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Find video protocols related to scientific articles indexed in Pubmed.
End Stage Renal Disease Among HIV-Infected Adults in North America.
Clin. Infect. Dis.
PUBLISHED: 11-20-2014
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?HIV-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks.
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Telemedicine-Based Collaborative Care for Posttraumatic Stress Disorder: A Randomized Clinical Trial.
JAMA Psychiatry
PUBLISHED: 11-20-2014
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Posttraumatic stress disorder (PTSD) is prevalent, persistent, and disabling. Although psychotherapy and pharmacotherapy have proven efficacious in randomized clinical trials, geographic barriers impede rural veterans from engaging in these evidence-based treatments.
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Assessing the spatial and temporal variability of diffusive methane and nitrous oxide emissions from subtropical freshwater reservoirs.
Environ. Sci. Technol.
PUBLISHED: 11-20-2014
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Surface water methane (CH4) and nitrous oxide (N2O) concentrations were measured and diffusive fluxes were estimated in three subtropical freshwater reservoirs (Little Nerang Dam (LND), Lake Wivenhoe (LW) and Lake Baroon (LB)) in southeast Queensland, Australia, during four seasons in 2011 - 2012. All reservoirs were strong sources of CH4 in all seasons. Surface water CH4 varied between 1,350 and 524,000% saturation, and was overall highest in spring and summer, and lowest in winter, however, with no clear patterns common to all reservoirs. In contrast, all reservoirs switched from weak N2O sinks in spring to strong N2O sources for the rest of the year. N2O saturation in all reservoirs varied between 70 and 1,230%. There were significant differences for CH4 concentrations and fluxes between the reservoirs. Within each reservoir, there was strong spatial CH4 variability but minimal N2O saturation variability. CH4 saturation was higher in inflow zones than in the main body. Area-weighted average fluxes were estimated using six water-air gas transfer velocity estimation models and resulted in fluxes in the range 4.8 - 20.5, 2.3 - 5.4, and 2.3 - 7.5 mg CH4 m(-2) d(-1) while N2O was 0.07 - 0.41, 0.09 - 0.22 and 0.03 - 0.09 mg N2O m(-2) d(-1) for LND, LW and LB, respectively. Total emissions, in carbon dioxide equivalents, from all measurement campaigns were CH4 dominated (67 - 86%). The measured degree of CH4 saturation and fluxes are among the highest reported thus far indicating that subtropical freshwater reservoirs could be significant aquatic greenhouse gas sources. This paper provides a comprehensive assessment of the interplay between biogeochemical processes and the physical forcing driving the water-air gas emissions. The high variability coupled with the lack of consensus amongst estimation models calls for concerted efforts to address uncertainty of measurements for reliable emissions accounting.
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Evaluating Public Housing Residents for Knowledge, Attitudes, and Practices Following Dengue Prevention Outreach in Key West, Florida.
Vector Borne Zoonotic Dis.
PUBLISHED: 11-20-2014
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Abstract Background: In 2009-2010, 93 cases of dengue were identified in Key West, Florida. This was the first outbreak of autochthonous transmission of dengue in Florida since 1934. In response to this outbreak, a multifaceted public education outreach campaign was launched. The aim of this study is to compare dengue prevention knowledge, attitudes, perceptions, and prevention practices among residents of subsidized public housing to the general population in Key West and to assess whether there were barriers preventing effective outreach from reaching specific vulnerable populations. Methods: A randomized population-based evaluation of knowledge, attitudes, and behaviors toward dengue prevention consisting of 521 separate household interviews was undertaken in July of 2011. A subset analysis was performed on interviews collected from 28 public housing units within four subsidized public housing complexes. Analysis was performed to determine whether knowledge, attitudes, and behaviors exhibited by public housing residents differed from the non-public housing study population. Results: Public housing residents recalled fewer outreach materials (p=0.01) and were 3.4 times (95% confidence interval [CI] 1.4-8.3) more likely not to recall any outreach materials. Public housing residents were less likely to correctly identify how dengue transmission occurs (61% vs. 89%), where mosquitoes lay their eggs (54% vs. 85%), or to identify any signs or symptoms related to dengue (36% vs. 64%). Public housing residents were less likely to perform dengue prevention practices such as removing standing water or always using air conditioning. Conclusions: Examination of public housing residents identified an at-risk population that recalled less exposure to outreach materials and had less knowledge about dengue infection and prevention than the randomized study population. This provides public health systems the opportunity to target or modify future health messages and interventions to this group. Differences identified in the demographics of this population suggest that alternative methods or non-English materials may be required to reach desired outcomes.
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Practice patterns of post-radical prostatectomy incontinence surgery in Ontario.
Can Urol Assoc J
PUBLISHED: 11-20-2014
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We assess the practice patterns of artificial urinary sphincter (AUS) and urethral sling insertion after radical prostatectomy (RP) from a large population-based cohort.
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Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective ?4?2-nAChR Ligands.
ACS Med Chem Lett
PUBLISHED: 11-13-2014
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We report the synthesis and characterization of a series of enantiopure 5-cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes that display low nanomolar binding affinities and act as functional agonists at ?4?2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity relationship studies revealed that incorporation of a cyclopropane-containing side chain at the 5-position of the pyridine ring provides ligands with improved subtype selectivity for nAChR ?2 subunit-containing nAChR subtypes (?2*-nAChRs) over ?4*-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for ?4?2- and ?4?2*-nAChRs with negligible interaction. Functional assays confirm selectivity for ?4?2-nAChRs. Furthermore, using the SmartCube assay system, this ligand showed antidepressant, anxiolytic, and antipsychotic features, while mouse forced-swim assay further confirm the antidepressant-like property of 15.
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Rapamycin Protection of Livers From Ischemia and Reperfusion Injury is Dependent on Both Autophagy Induction and Mammalian Target of Rapamycin Complex 2-Akt Activation.
Transplantation
PUBLISHED: 10-24-2014
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Although rapamycin (RPM) have been studied extensively in ischemia models, its functional mechanisms remains to be defined.
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Sources and distribution of surface water fecal contamination and prevalence of schistosomiasis in a brazilian village.
PLoS Negl Trop Dis
PUBLISHED: 10-01-2014
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The relationship between poor sanitation and the parasitic infection schistosomiasis is well-known, but still rarely investigated directly and quantitatively. In a Brazilian village we correlated the spatial concentration of human fecal contamination of its main river and the prevalence of schistosomiasis.
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Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy - ACTG A5286.
J. Infect. Dis.
PUBLISHED: 09-11-2014
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?Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART).
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Nuclear Factor Erythroid 2-Related Factor 2 Regulates Toll-Like Receptor 4 Innate Responses in Mouse Liver Ischemia-Reperfusion Injury Through Akt-Forkhead box Protein O1 Signaling Network.
Transplantation
PUBLISHED: 08-30-2014
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Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant host defense, maintains the cellular redox homeostasis.
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CD4 trajectory adjusting for dropout among HIV-positive patients receiving combination antiretroviral therapy in an East African HIV care centre.
J Int AIDS Soc
PUBLISHED: 08-14-2014
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Estimates of CD4 response to antiretroviral therapy (ART) obtained by averaging data from patients in care, overestimate population CD4 response and treatment program effectiveness because they do not consider data from patients who are deceased or not in care. We use mathematical methods to assess and adjust for this bias based on patient characteristics.
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Factors associated with CD8+ T-cell activation in HIV-1-infected patients on long-term antiretroviral therapy.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 07-30-2014
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Abnormal levels of CD8 T-cell activation persist in HIV-1-infected patients on suppressive antiretroviral therapy (ART) and may be deleterious.
