The role of serum levels of vitamin D in children's muscle strength: A systematic review

This review aims to investigate the different levels of vitamin D and its role in muscle strength in healthy children and non-athletes. A search conducted in three databases (PubMed, Scopus, and Psycinfo) resulted in 655 articles, which were systematically analyzed and selected based on the following criteria: (a) original cross-sectional studies and clinical trials; (b) healthy children aged 5-11 years; (c) no language restriction or year of publication; and (d) studies that assessed the possible relationship between vitamin D levels and muscle strength. Six studies were included because they met all the inclusion criteria. According to the findings of this review, factors such as sex, skin color, and vitamin D supplementation early in life modulate the levels of vitamin D in the body, and there is a relationship between muscle strength and vitamin D levels. Interestingly, vitamin D supplementation is not always significantly associated with increased muscle grip strength. However, there is a scarcity of studies that aim to analyze the possible effects of different levels of vitamin D on muscle function and neuromuscular variables in physically inactive children and non-athletes without previously diagnosed disease. Further studies are warranted in the future to address the gap in the literature.

Roles of water quality and disinfectant application on inactivation of fish pathogenic Streptococcus agalactiae with povidone iodine, quaternary ammonium compounds and glutaraldehyde.

Streptococcosis is an important bacterial disease in Nile tilapia causing severe economic losses to tilapia aquaculture worldwide. The effects of water quality (low- [LS] and high-level [HS] soiling, to mimic clean or dirty surface conditions and temperatures) and disinfectant application (diluted concentrations and exposure time) were characterized on the inactivation of Streptococcus agalactiae isolated from diseased tilapia. Five isolates were tested against three commercial disinfectant products with the main ingredients being povidone iodine (Anidine 100™; AD), benzalkonium chloride (Better BKC 80%™; BKC 80), and a mixture of quaternary ammonium compounds and glutaraldehyde (Chloraldehyde™; CR). CR demonstrated highest efficacy to S. agalactiae inactivation, followed by BKC 80 and AD, respectively. Higher-level soiling, low temperature, diluted concentrations and short exposure time all decreased the disinfectant efficacy. CR and BKC 80 provided more than 5-log inactivation at 1-min exposure at 20°C under HS conditions, and also with ten-fold-diluted concentrations at 60-min exposure time at 30°C. However, AD required 10-min exposure to effectively remove bacteria under LS conditions at 30°C. The results could facilitate aquaculture management planning that leads to operating cost reductions and improvements in biosecurity.

Identification of aldo-keto reductase (AKR7A1) and glutathione S-transferase pi (GSTP1) as novel renal damage biomarkers following exposure to mercury.

The kidney is one of the main targets for toxicity induced by xenobiotics. Sensitive detection of early impairment is critical to assess chemical-associated renal toxicity. The aim of this study was to identify potential nephrotoxic biomarkers in rat kidney tissues after exposure to mercury (Hg), a representative nephrotoxicant, and to evaluate these new biomarkers employing in vivo and in vitro systems. Mercuric chloride was administered orally to Sprague-Dawley rats for 2 weeks. Proteomic analysis revealed that aldo-keto reductase (AKR7A1) and glutathione S-transferase pi (GSTP1) were significantly elevated in kidney after Hg exposure. While the levels of conventional nephrotoxic clinical markers including blood urea nitrogen and serum creatinine were not elevated, the mRNA and protein levels of AKR7A1 and GSTP1 were increased upon Hg exposure in a dose-dependent manner. The increases in AKR7A1 and GSTP1 were also observed in rat kidneys after an extended exposure for 6 weeks to low-dose Hg. In in vitro rat kidney proximal tubular cells, changes in AKR7A1 and GSTP1 levels correlated well with the extent of cytotoxicity induced by Hg, cadmium, or cisplatin. AKR7A1 and GSTP1 were identified as new candidates for Hg-induced nephrotoxicity, suggesting that these biomarkers have potential for evaluating or predicting nephrotoxicity.

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders.

