Chromium Supplementation And The Essentiality Of Chromium To Human Nutrition: A Narrative Review

This narrative review evaluates the effect of chromium supplementation on glycemia and serum lipids, with an emphasis on patients with type 2 diabetes mellitus (T2DM). Additionally, this narrative review evaluates the essentiality of the trace mineral chromium to human nutrition. Meta-analyses and reviews were included, while certain clinical trials were specifically included to discuss flaws or impact. Overall, this narrative review concludes that chromium supplementation likely has no beneficial effect on glycemia or serum lipids (in subjects with or without T2DM). This narrative review also concludes the essentiality of chromium to human nutrition has become increasingly challenged over time, with some investigators postulating that chromium is pharmacologically active rather than an essential trace mineral. However, further randomized controlled trials (RCTs) are necessary to come to solid conclusions about the effect of chromium supplementation and the essentiality of chromium to human nutrition. This investigation is necessary as manufacturers continue to market chromium supplements as helpful aids to T2DM patients based on flawed studies.Comment: 4 page

Healing touch as an integrative therapy for cancer care: A review of evidence and implications for nursing

Life expectancies and survival rates of adults with cancer in the United States have significantly increased in recent history, primarily due to advancements in technology and early detection. More people are living longer with cancer and it has evolved to a complex, chronic illness. Although progress is being made in the treatment of cancer, pain and other symptoms related to the disease and its treatment are poorly managed by conventional care (Chapman, 2012; Deng, 2005). The use of complementary and alternative therapies is becoming increasingly popular in this population, in addition to conventional treatment from their primary providers. Healing Touch is a part of the biofield therapies and a growing body of literature is showing that it may be beneficial in the relief of pain and other symptoms related to cancer. The aim of this project is to review and evaluate sources of evidence supporting the effectiveness of healing touch as a complementary therapy in cancer care. Implications of the evidence and recommendations for the integration of Healing Touch with standard nursing care for cancer patients will be explored

Interaction of three regiospecific amino acid residues is required for OATP1B1 gain of OATP1B3 substrate specificity

The human organic anion-transporting polypeptides OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) are liver-enriched membrane transporters of major importance to hepatic uptake of numerous endogenous compounds, including bile acids, steroid conjugates, hormones, and drugs, including the 3-hydroxy-3- methylglutaryl Co-A reductase inhibitor (statin) family of cholesterol-lowering compounds. Despite their remarkable substrate overlap, there are notable exceptions: in particular, the gastrointestinal peptide hormone cholecystokinin-8 (CCK-8) is a high affinity substrate for OATP1B3 but not OATP1B1. We utilized homologous recombination of linear DNA by E. coli to generate a library of cDNA containing monomer size chimeric OATP1B1-1B3 and OATP1B3-1B1 transporters with randomly distributed chimeric junctions to identify three discrete regions of the transporter involved in conferring CCK-8 transport activity. Site-directed mutagenesis of three key residues in OATP1B1 transmembrane helices 1 and 10, and extracellular loop 6, to the corresponding residues in OATP1B3, resulted in a gain of CCK-8 transport by OATP1B1. The residues appear specific to CCK-8, as the mutations did not affect transport of the shared OATP1B substrate atorvastatin or the OATP1B1-specific substrate estrone sulfate. Regions involved in gain of CCK-8 transport by OATP1B1, when mapped to the crystal structures of bacterial transporters from the major facilitator superfamily, are positioned to suggest these regions could readily interact with drug substrates. Accordingly, our data provide new insight into the molecular determinants of the substrate specificity of these hepatic uptake transporters with relevance to targeted drug design and prediction of drug-drug interactions. © 2012 American Chemical Society

Delaying Chemotherapy in the Treatment of Stage IV Non-Small Cell Lung Cancer Does Not Adversely Affect Survival Outcome

