Background/Aims: Magnesium is an essential mineral for many metabolic functions. There is very little information on the effect of magnesium supplementation on me

/pdf/magnesium-replacement-improves-the-metabolic-profile-in-3li2qnmub4.pdf

Magnesium Replacement Improves the Metabolic Profile in Obese and Pre-Diabetic Patients with Mild-to-Moderate Chronic Kidney Disease: A 3-Month, Randomised, Double-Blind, Placebo-Controlled Study

admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

https://www.childrenshospital.org/~/media/research-and-innovation/research-labs/shi-lab/lsd1-regulation-2005.ashx?la=en

Regulation of LSD1 histone demethylase activity by its associated factors.

Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness. In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles. The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes. It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications.

/pdf/branched-chain-amino-acids-in-health-and-disease-metabolism-1zgyuhrxb6.pdf

Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements.

Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weak...

https://www.physiology.org/doi/pdf/10.1152/physrev.00028.2014

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

The ubiquitin–proteasome system (UPS) is a proteolytic system that is localized in cytosol and nucleus and requires ATP and mostly also the cofactor ubiquitin for proteolysis. Proteins to be degraded by UPS are tagged by polyubiquitin chain in a process precisely regulated by a system of ubiquitinating and deubiquitinating enzymes that assure the specificity and control of proteolysis. The proteasome contains protease active sites that account for the cleavage preferences: chymotryptic, tryptic and peptidylglutamyl (Glickman & Ciechanover 2002). The great importance of the UPS is now evident. It is responsible for the breakdown of a large variety of cell proteins, involved in important biological processes, including cell cycle, cell growth, gene expression, DNA repair, stress response and also programmed cell death (Drexler 1998; Hershko et al. 2000). The activated breakdown of myofibrillar proteins, i.e. actin and myosin, in many serious disorders, including cancer, renal failure, acidosis, infections, burns and sepsis, correlates with enhanced activity of the UPS (Tiao et al. 1994; Mitch & Price 2003).

Many proteasome inhibitors have been developed (Kisselev & Goldberg 2001). They are divided into several groups according to the chemical structure and proteasome specificity. Most of them (except the fungal metabolite, lactacystine) are based on short oligopeptidic sequences with an electrophilic structure at the C-terminus. This electrophilic structure can be an aldehyde, a boronate (reversible inhibitors), an epoxyketone or a vinylsulfone (irreversible inhibitors) (Lee & Goldberg 1998). Proteasome inhibitors have been introduced as novel therapeutic agents. The first drug of this class is Bortezomib (Velcade®, Millennium Pharmaceuticals, Cambridge, MA, USA), used for the treatment of multiple myeloma. This and other novel proteasome inhibitors are currently undergoing clinical trials as potential treatment for a growing number of other cancer types (Mack et al. 2003; Davis et al. 2004) and other diseases, such as stroke and inflammatory diseases (Di Napoli & Papa 2003).

The mechanism of action of proteasome inhibitors predicts large-scale effects in the organism. In general, proteasome inhibitors seem to have manageable adverse effects, e.g. thrombocytopenia, fatigue and peripheral neuropathy (Richardson et al. 2003). As it is presently believed, the proteasome is responsible for a substantial part of proteolysis in physiological state. Several authors studied the ability of proteasome inhibitors to reduce enhanced protein degradation in various catabolic diseases, including denervation, hyperthyroidism, burn and sepsis (Tawa et al. 1997; Fang et al. 1998; Hobler et al. 1998; Fischer et al. 2000), and their findings support the hypothesis that the ubiquitin–proteasome pathway plays a central role in muscle wasting in these catabolic states.

The aim of the present study is to evaluate the direct effects of MG132 and new proteasome inhibitors – ZL3VS and AdaAhx3L3VS – on protein and leucine metabolism in skeletal muscle. In addition to evaluating changes in proteolysis, we studied also changes in protein synthesis and leucine oxidation, as the effects of proteasome inhibitors on these parameters are not clear. The experiments were performed by means of isolated muscles of both intact and septic rats. MG132 belongs to the group of peptide aldehydes. It is a strong inhibitor of the proteasome, but inhibits partly also cathepsins and calpains. ZL3VS is a vinylsulphone inhibitor and AdaAhx3L3VS is a vinylsulphone inhibitor with extended peptide portion, which reveals equal potency to all individual catalytic activities of the proteasome (Kessler et al. 2001).

Effects of proteasome inhibitors MG132, ZL3VS and AdaAhx3L3VS on protein metabolism in septic rats.

Objective. This study was designed to evaluate vitamin D status with separate determination of 25-OH D2 and 25-OH D3 and its relationship to vitamin D binding protein (VDBP) in patients with chronic kidney disease (CKD) and long-term haemodialysis patients (HD). Methods. 45 CKD patients, 103 HD patients, and 25 controls (C) were included. Plasma vitamin D concentrations were determined using chromatography and VDBP in serum and urine in CKD using enzyme immunoassay. Results. Plasma vitamin D levels were lower in CKD (30.16&#x2009;&#xb1;&#x2009;16.74&#x2009;ng/mL) and HD (18.85&#x2009;&#xb1;&#x2009;15.85&#x2009;ng/mL) versus C (48.72&#x2009;&#xb1;&#x2009;18.35&#x2009;ng/mL), . 25-OH D3 was the dominant form of vitamin D. Serum VDBP was higher in CKD (273.2&#x2009;&#xb1;&#x2009;93.8&#x2009;ug/mL) versus C (222&#x2009;&#xb1;&#x2009;87.6&#x2009;ug/mL) and HD (213.8&#x2009;&#xb1;&#x2009;70.9&#x2009;ug/mL), . Vitamin D/VDBP ratio was the highest in C and the lowest in HD; however, there was no correlation between vitamin D and VDBP. Urinary concentration of VDBP in CKD (0.25&#x2009;&#xb1;&#x2009;0.13&#x2009;ug/mL) correlated with proteinuria , . Conclusions. Plasma levels of vitamin D are decreased in CKD patients and especially in HD patients. 25-OH D3 was the major form of vitamin D. Despite urinary losses of VDBP, CKD patients had higher serum VDBP concentrations, indicating compensatory enhanced production. Vitamin D binding protein is not involved in vitamin D deficiency.