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HIV-1 DNA Decay Dynamics in Blood During More Than a Decade of Suppressive Antiretroviral Therapy.
Clin. Infect. Dis.
PUBLISHED: 07-29-2014
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Human immunodeficiency virus type 1 (HIV-1) DNA dynamics during long-term antiretroviral therapy (ART) are not defined.
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Cardiac tamponade following liver transplant after intrapericardial control of suprahepatic vena cava.
Liver Transpl.
PUBLISHED: 07-16-2014
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Background: Trans-abdominal intrapericardial control of the suprahepatic inferior vena cava (S-IVC) is a rather uncommon procedure occasionally required in conjunction with complicated liver transplant (LT) and hepatobiliary surgery. Experience with this technique is limited. Here we report six cases of LT where transabdominal intrapericardial control of the S-IVC was necessary. Methods: After obtaining institutional review board approval, a single-center retrospective review was conducted from January 1991 to December 2013 to identify adult (age > 18 yrs) cases of LT where a transabdominal intrapericardial isolation of S-IVC was necessary. Results: Among 4102 adult liver transplants in the study period, 6 such cases were identified. To gain access to the pericardial space, a 6 cm to 9 cm vertical incision was made above the S-IVC. After reperfusion, the diaphragmatic incision was partially closed and selectively drained. Pericardial tamponade developed in one patient, which necessitated emergent reoperation and widespread drainage. Conclusions: Transabdominal intrapericardial isolation of S-IVC is easily achieved without the need for a separate thoracic incision. However, to be effective, the pericardial incision should only be partially closed, and pericardial sac should be drained liberally. Such patients should be carefully monitored for signs and symptoms of pericardial tamponade, development of which should prompt immediate return to the operating room for emergent decompression and widespread drainage. This article is protected by copyright. All rights reserved.
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Reoperative Complications after Primary Orthotopic Liver Transplantation: A Contemporary Single-Center Experience in the Post-Model for End-Stage Liver Disease Era.
J. Am. Coll. Surg.
PUBLISHED: 07-16-2014
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Data on complications requiring reoperation after orthotopic liver transplantation (OLT) are limited. We sought to describe the spectrum of reoperative complications after OLT, evaluate the associations with graft and patient survival, and identify predictors of need for reoperation.
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Roles for N-terminal Extracellular Domains of Nicotinic Acetylcholine Receptor (nAChR) ?3 Subunits in Enhanced Functional Expression of Mouse ?6?2?3- and ?6?4?3-nAChRs.
J. Biol. Chem.
PUBLISHED: 07-15-2014
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Functional heterologous expression of naturally expressed mouse ?6*-nicotinic acetylcholine receptors (m?6*-nAChRs; where "*" indicates the presence of additional subunits) has been difficult. Here we expressed and characterized wild-type (WT), gain-of-function, chimeric, or gain-of-function chimeric nAChR subunits, sometimes as hybrid nAChRs containing both human (h) and mouse (m) subunits, in Xenopus oocytes. Hybrid m?6m?4h?3- (?5-8-fold) or WT m?6m?4m?3-nAChRs (?2-fold) yielded higher function than m?6m?4-nAChRs. Function was not detected when m?6 and m?2 subunits were expressed together or in the additional presence of h?3 or m?3 subunits. However, function emerged upon expression of m?6m?2m?3(V9'S)-nAChRs containing ?3 subunits having gain-of-function V9'S (valine to serine at the 9'-position) mutations in transmembrane domain II and was further elevated 9-fold when h?3(V9'S) subunits were substituted for m?3(V9'S) subunits. Studies involving WT or gain-of-function chimeric mouse/human ?3 subunits narrowed the search for domains that influence functional expression of m?6*-nAChRs. Using h?3 subunits as templates for site-directed mutagenesis studies, substitution with m?3 subunit residues in extracellular N-terminal domain loops "C" (Glu(221) and Phe(223)), "E" (Ser(144) and Ser(148)), and "?2-?3" (Gln(94) and Glu(101)) increased function of m?6m?2*- (?2-3-fold) or m?6m?4* (?2-4-fold)-nAChRs. EC50 values for nicotine acting at m?6m?4*-nAChR were unaffected by ?3 subunit residue substitutions in loop C or E. Thus, amino acid residues located in primary (loop C) or complementary (loops ?2-?3 and E) interfaces of ?3 subunits are some of the molecular impediments for functional expression of m?6m?2?3- or m?6m?4?3-nAChRs.
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Infaunal zoogeography and intergeneric character blending: The case of Metaniphargus shiroi sp. nov. (Crustacea: Amphipoda: Hadziidae), from interstitial beach water on Akajima Island, the Kerama Islands, Southwestern Japan.
Zool. Sci.
PUBLISHED: 07-09-2014
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A survey of biogenic coralline sands in the littoral fringe of a tropical island in Japan brought a new amphipod species to light. This species represents the first record of the subterranean genus Metaniphargus from the West Pacific. The majority of the species in this genus occur in the Caribbean, but a report from Hawaii and now from Japan defies the endemic Caribbean status it kept for so long. Metaniphargus shiroi sp. nov. is described, and morphological comparisons are made with closely resembling species from Hawaii and the Cayman Islands (genus Metaniphargus), and the Great Barrier Reef and California (genus Dulzura). Involvement of non-congeners in the comparisons is necessary as character overlap is abundant. These comparisons suggest that the presence of form-related body types in the shallow marine interstitial realm is circumtropical and follows habitat suitability rather than sudden dispersal or vicariance events.
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The novel ?7?2-nicotinic acetylcholine receptor subtype is expressed in mouse and human basal forebrain: biochemical and pharmacological characterization.
Mol. Pharmacol.
PUBLISHED: 07-07-2014
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We examined ?7?2-nicotinic acetylcholine receptor (?7?2-nAChR) expression in mammalian brain and compared pharmacological profiles of homomeric ?7-nAChRs and ?7?2-nAChRs. ?-Bungarotoxin affinity purification or immunoprecipitation with anti-?7 subunit antibodies (Abs) was used to isolate nAChRs containing ?7 subunits from mouse or human brain samples. ?7?2-nAChRs were detected in forebrain, but not other tested regions, from both species, based on Western blot analysis of isolates using ?2 subunit-specific Abs. Ab specificity was confirmed in control studies using subunit-null mutant mice or cell lines heterologously expressing specific human nAChR subtypes and subunits. Functional expression in Xenopus oocytes of concatenated pentameric (?7)5-, (?7)4(?2)1-, and (?7)3(?2)2-nAChRs was confirmed using two-electrode voltage clamp recording of responses to nicotinic ligands. Importantly, pharmacological profiles were indistinguishable for concatenated (?7)5-nAChRs or for homomeric ?7-nAChRs constituted from unlinked ?7 subunits. Pharmacological profiles were similar for (?7)5-, (?7)4(?2)1-, and (?7)3(?2)2-nAChRs except for diminished efficacy of nicotine (normalized to acetylcholine efficacy) at ?7?2- versus ?7-nAChRs. This study represents the first direct confirmation of ?7?2-nAChR expression in human and mouse forebrain, supporting previous mouse studies that suggested relevance of ?7?2-nAChRs in Alzheimer disease etiopathogenesis. These data also indicate that ?7?2-nAChR subunit isoforms with different ?7/?2 subunit ratios have similar pharmacological profiles to each other and to ?7 homopentameric nAChRs. This supports the hypothesis that ?7?2-nAChR agonist activation predominantly or entirely reflects binding to ?7/?7 subunit interface sites.
