We report the results of a long-term follow-up of subjects in a phase 1 study of AAV2-hAADC (adeno-associated virus type 2-human aromatic L-amino acid decarboxylase) gene therapy for the treatment of ...Parkinson's disease (PD). Ten patients with moderately advanced PD received bilateral putaminal infusions of either a low or a high dose of AAV2-hAADC vector. An annual positron emission tomography (PET) imaging with (18)Ffluoro-L-m-tyrosine tracer was used for evaluation of AADC expression, and a standard clinical rating scale Unified Parkinson's Disease Rating Scale (UPDRS) was used to assess effect. Our previous analysis of the 6-month data suggested that this treatment was acutely safe and well tolerated. We found that the elevated PET signal observed in the first 12 months persisted over 4 years in both dose groups. A significantly increased PET value compared with the presurgery baseline was maintained over the 4-year monitoring period. The UPDRS in all patients off medication for 12 hr improved in the first 12 months, but displayed a slow deterioration in subsequent years. This analysis demonstrates that apparent efficacy continues through later years with an acceptable safety profile. These data indicate stable transgene expression over 4 years after vector delivery and continued safety, but emphasize the need for a controlled efficacy trial and the use of a higher vector dose.
Transfers of resources between generations are an essential element in current models of human life-history evolution accounting for prolonged development, extended lifespan and menopause. ...Integrating these models with Hamilton's theory of inclusive fitness, we predict that the interaction of biological kinship with the age-schedule of resource production should be a key driver of intergenerational transfers. In the empirical case of Tsimane’ forager–horticulturalists in Bolivian Amazonia, we provide a detailed characterization of net transfers of food according to age, sex, kinship and the net need of donors and recipients. We show that parents, grandparents and siblings provide significant net downward transfers of food across generations. We demonstrate that the extent of provisioning responds facultatively to variation in the productivity and demographic composition of families, as predicted by the theory. We hypothesize that the motivation to provide these critical transfers is a fundamental force that binds together human nuclear and extended families. The ubiquity of three-generational families in human societies may thus be a direct reflection of fundamental evolutionary constraints on an organism's life-history and social organization.
Social organization among human foragers is characterized by a three-generational system of resource provisioning within families, long-term pair-bonding between men and women, high levels of ...cooperation between kin and non-kin, and relatively egalitarian social relationships. In this paper, we suggest that these core features of human sociality result from the learning- and skill-intensive human foraging niche, which is distinguished by a late age-peak in caloric production, high complementarity between male and female inputs to offspring viability, high gains to cooperation in production and risk-reduction, and a lack of economically defensible resources. We present an explanatory framework for understanding variation in social organization across human societies, highlighting the interactive effects of four key ecological and economic variables: (i) the role of skill in resource production; (ii) the degree of complementarity in male and female inputs into production; (iii) economies of scale in cooperative production and competition; and (iv) the economic defensibility of physical inputs into production. Finally, we apply this framework to understanding variation in social and political organization across foraging, horticulturalist, pastoralist and agriculturalist societies.
Paternal provisioning among humans is puzzling because it is rare among primates and absent in nonhuman apes and because emergent provisioning would have been subject to paternity theft. A ...provisioning “dad” loses fitness at the hands of nonprovisioning, mate-seeking “cads.” Recent models require exacting interplay between male provisioning and female choice to overcome this social dilemma. We instead posit that ecological change favored widespread improvements in male provisioning incentives, and we show theoretically how social obstacles to male provisioning can be overcome. Greater availability of energetically rich, difficult-to-acquire foods enhances female–male and male–male complementarities, thus altering the fitness of dads versus cads. We identify a tipping point where gains from provisioning overcome costs from paternity uncertainty and the dad strategy becomes viable. Stable polymorphic states are possible, meaning that dads need not necessarily eliminate cads. Our simulations suggest that with sufficient complementarities, dads can emerge even in the face of high paternity uncertainty. Our theoretical focus on ecological change as a primary factor affecting the trade-off between male mating and parenting effort suggests different possibilities for using paleo-climatic, archaeological, and genomic evidence to establish the timing of and conditions associated with emergence of paternal provisioning in the hominin lineage.
Background & Aims Complications after colectomy for ulcerative colitis (UC) have not been well characterized in large, population-based studies. We characterized postoperative in-hospital ...complications, stratified them by severity, and assessed independent clinical predictors, including use of immunosuppressants. Methods We performed population-based surveillance using administrative databases to identify all adults (≥18 y) who had an International Classification of Diseases-9th/10th revisions code for UC and a colectomy from 1996 to 2009. All medical charts were reviewed. The primary outcome was severe postoperative complications, including in-hospital mortality. Logistic regression was used to assess predictors of complications after colectomy and then restricted to patients undergoing emergent or elective surgeries. Results Of the 666 UC patients who underwent a colectomy, a postoperative complication occurred in 27.0% and the mortality rate was 1.5%. Independent predictors of postoperative complications were age (for patients >64 vs 18–34 y: odds ratio OR, 1.95; 95% confidence interval CI, 1.07–3.54), comorbidities (>2 vs none: OR, 1.89; 95% CI, 1.06–3.37), and admission status (emergent vs elective colectomy: OR, 1.62; 95% CI, 1.14–2.30). Significant risk factors for an emergent colectomy included time from admission to colectomy (>14 vs 3–14 d: OR, 3.32; 95% CI, 1.62–6.80) and a preoperative complication (≥1 vs 0: OR, 3.04; 95% CI, 1.33–6.91). A prescription of immunosuppressants before colectomies did not increase the risk for postoperative complications. Conclusions Postoperative complications frequently occur after colectomy for UC, predominantly among elderly patients with multiple comorbidities. Patients who were admitted to the hospital under emergency conditions and did not respond to medical treatment had worse outcomes when surgery was performed 14 or more days after admission.
