The effects of zinc supplementation on serum zinc concentration and protein catabolic rate in hemodialysis patients.

OBJECTIVE: To examine the effect of zinc sulfate supplementation on serum zinc concentrations and protein catabolic rate (PCR) in hemodialysis (HD) patients. DESIGN: Randomized, double-blind, before-after trial. SETTING: Outpatient dialysis center in a large metropolitan city. PATIENTS: Twenty-eight maintenance HD patients were selected. Twenty (15 women, 5 men) subjects completed the study. Subjects were identified for inclusion in the study by the following criteria: a history of low PCR (<0.09 g/kg body weight), HD treatment for a minimum of 6 months, no signs of gastrointestinal disorders, and no record of hospitalizations for reasons other than access complication within the last 3 months. INTERVENTIONS: Patients consumed 7.7 pmol zinc sulfate (2,200 microg) or a cornstarch placebo capsule daily for 90 days. In addition, patients completed a 2-day food record representative of 1 dialysis day and 1 nondialysis day. MAIN OUTCOME MEASURE: Fasting, predialysis serum samples were collected on days 0, 40, and 90 to determine serum zinc concentration and PCR. Dietary parameters including intake of zinc, protein, and energy were analyzed on Days 0 and 90. RESULTS: Initial analysis at Day 0 of serum zinc concentration indicated subjects were below the normal range for serum zinc standards (12.2 micromol/L [80 microg/dL]). After supplementation, subjects in the zinc-supplemented group showed significant increases in serum zinc concentrations from 12.2 micromol/L (80 microg/dL) at Day 0 to 15.3 pmol/L (100 microg/dL) at Day 90. A significant positive correlation (r = +0.61) was shown between PCR and serum zinc concentrations at the end of the study. Reported dietary protein intake did not change with zinc supplementation. CONCLUSION: Low serum zinc concentrations are reversible with zinc supplementation. Improvement in serum zinc concentration increases the PCR of HD patients.     

Systemic levels and preportal organ release of tissue-type plasminogen activator are enhanced by PEEP in the pig

BACKGROUND: Endothelium-derived tissue-type plasminogen activator, t-PA, is the key enzyme in the initiation of endogenous thrombolysis. Plasma levels of t-PA increase in response to sympatho-adrenergic activation. In the mesenteric vascular bed an increased norepinephrine spillover has been observed during positive end-expiratory pressure ventilation, PEEP. This experimental study examines the effects of PEEP-induced alterations on regional release rates and systemic levels of t-PA in vivo. METHODS: The protocol included measurements of arterio-venous concentration gradients of t-PA and the respective plasma flow across the pulmonary, coronary, hepatic and preportal vascular beds, in pigs, during zero-PEEP and at 2, 4 and 10 min after the application of a PEEP of 10 cm H2O. Both total plasma t-PA antigen (ELISA with a porcine t-PA standard) and active t-PA (spectrophotometric functional assay) were determined. RESULTS: During zero-PEEP, a high preportal basal net release and hepatic net uptake of total t-PA was observed. With PEEP, the magnitude of the preportal net release of t-PA was markedly enhanced (+24+/-5%), as was hepatic net uptake (+21+/-8%), simultaneously to a significant decrease in liver plasma flow (-30+/-2%). PEEP-induced alterations in active t-PA mirrored those observed in total t-PA. No significant net fluxes of total or active t-PA were observed across the coronary or the pulmonary vascular beds. CONCLUSIONS: Clinically used levels of PEEP induce increases in net release of endothelially derived t-PA within preportal organs. The application of PEEP is associated with increased systemic levels of total and active t-PA, in spite of a simultaneous increase in hepatic net uptake, indicating that the preportal vascular bed can not account for the systemic t-PA response.     

A facilitated approach to evaluate the inhibitor mode and potency of compounds targeting microsomal prostaglandin e synthase-1

Microsomal prostaglandin E(2) synthase-1 (MPGES1) catalyzes the formation of prostaglandin E(2) from the endoperoxide prostaglandin H(2). MPGES1 expression is induced in inflammatory diseases, and this enzyme is regarded as a potential drug target. To aid in the drug discovery effort, a simple method for determination of inhibition mechanism and potency toward both prostaglandin H(2) and glutathione (GSH) has been developed. Using an assay with thiobarbituric acid-based detection, the inhibitory effects of six MPGES1 inhibitors were evaluated. The IC(50) values obtained at three substrate (S) concentrations ([S]K(M)) were used to estimate inhibition modality and inhibition constant values. This facilitated strategy is a useful and general screening method to evaluate the inhibitory effects of new drug compounds.     

