Iti Publications for January 2014 (74)

ITI PUBLICATIONS FOR JANUARY 2014 (74)

1)Am J Nucl Med Mol Imaging. 2013 Dec 15;4(1):89-95.

American Journal of Nuclear Medicine and Molecular Imaging: Editorial Board (2014) e-Century Publishing Corporation.

Seto B1, Jacobs PM2, Mach RH3, Bulte JW4, Cai W5, Alavi A6, Divgi CR7, Wu JC8.

Author information

PMID: 24380049 [PubMed] PMCID: PMC3867733

2)Proc Natl Acad Sci USA. 2013 Dec 30. [Epub ahead of print]

High-throughput platform for real-time monitoring of biological processes by multicolor single-molecule fluorescence.

Chen J, Dalal RV, Petrov AN, Tsai A, O'Leary SE, Chapin K, Cheng J, Ewan M, Hsiung PL, Lundquist P, Turner SW, Hsu DR, Puglisi JD.

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Zero-mode waveguides provide a powerful technology for studying single-molecule real-time dynamics of biological systems at physiological ligand concentrations. We customized a commercial zero-mode waveguide-based DNA sequencer for use as a versatile instrument for single-molecule fluorescence detection and showed that the system provides long fluorophore lifetimes with good signal to noise and low spectral cross-talk. We then used a ribosomal translation assay to show real-time fluidic delivery during data acquisition, showing it is possible to follow the conformation and composition of thousands of single biomolecules simultaneously through four spectral channels. This instrument allows high-throughput multiplexed dynamics of single-molecule biological processes over long timescales. The instrumentation presented here has broad applications to single-molecule studies of biological systems and is easily accessible to the biophysical community.PMID: 24379388 [PubMed - as supplied by publisher]

3)Hepatology. 2013 Dec 25. doi: 10.1002/hep.26986. [Epub ahead of print]

Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S.

Wong RJ, Cheung R, Ahmed A.

Nonalcoholic steatohepatitis (NASH) is currently the third leading indication for liver transplantation (LT) in the U.S. and is predicted to become the leading indication for LT in the near future. The trends in NASH-related hepatocellular carcinoma (HCC) among LT recipients in the U.S. remain undefined. We performed a retrospective cohort study to evaluate trends in the etiology of HCC among adult LT recipients in the U.S. from 2002 to 2012, utilizing national data from the United Network for Organ Sharing registry. From 2002-2012, there were 61,868 adults who underwent LT in the U.S., including 10,061 patients HCC. The total number and proportion of HCC LT recipients demonstrated a significant increase following the implementation of the model for end stage liver disease (MELD) scoring system in 2002 (3.3%, n=143 in 2000 vs. 12.2%, n=714 in 2005 vs. 23.3%, n=1336 in 2012). The proportion of HCV-related HCC increased steadily from 2002 to 2012, and HCV remained the leading etiology of HCC throughout the MELD era (43.4% in 2002 vs. 46.3% in 2007 vs. 49.9% in 2012). NASH-related HCC also increased significantly, and NASH is the second leading etiology of HCC-related LT (8.3% in 2002 vs. 10.3% in 2007 vs. 13.5% in 2012). From 2002 to 2012, the number of patients undergoing LT for HCC secondary to NASH increased by nearly 4-fold, and the number of LT patients with HCC secondary to HCV increased by 2-fold. Conclusion: NASH is the second leading etiology of HCC leading to LT in the U.S. More importantly, NASH is currently the most rapidly growing indication for LT in patients with HCC in the U.S. (Hepatology 2013;).

KEYWORDS:UNOS, alcoholic liver disease, fatty liver, hepatitis C virus, liver cancer

PMID: 24375711 [PubMed - as supplied by publisher]

4)Reprod Toxicol. 2013 Dec 26. pii: S0890-6238(13)00386-9. doi: 10.1016/j.reprotox.2013.12.005. [Epub ahead of print]

Investigation of maternal environmental exposures in association with self-reported preterm birth.

Patel CJ1, Yang T2, Hu Z2, Wen Q2, Sung J3, El-Sayed YY3, Cohen H4, Gould J5, Stevenson DK5, Shaw GM5, Ling XB6, Butte AJ7; on behalf of the March of Dimes Prematurity Research Center at Stanford University School of Medicine.