/pdf/vitamin-d-binding-protein-is-not-involved-in-vitamin-d-3gt9n27b71.pdf

Vitamin D Binding Protein Is Not Involved in Vitamin D Deficiency in Patients with Chronic Kidney Disease

Effect of acute acidosis on protein and amino acid metabolism in rats

The Ubiquitin-proteasome system has recently been shown to be involved in the regulation of cytokine expression. We tested the hypothesis of whether the in vivo administration of proteasome inhibitor MG-132 can modulate cytokine response and mortality in sepsis. Sepsis was induced in mice by caecal ligation and puncture (CLP). Animals were divided into four groups: control, CLP, CLP and 1 microg MG-132/g of b.w. intraperitoneally, and CLP and 10 microg MG-132/g of b.w. Plasma levels of interleukin (IL)-1, tumour necrosis factor-alpha (TNF-alpha, IL-6 and IL-10 were determined by ELISA 6 h after the induction of sepsis. CLP induced significant increase in plasma levels of all measured cytokines. MG-132 treatment resulted in lower increase in IL-1, TNF-alpha and IL-10 levels. IL-6 was not significantly affected. A mortality study revealed prolonged survival in MG-132 treated mice. We conclude that MG-132 treatment decreases inflammatory response and prolongs survival in the CLP model of sepsis.

Modulation of inflammatory response in sepsis by proteasome inhibition.

Traditionally, secondary hyperparathyroidism (SHPT) due to low calcitriol synthesis in failing kidneys has been treated with synthetic vitamin D receptor (VDR) activators. Recently, also the importance of low native vitamin D status beyond the issue of SHPT has been recognized in these patients. The aim of this work was to evaluate the effect of cholecalciferol supplementation in haemodialysis patients with low vitamin D serum levels. Another aim was to evaluate dual vitamin D therapy (cholecalciferol supplementation plus paricalcitol) in haemodialysis patients with vitamin D deficiency and concomitant SHPT. Ninety clinically stable maintenance haemodialysis patients were included. Supervised cholecalciferol supplementation was administered due to low vitamin D status. Patients with SHPT were also treated with synthetic VDR activator. Two pre hoc subgroups for statistical analysis were formed: patients treated solely with cholecalciferol (N = 34; 5,000 IU once weekly) and patients treated with a combination of cholecalciferol (identical dose, i.e. 5,000 IU/week) plus paricalcitol (N = 34, median dose 10 μg/week). Follow-up visit was scheduled 15 weeks later. Serum concentrations of calcidiol (25-D), parathyroid hormone (PTH) and beta-cross laps (CTX) were assessed at baseline and at follow-up. Serum calcium, phosphate and alkaline phosphatase (ALP) were monitored monthly. Only non-calcium gastrointestinal phosphate binders were administered. Dialysate calcium was 1.5 mmol/L in all patients, and no oral calcium-containing preparations were prescribed. Depending on data distribution, parametric or nonparametric statistical methods were used for comparison within each group (i.e. baseline vs. follow-up data) as well as between groups. In the whole group of 90 patients, mean baseline 25-D serum level was 20.3 (standard deviation 8.7) nmol/L, and it increased to 66.8 (19) nmol/L (p < 0.0001) after supplementation. In both preformed subgroups, the effect of vitamin D supplementation was almost identical. In cholecalciferol monotherapy, 25-D levels increased from 18.4 (8.2) to 68.6 (21.2) and in dual vitamin D therapy from 18.4 (5.0) to 67.6 (17.7) nmol/L (both p < 0.0001). In addition, both treatment modalities decreased serum PTH levels importantly: from 21.7 (interquartile range 17.3; 35.4) to 18.1 pmol/L (15.3; 24.7) in monotherapy (p = 0.05) and from 38.6 (31.8; 53.3) to 33.9 pmol/L (26.1; 47.5) in dual vitamin D therapy (p = 0.01). Serum calcium, phosphate, ALP and CTX did not change. We have not observed any episode of hypercalcemia in any subject during the whole period of follow-up. At baseline, slightly lower 25-D levels were observed in diabetic than in non-diabetic patients. This difference disappeared after substitution. Vitamin D status and its changes were not related to the patient’s age. Low 25-D levels were very common in haemodialysis patients. They were safely and effectively corrected with supervised low-dose cholecalciferol supplementation. In patients with higher baseline PTH levels, dual vitamin D therapy (cholecalciferol plus paricalcitol) was safely and effectively used.

Roman Safranek

Papers

Effects of proteasome inhibitors MG132, ZL3VS and AdaAhx3L3VS on protein metabolism in septic rats.

Vitamin D Binding Protein Is Not Involved in Vitamin D Deficiency in Patients with Chronic Kidney Disease

Effect of acute acidosis on protein and amino acid metabolism in rats

Modulation of inflammatory response in sepsis by proteasome inhibition.

Low-dose cholecalciferol supplementation and dual vitamin D therapy in haemodialysis patients.