss in early stage chronic kidney disease (CKD). We used 24-hour urinary creatinine excretion rate to assess determinants of muscle mass and its evolution with kidney function decline. We also described the range of urinary creatinine concentration in this population.

Methods

We included 1072 men and 537 women with non-dialysis CKD stages 1 to 5, all of them with repeated measurements of glomerular filtration rate (mGFR) by ⁵¹Cr-EDTA renal clearance and several nutritional markers. In those with stage 1 to 4 at baseline, we used a mixed model to study factors associated with urinary creatinine excretion rate and its change over time.

Results

Baseline mean urinary creatinine excretion decreased from 15.3±3.1 to 12.1±3.3 mmol/24 h (0.20±0.03 to 0.15±0.04 mmol/kg/24 h) in men, with mGFR falling from ≥60 to <15 mL/min/1.73 m², and from 9.6±1.9 to 7.6±2.5 (0.16±0.03 to 0.12±0.03) in women. In addition to mGFR, an older age, diabetes, and lower levels of body mass index, proteinuria, and protein intake assessed by urinary urea were associated with lower mean urinary creatinine excretion at baseline. Mean annual decline in mGFR was 1.53±0.12 mL/min/1.73 m² per year and that of urinary creatinine excretion rate, 0.28±0.02 mmol/24 h per year. Patients with fast annual decline in mGFR of 5 mL/min/1.73 m² had a decrease in urinary creatinine excretion more than twice as big as in those with stable mGFR, independent of changes in urinary urea as well as of other determinants of low muscle mass.

Conclusions

Decrease in 24-hour urinary creatinine excretion rate may appear early in CKD patients, and is greater the more mGFR declines independent of lowering protein intake assessed by 24-hour urinary urea. Normalizing urine analytes for creatininuria may overestimate their concentration in patients with reduced kidney function and low muscle mass.     

Sustainability,equity, and natural resource development in Northwest Siberia and Arctic Alaska

Today, the search for new energy sources continues unabated throughout the North. At the same time, scientists are increasingly concerned over the degradation of the Arctic and sub-Arctic environment stemming from fossil fuel and other large-scale energy projects already underway. Similar apprehensions are expressed by indigenous peoples who have often suffered from the impact of such development. While the most dramatic evidence of environmental devastation and social disruption is found in the Russian North, serious problems are by no means confined to that area alone. Nor are these negative effects necessarily limited to the borders of the country in which they originated. Indeed, the deleterious environmental impact of our global industrial economy has become sufficiently profound that social analysts are beginning to ask whether development strategies that cause such harm to the Arctic and sub-Arctic region should continue; and if not, what should replace them. This article addresses these issues as they relate to questions of sustainability, equity, political empowerment, and human rights in northwest Siberia and northern North America.     

Pressure Drops in a Distensible Model of End-to-side Anastomosis in Systemic-to-pulmonary Shunts

The modified Blalock-Taussig shunt is a surgical procedure used as a palliation to treat complex congenital heart defects. It consists of an interposing prosthetic tube between the innominate/subclavian artery and the right pulmonary artery. Previous experience indicates that the pressure drop across the shunt is affected by the pulmonary pressure at the distal anastomosis combined with the distensibility of the anastomosis. In this study, a computational fluid-structure interaction approach is presented to investigate the haemodynamic behaviour. Steady-state fluid dynamics and structural analyses were carried out using commercial codes based on the finite element method (FIDAP and ABAQUS) coupled by means of a purposely-developed procedure to transfer boundary conditions. Both prosthetic tube and artery walls were characterised by non-linear material properties. Three different pulmonary pressures (2, 5 and 15 mmHg) and two volume flow rates (0.4 and 0.8 l/min) were investigated. Results indicate that the effects of distensibility at the distal anastomosis on the shunt pressure drop are relevant only when the distal anastomosis on the shunt pressure drop are relevant only when the distal anastomosis is not fully distended, which occurs when the pulmonary pressure is lower than 5 mmHg.     

Selective Vulnerability of Spinal and Cortical Motor Neuron Subpopulations in delta7 SMA Mice

Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most common inherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinal motor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of ∆7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the ∆7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely more complex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping better therapeutic options for affected patients.     

Plasmon Features of Coinage Metal Nanoparticles Supported on Zeolites

The plasmonic features in the optical response of coinage metal nanoparticles supported on different type of zeolites were studied. The shifts in the plasmon frequency were analyzed for Cu, Ag, and Au nanoparticles in mordenite, β-zeolite, and Y-zeolite. It was shown experimentally that the resonance energy is sensitive both to type of zeolite structure and counter-cation of zeolite, as well as to annealing temperature and chemical composition of zeolite, their SiO₂/Al₂O₃ molar ratio. A theoretical framework was employed to identify physical mechanism for this sensitivity. Within a simple model, the width of the absorption window identified in the imaginary part of the bulk dielectric function of the different metals was seen to play the important role in establishing the range of the plasmon energies available. In terms of an effective dielectric function, the composite medium was fully described by the complex dielectric function of the metal involved, the dissipation-free dielectric function of the zeolite matrix, and the filling fraction which relates the volume of metal inclusions as a fraction of the total sample volume. The sensitivity of the optical spectra is understood in terms of variations in both the dielectric response of the zeolite matrix as well as nanoparticle size.     