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Recent Developments in Novel Antidepressants Targeting ?4?2-Nicotinic Acetylcholine Receptors.
J. Med. Chem.
PUBLISHED: 07-02-2014
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Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of ?4?2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the ?4?2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.
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Blautia and Prevotella sequences distinguish human and animal fecal pollution in Brazil surface waters.
Environ Microbiol Rep
PUBLISHED: 06-09-2014
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Untreated sewage discharges and limited agricultural manure management practices contribute to fecal pollution in rural Brazilian waterways. Most microbial source tracking studies have focused on Bacteroidales, and few have tested host-specific indicators in underdeveloped regions. Sequencing of sewage and human and animal feces with Illumina HiSeq revealed Prevotellaceae as the most abundant family in humans, with Lachnospiraceae and Ruminococcaceae also comprising a large proportion of the microbiome. These same families were also dominant in animals. Bacteroides, the genus containing the most commonly utilized human-specific marker in the United States was present in very low abundance. We used oligotyping to identify Prevotella and Blautia sequences that can distinguish human fecal contamination. Thirty-five of 61 Blautia oligotypes and 13 of 108 Prevotella oligotypes in humans were host-specific or highly abundant (i.e. host-preferred) compared to pig, dog, horse and cow sources. Certain human Prevotella and Blautia oligotypes increased more than an order of magnitude along a polluted river transect in rural Brazil, but traditional fecal indicator levels followed a steady or even decreasing trend. While both Prevotella and Blautia oligotypes distinguished human and animal fecal pollution in Brazil surface waters, Blautia appears to contain more discriminatory and globally applicable markers for tracking sources of fecal pollution.
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Sevelamer Does Not Decrease Lipopolysaccharide or Soluble CD14 Levels But Decreases Soluble Tissue Factor, Low-Density Lipoprotein (LDL) Cholesterol, and Oxidized LDL Cholesterol Levels in Individuals With Untreated HIV Infection.
J. Infect. Dis.
PUBLISHED: 05-26-2014
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Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits.
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The correlation between ancestry and color in two cities of Northeast Brazil with contrasting ethnic compositions.
Eur. J. Hum. Genet.
PUBLISHED: 05-21-2014
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The degree of admixture in Brazil between historically isolated populations is complex and geographically variable. Studies differ as to what the genetic and phenotypic consequences of this mixing have been. In Northeastern Brazil, we enrolled 522 residents of Salvador and 620 of Fortaleza whose distributions of self-declared color were comparable to those in the national census. Using the program Structure and principal components analysis there was a clear correlation between biogeographic ancestry and categories of skin color. This correlation with African ancestry was stronger in Salvador (r=0.585; P<0.001) than in Fortaleza (r=0.236; P<0.001). In Fortaleza, although self-declared blacks had a greater proportion of European ancestry, they had more African ancestry than the other categories. When the populations were analyzed without pseudoancestors, as in some studies, the relationship of 'race' to genetic ancestry tended to diffuse or disappear. The inclusion of different African populations also influenced ancestry estimates. The percentage of unlinked ancestry informative markers in linkage disequilibrium, a measure of population structure, was 3-5 times higher in both Brazilian populations than expected by chance. We propose that certain methods, ascertainment bias and population history of the specific populations surveyed can result in failure to demonstrate a correlation between skin color and genetic ancestry. Population structure in Brazil has important implications for genetic studies, but genetic ancestry is irrelevant for how individuals are treated in society, their health, their income or their inclusion. These track more closely with perceived skin color than genetic ancestry.European Journal of Human Genetics advance online publication, 8 October 2014; doi:10.1038/ejhg.2014.215.
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Donor-derived West Nile virus infection in solid organ transplant recipients: report of four additional cases and review of clinical, diagnostic, and therapeutic features.
Transplantation
PUBLISHED: 05-16-2014
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We describe four solid-organ transplant recipients with donor-derived West Nile virus (WNV) infection (encephalitis 3, asymptomatic 1) from a common donor residing in a region of increased WNV activity. All four transplant recipients had molecular evidence of WNV infection in their serum and/or cerebrospinal fluid (CSF) by reverse transcription polymerase chain reaction (RT-PCR) testing. Serum from the organ donor was positive for WNV IgM but negative for WNV RNA, whereas his lymph node and spleen tissues tested positive for WNV by RT-PCR. Combination therapy included intravenous immunoglobulin (4 cases), interferon (3 cases), fresh frozen plasma with WNV IgG (2 cases), and ribavirin (1 case). Two of the four transplant recipients survived.Review of the 20 published cases of organ-derived WNV infection found that this infection is associated with a high incidence of neuroinvasive disease (70%) and severe morbidity and mortality (30%). Median time to onset of symptomatic WNV infection was 13 days after transplantation (range 5-37 days). Initial unexplained fever unresponsive to antibiotic therapy followed by rapid onset of neurologic deficits was the most common clinical presentation. Confirmation of infection was made by testing serum and CSF for both WNV RNA by RT-PCR and WNV IgM by serological assays. Treatment usually included supportive care, reduction of immunosuppression, and frequent intravenous immunoglobulin. The often negative results for WNV by current RT-PCR and serological assays and the absence of clinical signs of acute infection in donors contribute to the sporadic occurrence of donor-derived WNV infection. Potential organ donors should be assessed for unexplained fever and neurological symptoms, particularly if they reside in areas of increased WNV activity.
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Adoptive Transfer of Heme Oxygenase-1 (HO-1)-Modified Macrophages Rescues the Nuclear Factor Erythroid 2-Related Factor (Nrf2) Antiinflammatory Phenotype in Liver Ischemia/Reperfusion Injury.
Mol. Med.
PUBLISHED: 05-09-2014
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Macrophages are instrumental in the pathophysiology of liver ischemia/reperfusion injury (IRI). Although Nrf2 regulates macrophage-specific heme oxygenase-1 (HO-1) antioxidant defense, it remains unknown whether HO-1 induction might rescue macrophage Nrf2-dependent antiinflammatory functions. This study explores the mechanisms by which the Nrf2-HO-1 axis regulates sterile hepatic inflammation responses after adoptive transfer of ex vivo modified HO-1 overexpressing bone marrow-derived macrophages (BMMs). Livers in Nrf2-deficient mice preconditioned with Ad-HO-1 BMMs, but not Ad-?-Gal-BMMs, ameliorated liver IRI (at 6 h of reperfusion after 90 min of warm ischemia), evidenced by improved hepatocellular function (serum alanine aminotransferase [sALT] levels) and preserved hepatic architecture (Suzuki histological score). Treatment with Ad-HO-1 BMMs decreased neutrophil accumulation, proinflammatory mediators and hepatocellular necrosis/apoptosis in ischemic livers. Moreover, Ad-HO-1 transfection of Nrf2-deficient BMMs suppressed M1 (Nos2(+)) while promoting the M2 (Mrc-1/Arg-1(+)) phenotype. Unlike in controls, Ad-HO-1 BMMs increased the expression of Notch1, Hes1, phosphorylation of Stat3 and Akt in IR-stressed Nrf2-deficient livers as well as in lipopolysaccharide (LPS)-stimulated BMMs. Thus, adoptive transfer of ex vivo generated Ad-HO-1 BMMs rescued Nrf2-dependent antiinflammatory phenotype by promoting Notch1/Hes1/Stat3 signaling and reprogramming macrophages toward the M2 phenotype. These findings provide the rationale for a novel clinically attractive strategy to manage IR liver inflammation/damage.
