Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential.

Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO(3)(*-), peroxyl radical, and less efficiently H(2)O(2). By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and/or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds.

Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.

Decision making across social contexts: Competition increases preferences for risk in chimpanzees and bonobos

Context can have a powerful influence on decision-making strategies in humans. In particular, people sometimes shift their economic preferences depending on the broader social context, such as the presence of potential competitors or mating partners. Despite the important role of competition in primate conspecific interactions, as well as evidence that competitive social contexts impact primates' social cognitive skills, there has been little study of how social context influences the strategies that nonhumans show when making decisions about the value of resources. Here we investigate the impact of social context on preferences for risk (variability in payoffs) in our two closest phylogenetic relatives, chimpanzees, Pan troglodytes, and bonobos, Pan paniscus. In a first study, we examine the impact of competition on patterns of risky choice. In a second study, we examine whether a positive play context affects risky choices. We find that (1) apes are more likely to choose the risky option when making decisions in a competitive context; and (2) the play context did not influence their risk preferences. Overall these results suggest that some types of social contexts can shift patterns of decision making in nonhuman apes, much like in humans. Comparative studies of chimpanzees and bonobos can therefore help illuminate the evolutionary processes shaping human economic behaviour. © 2012 The Association for the Study of Animal Behaviour.

Considering the role of social dynamics and positional behavior in gestural communication research.

While the hominin fossil record cannot inform us on either the presence or extent of social and cognitive abilities that may have paved the way for the emergence of language, studying non-vocal communication among our closest living relatives, the African apes, may provide valuable information about how language originated. Although much has been learned from gestural signaling in non-human primates, we have not yet established how and why gestural repertoires vary across species, what factors influence this variation, and how knowledge of these differences can contribute to an understanding of gestural signaling's contribution to language evolution. In this paper, we review arguments surrounding the theory that language evolved from gestural signaling and suggest some important factors to consider when conducting comparative studies of gestural communication among African apes. Specifically, we propose that social dynamics and positional behavior are critical components that shape the frequency and nature of gestural signaling across species and we argue that an understanding of these factors could shed light on how gestural communication may have been the basis of human language. We outline predictions for the influence of these factors on the frequencies and types of gestures used across the African apes and highlight the importance of including these factors in future gestural communication research with primates.

Outcomes after Unrelated Umbilical Cord Blood Transplantation for Children with Osteopetrosis.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for most children with osteopetrosis (OP). Timing of HSCT is critical; therefore, umbilical cord blood transplantation (UCBT) is an attractive option. We analyzed outcomes after UCBT in 51 OP children. Median age at UCBT was 6 months. Seventy-seven percent of the cord blood grafts had 0 or 1 HLA disparity with the recipient. Conditioning regimen was myeloablative (mostly busulfan-based in 84% and treosulfan-based in 10%). Antithymocyte globulin was given to 90% of patients. Median number of total nucleated and CD34(+) cells infused was 14 × 10(7)/kg and 3.4 × 10(5)/kg, respectively. Median follow-up for survivors was 74 months. Cumulative incidence (CI) of neutrophil recovery was 67% with a median time to recovery of 23 days; 33% of patients had graft failure, 81% of engrafted patients had full donor engraftment, and 19% had mixed donor chimerism. Day 100 CI of acute graft-versus-host disease (grades II to IV) was 31% and 6-year CI of chronic graft-versus-host disease was 21%. Mechanical ventilation was required in 28%, and veno-occlusive disease was diagnosed in 16% of cases. Six-year overall survival rate was 46%. Comparative studies with other alternative donors should be performed to evaluate whether UCBT remains a valid alternative for children with OP without an HLA-matched donor.