Various complement-mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n = 12), C3 glomerulopathies (C3G, n = 9) and acute antibody-mediated renal graft rejection (AMR, n = 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analysing the haemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3 and the activation products C3d, C5a and sC5b-9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific enzyme-linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082 µg/ml point to drug accumulation, especially in paediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56 µg/ml correlated with proteinuria. In aHUS patients, effective complement inhibition was demonstrated by significant reductions of CH50, APH50, C3d and sC5b-9 levels, whereas C5a levels were only reduced significantly after 6 months' treatment. C3G patients presented increased C3d and consistently low C3 levels, reflecting ongoing complement activation and consumption at the C3 level, despite eculizumab treatment. A comprehensive complement analysis together with drug monitoring is required to distinguish mode of complement activation and efficacy of eculizumab treatment in distinct renal disorders. Accumulation of the anti-C5 antibody points to the need for a patient-orientated tailored therapy.

Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening.

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility.

Histological Changes in Pancreatic Islets of Animals with Experimental Diabetes Caused by Xanthurenic Acid under Condition of Suppression of Its Endogenous Synthesis.

Long-term administration of pyridoxine to rats kept on a diabetogenic diet stimulating endogenous synthesis of xanthurenic acid resulted in minimal glycemia, less pronounced decrease in insulin content in ß-cells, and more intensive excretion of xanthurenic acid with urine. Histological changes were observed in 23% pancreatic islets, whereas in rats not treated with pyridoxine, destruction and necrosis of 40-45% ß-cells were found in 38% of studied islets.

The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits.

The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study.

Procoagulant and prothrombotic effects of the herbal medicine, Dipsacus asper and its active ingredient, dipsacus saponin C, on human platelets.

BACKGROUND: In spite of the growing popularity of herbal medicines and natural food supplements, their effects on cardiovascular homeostasis remain largely unknown, especially regarding pro-thrombotic risks. OBJECTIVE: In the present study, 21 herbal tea extracts were screened for the procoagulant activities on platelets, an important promoter of thrombosis to examine if herbal medicines or natural products may have prothrombotic risks. We discovered that Dipsacus asper (DA), known to have analgesic and anti-inflammatory effects, potently induced procoagulant activities in platelets. We tried to identify the active ingredient and elucidate the underlying mechanism. RESULTS: Among 10 major ingredients of DA, dipsacus saponin C (DSC) was identified as a key active ingredient in DA-induced procoagulant activities. DSC-induced procoagulant activities were achieved by the exposure of phosphatidylserine (PS) and PS-bearing microparticle generation that were caused by the alteration in the activities of phospholipid translocases: scramblase and flippase. These events were initiated by increased intracellular calcium and ATP depletion. Notably, DSC induced a series of apoptotic events including the disruption of mitochondrial membrane potential, translocation of Bax and Bak, cytochrome c release and caspase-3 activation. The key roles of apoptotic pathway and caspase activation were demonstrated by the reversal of DSC-induced PS exposure and procoagulant activities with the pretreatment of caspase inhibitors. Interestingly, EGTA reversed DSC-induced procoagulant activities and apoptotic events suggesting that an intracellular calcium increase may play a central role. These results were also confirmed in vivo where platelets of the rats exposed to DSC or DA exhibited PS exposure. Most importantly, DSC or DA administration led to increased thrombus formation. CONCLUSION: These results demonstrate that herbal medicines or natural products such as DA or DSC might have prothrombotic risks through procoagulant activation of platelets.

Extending Data Reliability Measure to a Filter Approach for Soft Subspace Clustering.

The measure of data reliability has recently proven useful for a number of data analysis tasks. This paper extends the underlying metric to a new problem of soft subspace clustering. The concept of subspace clustering has been increasingly recognized as an effective alternative to conventional algorithms (which search for clusters without differentiating the significance of different data attributes). While a large number of crisp subspace approaches have been proposed, only a handful of soft counterparts are developed with the common goal of acquiring the optimal cluster-specific dimension weights. Most soft subspace clustering methods work based on the exploitation of k-means and greatly rely on the iteratively disclosed cluster centers for the determination of local weights. Unlike such wrapper techniques, this paper presents a filter approach which is efficient and generally applicable to different types of clustering. Systematical experimental evaluations have been carried out over a collection of published gene expression data sets. The results demonstrate that the reliability-based methods generally enhance their corresponding baseline models and outperform several well-known subspace clustering algorithms.