Genome-Wide Association Studies Identify Heavy Metal ATPase3 as the Primary Determinant of Natural Variation in Leaf Cadmium in Arabidopsis thaliana

Understanding the mechanism of cadmium (Cd) accumulation in plants is important to help reduce its potential toxicity to both plants and humans through dietary and environmental exposure. Here, we report on a study to uncover the genetic basis underlying natural variation in Cd accumulation in a world-wide collection of 349 wild collected Arabidopsis thaliana accessions. We identified a 4-fold variation (0.5-2 μg Cd g(-1) dry weight) in leaf Cd accumulation when these accessions were grown in a controlled common garden. By combining genome-wide association mapping, linkage mapping in an experimental F2 population, and transgenic complementation, we reveal that HMA3 is the sole major locus responsible for the variation in leaf Cd accumulation we observe in this diverse population of A. thaliana accessions. Analysis of the predicted amino acid sequence of HMA3 from 149 A. thaliana accessions reveals the existence of 10 major natural protein haplotypes. Association of these haplotypes with leaf Cd accumulation and genetics complementation experiments indicate that 5 of these haplotypes are active and 5 are inactive, and that elevated leaf Cd accumulation is associated with the reduced function of HMA3 caused by a nonsense mutation and polymorphisms that change two specific amino acids.     

DHA induces apoptosis by altering the expression and cellular location of GRP78 in colon cancer cell lines

n-3 polyunsaturated fatty acids exert growth-inhibitory and pro-apoptotic effects in colon cancer cells. We hypothesized that the anti-apoptotic glucose related protein of 78kDa (GRP78), originally described as a component of the unfolded protein response in endoplasmic reticulum (ER), could be a molecular target for docosahexaenoic acid (DHA) in these cells. GRP78 total and surface overexpression was previously associated with a poor prognosis in several cancers, whereas its down-regulation with decreased cancer growth in animal models. DHA treatment induced apoptosis in three colon cancer cell lines (HT-29, HCT116 and SW480), and inhibited their total and surface GRP78 expression. The cell ability to undergo DHA-induced apoptosis was inversely related to their level of GRP78 expression. The transfection of the low GRP78-expressing SW480 cells with GRP78-GFP cDNA significantly induced cell growth and inhibited the DHA-driven apoptosis, thus supporting the essential role of GRP78 in DHA pro-apoptotic effect. We suggest that pERK1/2 could be the first upstream target for DHA, and demonstrate that, downstream of GRP78, DHA may exert its proapoptotic role by augmenting the expression of the ER resident factors ERdj5 and inhibiting the phosphorylation of PKR-like ER kinase (PERK), known to be both physically associated with GRP78, and by activating caspase-4. Overall, the regulation of cellular GRP78 expression and location is suggested as a possible route through which DHA can exert pro-apoptotic and antitumoral effects in colon cancer cells.     

Distribution of Serotonin Receptor of Type 6 (5-HT6) in Human Brain Post-mortem. A Pharmacology, Autoradiography and Immunohistochemistry Study

The aim of this study was to investigate the distribution of serotonin (5-HT) receptors of type 6 (5-HT(6)) in postmortem human prefrontal cortex, striatum and hippocampus. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT(6) receptor distribution was explored by the [(125)I]SB-258585 binding to brain membranes followed by the pharmacological characterization, where possible, and by autoradiographic, immunohistochemical and immunofluorescence evaluations. A specific and saturable [(125)I]SB-258585 binding was detected in striatum only, with a pharmacological characterization consistent with that of a 5-HT(6) receptor. The autoradiography showed the presence of a specific [(125)I]SB-258585 binding distributed homogeneously in caudate, putamen and accumbens. The immunohistochemistry, carried out in the striatum only, coupled with the immunofluorescence with glial fibrillary acidic protein (GFAP) and parvalbumin (PV) showed the co-localization of 5-HT(6) receptor with PV, while indicating that this receptor subtype was expressed in neurons and not in astrocytes. Taken together, the present findings showed the presence of a higher density of 5-HT(6) receptors, as labeled by [(125)I]SB-258585, in striatum than in hippocampus and prefrontal cortex, and specifically within the neuronal body. In addition, they would suggest that striatum is one of the major potential CNS targets linked to 5-HT(6) receptor modulation.     

Wasting syndrome with deep bradycardia as presenting manifestation of long-standing severe male hypogonadotropic hypogonadism: a case series

Background

Non-thyroidal illness (NTI) refers to changes in thyroid hormone levels in critically ill patients in the absence of primary hypothalamic-pituitary-thyroid dysfunction, and these abnormalities usually resolve after clinical recovery. However, NTI can be accompanied by primary thyroid dysfunction. We report herein a case of a woman with NTI accompanied by primary hyperthyroidism.

Case presentation

A 52-year-old female was admitted to the intensive care unit with heart failure and atrial fibrillation. She had a longstanding thyroid nodule, and a thyroid function test revealed low levels of triiodothyronine and free thyroxine as well as undetectable thyroid stimulating hormone (TSH). She was diagnosed with NTI, and her TSH level began to recover but not completely at discharge. The thyroid function test was repeated after 42 months to reveal primary hyperthyroidism, and a thyroid scan confirmed a toxic nodule.

Conclusion

This case suggests that although NTI was diagnosed, primary hyperthyroidism should be considered as another possible diagnosis if TSH is undetectable. Thyroid function tests should be repeated after clinical recovery from acute illness.