Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

Sonication of removed breast implants for improved detection of subclinical infection.

BACKGROUND: Capsular fibrosis is a severe complication after breast implantation with an uncertain etiology. Microbial colonization of the prosthesis is hypothesized as a possible reason for the low-grade infection and subsequent capsular fibrosis. Current diagnostic tests consist of intraoperative swabs and tissue biopsies. Sonication of removed implants may improve the diagnosis of implant infection by detachment of biofilms from the implant surface. METHODS: Breast implants removed from patients with Baker grades 3 and 4 capsular contracture were analyzed by sonication, and the resulting sonication fluid was quantitatively cultured. RESULTS: This study investigated 22 breast implants (6 implants with Baker 3 and 16 implants with Baker 4 capsular fibrosis) from 13 patients. The mean age of the patients was 49 years (range, 31-76 years). The mean implant indwelling time was 10.4 years (range, 3 months to 30 years). Of the 22 implants, 12 were used for breast reconstruction and 10 for aesthetic procedures. The implants were located subglandularly (n = 12), submuscularly (n = 6), and subcutaneously (n = 4). Coagulase-negative staphylococci, Propionibacterium acnes, or both were detected in the sonication fluid cultures of nine implants (41%), eight of which grew significant numbers of microorganisms (>100 colonies/ml of sonication fluid). CONCLUSIONS: Sonication detected bacteria in 41% of removed breast implants. The identified bacteria belonged to normal skin flora. Further investigation is needed to determine any causal relation between biofilms and capsular fibrosis.

Altruismo y solidaridad en el estado de bienestar

La hipótesis central de este trabajo plantea una relación causal entre las motivaciones altruistas y solidarias, y los Estados de Bienestar; concretamente, en la misma se esboza una relación causal bidireccional entre estas dos dimensiones: por una parte, el altruismo y la solidaridad se presentan como dos de los factores sociales que posibilitan la existencia de los Estados de Bienestar, y fomentan su mantenimiento y desarrollo; por otra parte, los Estados de Bienestar pueden generar, a su vez, un mayor nivel de motivaciones y conductas de este tipo.

Controversies about a common etiology for eating and mood disorders.

Obesity and depression represent a growing health concern worldwide. For many years, basic science and medicine have considered obesity as a metabolic illness, while depression was classified a psychiatric disorder. Despite accumulating evidence suggesting that obesity and depression may share commonalities, the causal link between eating and mood disorders remains to be fully understood. This etiology is highly complex, consisting of multiple environmental and genetic risk factors that interact with each other. In this review, we sought to summarize the preclinical and clinical evidence supporting a common etiology for eating and mood disorders, with a particular emphasis on signaling pathways involved in the maintenance of energy balance and mood stability, among which orexigenic and anorexigenic neuropeptides, metabolic factors, stress responsive hormones, cytokines, and neurotrophic factors.

Criptosporidiose em crianças de 1 a 2 anos de idade, com diarréia aguda em Belém, Pará, Brasil

Num período de 12 meses, 201 espécimes fecais de 61 crianças foram examiandos com vista a detecção de Cryptosporidium. Cento e quinze espécimes foram obtidos durante os episódios diarréicos e 86 de crianças sem diarréia (grupo controle). Todos os espécimes fecais foram examinados pelo método de coloração de Ziehl-Neelsen modificado. Cryptosporidum foi identificado em seis (5,2%) das 115 amostras das crianças com diarréia. Em nenhum dos controles foi obtida a presença desse parasito. O presente estudo sugere que o Cryptosporidium é um agente causal de diarréia auto-limitada em crianças imunocompetentes em Belém, Pará.

Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family.

NR2E3, a photoreceptor-specific nuclear receptor (PNR), represses cone-specific genes and activates several rod-specific genes. In humans, mutations in NR2E3 have been associated with the recessively-inherited enhanced short-wavelength sensitive S-cone syndrome (ESCS) and, recently, with autosomal dominant (ad) retinitis pigmentosa (RP) (adRP). In the present work, we describe two additional families affected by adRP that carry a heterozygous c.166G>A (p.G56R) mutation in the NR2E3 gene. Functional analysis determined the dominant negative activity of the p.G56R mutant protein as the molecular mechanism of adRP. Interestingly, in one pedigree, the most common causal variant for ESCS (p.R311Q) cosegregated with the adRP-linked p.G56R mutation, and the compound heterozygotes exhibited an ESCS-like phenotype, which in 1 of the 2 cases was strikingly "milder" than the patients carrying the p.G56R mutation alone. Impaired repression of cone-specific genes by the corepressors atrophin-1 (dentatorubral-pallidoluysian atrophy [DRPLA] gene product) and atrophin-2 (arginine-glutamic acid dipeptide repeat [RERE] protein) appeared to be a molecular mechanism mediating the beneficial effect of the p.R311Q mutation. Finally, the functional dominance of the p.R311Q variant to the p.G56R mutation is discussed.