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Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment.
J. Infect. Dis.
PUBLISHED: 05-01-2014
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Defining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)-infected persons with antiretroviral therapy (ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events.
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Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation.
J. Immunol.
PUBLISHED: 04-25-2014
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Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation is well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knockout (KO) resulted in liver protection from ischemia reperfusion injury (IRI) by deviating the local innate immune response against ischemia reperfusion toward the regulatory type: expression of proinflammatory genes was selectively decreased and anti-inflammatory IL-10 was simultaneously increased in ischemia reperfusion livers of PTEN KO mice compared with those of wild-type (WT) mice. PI3K inhibitor and IL-10-neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells and peritoneal macrophages isolated from KO mice expressed higher levels of M2 markers and produced lower TNF-? and higher IL-10 in response to TLR ligands than did their WT counterparts. They had enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation. Inactivation of Kupffer cells by gadolinium chloride enhanced proinflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation.
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T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia-reperfusion injury.
Hepatology
PUBLISHED: 04-08-2014
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Hepatic ischemia-reperfusion injury (IRI), an innate immunity-driven inflammation response, occurs in multiple clinical settings including liver resection, transplantation, trauma, and shock. T-cell immunoglobulin and mucin (TIM)-4, the only TIM protein not expressed on T cells, is found on macrophages and dendritic cells. The regulatory function of macrophage TIM-4 in the engulfment of apoptotic/necrotic bodies in innate immunity-mediated disease states remains unknown. This study focuses on the putative role of TIM-4 signaling in a model of liver warm ischemia (90 minutes) and reperfusion. The ischemia insult triggered TIM-4 expression by stressed hepatocellular phosphatidylserine (PS) presentation, peaking at 6 hours of reperfusion, and coinciding with the maximal hepatocellular damage. TIM-4-deficient or wild-type WT mice treated with antagonistic TIM-4 monoclonal antibody (mAb) were resistant against liver IRI, evidenced by diminished serum alanine aminotransferase (sALT) levels and well-preserved hepatic architecture. Liver hepatoprotection rendered by TIM-4 deficiency was accompanied by diminished macrophage infiltration/chemoattraction, phagocytosis, and activation of Toll-like receptor (TLR)2/4/9-dependent signaling. Correlating with in vivo kinetics, the peak of TIM-4 induction in lipopolysaccharide (LPS)-activated bone marrow derived-macrophages (BMM) was detected in 6-hour cultures. To mimic liver IRI, we employed hydrogen peroxide-necrotic hepatocytes, which readily present PS. Indeed, necrotic hepatocytes were efficiently captured/engulfed by WT (TIM-4+) but not by TIM-4-deficient BMM. Finally, in a newly established model of liver IRI, adoptive transfer of WT but not TIM-4-deficient BMM readily recreated local inflammation response/hepatocellular damage in the CD11b-DTR mouse system. Conclusion: These findings document the importance of macrophage-specific TIM-4 activation in the mechanism of hepatic IRI. Macrophage TIM-4 may represent a therapeutic target to minimize innate inflammatory responses in IR-stressed organs. (Hepatology 2014).
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Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 03-31-2014
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Reversal of proviral latency is being pursued as a curative strategy for HIV-1 infection. Recent clinical studies of in vivo administration of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat) show increases in unspliced cellular HIV-1 RNA levels in resting CD4(+) T cells. A critical unknown, however, is the proportion of latent proviruses that can be transcriptionally reactivated by SAHA or T-cell activation. In this study, we quantified the fraction of HIV-1 proviruses in resting CD4(+) T cells from patients on suppressive antiretroviral therapy that were reactivated ex vivo with SAHA or antibodies to CD3/CD28. At concentrations of SAHA achieved clinically, only 0.079% of proviruses in resting CD4(+) T cells were reactivated to produce virions, compared with 1.5% of proviruses in cells treated with anti-CD3/CD28 antibodies after correcting for spontaneous virion production in the medium control. A significant positive correlation (? = 0.67, P < 0.001) was found between levels of virions in the supernatant and unspliced cellular HIV-1 RNA following anti-CD3/CD28 treatment, but not following SAHA treatment (? = 0.21, P = 0.99). These results reveal that the majority of HIV-1 proviruses are not reactivated by current therapeutic approaches and that more effective means of reversing proviral latency will likely be required to deplete HIV-1 reservoirs.
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Tumor necrosis factor ? is associated with viral control and early disease progression in patients with HIV type 1 infection.
J. Infect. Dis.
PUBLISHED: 03-31-2014
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Inflammation in early human immunodeficiency virus type 1 (HIV-1) disease progression is not well characterized. Ninety patients with untreated primary HIV-1 infection were studied to determine associations of inflammatory proteins with early disease progression. High plasma tumor necrosis factor ? (TNF-?) levels (?8.5 pg/mL) were significantly associated with an increased viral load set point and shorter times to reaching a CD4(+) T-cell count of <500 cells/mm(3) and initiating antiretroviral therapy. The increased risk of reaching a CD4(+) T-cell count of <500 cells/mm(3) in the group with high TNF-? levels was driven by viral load but was independent of concurrent CD4(+) T-cell count. Thus, TNF-? appears to be an important mediator of inflammation in patients with poor viral control and early HIV-1 disease progression.
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Phylogenetic evidence of HIV-1 sequence evolution in subjects with persistent low-level viremia.
Antivir. Ther. (Lond.)
PUBLISHED: 03-24-2014
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Persistent low-level viremia (LLV) during the treatment of antiretroviral therapy (ART) is associated with emergent drug resistance mutation (DRM); however insight into its driver is limited. The objectives were to study HIV-1 pol sequence evolution in subjects with persistent LLV and evaluate factors associated with sequence changes.
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HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat.
J. Infect. Dis.
PUBLISHED: 03-11-2014
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A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge.
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Vitamin B-12 supplementation during pregnancy and early lactation increases maternal, breast milk, and infant measures of vitamin B-12 status.
J. Nutr.
PUBLISHED: 03-05-2014
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Pregnant women in resource-poor areas are at risk of multiple micronutrient deficiencies, and indicators of low vitamin B-12 status have been associated with adverse pregnancy outcomes, including anemia, low birth weight, and intrauterine growth retardation. To evaluate whether daily oral vitamin B-12 supplementation during pregnancy increases maternal and infant measures of vitamin B-12 status, we performed a randomized, placebo-controlled clinical trial. Pregnant women <14 wk of gestation in Bangalore, India, were randomly assigned to receive daily oral supplementation with vitamin B-12 (50 ?g) or placebo through 6 wk postpartum. All women were administered iron and folic acid supplements throughout pregnancy. One hundred eighty-three women were randomly assigned to receive vitamin B-12 and 183 to receive placebo. Compared with placebo recipients, vitamin B-12-supplemented women had significantly higher plasma vitamin B-12 concentrations at both the second (median vitamin B-12 concentration: 216 vs. 111 pmol/L, P < 0.001) and third (median: 184 vs. 105 pmol/L, P < 0.001) trimesters. At 6 wk postpartum, median breast milk vitamin B-12 concentration was 136 pmol/L in vitamin B-12-supplemented women vs. 87 pmol/L in the placebo group (P < 0.0005). Among vitamin B-12-supplemented women, the incidence of delivering an infant with intrauterine growth retardation was 33 of 131 (25%) vs. 43 of 125 (34%) in those administered placebo (P = 0.11). In a subset of infants tested at 6 wk of age, median plasma vitamin B-12 concentration was 199 pmol/L in those born to supplemented women vs. 139 pmol/L in the placebo group (P = 0.01). Infant plasma methylmalonic acid and homocysteine concentrations were significantly lower in the vitamin B-12 group as well. Oral supplementation of urban Indian women with vitamin B-12 throughout pregnancy and early lactation significantly increases vitamin B-12 status of mothers and infants. It is important to determine whether there are correlations between these findings and neurologic and metabolic functions. This trial was registered at clinicaltrials.gov as NCT00641862.