Reckoning With Apartheid: The Conundrum of Working Through the Past, An Introduction

From April 26-29, 1994, South Africa held its first universal, democratic elections. Witnessed by the world, South Africans of all races waited patiently in line to cast their ballots, signaling the official and symbolic birth of the “new” South Africa. The subsequent years, marked initially with euphoric hopes for racial healing enabled by institutional processes such as the Truth and Reconciliation Commission (TRC), have instead, most recently, inspired deep concern about epidemic levels of HIV/AIDS, violent crime, state corruption, and unbridled market reforms directed at everything from property to bodies to babies. Now, seemingly beleaguered state officials deploy the mantra “TINA” (There Is No Alternative [to neoliberal development]) to fend off criticism of growing income and wealth disparities. To coincide, more or less, with the anniversary of 1994—less to commemorate than to signal something about the trajectory of the past twenty years—we are proposing an interdisciplinary, special theme section of Comparative Studies in South Asia, Africa, and the Middle East (CSSAAME) entitled “The Haunted Present: Reckoning After Apartheid” (tentative title). The special theme section is framed around questions of reckoning in the double sense of both a moral and practical accounting for historical injury alongside the challenges and failures of the no-longer “new” South Africa. Against accounts depicting the liberation era as non-violent and peaceable, more nuanced analysis we argue suggests not only that South Africa’s “revolution” was marked by both collective and individual violence—on the part of the state and the liberation movements—but that reckoning with the present demands of scholars, the media, and cultural commentators that they begin to grapple more fully with the dimensions and different figurations of South Africa’s violent colonial history. Indeed, violence and reckoning appear as two central forces in contemporary South African political, economic, and social life. In response, we are driven to pose the following questions: In the post-apartheid period, what forms of (individual, structural) violence have come to bear on South African life? How does this violence reckon with apartheid and its legacies? Does it in fact reckon with the past? How can we or should we think about violence as a response to the (failed?) reckoning of state initiatives like the TRC? What has enabled or enables aesthetic forms—literature, photography, plastic arts, and other modes of expressive culture—to respond to the difficulties of South Africa’s ongoing transition? What, in fact, would a practice or ethic of reckoning defined in the following way look like? ˈrekəniNG/ noun: • the action or process of calculating or estimating something: last year was not, by any reckoning, a particularly good one; the system of time reckoning in Babylon • a person’s view, opinion, or judgment: by ancient reckoning, bacteria are plants • archaic, a bill or account, or its settlement • the avenging or punishing of past mistakes or misdeeds: the fear of being brought to reckoning there will be a terrible reckoning (Oxford English Dictionary) Looking back on the period, just before 1994, is sobering indeed. At the time, many saw in the energies and courage of those fighting for liberation the possibilities of a post-racial, post-conflict society. Yet as much as the new was ushered in, old apartheid forms lingered. Recalling Nadine Gordimer’s invocation of Gramsci’s “morbid symptoms” more and more it seems “the old is dying and the new cannot be born” (Gramsci cited in Gordimer 1982). And even as the new began to emerge other forces—both internal and external to South Africa—redefined the conditions for transformation. The so-called “new” South Africa, as Jennifer Wenzel has argued, was really more than anything “the changing face of old oppressions” (Wenzel 2009:159). The implications for our special theme section of CSSAAME are many. We begin by exploring the gender, race, and class dimensions of contemporary South African life by way of its literatures, histories, and politics, its reversion to custom, the claims of ancestors on the living, in brief, the various cultural expressive modes in which contemporary South Africa reckons with its past and in so doing accounts, day by day, for the ways in which the present can be lived, pragmatically. This moves us some distance from the exercise in “truth and reconciliation” of the earlier post-transition years to consider more fully the nature of post-conflict, the suturing of old enmities in the present, and the ways of resolving those lingering suspicions both ordinary and the stuff of the dark night of the soul (Nelson 2009:xv).

