Cancer cachexia - Adopting a systems wide approach

Cancer cachexia results in the death of approximately 2 million people worldwide annually. Despite the impact of this devastating condition, there is limited therapy and no standard of care. Although multiple definitions exist, confusion remains as a true understanding of the biology has not yet been achieved and distinct phases of cachexia have not been examined. Research has mainly focused on weight loss and muscle wasting, but cachexia is increasingly recognized as a multiorgan disorder involving adipose tissue, liver, brain, gut and heart, with systemic inflammation a central unifying feature

GLP-1 receptor stimulation of the lateral parabrachial nucleus reduces food intake: neuroanatomical, electrophysiological, and behavioral evidence.

The parabrachial nucleus (PBN) is a key nucleus for the regulation of feeding behavior. Inhibitory inputs from the hypothalamus to the PBN play a crucial role in the normal maintenance of feeding behavior, because their loss leads to starvation. Viscerosensory stimuli result in neuronal activation of the PBN. However, the origin and neurochemical identity of the excitatory neuronal input to the PBN remain largely unexplored. Here, we hypothesize that hindbrain glucagon-like peptide 1 (GLP-1) neurons provide excitatory inputs to the PBN, activation of which may lead to a reduction in feeding behavior. Our data, obtained from mice expressing the yellow fluorescent protein in GLP-1-producing neurons, revealed that hindbrain GLP-1-producing neurons project to the lateral PBN (lPBN). Stimulation of lPBN GLP-1 receptors (GLP-1Rs) reduced the intake of chow and palatable food and decreased body weight in rats. It also activated lPBN neurons, reflected by an increase in the number of c-Fos-positive cells in this region. Further support for an excitatory role of GLP-1 in the PBN is provided by electrophysiological studies showing a remarkable increase in firing of lPBN neurons after Exendin-4 application. We show that within the PBN, GLP-1R activation increased gene expression of 2 energy balance regulating peptides, calcitonin gene-related peptide (CGRP) and IL-6. Moreover, nearly 70% of the lPBN GLP-1 fibers innervated lPBN CGRP neurons. Direct intra-lPBN CGRP application resulted in anorexia. Collectively, our molecular, anatomical, electrophysiological, pharmacological, and behavioral data provide evidence for a functional role of the GLP-1R for feeding control in the PBN

The tip of the iceberg: a giant pelvic atypical lipoma presenting as a sciatic hernia

BACKGROUND: This case report highlights two unusual surgical phenomena: lipoma-like well-differentiated liposarcomas and sciatic hernias. It illustrates the need to be aware that hernias may not always simply contain intra-abdominal viscera. CASE PRESENTATION: A 36 year old woman presented with an expanding, yet reducible, right gluteal mass, indicative of a sciatic hernia. However, magnetic resonance imaging demonstrated a large intra- and extra-pelvic fatty mass traversing the greater sciatic foramen. The tumour was surgically removed through an abdomino-perineal approach. Subsequent pathological examination revealed an atypical lipomatous tumour (synonym: lipoma-like well-differentiated liposarcoma). The patient remains free from recurrence two years following her surgery. CONCLUSION: The presence of a gluteal mass should always suggest the possibility of a sciatic hernia. However, in this case, the hernia consisted of an atypical lipoma spanning the greater sciatic foramen. Although lipoma-like well-differentiated liposarcomas have only a low potential for recurrence, the variable nature of fatty tumours demands that patients require regular clinical and radiological review

Cognitive architectures as Lakatosian research programmes: two case studies

Cognitive architectures - task-general theories of the structure and function of the complete cognitive system - are sometimes argued to be more akin to frameworks or belief systems than scientific theories. The argument stems from the apparent non-falsifiability of existing cognitive architectures. Newell was aware of this criticism and argued that architectures should be viewed not as theories subject to Popperian falsification, but rather as Lakatosian research programs based on cumulative growth. Newell's argument is undermined because he failed to demonstrate that the development of Soar, his own candidate architecture, adhered to Lakatosian principles. This paper presents detailed case studies of the development of two cognitive architectures, Soar and ACT-R, from a Lakatosian perspective. It is demonstrated that both are broadly Lakatosian, but that in both cases there have been theoretical progressions that, according to Lakatosian criteria, are pseudo-scientific. Thus, Newell's defense of Soar as a scientific rather than pseudo-scientific theory is not supported in practice. The ACT series of architectures has fewer pseudo-scientific progressions than Soar, but it too is vulnerable to accusations of pseudo-science. From this analysis, it is argued that successive versions of theories of the human cognitive architecture must explicitly address five questions to maintain scientific credibility

Predicting the long-term impact of antiretroviral therapy scale-up on population incidence of tuberculosis.