Paper de l’agmatina i les poliamines en el fracàs renal d’animals diabètics

Projecte de recerca elaborat a partir d’una estada a la University of California, Estats Units entre febrer i maig de 2007. L’arginina és un component de les proteïnes i juga un paper important en respostes inflamatòries. S’ha demostrat que l’agmatina pot inhibir el creixement mitjançant la supressió de la biosíntesi i el transport de poliamines. Actualment s’està avaluant el mecanisme de l’aturada d’aquest creixement. S’està estudiant també l’impacte en l’apoptosi i la senescència, ja que els models apoptòtics impliquen un descens de poliamines com a factor comú i causal d’apoptosi. En la diabetis el ronyó creix i l’índex de filtració glomerular esdevé supranormal. Aquest creixement renal precoç és considerat una resposta compensatòria a l’increment de la càrrega hiperfiltrada. Nosaltres considerem que aquesta hiperfiltració glomerular diabètica es deguda a esdeveniments que ocorren en el creixement del túbul proximal, i en aquest creixement hi poden estar involucrades les poliamines.

Effect of rufinamide on gating properties of voltage-gated sodium channel Na(v)1.7

Background: Voltage-gated sodium channels (Nav1.x) are important players in chronic pain. A particular interest has grown in Nav1.7, expressed in nociceptors, since mutations in its gene are associated to two inherited pain syndromes or insensitivity to pain. Rufinamide, a drug used to treat refractory epilepsy such as the Lennox-Gastaut syndrome, has been shown to reduce the number of action potentials in cortical neurons without completely blocking Na channels. Aim: The goal of this study was to investigate the effect of rufinamide on Nav1.7 current. Methods and results: Whole-cell patch clamp experiments were performed using HEK293 cells stably expressing Nav1.7. Rufinamide significantly decreased peak sodium current by 28.3, 21.2 and 12.5% at concentrations of 500, 100 and 50μM respectively (precise EC50 could not be calculated since higher rufinamide concentrations could not be achieved in physiological buffer solution). No significant difference on the V1/2 of voltage-dependence of activation was seen; however a shift in the steady-state inactivation curve was observed (-82.6 mV to -88.8 mV and -81.8 to -87.6 mV for 50 and 100 μM rufinamide respectively, p <0.005). Frequency-dependent inhibition of Nav1.7 was also influenced by the drug. One hundred μM rufinamide reduced the peak sodium current (in % of the peak current taken at the first sweep of a train of 50) from 90.8 to 80.8% (5Hz), 88.7 to 71.8% (10 Hz), 69.1 to 49.2% (25 Hz) and 22.3 to 9.8% (50 Hz) (all p <0.05). Onset of fast inactivation was not influenced by the drug since no difference in the time constant of current decay was observed. Conclusion: In the concentration range of plasma level in human treated for epilepsy, 15 μM, rufinamide only minimally blocks Nav1.7. However, it stabilizes the inactivated state and exerts frequencydependent inhibition of Nav1.7. These pharmacological properties may be of use in reducing ectopic discharges as a causal and symptom related contributor of neuropathic pain syndrome.

Inflation Uncertainty, Exchange Rate Depreciation and Volatility: Evidence from Ghana, Mozambique and Tanzania

While flexible exchange rates facilitate stabilisation, exchange rate fluctuations can cause real volatility. This gives policy importance to the causal relationship between exchange rate depreciation and its volatility. An exchange rate may be expected to become more volatile when the underlying currency loses value. We conjecture that a reverse causation, which further weakens the currency, may be mitigated by price stability. Data from Ghana, Mozambique and Tanzania support this: depreciation makes exchange rate more volatile for all but volatility does not causes depreciation in Tanzania which has enjoyed a more stable inflation despite all countries adopting similar macro-policies since early 1990s.

Where is the economics in spatial econometrics?

Spatial econometrics has been criticized by some economists because some model specifications have been driven by data-analytic considerations rather than having a firm foundation in economic theory. In particular this applies to the so-called W matrix, which is integral to the structure of endogenous and exogenous spatial lags, and to spatial error processes, and which are almost the sine qua non of spatial econometrics. Moreover it has been suggested that the significance of a spatially lagged dependent variable involving W may be misleading, since it may be simply picking up the effects of omitted spatially dependent variables, incorrectly suggesting the existence of a spillover mechanism. In this paper we review the theoretical and empirical rationale for network dependence and spatial externalities as embodied in spatially lagged variables, arguing that failing to acknowledge their presence at least leads to biased inference, can be a cause of inconsistent estimation, and leads to an incorrect understanding of true causal processes.