Reckoning With Apartheid: The Conundrum of Working Through the Past

From April 26-29, 1994, South Africa held its first universal, democratic elections. Witnessed by the world, South Africans of all races waited patiently in line to cast their ballots, signaling the official and symbolic birth of the “new” South Africa. The subsequent years, marked initially with euphoric hopes for racial healing enabled by institutional processes such as the Truth and Reconciliation Commission (TRC), have instead, most recently, inspired deep concern about epidemic levels of HIV/AIDS, violent crime, state corruption, and unbridled market reforms directed at everything from property to bodies to babies. Now, seemingly beleaguered state officials deploy the mantra “TINA” (There Is No Alternative [to neoliberal development]) to fend off criticism of growing income and wealth disparities. To coincide, more or less, with the anniversary of 1994—less to commemorate than to signal something about the trajectory of the past twenty years—we are proposing an interdisciplinary, special theme section of Comparative Studies in South Asia, Africa, and the Middle East (CSSAAME) entitled “The Haunted Present: Reckoning After Apartheid” (tentative title). The special theme section is framed around questions of reckoning in the double sense of both a moral and practical accounting for historical injury alongside the challenges and failures of the no-longer “new” South Africa. Against accounts depicting the liberation era as non-violent and peaceable, more nuanced analysis we argue suggests not only that South Africa’s “revolution” was marked by both collective and individual violence—on the part of the state and the liberation movements—but that reckoning with the present demands of scholars, the media, and cultural commentators that they begin to grapple more fully with the dimensions and different figurations of South Africa’s violent colonial history. Indeed, violence and reckoning appear as two central forces in contemporary South African political, economic, and social life. In response, we are driven to pose the following questions: In the post-apartheid period, what forms of (individual, structural) violence have come to bear on South African life? How does this violence reckon with apartheid and its legacies? Does it in fact reckon with the past? How can we or should we think about violence as a response to the (failed?) reckoning of state initiatives like the TRC? What has enabled or enables aesthetic forms—literature, photography, plastic arts, and other modes of expressive culture—to respond to the difficulties of South Africa’s ongoing transition? What, in fact, would a practice or ethic of reckoning defined in the following way look like? ˈrekəniNG/ noun: • the action or process of calculating or estimating something: last year was not, by any reckoning, a particularly good one; the system of time reckoning in Babylon • a person’s view, opinion, or judgment: by ancient reckoning, bacteria are plants • archaic, a bill or account, or its settlement • the avenging or punishing of past mistakes or misdeeds: the fear of being brought to reckoning there will be a terrible reckoning (Oxford English Dictionary) Looking back on the period, just before 1994, is sobering indeed. At the time, many saw in the energies and courage of those fighting for liberation the possibilities of a post-racial, post-conflict society. Yet as much as the new was ushered in, old apartheid forms lingered. Recalling Nadine Gordimer’s invocation of Gramsci’s “morbid symptoms” more and more it seems “the old is dying and the new cannot be born” (Gramsci cited in Gordimer 1982). And even as the new began to emerge other forces—both internal and external to South Africa—redefined the conditions for transformation. The so-called “new” South Africa, as Jennifer Wenzel has argued, was really more than anything “the changing face of old oppressions” (Wenzel 2009:159). The implications for our special theme section of CSSAAME are many. We begin by exploring the gender, race, and class dimensions of contemporary South African life by way of its literatures, histories, and politics, its reversion to custom, the claims of ancestors on the living, in brief, the various cultural expressive modes in which contemporary South Africa reckons with its past and in so doing accounts, day by day, for the ways in which the present can be lived, pragmatically. This moves us some distance from the exercise in “truth and reconciliation” of the earlier post-transition years to consider more fully the nature of post-conflict, the suturing of old enmities in the present, and the ways of resolving those lingering suspicions both ordinary and the stuff of the dark night of the soul (Nelson 2009:xv).

Comparative immunogenicity of HIV-1 clade C envelope proteins for prime/boost studies.

BACKGROUND: Previous clinical efficacy trials failed to support the continued development of recombinant gp120 (rgp120) as a candidate HIV vaccine. However, the recent RV144 HIV vaccine trial in Thailand showed that a prime/boost immunization strategy involving priming with canarypox vCP1521 followed by boosting with rgp120 could provide significant, although modest, protection from HIV infection. Based on these results, there is renewed interest in the development of rgp120 based antigens for follow up vaccine trials, where this immunization approach can be applied to other cohorts at high risk for HIV infection. Of particular interest are cohorts in Africa, India, and China that are infected with clade C viruses. METHODOLOGY/PRINCIPAL FINDINGS: A panel of 10 clade C rgp120 envelope proteins was expressed in 293 cells, purified by immunoaffinity chromatography, and used to immunize guinea pigs. The resulting sera were collected and analyzed in checkerboard experiments for rgp120 binding, V3 peptide binding, and CD4 blocking activity. Virus neutralization studies were carried out with two different assays and two different panels of clade C viruses. A high degree of cross reactivity against clade C and clade B viruses and viral proteins was observed. Most, but not all of the immunogens tested elicited antibodies that neutralized tier 1 clade B viruses, and some sera neutralized multiple clade C viruses. Immunization with rgp120 from the CN97001 strain of HIV appeared to elicit higher cross neutralizing antibody titers than the other antigens tested. CONCLUSIONS/SIGNIFICANCE: While all of the clade C antigens tested were immunogenic, some were more effective than others in eliciting virus neutralizing antibodies. Neutralization titers did not correlate with rgp120 binding, V3 peptide binding, or CD4 blocking activity. CN97001 rgp120 elicited the highest level of neutralizing antibodies, and should be considered for further HIV vaccine development studies.