Vertex centralities in input-output networks reveal the structure of modern economies.

Input-output tables describe the flows of goods and services between the sectors of an economy. These tables can be interpreted as weighted directed networks. At the usual level of aggregation, they contain nodes with strong self-loops and are almost completely connected. We derive two measures of node centrality that are well suited for such networks. Both are based on random walks and have interpretations as the propagation of supply shocks through the economy. Random walk centrality reveals the vertices most immediately affected by a shock. Counting betweenness identifies the nodes where a shock lingers longest. The two measures differ in how they treat self-loops. We apply both to data from a wide set of countries and uncover salient characteristics of the structures of these national economies. We further validate our indices by clustering according to sectors' centralities. This analysis reveals geographical proximity and similar developmental status.

Doxorubicin-induced platelet cytotoxicity: a new contributory factor for doxorubicin-mediated thrombocytopenia.

BACKGROUND: Doxorubicin (DOX) is a widely used anticancer drug for solid tumors and hematologic malignancy, but its active use is hampered by serious adverse effects, including thrombocytopenia. Although bone marrow toxicity of DOX has been suggested to be the sole mechanism underlying the reduced platelet counts, the direct effects of DOX on platelets have never been examined. OBJECTIVE: Here, we investigated the DOX-induced platelet cytotoxicity and its underlying mechanism in an effort to elucidate the contribution of platelet cytotoxicity to DOX-induced thrombocytopenia. RESULTS: In freshly isolated human platelets, DOX induced platelet cytotoxicity in a time-dependent and concentration-dependent manner. Reactive oxygen species (ROS) generation, decreased glutathione levels and subsequent protein thiol depletion were shown to underlie the DOX-induced platelet cytotoxicity. Conspicuously, DOX-treated platelets displayed apoptotic features such as caspase-3 activation, reduced mitochondrial transmembrane potential, and phosphatidylserine exposure. Decreased glutathiolation of procaspase-3 was shown to be a link between protein thiol depletion and caspase-3 activation. It is of note that DOX-mediated platelet cytotoxicity was significantly enhanced by shear stress, a common complicating factor in cancer patients. These in vitro results were further confirmed by an in vivo animal model, where administration of DOX induced a platelet count decrease, ROS generation, caspase-3 activation, protein thiol depletion, and damaged platelet integrity. CONCLUSION: We demonstrated that DOX can directly induce platelet cytotoxicity through ROS generation, decreased glutathione levels, and protein thiol depletion. We believe that this study provides important evidence for the role of DOX-induced platelet cytotoxicity in the development of thrombocytopenia in DOX-treated patients.

A prospective, randomized, placebo controlled, double-blind study of pelvic electromagnetic therapy for the treatment of chronic pelvic pain syndrome with 1 year of followup.

PURPOSE: Male chronic pelvic pain syndrome is a condition of uncertain etiology and treatment is often unsatisfactory. There is evidence that the symptom complex may result from pelvic floor muscular dysfunction and/or neural hypersensitivity/inflammation. We hypothesized that the application of electromagnetic therapy may have a neuromodulating effect on pelvic floor spasm and neural hypersensitivity. MATERIALS AND METHODS: Following full Stamey localization men with National Institute of Diabetes and Digestive and Kidney Diseases category III prostatitis were prospectively randomized to receive active electromagnetic or placebo therapy. Active therapy consisted of 15 minutes of pelvic floor stimulation at a frequency of 10 Hz, followed by a further 15 minutes at 50 Hz, twice weekly for 4 weeks. Patients were evaluated at baseline, 3 months and 1 year after treatment using validated visual analog scores. RESULTS: A total of 21 men with a mean age of 47.8 years (range 25 to 67) were analyzed. Mean symptom scores decreased significantly in the actively treated group at 3 months and 1 year (p <0.05), unlike the placebo group, which showed no significant change (p >0.05). Subanalysis of those receiving active treatment showed that the greatest improvement was in pain related symptoms. CONCLUSIONS: The novel use of pelvic floor electromagnetic therapy may be a promising new noninvasive option for chronic pelvic pain syndrome in men.