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A 20-year experience with liver transplantation for polycystic liver disease: does previous palliative surgical intervention affect outcomes?
J. Am. Coll. Surg.
PUBLISHED: 02-07-2014
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Although it is the only curative treatment for polycystic liver disease (PLD), orthotopic liver transplantation (OLT) has been reserved for severely symptomatic, malnourished, or refractory patients who are not candidates for palliative disease-directed interventions (DDI). Data on the effect of previous DDIs on post-transplant morbidity and mortality are scarce. We analyzed the outcomes after OLT for PLD recipients, and determined the effects of previous palliative surgical intervention on post-transplantation morbidity and mortality.
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Bupropion and bupropion analogs as treatments for CNS disorders.
Adv. Pharmacol.
PUBLISHED: 02-04-2014
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Bupropion, introduced as an antidepressant in the 1980s, is also effective as a smoking cessation aid and is beneficial in the treatment of methamphetamine addiction, cocaine dependence, addictive behaviors such as pathological gambling, and attention deficit hyperactivity disorder. (2S,3S)-hydroxybupropion is an active metabolite of bupropion produced in humans that contributes to antidepressant and smoking cessation efficacy and perhaps benefits in other CNS disorders. Mechanisms underlying its antidepressant and smoking abstinence remain elusive. However, it seems likely that efficacy is due to a combination of the effects of bupropion and/or its active metabolite (2S,3S)-hydroxybupropion involving the inhibition of reuptake of dopamine (DA) and NE in reward centers of the brain and the noncompetitive antagonism of ?4?2- and ?3?4*-nAChRs. These combined effects of bupropion and its active metabolite may be responsible for its ability to decrease nicotine reward and withdrawal. Studies directed toward development of a bupropion analog for treatment of cocaine addiction led to compounds, typified by 2-(N-cyclopropylamino)-3'-chloropropiophenone (RTI-6037-39), thought to act as indirect DA agonists. In addition, (2S,3S)-hydroxybupropion analogs were developed, which had varying degrees of DA and NE uptake inhibition and antagonism of nAChRs. These compounds will be valuable tools for animal behavioral studies and as clinical candidates. Here, we review the (1) early studies leading to the development of bupropion, (2) bupropion metabolism and the identification of (2S,3R)-hydroxybupropion as an active metabolite, (3) mechanisms of bupropion and metabolite action, (4) effects in animal behavioral studies, (5) results of clinical studies, and (6) development of bupropion analogs as potential pharmacotherapies for treating nicotine and cocaine addiction.
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Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study.
Lancet Oncol.
PUBLISHED: 01-17-2014
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Studies of complications resulting from surgery or radiotherapy for prostate cancer have mainly focused on incontinence and erectile dysfunction. We aimed to assess other important complications associated with these treatments for prostate cancer.
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A signal peptide missense mutation associated with nicotine dependence alters ?2*-nicotinic acetylcholine receptor function.
Neuropharmacology
PUBLISHED: 01-10-2014
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A cytosine to thymidine (C ? T) missense mutation in the signal peptide (SP) sequence (rs2472553) of the nicotinic acetylcholine receptor (nAChR) ?2 subunit produces a threonine-to-isoleucine substitution (T22I) often associated with nicotine dependence (ND). We assessed effects on function of ?2*-nAChR ('*'indicates presence of additional subunits) of this mutation, which could alter SP cleavage, RNA/protein secondary structure, and/or efficiency of transcription, translation, subunit assembly, receptor trafficking or cell surface expression. Two-electrode voltage clamp analyses indicate peak current responses to ACh or nicotine are decreased 2.8-5.8-fold for putative low sensitivity (LS; 10:1 ratio of ?:? subunit cRNAs injected) ?2?2- or ?2?4-nAChR and increased for putative high sensitivity (HS; 1:10 ?:? subunit ratio) ?2?2- (5.7-15-fold) or ?2?4- (1.9-2.2-fold) nAChR as a result of the mutation. Agonist potencies are decreased 1.6-4-fold for putative LS or HS ?2(T22I)?2-nAChR or for either ?2*-nAChR subtype formed in the presence of equal amounts of subunit cRNA, slightly decreased for LS ?2(T22I)?4-nAChR, but increased 1.4-2.4-fold for HS ?2(T22I)?4-nAChR relative to receptors containing wild-type ?2 subunits. These effects suggest that the ?2 subunit SP mutation generally favors formation of LS receptor isoforms. We hypothesize that lower sensitivity of human ?2*-nAChR to nicotine could contribute to increased susceptibility to ND. To our knowledge this is the first report of a SP mutation having a functional effect in a member of cys-loop family of ligand-gated ion channels.
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Innovations in nutrition education and global health: the Bangalore Boston nutrition collaborative.
BMC Med Educ
PUBLISHED: 01-02-2014
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India has a wide range of nutrition and health problems which require professionals with appropriate skills, knowledge and trans-disciplinary collaborative abilities to influence policy making at the national and global level.
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Ingolfiellamaldivensis sp. n. (Crustacea, Amphipoda, Ingolfiellidae) from coral reef sand off Magoodhoo island, Maldives.
Zookeys
PUBLISHED: 01-01-2014
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A new species of marine interstitial wormshrimp, Ingolfiellamaldivensis, is described from coral sand on the inner and outer reef off Magoodhoo island, Faafu atoll, Maldives. Six females were found and compared to other species from the Maldives and those bordering the Indian Ocean and beyond. Morphological resemblance ties it to a species from the Caribbean island of Curaçao. Both species are found in shallow sublittoral interstitial spaces.
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Hepatic ischemia and reperfusion injury in the absence of myeloid cell-derived COX-2 in mice.
PLoS ONE
PUBLISHED: 01-01-2014
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Cyclooxygenase-2 (COX-2) is a mediator of hepatic ischemia and reperfusion injury (IRI). While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2-M/-M) to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2-M/-M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2-M/-M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2-M/-M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2-M/-M and WT mice. COX-2-M/-M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9) expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2-M/-M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s) other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype.
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HIV-1 RNA levels and antiretroviral drug resistance in blood and non-blood compartments from HIV-1-infected men and women enrolled in AIDS clinical trials group study A5077.
PLoS ONE
PUBLISHED: 01-01-2014
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Detectable HIV-1 in body compartments can lead to transmission and antiretroviral resistance. Although sex differences in viral shedding have been demonstrated, mechanisms and magnitude are unclear. We compared RNA levels in blood, genital-secretions and saliva; and drug resistance in plasma and genital-secretions of men and women starting/changing antiretroviral therapy (ART) in the AIDS Clinical Trials Group (ACTG) 5077 study.
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The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy.
AIDS
PUBLISHED: 12-12-2013
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To assess whether CD8 T-cell activation predicts risk of AIDS and non-AIDS morbidity during suppressive antiretroviral treatment (ART).
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Characteristics of the Human Host Have Little Influence on Which Local Schistosoma mansoni Populations Are Acquired.