Comparative effectiveness studies to improve clinical outcomes in end stage renal disease: the DEcIDE patient outcomes in end stage renal disease study.

BACKGROUND: Evidence is lacking to inform providers' and patients' decisions about many common treatment strategies for patients with end stage renal disease (ESRD). METHODS/DESIGN: The DEcIDE Patient Outcomes in ESRD Study is funded by the United States (US) Agency for Health Care Research and Quality to study the comparative effectiveness of: 1) antihypertensive therapies, 2) early versus later initiation of dialysis, and 3) intravenous iron therapies on clinical outcomes in patients with ESRD. Ongoing studies utilize four existing, nationally representative cohorts of patients with ESRD, including (1) the Choices for Healthy Outcomes in Caring for ESRD study (1041 incident dialysis patients recruited from October 1995 to June 1999 with complete outcome ascertainment through 2009), (2) the Dialysis Clinic Inc (45,124 incident dialysis patients initiating and receiving their care from 2003-2010 with complete outcome ascertainment through 2010), (3) the United States Renal Data System (333,308 incident dialysis patients from 2006-2009 with complete outcome ascertainment through 2010), and (4) the Cleveland Clinic Foundation Chronic Kidney Disease Registry (53,399 patients with chronic kidney disease with outcome ascertainment from 2005 through 2009). We ascertain patient reported outcomes (i.e., health-related quality of life), morbidity, and mortality using clinical and administrative data, and data obtained from national death indices. We use advanced statistical methods (e.g., propensity scoring and marginal structural modeling) to account for potential biases of our study designs. All data are de-identified for analyses. The conduct of studies and dissemination of findings are guided by input from Stakeholders in the ESRD community. DISCUSSION: The DEcIDE Patient Outcomes in ESRD Study will provide needed evidence regarding the effectiveness of common treatments employed for dialysis patients. Carefully planned dissemination strategies to the ESRD community will enhance studies' impact on clinical care and patients' outcomes.

A cross-site, comparative effectiveness study of an integrated HIV and substance use treatment program.

Co-occurrence of HIV and substance abuse is associated with poor outcomes for HIV-related health and substance use. Integration of substance use and medical care holds promise for HIV patients, yet few integrated treatment models have been reported. Most of the reported models lack data on treatment outcomes in diverse settings. This study examined the substance use outcomes of an integrated treatment model for patients with both HIV and substance use at three different clinics. Sites differed by type and degree of integration, with one integrated academic medical center, one co-located academic medical center, and one co-located community health center. Participants (n=286) received integrated substance use and HIV treatment for 12 months and were interviewed at 6-month intervals. We used linear generalized estimating equation regression analysis to examine changes in Addiction Severity Index (ASI) alcohol and drug severity scores. To test whether our treatment was differentially effective across sites, we compared a full model including site by time point interaction terms to a reduced model including only site fixed effects. Alcohol severity scores decreased significantly at 6 and 12 months. Drug severity scores decreased significantly at 12 months. Once baseline severity variation was incorporated into the model, there was no evidence of variation in alcohol or drug score changes by site. Substance use outcomes did not differ by age, gender, income, or race. This integrated treatment model offers an option for treating diverse patients with HIV and substance use in a variety of clinic settings. Studies with control groups are needed to confirm these findings.

How does cognition evolve? Phylogenetic comparative psychology.