Antitumor activity of metal-chelating compound Dp44mT is mediated by formation of a redox-active copper complex that accumulates in lysosomes

The metal-chelating compound Dp44mT is a di-2-pyridylketone thiosemicarbazone (DpT) which displays potent and selective antitumor activity. This compound is receiving translational attention, but its mechanism is poorly understood. Here, we report that Dp44mT targets lysosome integrity through copper binding. Studies using the lysosomotropic fluorochrome acridine orange established that the copper-Dp44mT complex (Cu[Dp44mT]) disrupted lysosomes. This targeting was confirmed with pepstatin A-BODIPY FL, which showed redistribution of cathepsin D to the cytosol with ensuing cleavage of the proapoptotic BH3 protein Bid. Redox activity of Cu[Dp44mT] caused cellular depletion of glutathione, and lysosomal damage was prevented by cotreatment with the glutathione precursor N-acetylcysteine. Copper binding was essential for the potent antitumor activity of Dp44mT, as coincubation with nontoxic copper chelators markedly attenuated its cytotoxicity. Taken together, our studies show how the lysosomal apoptotic pathway can be selectively activated in cancer cells by sequestration of redox-active copper. Our findings define a novel generalized strategy to selectively target lysosome function for chemotherapeutic intervention against cancer.     

Biological functions of GCS3, a novel plasminogen-binding protein of Streptococcus dysgalactiae ssp. equisimilis

Increasing awareness of the relevance of Streptococcus dysgalactiae ssp. equisimilis as a human pathogen motivates the analysis of its pathomechanisms. One of the mechanisms that increases infectivity and dissemination of several streptococcal species is the recruitment and subsequent activation of host plasminogen on the streptococcal surface. This study identified GCS3 as a novel plasminogen-binding M protein of S. dysgalactiae ssp. equisimilis and revealed a difference in the mode of binding as compared to the plasminogen-binding protein PAM of S. pyogenes. In contrast to PAM, GCS3 did not bind to the kringle 1-3 region of plasminogen. Despite this difference, GCS3 exerts the same function of recruiting plasminogen to the streptococcal surface, which can be activated by streptokinase and host plasminogen activators to serve as a spreading factor. Moreover, we demonstrate a role of GCS3 in plasminogen-dependent streptococcal adherence to human pharyngeal cells (cell line Detroit 562) that indicates an additional function of the protein as an adhesin in the oral cavity.     

Genetic variation in complement component C3 shows association with ischaemic stroke

Background and purpose: The aim of this study was to investigate whether genetic variation at the third complement component (C3) locus is associated with ischaemic stroke (IS). Methods: The Sahlgrenska Academy Study on Ischaemic Stroke comprises 844 patients with IS, and 668 healthy controls. Sixteen SNPs were analyzed. Results: Two SNPs, rs2277984 and rs3745565, showed a significant association with overall IS. The SNP rs2277984 also showed association with the IS subtype cryptogenic stroke. These associations were independent of hypertension, diabetes, and smoking. The independent association between rs3745565 and overall IS withstands correction for multiple testing. Conclusion: In this sample of patients with IS, genetic variation in C3 is associated with IS.     

Hybrid 18F-FDG PET�CMRI of the hand in rheumatoid arthritis: initial results

18F-fluorodeoxyglucose PET (18F-FDG PET) is highly sensitive to inflammatory changes within the synovial tissue in rheumatoid arthritis (RA). However, the highest spatial resolution for soft tissue can be achieved with MRI. Here, we report on the first true hybrid PET-MRI examination of the hand in early RA exploiting the advantages of both modalities. PET-MRI was performed with a prototype of an APD-based magneto-insensitive BrainPET detector (Siemens Healthcare, Erlangen, Germany) operated within a standard 3T MR scanner (MAGNETOM Trio, Siemens). PET images were normalized, random, attenuation and scatter-corrected, iteratively reconstructed and calibrated to yield standardized uptake values (SUV) of 18F-FDG uptake. T1-weighted TSE in coronal as well as sagittal orientation prior to and following Gadolinium administration were acquired. Increased 18F-FDG uptake was present in synovitis and tenovaginitis as identified on contrast-enhanced MRI. The tracer distribution was surrounding the metacarpophalangeal joints II and III. Maximum SUV of 3.1 was noted. In RA, true hybrid 18F-FDG PET-MRI of the hand is technically feasible and bears the potential to directly visualize inflammation.     

Deep brain stimulation in the posterior subthalamic area in the treatment of essential tremor

To evaluate the posterior subthalamic area (PSA) as a target for deep brain stimulation (DBS) in the treatment of essential tremor (ET). The ventral intermediate nucleus of the thalamus is the traditional target for DBS in the treatment of ET. Recent studies have presented beneficial effects of DBS in the PSA in the treatment of tremor. Twenty‐one patients with ET were included in this study. All patients were evaluated before and 1 year after surgery, on and off stimulation, using the essential tremor rating scale (ETRS). A marked microlesional effect was noticed in 83%, in some cases obviating the need for electrical stimulation for many months. The total ETRS was reduced from 46.2 at baseline to 18.7 (60%). Item 5/6 (tremor of the upper extremity) was improved from 6.2 to 0.3 (95%), and items 11 to 14 (hand function) from 9.7 to 1.3 (87%) concerning the contralateral hand. Activities of daily living were improved by 66%. No severe complication occurred. Eight patients presented a postoperative mild dysphasia that regressed within days to weeks. DBS in the PSA resulted in a marked reduction of tremor. © 2010 Movement Disorder Society