Identification of maternal environmental factors influencing preterm birth risks is important to understand the reasons for the increase in prematurity since 1990. Here, we utilized a health survey, the US National Health and Nutrition Examination Survey (NHANES) to search for personal environmental factors associated with preterm birth. 201 urine and blood markers of environmental factors, such as allergens, pollutants, and nutrients were assayed in mothers (range of N: 49 to 724) who answered questions about any children born preterm (delivery <37 weeks). We screened each of the 201 factors for association with any child born preterm adjusting by age, race/ethnicity, education, and household income. We attempted to verify the top finding, urinary bisphenol A, in an independent study of pregnant women attending Lucile Packard Children's Hospital. We conclude that the association between maternal urinary levels of bisphenol A and preterm birth should be evaluated in a larger epidemiological investigation.

KEYWORDS:CDC, Centers for Disease Control and Prevention, EWAS, Environment-wide association study, FDR, LPCH, Lucile Packard Children's Hospital, NCHS, NHANES, National Centers for Health Statistics, National Health and Nutrition Examination Survey, SES, environment-wide association study, environmental exposure, false discovery rate, preterm birth, socioeconomic status

PMID: 24373932 [PubMed - as supplied by publisher]

5)Neurochem Int. 2013 Dec 25. pii: S0197-0186(13)00324-0. doi: 10.1016/j.neuint.2013.12.006. [Epub ahead of print]

microRNAs affect BCL-2 family proteins in the setting of cerebral ischemia.

Ouyang YB1, Giffard RG2.

The BCL-2 family is centrally involved in the mechanism of cell death after cerebral ischemia. It is well known that the proteins of the BCL-2 family are key regulators of apoptosis through controlling mitochondrial outer membrane permeabilization. Recent findings suggest that many BCL-2 family members are also directly involved in controlling transmission of Ca2+ from the endoplasmic reticulum (ER) to mitochondria through a specialization called the mitochondria-associated ER membrane (MAM). Increasing evidence supports the involvement of microRNAs (miRNAs), some of them targeting BCL-2 family proteins, in the regulation of cerebral ischemia. In this mini-review, after highlighting current knowledge about the multiple functions of BCL-2 family proteins and summarizing their relationship to outcome from cerebral ischemia, we focus on the regulation of BCL-2 family proteins by miRNAs, especially miR-29 which targets multiple BCL-2 family proteins.Copyright © 2013. Published by Elsevier Ltd.

KEYWORDS:BCL-2, Cerebral ischemia, Stroke, miR-29, microRNA

PMID: 24373752 [PubMed - as supplied by publisher]

6)Biol Blood Marrow Transplant. 2013 Dec 23. pii: S1083-8791(13)01161-0. doi: 10.1016/j.bbmt.2013.12.564. [Epub ahead of print]

Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant for Patients with Hemoglobinopathies using a Reduced Intensity Conditioning Regimen and Third-party Mesenchymal Stromal Cells.

Kharbanda S1, Smith AR2, Hutchinson SK3, McKenna DH2, Ball JB4, Lamb LS Jr4, Agarwal R3, Weinberg KI3, Wagner JE Jr2.

Allogeneic hematopoietic stem cell transplantation (HSCT) for patients with a hemoglobinopathy can be curative but is limited by donor availability. While positive results are frequently observed in those with a HLA matched sibling donor, the use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced intensity conditioning (RIC) and mesenchymal stromal cells (MSCs). Six patients were enrolled including four with high risk Sickle Cell Disease (SCD) and two with transfusion dependent thalassemia major. Conditioning consisted of Fludarabine (150mg/m2), Melphalan (140mg/m2), and Alemtuzumab (60mg for patients weighing >30kg and 0.9mg/kg for patients weighing <30kg). Two patients received a HLA 7/8 allele matched bone marrow and four received 4-5/6 HLA matched umbilical cord blood (UCB) as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in one patient and unrelated third party donor in the remaining five patients. GVHD prophylaxis consisted of cyclosporine A (CSA) and mycophenolate mofetil (MMF). One patient had neutropenic graft failure, two had autologous hematopoietic recovery and three had hematopoietic recovery with complete chimerism. The two SCD patients with autologous hematopoietic recovery are alive. The remaining four died either from opportunistic infection, GVHD, or intracranial hemorrhage. While there was no infusion-related toxicity, the co-transplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. While poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSC had any positive impact on engraftment. Due to lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.

