Extending the capability paradigm to address the complexity of disability

Amartya Sen looks at people's well-being in terms of functioning and freedom, rather than in terms of the amount of goods or services consumed. The capability approach, developed by Sen, deals with what people are able to achieve by using these commodities. Concerning disability, he wrote: “We must take note that a disabled person may not be able to do the many things that an able-bodied individual can, with the same bundle of commodities” [Sen, A. K. (1985). Commodities and capabilities. Oxford: Oxford University Press [1999], p. 7]. The capability approach makes it possible to analyse the economic situation of people with disabilities in a different way. What becomes important is their functioning, i.e. what they are able to achieve within a given context. In fact, the capability set includes not only what a person is effectively able to achieve, but also the potential functionings that he/she can choose. This expresses the degree of freedom that a person with disability benefits from in a given environment. The challenge is therefore to reduce the constraints that the environment adds to a person's impairment in order to expand their capability set and to allow them to live a life which they value. This paper reviews the paradigms that address disability and the ways of assessing a person's capability set within this framework. Achieved functionings are easily measured through cross-sectional surveys, using counterfactual analysis to compare the situations of disabled and non-disabled people. This was done in 2005 in Afghanistan when a national disability survey was carried out on a random sample of households. Measuring detailed capabilities, especially their freedom dimension, is quite complex and requires identifying people's potential choices in an ever-changing environment. This implies a need to extend the philosophical framework and to adopt appropriate statistical methodologies.     

The atheroprotective effect of 17beta-estradiol depends on complex interactions in adaptive immunity

Estradiol prevents fatty streak formation in chow-fed atherosclerosis-prone apolipoprotein E (ApoE)-deficient mice. We previously reported that fatty streak development of immunodeficient ApoE(-/-)/recombination activating gene 2 (RAG-2(-/-)) double-deficient mice was insensitive to estradiol. In the present work, we demonstrate that the reconstitution of ApoE(-/-)/RAG-2(-/-) with bone marrow from immunocompetent ApoE(-/-)/RAG-2(+/+) mice restores the protective effect of estradiol on fatty streak constitution. We extended this demonstration to the model of low-density lipoprotein receptor-deficient mice, establishing the obligatory role of mature lymphocytes in this process. We then investigated whether the protective effect of estradiol was mediated by a specific lymphocyte subpopulation by studying the hormonal effect on fatty streak constitution in recently developed models of ApoE(-/-) mice deficient in selective T-lymphocyte subsets (either TCRalphabeta+, CD4+, CD8+, or TCRgammadelta+ lymphocytes) or B lymphocytes. In all these specifically immunodeficient mice, estradiol administration to ovariectomized mice conferred protection as in immunocompetent ApoE(-/-) mice, clearly demonstrating that no single lymphocyte subpopulation was specifically required for this effect. These results point to additional lymphocyte-dependent mechanisms such as modulating the interactions among lymphocytes and between lymphocytes and endothelial and/or antigen-presenting cells.     

Fatal Dieulafoy's type ulcer in a case of gastric AL-amyloidosis

Dieulafoy's ulcer is a particular form of gastric ulcer confined to a persistent caliber artery and may lead to severe hemorrhage. We report a case of fatal gastric bleeding in a woman with benign biclonal gammapathy. Autopsy found a typical Dieulafoy's ulcer centered by a persistent caliber artery which wall was thickened by AL-amyloid deposits. Amyloidosis involved the gastric wall, but also middle caliber arteries of the liver, the lung, the pancreas, the kidney and the myocardium. AL-amyloidosis is a rare and late complication of monoclonal gammapathy and may be asymptomatic. Pathogenesis of Dieulafoy's ulcer remains unclear. In our case, local ischemia may have facilitated gastric ulceration, and amyloid deposits may have contributed to arterial rupture.     

HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation

The supply of naive T cells by the thymus normally requires precursor T cell proliferation within the thymus and would be particularly important in the setting of HIV infection when both naive and memory T cells are progressively depleted. As a robust, quantitative index of intrathymic proliferation, the ratio of different T cell receptor excision circles (TRECs), molecular markers of distinct T cell receptor rearrangements occurring at different stages of thymocyte development, was measured in peripheral blood-mononuclear cells (PBMCs). This ratio has the virtue that it is a "signature" of thymic emigrants throughout their entire life and, thus, can be measured in peripheral cell populations that are easy to obtain. Using the new assay, we evaluated the effect of HIV infection on intrathymic precursor T cell proliferation by longitudinal analysis of PBMCs from recently infected individuals. Our findings reveal a substantial reduction in intrathymic proliferation. The analysis also indicates the existence of a compensatory mechanism acting to sustain the numbers of recent thymic emigrants (RTEs) in the periphery.     

The interferon antagonist sarcolectin in the progress of HIV-1 infection and in AIDS.

Sarcolectin (SCL) is a nonspecific stimulator of cellular DNA synthesis that was found in all animal sera tested to date. It inhibits the established interferon (IFN)-dependent antiviral state, restoring cells to their normal status. In this study, we examined the excretion/secretion of the IFN antagonist SCL in sera from healthy donors and in sera collected during different periods of human immunodeficiency virus type 1 (HIV-1) infection. We followed HIV-1-infected patients during all stages of development (seroconversion, initial and advanced phases of AIDS) and found a significant increase in SCL in sera of HIV-infected patients compared with seronegative subjects used as controls. This increase was established during seroconversion, and then the titers leveled off. In the final stage of the disease, the SCL titer increased again very significantly. We attribute this rapid rise to the virus-dependent destruction of T cells that can no longer be repaired. The high SCL level observed at this final stage, which is most predictive of the disease's progression, suggests that the action, rather than the production, of IFN is impaired.     

High-grade dysplasia and superficial adenocarcinoma in Barrett's esophagus: histological mapping and expression of p53, p21 and Bcl-2 oncoproteins

In order to characterize the early morphological and molecular stages of the neoplastic progression of Barrett's mucosa, we performed the entire histological examination of ten specimens of resected Barrett's esophagus with high-grade dysplasia or superficial adenocarcinoma. The expression of p53, p21 and Bcl-2 proteins was assessed by immunohistochemistry. The surface of Barrett's mucosa ranged from 2.6 cm(2) to 31 cm(2). Dysplasia and adenocarcinoma always developed in specialized mucosa and often occupied small surfaces. High-grade dysplasia was multifocal in eight cases. There was no preferential site for neoplastic transformation into high-grade dysplasia or superficial adenocarcinoma in Barrett's mucosa. Three superficial adenocarcinomas and four high-grade dysplasias overexpressed p53 protein. p21 protein was focally expressed in nondysplastic mucosa and overexpressed in two superficial adenocarcinomas, one high-grade dysplasia and two low-grade dysplasias. In most cases, the expression of p21 and p53 proteins was unrelated. Bcl-2 protein was detected in only one area of low-grade dysplasia. In our study, high-grade dysplasia and superficial adenocarcinoma appeared as tiny lesions, often multifocal for high-grade dysplasia confirming the need for an extensive sampling of Barrett's mucosa in the endoscopic surveillance. p53 dysfunction plays a major role in the progression from dysplasia to carcinoma in Barrett's esophagus and appears unrelated to p21 and Bcl-2 expression.     

LARP7 variants and further delineation of the Alazami syndrome phenotypic spectrum among primordial dwarfisms: 2 sisters

Alazami syndrome (AS) (MIM# 615071) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full lips and abnormally set teeth. We also report significant new findings enabling further delineation of this syndrome: disproportionately mild microcephaly, stereotypic hand wringing and severe anxiety, thickened skin over the hands and feet, and skeletal, eye and heart malformations. From previous reviews, we summarize the main etiologies of PD according to the involved mechanisms and cellular pathways, highlighting their clinical core features.