Now more than ever animal studies have the potential to test hypotheses regarding how cognition evolves. Comparative psychologists have developed new techniques to probe the cognitive mechanisms underlying animal behavior, and they have become increasingly skillful at adapting methodologies to test multiple species. Meanwhile, evolutionary biologists have generated quantitative approaches to investigate the phylogenetic distribution and function of phenotypic traits, including cognition. In particular, phylogenetic methods can quantitatively (1) test whether specific cognitive abilities are correlated with life history (e.g., lifespan), morphology (e.g., brain size), or socio-ecological variables (e.g., social system), (2) measure how strongly phylogenetic relatedness predicts the distribution of cognitive skills across species, and (3) estimate the ancestral state of a given cognitive trait using measures of cognitive performance from extant species. Phylogenetic methods can also be used to guide the selection of species comparisons that offer the strongest tests of a priori predictions of cognitive evolutionary hypotheses (i.e., phylogenetic targeting). Here, we explain how an integration of comparative psychology and evolutionary biology will answer a host of questions regarding the phylogenetic distribution and history of cognitive traits, as well as the evolutionary processes that drove their evolution.

Structuring the Calibration of Qualitative Data as Sets for Qualitative Comparative Analysis (QCA)

Most studies that apply qualitative comparative analysis (QCA) rely on macro-level data, but an increasing number of studies focus on units of analysis at the micro or meso level (i.e., households, firms, protected areas, communities, or local governments). For such studies, qualitative interview data are often the primary source of information. Yet, so far no procedure is available describing how to calibrate qualitative data as fuzzy sets. The authors propose a technique to do so and illustrate it using examples from a study of Guatemalan local governments. By spelling out the details of this important analytic step, the authors aim at contributing to the growing literature on best practice in QCA. © The Author(s) 2012.

Comparative analyses of seven algorithms for copy number variant identification from single nucleotide polymorphism arrays.

Determination of copy number variants (CNVs) inferred in genome wide single nucleotide polymorphism arrays has shown increasing utility in genetic variant disease associations. Several CNV detection methods are available, but differences in CNV call thresholds and characteristics exist. We evaluated the relative performance of seven methods: circular binary segmentation, CNVFinder, cnvPartition, gain and loss of DNA, Nexus algorithms, PennCNV and QuantiSNP. Tested data included real and simulated Illumina HumHap 550 data from the Singapore cohort study of the risk factors for Myopia (SCORM) and simulated data from Affymetrix 6.0 and platform-independent distributions. The normalized singleton ratio (NSR) is proposed as a metric for parameter optimization before enacting full analysis. We used 10 SCORM samples for optimizing parameter settings for each method and then evaluated method performance at optimal parameters using 100 SCORM samples. The statistical power, false positive rates, and receiver operating characteristic (ROC) curve residuals were evaluated by simulation studies. Optimal parameters, as determined by NSR and ROC curve residuals, were consistent across datasets. QuantiSNP outperformed other methods based on ROC curve residuals over most datasets. Nexus Rank and SNPRank have low specificity and high power. Nexus Rank calls oversized CNVs. PennCNV detects one of the fewest numbers of CNVs.

Comparative analyses of clinical and environmental populations of Cryptococcus neoformans in Botswana.

Cryptococcus neoformans var. grubii (Cng) is the most common cause of fungal meningitis, and its prevalence is highest in sub-Saharan Africa. Patients become infected by inhaling airborne spores or desiccated yeast cells from the environment, where the fungus thrives in avian droppings, trees and soil. To investigate the prevalence and population structure of Cng in southern Africa, we analysed isolates from 77 environmental samples and 64 patients. We detected significant genetic diversity among isolates and strong evidence of geographic structure at the local level. High proportions of isolates with the rare MATa allele were observed in both clinical and environmental isolates; however, the mating-type alleles were unevenly distributed among different subpopulations. Nearly equal proportions of the MATa and MATα mating types were observed among all clinical isolates and in one environmental subpopulation from the eastern part of Botswana. As previously reported, there was evidence of both clonality and recombination in different geographic areas. These results provide a foundation for subsequent genomewide association studies to identify genes and genotypes linked to pathogenicity in humans.