PLoS Negl Trop Dis
PUBLISHED: 12-01-2013
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Brazil remains the country in the Americas with the highest prevalence of schistosomiasis. A combination of control efforts and development, however, has sharply reduced its intensity and distribution. The acquisition of specific schistosome populations may be dependent on host characteristics such as sex, age, geography, work, habits and culture. How these and other host characteristics align with parasite subpopulations may guide approaches to improve control.
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Vitamin D status and TB treatment outcomes in adult patients in Tanzania: a cohort study.
BMJ Open
PUBLISHED: 11-20-2013
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Vitamin D is an immunomodulator and can alter response to tuberculosis (TB) treatment, though randomised trials have been inconclusive to date. We present one of the first comprehensive analysis of the associations between vitamin D status and TB treatment, T-cell counts and nutritional outcomes by HIV status.
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Plasma Apolipoprotein L1 Levels Do Not Correlate with CKD.
J. Am. Soc. Nephrol.
PUBLISHED: 11-14-2013
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Polymorphisms in APOL1 are associated with CKD, including HIV-related CKD, in individuals of African ancestry. The apolipoprotein L1 (APOL1) protein circulates and is localized in kidney cells, but the contribution of APOL1 location to CKD pathogenesis is unclear. We examined associations of plasma APOL1 levels with plasma cytokine levels, dyslipidemia, and APOL1 genotype in a nested case-control study (n=270) of HIV-infected African Americans enrolled in a multicenter prospective observational study. Patients were designated as having CKD when estimated GFR (eGFR) decreased to <60 ml/min per 1.73 m(2) (eGFR<60 cohort) or protein-to-creatinine ratios became >3.5 g/g (nephrotic proteinuria cohort). Circulating APOL1 levels did not associate with APOL1 genotype, CKD status, or levels of proinflammatory cytokines, but did correlate with fasting cholesterol, LDL cholesterol, and triglyceride levels. At ascertainment, CKD-associated polymorphisms (risk variants) in APOL1 associated with the eGFR<60 cohort, but not the nephrotic-range proteinuria cohort. Of note, in both the eGFR<60 and nephrotic proteinuria cohorts, CKD cases with two APOL1 risk variants had significant declines in eGFR over a median of 4 years compared with individuals with one or no risk variants. APOL1 risk genotype was not associated with changes in proteinuria. Higher circulating proinflammatory cytokine levels were independently associated with CKD but not APOL1 genotype. In conclusion, the function of variant APOL1 proteins derived from circulation or synthesized in the kidney, but not the level of circulating APOL1, probably mediates APOL1-associated kidney disease in HIV-infected African Americans.
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The Unique ?4(+)/(-)?4 Agonist Binding Site in (?4)3(?2)2 Subtype Nicotinic Acetylcholine Receptors Permits Differential Agonist Desensitization Pharmacology versus the (?4)2(?2)3 Subtype.
J. Pharmacol. Exp. Ther.
PUBLISHED: 11-04-2013
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Selected nicotinic agonists were used to activate and desensitize high-sensitivity (HS) (?4)2(?2)3) or low-sensitivity (LS) (?4)3(?2)2) isoforms of human ?4?2-nicotinic acetylcholine receptors (nAChRs). Function was assessed using (86)Rb(+) efflux in a stably transfected SH-EP1-h?4?2 human epithelial cell line, and two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes expressing concatenated pentameric HS or LS ?4?2-nAChR constructs (HSP and LSP). Unlike previously studied agonists, desensitization by the highly selective agonists A-85380 [3-(2(S)-azetidinylmethoxy)pyridine] and sazetidine-A (Saz-A) preferentially reduced ?4?2-nAChR HS-phase versus LS-phase responses. The concatenated-nAChR experiments confirmed that approximately 20% of LS-isoform acetylcholine-induced function occurs in an HS-like phase, which is abolished by Saz-A preincubation. Six mutant LSPs were generated, each targeting a conserved agonist binding residue within the LS-isoform-only ?4(+)/(-)?4 interface agonist binding site. Every mutation reduced the percentage of LS-phase function, demonstrating that this site underpins LS-phase function. Oocyte-surface expression of the HSP and each of the LSP constructs was statistically indistinguishable, as measured using ?2-subunit-specific [(125)I]mAb295 labeling. However, maximum function is approximately five times greater on a "per-receptor" basis for unmodified LSP versus HSP ?4?2-nAChRs. Thus, recruitment of the ?4(+)/(-)?4 site at higher agonist concentrations appears to augment otherwise-similar function mediated by the pair of ?4(+)/(-)?2 sites shared by both isoforms. These studies elucidate the receptor-level differences underlying the differential pharmacology of the two ?4?2-nAChR isoforms, and demonstrate that HS versus LS ?4?2-nAChR activity can be selectively manipulated using pharmacological approaches. Since ?4?2 nAChRs are the predominant neuronal subtype, these discoveries likely have significant functional implications, and may provide important insights for drug discovery and development.
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Invasive cervical cancer risk among HIV-infected women: a North American multicohort collaboration prospective study.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 10-30-2013
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HIV infection and low CD4+ T-cell count are associated with an increased risk of persistent oncogenic human papillomavirus infection-the major risk factor for cervical cancer. Few reported prospective cohort studies have characterized the incidence of invasive cervical cancer (ICC) in HIV-infected women.
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Factors associated with remaining on initial randomized efavirenz-containing regimens.
AIDS
PUBLISHED: 08-09-2013
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Efavirenz (EFV) along with two nucleoside reverse transcriptase inhibitors (NRTIs) is a recommended initial antiretroviral regimen. Understanding characteristics related to EFV success is clinically useful.
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Peripheral neuropathy in ART-experienced patients: prevalence and risk factors.
J. Neurovirol.
PUBLISHED: 08-05-2013
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Peripheral neuropathy (PN) is a common neurological complication of HIV infection that has debilitating effects on quality of life. While there has been a comprehensive evaluation of the prevalence of neuropathic signs/symptoms and risk factors (RFs) for PN or symptomatic PN (SPN) with initiation of combination antiretroviral therapy (cART) in ART-naïve patients, similar evaluation in ART-experienced patients is limited. This study investigated the prevalence and RFs for PN/SPN in ART-experienced patients enrolled in clinical salvage therapy studies. Between February 2000 and June 2007, 522 ART-experienced participants who experienced virologic failure with a prior regimen and started new regimens were followed longitudinally and annually screened for signs and symptoms of PN. Rates of PN/SPN at 3 years since parent study entry were 52.8 and 24.0 %, respectively. Aging, taller height, protease inhibitor use, and female sex were significant RFs for PN/SPN. The use of statin drugs was significantly associated with lower odds of SPN, and it may prevent progression from no SPN to SPN.
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Chemistry, Pharmacology, and Behavioral Studies Identify Chiral Cyclopropanes as Selective ?4?2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part II.
J. Med. Chem.
PUBLISHED: 06-26-2013
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A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at ?4?2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds, 24, 26, and 30, demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline.
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Vector control measures failed to affect genetic structure of Aedes aegypti in a sentinel metropolitan area of Brazil.
Acta Trop.