Biopsy of the red patch at cystoscopy: is it worthwhile?

OBJECTIVE: At cystoscopy red patches of urothelium are commonly seen within the bladder and frequently biopsied in order to exclude carcinoma in situ (CIS), which classically presents as a red, velvety patch. This appearance however is not specific and it is possible that many lesions are biopsied without significant benefit to the patient. The objective of this study was to determine whether routine biopsy of red patches seen in the bladder at cystoscopy is warranted. PATIENTS AND METHODS: 193 biopsies were taken from red patches seen at flexible and rigid cystoscopy during a 4-year period from December 1997 to January 2002 and examined by histopathology. Patients included in the study were those on cystoscopic follow-up for transitional cell carcinoma (TCC) of the bladder and those undergoing investigation for haematuria or lower urinary tract symptoms. RESULTS: In 193 (17.7% of total biopsies) red patch biopsies, malignancy was found in 23 (11.9%) and 18 of 23 (78.3%) were CIS. No malignancies were detected in red patches from patients under the age of 60 years. CONCLUSION: Red patch biopsy yields a positive finding of malignancy in 12% and was concluded to be a valuable exercise, particularly in those over the age of 60 years and on follow-up for TCC.

Pyrrolidine-5,5-trans-lactams. 4. Incorporation of a P3/P4 urea leads to potent intracellular inhibitors of hepatitis C virus NS3/4A protease.

[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.

Pyrrolidine-5,5-trans-lactams. 2. The use of X-ray crystal structure data in the optimization of P3 and P4 substituents.

[reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.

Population pharmacokinetics of intravenous valproic acid in Korean patients.

OBJECTIVE: To determine population-based pharmacokinetic parameters for intravenous valproic acid, and the factors influencing these parameters, in Korean adults. METHODS: Valproic acid concentrations were obtained using a peak and trough sampling scheme for 102 Korean epileptic patients who were not taking concurrent antiepileptic medication. Three hundred and fifty-four serum concentrations were analysed according to a one-compartment model with a mixed effect modelling method (NONMEM Ver 5.0). The influence of body-weight (kg), height, daily valproic acid dose (mg/day), body mass index (kg/m2), sex, and age on volume of distribution (Vd) and clearance (CL) was assessed in the course of analysis. RESULTS: Vd and CL of valproic acid increased with body-weight. No significant influence of the other screened covariates was observed. The final regression model was: [equation: see text]. Interindividual variabilities (coefficient of variation) for CL and Vd were 32 and 18%, respectively. Residual error including intraindividual variability was 26.7%. CONCLUSION: The current results may be used as a basic reference to optimize drug therapy with intravenous valproic acid. Further research on the paediatric population is necessary to confirm the non-linearity of the relation between body-weight and Vd.

Multiple interactions of cimetidine and probenecid with valaciclovir and its metabolite acyclovir.

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C(max)) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C(max) by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.

Tonsillar fossa steroid injection for reduction of the post-tonsillectomy pain.

Fifty patients (26 males and 24 females) who underwent tonsillectomy were then treated with injection of the long acting steroid (Kenacort-A) into the right tonsillar fossa after the operation. The left side was used as the control. Post-operative pain was assesed by the patients and was graded and recorded daily as mild, moderate, and severe pain on both sides of the throat for 2 weeks. A significant reduction of pain in the tested side (right side) was noted in the majority of the patients. The duration of pain was shorter in the right side than the left side. It seemed to significantly reduce the post-tonsillectomy pain. Because of its simplicity, cost effectiveness, and no complications, the technique should be used for pain-free tonsillectomy in non-contraindicated cases.