KEYWORDS:Hemoglobinopathies, bone marrow, engraftment, graft-versus-host disease, hematopoietic stem cell transplant, mesenchymal stromal cells, reduced intensity conditioning, sickle cell disease, thalassemia, umbilical cord

PMID: 24370862 [PubMed - as supplied by publisher]

7)Clin J Am Soc Nephrol. 2014 Jan;9(1):73-81. doi: 10.2215/CJN.04200413. Epub 2013 Dec 26.

Comparison of Hospitalization Rates among For-Profit and Nonprofit Dialysis Facilities.

Dalrymple LS, Johansen KL, Romano PS, Chertow GM, Mu Y, Ishida JH, Grimes B, Kaysen GA, Nguyen DV.

BACKGROUND AND OBJECTIVES:The vast majority of US dialysis facilities are for-profit and profit status has been associated with processes of care and outcomes in patients on dialysis. This study examined whether dialysis facility profit status was associated with the rate of hospitalization in patients starting dialysis.

DESIGN, SETTING, PARTICIPANTS, & METHODS:This was a retrospective cohort study of Medicare beneficiaries starting dialysis between 2005 and 2008 using data from the US Renal Data System. All-cause hospitalization was examined and compared between for-profit and nonprofit dialysis facilities through 2009 using Poisson regression. Companion analyses of cause-specific hospitalization that are likely to be influenced by dialysis facility practices including hospitalizations for heart failure and volume overload, access complications, or hyperkalemia were conducted.

RESULTS:The cohort included 150,642 patients. Of these, 12,985 (9%) were receiving care in nonprofit dialysis facilities. In adjusted models, patients receiving hemodialysis in for-profit facilities had a 15% (95% confidence interval [95% CI], 13% to 18%) higher relative rate of hospitalization compared with those in nonprofit facilities. Among patients receiving peritoneal dialysis, the rate of hospitalization in for-profit versus nonprofit facilities was not significantly different (relative rate, 1.07; 95% CI, 0.97 to 1.17). Patients on hemodialysis receiving care in for-profit dialysis facilities had a 37% (95% CI, 31% to 44%) higher rate of hospitalization for heart failure or volume overload and a 15% (95% CI, 11% to 20%) higher rate of hospitalization for vascular access complications.

CONCLUSIONS:Hospitalization rates were significantly higher for patients receiving hemodialysis in for-profit compared with nonprofit dialysis facilities.

PMID: 24370770 [PubMed - in process]

8)J Perinatol. 2013 Dec 26. doi: 10.1038/jp.2013.162. [Epub ahead of print]

Outcomes of extremely preterm infants following severe intracranial hemorrhage.

Davis AS1, Hintz SR1, Goldstein RF2, Ambalavanan N3, Bann CM4, Stoll BJ5, Bell EF6, Shankaran S7, Laptook AR8, Walsh MC9, Hale EC5, Newman NS9, Das A10, Higgins RD11.

Objective:Severe intracranial hemorrhage (ICH) is an important prognostic variable in extremely preterm (EPT) infants. We examined imaging and clinical variables that predict outcomes in EPT infants with severe ICH.Study design:Retrospective analysis of 353 EPT infants with severe ICH. Outcomes were compared by examining: (i) unilateral vs bilateral ICH; and (ii) presence vs absence of hemorrhagic parenchymal infarction (HPI). Regression analyses identified variables associated with death or neurodevelopmental impairment (NDI).Result:Bilateral ICH and HPI had higher rates of adverse outcomes and were independently associated with death/NDI. HPI was the most important variable for infants of lower birth weight, and bilateral ICH for larger infants. For infants surviving to 36 weeks, shunt placement was most associated with death/NDI.Conclusion:Bilateral ICH and the presence of HPI in EPT infants with severe ICH are associated with death/NDI, though the importance depends on birth weight and survival to 36 weeks.Journal of Perinatology advance online publication, 26 December 2013; doi:10.1038/jp.2013.162.