PUBLISHED: 06-21-2013
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In order to evaluate subpopulation differentiation, effective population size (Ne) and evidence for population bottlenecks at various geographic levels, Aedes aegypti larvae were collected longitudinally from 2007 to 2009 from four areas in the city of Salvador, Brazil. The DNA from each larva was isolated and genotyped with five independent microsatellite markers. FST and Josts D revealed significant population structuring (P<0.05) at the municipal and regional levels, while only RST was able to detect genetic differentiation at the level of strata within these areas. Ne analysis from longitudinal data did not show any evidence of significant change in population structure. The census population measured by the house index, however, showed a significant trend toward decrease in these areas. Active vector control measures did contribute to vector reduction, but this was not enough to decrease A. aegypti population genetic diversity in Salvador. The understanding of A. aegypti population dynamics may be helpful for planning and evaluation of control measures to make them more effective.
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Higher expression of several interferon-stimulated genes in HIV-1-infected females after adjusting for the level of viral replication.
J. Infect. Dis.
PUBLISHED: 06-10-2013
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Clinical studies have shown faster disease progression and stronger immune activation in human immunodeficiency virus (HIV)-1-infected females when compared with males for the same level of HIV-1 replication. Here we determine whether the elevated levels of HIV-1-induced interferon-alpha (IFN-?) production observed in females are associated with higher interferon-stimulated gene (ISG) expression levels in T cells, hence suggesting type-I IFN as a mechanism for the higher HIV-1-associated immune activation observed.
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Multivitamin supplementation improves haematologic status in children born to HIV-positive women in Tanzania.
J Int AIDS Soc
PUBLISHED: 05-20-2013
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Anaemia is prevalent among children born to HIV-positive women, and it is associated with adverse effects on cognitive and motor development, growth, and increased risks of morbidity and mortality.
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A novel nicotinic mechanism underlies ?-amyloid-induced neuronal hyperexcitation.
J. Neurosci.
PUBLISHED: 04-26-2013
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There is a significantly elevated incidence of epilepsy in Alzheimers disease (AD). Moreover, there is neural hyperexcitation/synchronization in transgenic mice expressing abnormal levels or forms of amyloid precursor protein and its presumed, etiopathogenic product, amyloid-?1-42 (A?). However, the underlying mechanisms of how A? causes neuronal hyperexcitation remain unclear. Here, we report that exposure to pathologically relevant levels of A? induces A? form-dependent, concentration-dependent, and time-dependent neuronal hyperexcitation in primary cultures of mouse hippocampal neurons. Similarly, A? exposure increases levels of nicotinic acetylcholine receptor (nAChR) ?7 subunit protein on the cell surface and ?7-nAChR function, but not ?7 subunit mRNA, suggesting post-translational upregulation of functional ?7-nAChRs. These effects are prevented upon coexposure to brefeldin A, an inhibitor of endoplasmic reticulum-to-Golgi protein transport, consistent with an effect on trafficking of ?7 subunits and assembled ?7-nAChRs to the cell surface. A? exposure-induced ?7-nAChR functional upregulation occurs before there is expression of neuronal hyperexcitation. Pharmacological inhibition using an ?7-nAChR antagonist or genetic deletion of nAChR ?7 subunits prevents induction and expression of neuronal hyperexcitation. Collectively, these results, confirmed in studies using slice cultures, indicate that functional activity and perhaps functional upregulation of ?7-nAChRs are necessary for production of A?-induced neuronal hyperexcitation and possibly AD pathogenesis. This novel mechanism involving ?7-nAChRs in mediation of A? effects provides potentially new therapeutic targets for treatment of AD.
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Immune Activation While on Potent Antiretroviral Therapy Can Predict Subsequent CD4+ T-Cell Increases Through 15 Years of Treatment.
HIV Clin Trials
PUBLISHED: 04-25-2013
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While persistent T-cell activation has been cross-sectionally associated with poor CD4+ T-cell restoration in HIV-infected individuals maintaining antiretroviral treatment (ART)-mediated viral suppression, it remains unclear whether CD8+ T-cell activation is of predictive effect on CD4+ T-cell recovery.
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Multivitamin supplements have no effect on growth of Tanzanian children born to HIV-infected mothers.
J. Nutr.
PUBLISHED: 03-20-2013
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Growth faltering and micronutrient deficiencies commonly coexist in HIV-exposed children in sub-Saharan Africa, and correcting deficiencies, such as those of vitamins B-complex, C, and E, may improve HIV-related endpoints and child growth. We therefore examined the effect of daily oral supplementation of vitamins B-complex, C, and E on growth among 2341 children born to HIV-infected mothers in Tanzania. HIV-infected women pregnant at ?32 wk of gestation were enrolled in the study. Children were randomized at age 6 wk to receive multivitamins or placebo until age 104 wk. All women received the same types of vitamins pre- and postnatally. At 6 wk, 256 children (11.1%) were HIV infected and the mean (SD) Z-scores for length for age (LAZ), weight for length (WLZ), and weight for age (WAZ) were -0.39 ± 1.20, -0.21 ± 1.23, and -0.52 ± 1.11, respectively. There was no overall treatment effect on LAZ, WLZ, or WAZ profiles during the follow-up (P ? 0.15). There was no treatment effect from 6 to 104 wk on LAZ [(95% CI: -0.14, 0.13); P = 0.94], WLZ [(95% CI: -0.17, 0.13); P = 0.78], or WAZ [(95% CI: -0.15, 0.16); P = 0.97] or on the incidence of growth failure, defined as respective Z-scores < -2 (P ? 0.29). Among the subgroup of HIV-uninfected children, there was no treatment effect from 6 to 104 wk on LAZ, WLZ, and WAZ (P ? 0.71) or on the incidence of growth failure (P ? 0.16). Multivitamin supplements had no effect on growth among children born to HIV-infected women who were themselves receiving multivitamins.
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Residual plasma viraemia and infectious HIV-1 recovery from resting memory CD4 cells in patients on antiretroviral therapy: results from ACTG A5173.
Antivir. Ther. (Lond.)
PUBLISHED: 02-15-2013
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In HIV-1-infected patients receiving antiretroviral therapy (ART), the relationship between residual viraemia and ex vivo recovery of infectious virus from latently infected CD4 cells is uncertain.
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Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies.
PLoS Pathog.
PUBLISHED: 02-14-2013
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HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research.
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Differential modulation of EAE by ?9*- and ?2*-nicotinic acetylcholine receptors.
Immunol. Cell Biol.
PUBLISHED: 02-12-2013
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Nicotine is a potent inhibitor of the immune response and is protective against experimental autoimmune encephalomyelitis (EAE). Initial studies suggested that the cholinergic system modulates inflammation via the ?7-nicotinic acetylcholine receptor (nAChR) subtype. We recently have shown that effector T cells and myeloid cells constitutively express mRNAs encoding nAChR ?9 and ?2 subunits and found evidence for immune system roles for non-?7-nAChRs. In the present study, we assessed the effects of nAChR ?9 or ?2 subunit gene deletion on EAE onset and severity, with or without nicotine treatment. We report again that disease onset is delayed and severity is attenuated in nicotine-treated, wild-type mice, an effect that also is observed in ?9 subunit knock-out (KO) mice irrespective of nicotine treatment. On the other hand, ?2 KO mice fail to recover from peak measures of disease severity regardless of nicotine treatment, despite retaining sensitivity to nicotines attenuation of disease severity. Prior to disease onset, we found significantly less reactive oxygen species production in the central nervous system (CNS) of ?2 KO mice, elevated proportions of CNS myeloid cells but decreased ratios of CNS macrophages/microglia in ?9 or ?2 KO mice, and some changes in iNOS, TNF-? and IL-1? mRNA levels in ?9 KO and/or ?2 KO mice. Our data thus suggest that ?2*- and ?9*-nAChRs, in addition to ?7-nAChRs, have different roles in endogenous and nicotine-dependent modulation of immune functions and could be exploited as therapeutic targets to modulate inflammation and autoimmunity.