OBJECTIVE: To investigate the impact of antiretroviral therapy (ART) on long-term population-level tuberculosis disease (TB) incidence in sub-Saharan Africa. METHODS: We used a mathematical model to consider the effect of different assumptions about life expectancy and TB risk during long-term ART under alternative scenarios for trends in population HIV incidence and ART coverage. RESULTS: All the scenarios we explored predicted that the widespread introduction of ART would initially reduce population-level TB incidence. However, many modelled scenarios projected a rebound in population-level TB incidence after around 20 years. This rebound was predicted to exceed the TB incidence present before ART scale-up if decreases in HIV incidence during the same period were not sufficiently rapid or if the protective effect of ART on TB was not sustained. Nevertheless, most scenarios predicted a reduction in the cumulative TB incidence when accompanied by a relative decline in HIV incidence of more than 10% each year. CONCLUSIONS: Despite short-term benefits of ART scale-up on population TB incidence in sub-Saharan Africa, longer-term projections raise the possibility of a rebound in TB incidence. This highlights the importance of sustaining good adherence and immunologic response to ART and, crucially, the need for effective HIV preventive interventions, including early widespread implementation of ART

Discrete and fuzzy dynamical genetic programming in the XCSF learning classifier system

A number of representation schemes have been presented for use within learning classifier systems, ranging from binary encodings to neural networks. This paper presents results from an investigation into using discrete and fuzzy dynamical system representations within the XCSF learning classifier system. In particular, asynchronous random Boolean networks are used to represent the traditional condition-action production system rules in the discrete case and asynchronous fuzzy logic networks in the continuous-valued case. It is shown possible to use self-adaptive, open-ended evolution to design an ensemble of such dynamical systems within XCSF to solve a number of well-known test problems

The Relationship Between Financial Distress and Life-Course Socioeconomic Inequalities in Well-Being:Cross-National Analysis of European Welfare States

Objectives. We investigated to what extent current financial distress explains the relationship between life-course socioeconomic position and well-being in Southern, Scandinavian, Postcommunist, and Bismarckian welfare regimes. Methods. We analyzed individuals (n = 18 324) aged 50 to 75 years in the Survey of Health, Ageing, and Retirement in Europe, 2006–2009. Well-being was measured with CASP-12 (which stands for control, autonomy, self-realization, and pleasure) and life satisfaction. We generated a life-course socioeconomic index from 8 variables and calculated multilevel regression models (containing individuals nested within 13 countries), as well as stratified single-level models by welfare regime. Results. Life-course socioeconomic advantage was related to higher well-being; the difference in life satisfaction between the most and least advantaged was 2.09 (95% confidence interval = 1.87, 2.31) among women and 1.65 (95% confidence interval = 1.43, 1.87) among men. The weakest associations were found among Scandinavian countries. Financial distress was associated with lower well-being and attenuated the relationship between life-course socioeconomic position and well-being in all regimes (ranging from 34.26% in Postcommunist to 72.22% in Scandinavian countries). Conclusions. We found narrower inequalities in well-being in the Scandinavian regime. Reducing financial distress may help improve well-being and reduce inequalities

Glue ear, hearing loss and IQ:an association moderated by the child's home environment

BACKGROUND: Glue ear or otitis media with effusion (OME) is common in children and may be associated with hearing loss (HL). For most children it has no long lasting effects on cognitive development but it is unclear whether there are subgroups at higher risk of sequelae. OBJECTIVES: To examine the association between a score comprising the number of times a child had OME and HL (OME/HL score) in the first four/five years of life and IQ at age 4 and 8. To examine whether any association between OME/HL and IQ is moderated by socioeconomic, child or family factors. METHODS: Prospective, longitudinal cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC). 1155 children tested using tympanometry on up to nine occasions and hearing for speech (word recognition) on up to three occasions between age 8 months and 5 years. An OME/HL score was created and associations with IQ at ages 4 and 8 were examined. Potential moderators included a measure of the child's cognitive stimulation at home (HOME score). RESULTS: For the whole sample at age 4 the group with the highest 10% OME/HL scores had performance IQ 5 points lower [95% CI -9, -1] and verbal IQ 6 points lower [95% CI -10, -3] than the unaffected group. By age 8 the evidence for group differences was weak. There were significant interactions between OME/HL and the HOME score: those with high OME/HL scores and low 18 month HOME scores had lower IQ at age 4 and 8 than those with high OME/HL scores and high HOME scores. Adjusted mean differences ranged from 5 to 8 IQ points at age 4 and 8. CONCLUSIONS: The cognitive development of children from homes with lower levels of cognitive stimulation is susceptible to the effects of glue ear and hearing loss

Compact convex sets with prescribed facial dimensions

While faces of a polytope form a well structured lattice, in which faces of each possible dimension are present, this is not true for general compact convex sets. We address the question of what dimensional patterns are possible for the faces of general closed convex sets. We show that for any finite sequence of positive integers there exist compact convex sets which only have extreme points and faces with dimensions from this prescribed sequence. We also discuss another approach to dimensionality, considering the dimension of the union of all faces of the same dimension. We show that the questions arising from this approach are highly nontrivial and give examples of convex sets for which the sets of extreme points have fractal dimension