PMID: 24370654 [PubMed - as supplied by publisher]

9)Onco Targets Ther. 2013 Dec 17;7:13-21. doi: 10.2147/OTT.S53348.

Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes.

Verstovsek S1, Gotlib J2, Gupta V3, Atallah E4, Mascarenhas J5, Quintas-Cardama A1, Sun W6, Sarlis NJ6, Sandor V6, Levy RS6, Kantarjian HM1, Mesa RA7.

PURPOSE:Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate-or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with ORal JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures.

PATIENTS AND METHODS:COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 10(9)/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100-200 × 10(9)/L and >200 × 10(9)/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24).

RESULTS:The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8-12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses.

CONCLUSION:This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.

KEYWORDS:COMFORT-I, JAK2 inhibitor, dose titration, myelofibrosis, ruxolitinib, treatment-related cytopenias

PMID: 24368888 [PubMed] PMCID: PMC3869911

10)JAMA. 2013 Dec 25;310(24):2640-9. doi: 10.1001/jama.2013.282833.

Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial.

Parkman HP1, Van Natta ML2, Abell TL3, McCallum RW4, Sarosiek I4, Nguyen L5, Snape WJ6, Koch KL7, Hasler WL8, Farrugia G9, Lee L2, Unalp-Arida A2, Tonascia J2, Hamilton F10, Pasricha PJ11.

IMPORTANCE:Gastroparesis remains a challenging syndrome to manage, with few effective treatments and a lack of rigorously controlled trials. Tricyclic antidepressants are often used to treat refractory symptoms of nausea, vomiting, and abdominal pain. Evidence from well-designed studies for this use is lacking.

OBJECTIVE:To determine whether treatment with nortriptyline results in symptomatic improvement in patients with idiopathic gastroparesis.

DESIGN, SETTING, AND PARTICIPANTS:The NORIG (Nortriptyline for Idiopathic Gastroparesis) trial, a 15-week multicenter, parallel-group, placebo-controlled, double-masked, randomized clinical trial from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC), comparing nortriptyline with placebo for symptomatic relief in idiopathic gastroparesis. One hundred thirty patients with idiopathic gastroparesis were enrolled between March 2009 and June 2012 at 7 US academic medical centers. Patient follow-up was completed in October 2012. Inclusion criteria included delayed gastric emptying and moderate to severe symptom scores using the Gastroparesis Cardinal Symptom Index (GCSI). INTERVENTIONS Nortriptyline vs placebo. Study drug dose was increased at 3-week intervals (10, 25, 50, 75 mg) up to 75 mg at 12 weeks.

MAIN OUTCOMES AND MEASURES:The primary outcome measure of symptomatic improvement was a decrease from the patient's baseline GCSI score of at least 50% on 2 consecutive 3-week GCSI assessments during 15 weeks of treatment.

RESULTS:The primary symptomatic improvement outcome did not differ between 65 patients randomized to nortriptyline vs 65 patients randomized to placebo: 15 (23% [95% CI, 14%-35%]) in the nortriptyline group vs 14 (21% [95% CI, 12%-34%]) in the placebo group (P = .86). Treatment was stopped more often in the nortriptyline group (19 [29% {95% CI, 19%-42%}]) than in the placebo group (6 [9%] {95% CI, 3%-19%}]) (P = .007), but numbers of adverse events were not different (27 [95% CI, 18-39] vs 28 [95% CI, 19-40]) (P = .89).

CONCLUSIONS AND RELEVANCE:Among patients with idiopathic gastroparesis, the use of nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms. These findings do not support the use of nortriptyline for idiopathic gastroparesis.

TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00765895.

PMID: 24368464 [PubMed - indexed for MEDLINE]

11)Proc Natl Acad Sci USA. 2013 Dec 23. [Epub ahead of print]

Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination.

Furman D, Hejblum BP, Simon N, Jojic V, Dekker CL, Thiébaut R, Tibshirani RJ, Davis MM.

Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.