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CD8+ T-cell activation in HIV-1-infected patients experiencing transient low-level viremia during antiretroviral therapy.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 02-09-2013
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Transient low-level viremia (TLLV) of 50-400 HIV RNA copies per milliliter is common during antiretroviral therapy, but its pathogenesis, consequences, and optimal management are unclear. Heightened immune activation is associated with detrimental outcomes, including impaired CD4 T-cell reconstitution. Using CD38/HLA-DR expression on CD8 T cells measured in 2 large studies, we determined associations between TLLV and immune activation levels before, during, and after TLLV. We found that TLLV does not significantly change CD8 T-cell activation and that higher CD8 T-cell activation during viral suppression <50 copies per milliliter is associated with a modest increase in the risk of a subsequent TLLV.
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Study design issues in evaluating immune biomarkers.
Curr Opin HIV AIDS
PUBLISHED: 02-06-2013
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The dramatic increase in the number and type of immune biomarkers that can be measured, particularly those assessing immune activation, has led to numerous investigations in HIV-infected individuals to explore pathogenesis and to assess therapeutic interventions that aim to attenuate immune activation. An overview is provided on study designs and related statistical and operational issues relevant to these investigations.
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Nicotine-morphine interactions at ?4?2, ?7 and ?3(?) nicotinic acetylcholine receptors.
Eur. J. Pharmacol.
PUBLISHED: 01-09-2013
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Nicotine and opioids share several behavioral and rewarding properties. Although both opioids and nicotine have their own specific mechanism of action, there is empirical and experimental evidence of interactions between these drugs. We studied receptor-level interactions of nicotine and morphine at ?4?2, ?7 and ?3(?) nicotinic acetylcholine receptors. [(3)H]epibatidine displacement was used to determine if morphine binds competitively to nicotinic acetylcholine receptors. Functional interactions of morphine and nicotine were studied with calcium fluorometry and (86)Rb(+) efflux assays. Morphine displaced [(3)H]epibatidine from nicotinic agonist binding sites in all cell lines studied. The Ki values for morphine were 13.2?M in SH-EP1-h?4?2 cells, 0.16?M and 126?M in SH-SY5Y cells and 43.7?M in SH-EP1-h?7 cells. In SH-EP1-h?4?2 cells expressing ?4?2 nicotinic acetylcholine receptors, morphine acted as a partial agonist of (86)Rb(+) efflux comparable to cytisine (with EC50 values of 53.3?M for morphine and 5.38?M for cytisine). The effect of morphine was attenuated concentration-dependently by the nicotinic antagonist mecamylamine. In the SH-SY5Y cell line expressing several subtypes of nicotinic acetylcholine receptors morphine had an inhibitory effect on nicotine induced (86)Rb(+) ion efflux mediated by ?3(?) nicotinic acetylcholine receptors. These results suggest that morphine acts as a partial agonist at ?4?2 nicotinic acetylcholine receptors and as a weak antagonist at ?3(?) nicotinic acetylcholine receptors.
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Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada.
PLoS ONE
PUBLISHED: 01-01-2013
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Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000-2007 in the U.S. and Canada.
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A new Ingolfiellid (Crustacea, Amphipoda, Ingolfiellidae) from an anchialine pool on Abd al Kuri Island, Socotra Archipelago, Yemen.
Zookeys
PUBLISHED: 01-01-2013
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Ingolfiella arganoi sp. n. from Abd al Kuri Island in the Arabian Sea is described from two specimens, a male and a female. The western shore of the Indian Ocean was hitherto a vacant spot in the distribution of circumtropical shallow marine interstitial ingolfiellids and therefore the location of the new species fills a meaningful gap in the geography of the family. Morphologically, the new species shows close affinities with Ingolfiella xarifae from the Maldives.
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Iron deficiency and anemia predict mortality in patients with tuberculosis.
J. Nutr.
PUBLISHED: 12-21-2011
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Many studies have documented a high prevalence of anemia among tuberculosis (TB) patients and anemia at TB diagnosis has been associated with an increased risk of death. However, little is known about the factors contributing to the development of TB-associated anemia and their importance in TB disease progression. Data from a randomized clinical trial of micronutrient supplementation in patients with pulmonary TB in Tanzania were analyzed. Repeated measures of anemia with iron deficiency, anemia without iron deficiency, and iron deficiency without anemia were assessed as risk factors for treatment failure, TB recurrence, and mortality. The prevalence of anemia (hemoglobin < 110 g/L) at baseline was 64%, more than one-half of which was related to iron deficiency (mean corpuscular volume , 80 fL). We found no evidence of an association between anemia (with or without iron deficiency) or iron deficiency without anemia at baseline and the risk of treatment failure at 1 mo after initiation. Anemia without iron deficiency was associated with an independent, 4-fold increased risk of TB recurrence [adjusted RR = 4.10 (95% CI = 1.88, 8.91); P < 0.001]. Iron deficiency and anemia (with and without iron deficiency) were associated with a 2- to nearly 3-fold independent increase in the risk of death [adjusted RR for iron deficiency without anemia = 2.89 (95% CI = 1.53, 5.47); P = 0.001; anemia without iron deficiency = 2.72 (95% CI = 1.50, 4.93); P = 0.001; iron deficiency anemia = 2.13 (95% CI = 1.10, 4.11); P = 0.02]. Efforts to identify and address the conditions contributing to TB-associated anemia, including iron deficiency, could play an important role in reducing morbidity and mortality in areas heavily affected by TB.
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Improvement in short-term pancreas transplant outcome by targeted antimicrobial therapy and refined donor selection.
Am Surg
PUBLISHED: 12-01-2011
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Graft thrombosis and infectious complications are the main early causes of pancreatic allograft loss in recipients of whole vascularized pancreas transplants, resulting in loss rates up to 10 per cent in the first post transplant week. In this study we sought to determine if initiation of a standardized selection criteria and posttransplant chemoprophylaxis regimen could reduce the rate of early allograft loss; we compared the rate of early allograft loss after introduction of these changes. Of the 61 diabetic recipients who underwent these protocols, 50.8 per cent were female. Average age was 42.9 ± 7.4 years of age, average length of stay was 12.7 ± 8.7 days, with all transplants performed heterotopic to the right lower quadrant with venous drainage to the proximal external or common iliac vein. Organ donors were 21.4 ± 4.8 years of age, body mass index was 23.9 ± 2.8 kg/m(2), with a length of stay of 3.7 ± 1.6 days. One-week pancreatic allograft survival for the protocolized versus nonprotocolized patients was 100 per cent versus 96.7 per cent, 1 month was 98.4 per cent versus 93.4 per cent, and 1 year was 96.7 per cent versus 88.5 per cent, respectively. In the protocolized group there were two graft losses due to infectious complications and none due to thrombosis. Before initiation of the protocols patient survival at 1 year was 91.8 per cent and after was 100 per cent. Pancreas transplantation is arguably the most technically demanding organ transplant from a complication and loss standpoint. However, highly successful outcomes can be obtained with standardized protocols beginning pretransplant to reduce the incidence of posttransplant complications.
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Body mass index and CD4+ T-lymphocyte recovery in HIV-infected men with viral suppression on antiretroviral therapy.
HIV Clin Trials
PUBLISHED: 11-03-2011
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To better characterize the relationship between body mass index (BMI) and CD4+ T-lymphocyte recovery in HIV disease.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.