Background: Whether a delay in the initiation of chemotherapy for advanced non-small cell lung cancer (NSCLC) can affect overall survival is not well studied. We aim to evaluate the effect of the time interval between diagnosis and initiation of chemotherapy on overall survival in patients with stage IV NSCLC. Methods: A retrospective review of newly diagnosed stage IV NSCLC patients who received chemotherapy between 1995 and 2012 was conducted. Demographics, histology and site(s) of metastases of patients were reviewed. Time interval between the date of diagnosis and the date of starting chemotherapy was calculated in days. Patients were divided in two groups based on median time interval: Group A \u3c 46 days and group B \u3e 46 days. The primary end point was the difference in overall survival between the two groups. Results: A total of 172 patients were reviewed. Each group had 86 patients. Median age for both groups was 61 years. The most common histology was adenocarcinoma in A and B (43% vs. 45%, respectively). The sites of metastases in A and B were: brain (25% vs. 28%), liver (20% vs. 9%), bone (30% vs. 30%), respectively. Performance status of ECOG (Eastern Cooperative Oncology Group) :( 0-1) was 82% vs. 76% in A and B, respectively. The median overall survival for A was 7 months vs.12 months for B (p=0.04). Conclusion: In this single institution review, delayed chemotherapy for stage IV NSCLC more than 46 days did not have a detrimental effect on overall survival and even suggested a better outcome. Further larger and prospective studies are warranted to validate these findings

Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance

The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vacciniabased method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared with singletransfected (MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (P \u3c 0.05) or control (MDCKII-Co) cells (P \u3c 0.001). In vivo docetaxel transport studies in Slco1b2-/- mice showed approximately \u3e5.5-fold higher plasma concentrations (P \u3c 0.01) and approximately 3-fold decreased liver-to-plasma ratio (P \u3c 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2-/- mice was 83% lower than WT mice (P \u3c 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics

Adrenal Cushing Syndrome Diagnosed during Pregnancy: Successful Medical Management with Metyrapone

Adrenal Cushing syndrome during pregnancy is rare, and there is limited information on the effect and safety of metyrapone treatment both for mother and fetus. We present a 24-year-old woman diagnosed with adrenal Cushing syndrome at the end of the second trimester. We elected treatment with metyrapone titrated to 250 mg 3 times daily, resulting in good clinical response and maternal serum and saliva cortisol levels in the upper half of the normal pregnancy range. A healthy male infant was born at 35 weeks\u27 gestation, with no clinical signs of adrenal insufficiency, this despite a low cortisol of 5 nmol/L on the first day of life. We measured metyrapone in maternal and umbilical cord blood samples, demonstrating fetal venous metyrapone levels similar to maternal venous concentration, and a fetal arterial cord concentration at about 60% of the fetal venous cord concentration. This case demonstrates that salivary cortisol levels may be used to monitor the effect of metyrapone on adrenal Cushing syndrome during pregnancy. We show, for the first time in humans, that metyrapone does cross the placenta and may suppress fetal cortisol production without necessarily causing clinical signs of adrenal insufficiency

Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial

AIM To evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of nonalcoholic steatohepatitis (NASH). METHODS Twelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy. RESULTS Sitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 μg/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002. CONCLUSION Sitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis

Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements

IT-101, a cyclodextrin polymer-based nanoparticle containing camptothecin, is in clinical development for the treatment of cancer. Multiorgan pharmacokinetics and accumulation in tumor tissue of IT-101 is investigated by using PET. IT-101 is modified through the attachment of a 1,4,7,10-tetraazacyclododecane-1,4,7-Tris-acetic acid ligand to bind ^(64)Cu^(2+). This modification does not affect the particle size and minimally affects the surface charge of the resulting nanoparticles. PET data from ^(64)Cu-labeled IT-101 are used to quantify the in vivo biodistribution in mice bearing Neuro2A s.c. tumors. The ^(64)Cu-labeled IT-101 displays a biphasic plasma elimination. Approximately 8% of the injected dose is rapidly cleared as a low-molecular-weight fraction through the kidneys. The remaining material circulates in plasma with a terminal half-life of 13.3 h. Steadily increasing concentrations, up to 11% injected dose per cm^3, are observed in the tumor over 24 h, higher than any other tissue at that time. A 3-compartment model is used to determine vascular permeability and nanoparticle retention in tumors, and is able to accurately represent the experimental data. The calculated tumor vascular permeability indicates that the majority of nanoparticles stay intact in circulation and do not disassemble into individual polymer strands. A key assumption to modeling the tumor dynamics is that there is a “sink” for the nanoparticles within the tumor. Histological measurements using confocal microscopy show that IT-101 localizes within tumor cells and provides the sink in the tumor for the nanoparticles