Two types of models aim to account the origins of rank differentiation and social hierarchy in human societies. Conflict models suggest that the formation of social hierarchies is synonymous with the ...establishment of relationships of coercive social dominance and exploitation. Voluntary or 'integrative' models, on the other hand, suggest that rank differentiation – the differentiation of leader from follower, ruler from ruled, or state from subject – may sometimes be preferred over more egalitarian social arrangements as a solution to the challenges of life in social groups, such as conflict over resources, coordination failures, and free-riding in cooperative relationships. Little formal theoretical work, however, has established whether and under what conditions individuals would indeed prefer the establishment of more hierarchical relationships over more egalitarian alternatives. This paper provides an evolutionary game theoretical model for the acceptance of leadership in cooperative groups. We propose that the effort of a leader can reduce the likelihood that cooperation fails due to free-riding or coordination errors, and that under some circumstances, individuals would prefer to cooperate in a group under the supervision of a leader who receives a share of the group's productivity than to work in an unsupervised group. We suggest, in particular, that this becomes an optimal solution for individual decision makers when the number of group members required for collective action exceeds the maximum group size at which leaderless cooperation is viable.
Background:
Fusobacterium nucleatum is a heterogeneous oral pathogen that is also a common resident of the human gut mucosa. Given that some strains of F. nucleatum are known to be invasive and ...proinflammatory in the oral mucosa, we compared strains isolated from patients with inflammatory bowel disease (IBD) with strains isolated from healthy controls to determine 1) whether this species was more commonly associated with IBD patients; and 2) whether gut‐derived F. nucleatum strains from IBD patients showed an increased capacity for invasion.
Methods:
Biopsy material was obtained from 56 adult patients undergoing colonoscopy for colon cancer screening purposes or assessment of irritable bowel syndrome status (34 patients), or to assess for presence of gastrointestinal disease (i.e., IBD or indeterminate colitis, 22 patients). We enumerated Fusobacterium spp. strains isolated from human gut biopsy material in a blinded fashion, and then compared the virulence potential of a subset of F. nucleatum strains using an invasion assay in a Caco‐2 model system.
Results:
Fusobacterium spp. were isolated from 63.6% of patients with gastrointestinal disease compared to 26.5% of healthy controls (P = 0.01). In total, 69% of all Fusobacterium spp. recovered from patients were identified as F. nucleatum. F. nucleatum strains originating from inflamed biopsy tissue from IBD patients were significantly more invasive in a Caco‐2 cell invasion assay than strains that were isolated from healthy tissue from either IBD patients or control patients (P < 0.05 to 0.001).
Conclusions:
This study indicates that colonization of the intestinal mucosa by highly invasive strains of F. nucleatum may be a useful biomarker for gastrointestinal disease. (Inflamm Bowel Dis 2011;)
The role that social status plays in small-scale societies suggests that status may be important for understanding the evolution of human fertility decisions, and for understanding how such decisions ...play out in modern contexts. This paper explores whether modelling competition for status—in the sense of relative rank within a society—can help shed light on fertility decline and the demographic transition. We develop a model of how levels of inequality and status competition affect optimal investment by parents in the embodied capital (health, strength, and skills) and social status of offspring, focusing on feedbacks between individual decisions and socio-ecological conditions. We find that conditions similar to those in demographic transition societies yield increased investment in both embodied capital and social status, generating substantial decreases in fertility, particularly under conditions of high inequality and intense status competition. We suggest that a complete explanation for both fertility variation in small-scale societies and modern fertility decline will take into account the effects of status competition and inequality.
We introduce the new, substantially updated, and revised version of the Dyadic Militarized Interstate Disputes (MIDs) dataset. We discuss the underlying logic of constructing dyadic MIDs and ...demonstrate that these operations generate significant differences between the actual occurrence and properties of MID dyads and those extracted from machine-generated programs such as EUGene, or from the MID participant dataset. We provide some descriptive measures of dyadic MIDs over the period of 1816 to 2010 and compare some of the key dyadic results on the correlates of MIDs using different datasets. We discuss the theoretical and empirical implications of our results.
Metabolomic analyses of human gut microbiome samples can unveil the metabolic potential of host tissues and the numerous microorganisms they support, concurrently. As such, metabolomic information ...bears immense potential to improve disease diagnosis and therapeutic drug discovery. Unfortunately, as cohort sizes increase, comprehensive metabolomic profiling becomes costly and logistically difficult to perform at a large scale. To address these difficulties, we tested the feasibility of predicting the metabolites of a microbial community based solely on microbiome sequencing data. Paired microbiome sequencing (16S rRNA gene amplicons, shotgun metagenomics, and metatranscriptomics) and metabolome (mass spectrometry and nuclear magnetic resonance spectroscopy) datasets were collected from six independent studies spanning multiple diseases. We used these datasets to evaluate two reference-based gene-to-metabolite prediction pipelines and a machine-learning (ML) based metabolic profile prediction approach. With the pre-trained model on over 900 microbiome-metabolome paired samples, the ML approach yielded the most accurate predictions (i.e., highest F1 scores) of metabolite occurrences in the human gut and outperformed reference-based pipelines in predicting differential metabolites between case and control subjects. Our findings demonstrate the possibility of predicting metabolites from microbiome sequencing data, while highlighting certain limitations in detecting differential metabolites, and provide a framework to evaluate metabolite prediction pipelines, which will ultimately facilitate future investigations on microbial metabolites and human health.
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