Acute infantile encephalopathy predominantly affecting the frontal lobe (AIEF): A European case.

Acute infantile encephalopathy predominantly affecting the frontal lobes (AIEF) has been described as a new entity, based on MRI findings (acute abnormal diffusion-weighted imaging signals in the frontal lobes followed by atrophy) and exclusion of other acute encephalopathies. Patients present with acute onset of fever, status epilepticus, and coma. Different causal mechanisms have been suggested such as localized viral infection, toxic insult due to cytokines, or postictal damage. Only children of Japanese descent have been described. We report the case of a Caucasian girl whose history and MRI findings were similar to the Japanese cases. She had a massive regression with verbal apraxia, while cognitive development was less affected; she initially presented with a cluster of complex partial seizures (and not convulsive status epilepticus), making epileptic or post anoxic-ischemic sequelae highly unlikely. The place of this proposed entity among other recently described acute encephalopathies with abnormal diffusion on MRI is discussed.

Sharp Bounds on Heterogeneous Individual Treatment Responses

This paper discusses how to identify individual-specific causal effects of an ordered discrete endogenous variable. The counterfactual heterogeneous causal information is recovered by identifying the partial differences of a structural relation. The proposed refutable nonparametric local restrictions exploit the fact that the pattern of endogeneity may vary across the level of the unobserved variable. The restrictions adopted in this paper impose a sense of order to an unordered binary endogeneous variable. This allows for a uni.ed structural approach to studying various treatment effects when self-selection on unobservables is present. The usefulness of the identi.cation results is illustrated using the data on the Vietnam-era veterans. The empirical findings reveal that when other observable characteristics are identical, military service had positive impacts for individuals with low (unobservable) earnings potential, while it had negative impacts for those with high earnings potential. This heterogeneity would not be detected by average effects which would underestimate the actual effects because different signs would be cancelled out. This partial identification result can be used to test homogeneity in response. When homogeneity is rejected, many parameters based on averages may deliver misleading information.

Nominal Stability and Financial Globalization

Over the past four decades, advanced economies experienced a large growth in gross external portfolio positions. This phenomenon has been described as Financial Globalization. Over roughly the same time frame, most of these countries also saw a substantial fall in the level and variability of inflation. Many economists have conjectured that financial globalization contributed to the improved performance in the level and predictability of inflation. In this paper, we explore the causal link running in the opposite direction. We show that a monetary policy rule which reduces inflation variability leads to an increase in the size of gross external positions, both in equity and bond portfolios. This appears to be a robust prediction of open economy macro models with endogenous portfolio choice. It holds across different modeling specifications and parameterizations. We also present preliminary empirical evidence which shows a negative relationship between inflation volatility and the size of gross external positions.

Coordination in Public Good Provision: How Individual Volunteering is Impacted by the Volunteering of Others

In this analysis, we examine the relationship between an individual's decision to volunteer and the average level of volunteering in the community where the individual resides. Our theoretical model is based on a coordination game , in which volunteering by others is informative regarding the benefit from volunteering. We demonstrate that the interaction between this information and one's private information makes it more likely that he or she will volunteer, given a higher level of contributions by his or her peers. We complement this theoretical work with an empirical analysis using Census 2000 Summary File 3 and Current Population Survey (CPS) 2004-2007 September supplement file data. We control for various individual and community characteristics, and employ robustness checks to verify the results of the baseline analysis. We additionally use an innovative instrumental variables strategy to account for reflection bias and endogeneity caused by selective sorting by individuals into neighborhoods, which allows us to argue for a causal interpretation. The empirical results in the baseline, as well as all robustness analyses, verify the main result of our theoretical model, and we employ a more general structure to further strengthen our results.

Effects of Experience, Knowledge and Signals on Willingness to Pay for a Public Good

This paper compares how increases in experience versus increases in knowledge about a public good affect willingness to pay (WTP) for its provision. This is challenging because while consumers are often certain about their previous experiences with a good, they may be uncertain about the accuracy of their knowledge. We therefore design and conduct a field experiment in which treated subjects receive a precise and objective signal regarding their knowledge about a public good before estimating their WTP for it. Using data for two different public goods, we show qualitative equivalence of the effect of knowledge and experience on valuation for a public good. Surprisingly, though, we find that the causal effect of objective signals about the accuracy of a subject’s knowledge for a public good can dramatically affect their valuation for it: treatment causes an increase of $150-$200 in WTP for well-informed individuals. We find no such effect for less informed subjects. Our results imply that WTP estimates for public goods are not only a function of true information states of the respondents but beliefs about those information states.