Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation.

BACKGROUND: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models. METHODS: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin α(4)β(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells. CONCLUSIONS: We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation

Ice loss from the East Antarctic Ice Sheet during late Pleistocene interglacials

Understanding ice sheet behaviour in the geological past is essential for evaluating the role of the cryosphere in the climate system and for projecting rates and magnitudes of sea level rise in future warming scenarios1,2,3,4. Although both geological data5,6,7 and ice sheet models3,8 indicate that marine-based sectors of the East Antarctic Ice Sheet were unstable during Pliocene warm intervals, the ice sheet dynamics during late Pleistocene interglacial intervals are highly uncertain3,9,10. Here we provide evidence from marine sedimentological and geochemical records for ice margin retreat or thinning in the vicinity of the Wilkes Subglacial Basin of East Antarctica during warm late Pleistocene interglacial intervals. The most extreme changes in sediment provenance, recording changes in the locus of glacial erosion, occurred during marine isotope stages 5, 9, and 11, when Antarctic air temperatures11 were at least two degrees Celsius warmer than pre-industrial temperatures for 2,500 years or more. Hence, our study indicates a close link between extended Antarctic warmth and ice loss from the Wilkes Subglacial Basin, providing ice-proximal data to support a contribution to sea level from a reduced East Antarctic Ice Sheet during warm interglacial intervals. While the behaviour of other regions of the East Antarctic Ice Sheet remains to be assessed, it appears that modest future warming may be sufficient to cause ice loss from the Wilkes Subglacial Basin

Influence of age on the control of thyrotropin secretion by thyrotropin-releasing hormone in the male rat

Alterations with age in the control of thyrotropin (TSH) secretion by thyrotropin-releasing hormone (TRH) were evaluated at the hypothalamic and pituitary levels in young (3-5 months) and old (22-24 months) male rats. In the hypothalamus, TRH was quantified in the median eminence and in the mediobasal hypothalamus; in the adenohypophysis the membrane receptors for TRH were evaluated as well as the accumulation of TRH in the gland. As for TSH, its concentration was determined in the anterior pituitary gland and in plasma. In the hypothalamus, the concentration of TRH did not differ between young and old rats in the whole mediobasal hypothalamus, but it was significantly less in the old rats at the level of the median eminence (29.9 +/- 2.8 vs. 52.2 +/- 4.3 ng/mg protein). In the adenohypophysis, the density of receptors for TRH was greater in the old than in the young rats (23.2 +/- 3.2 vs. 13.7 +/- 1.1 fmol MeTRH/mg gland)--with no change in the affinity constant--, and the amount of TRH detected was larger (10.8 +/- 1.8 vs. 2.8 +/- 0.6 pg/mg gland), illustrative of an age-related increase in TRH accumulation in the pituitary gland. The latter results are contrasting with the findings of unchanged pituitary and plasma concentrations of TSH as well as unmodified TSH response to TRH in old rats. The present data concerning TRH and the analogy with previous observations regarding dopamine in old rats are indicative of reduced neuronal activities with age at the hypothalamic level associated with impairments in the processing of the hypothalamic hormones at the pituitary level

Neuroendocrine aspects of aging: experimental data

Aging is characterized by changes in neuroendocrine/endocrine functions which are manifest in female reproductive physiology and less perceptible in other functions such as thyroid, adrenal or growth/metabolic functions. The contribution of each level of the axis - hypothalamus, adenohypophysis or peripheral tissues - is not clearly established. Functional impairments with age are recognized in the peripheral glands (gonad, thyroid, adrenal) as well as in the pituitary, but increasing evidence is accumulating for a marked contribution of the hypothalamus in the age-associated endocrine changes observed in animals and humans. In old rats, multineuronal dysfunctions are demonstrated in the hypothalamus, with a documented decline in the activity of the neurons producing dopamine and thyrotropin-releasing hormone, and to a lesser extent luteinizing hormone- and growth hormone-releasing hormones, and alterations in regulatory mechanisms of these neurons are disclosed. Moreover, impairments are observed in the processing - binding, accumulation and intracellular distribution - of hypothalamic hormones in the adenohypophysis of old rats. Taken together, these observations are supportive of the view that the neuroendocrine/endocrine changes appearing with age result from a complex balance of functional alterations occurring at each level - central and peripheral - of the axis

Assimilating South African medical students trained in Cuba into the South African medical education system: reflections from an identity perspective

Abstract Background In terms of the Nelson Mandela Fidel Castro Medical Collaboration programme, an agreement between the governments of South Africa and Cuba, cohorts of South African students receive their initial five years medical training at a Cuban university before returning to South Africa for a six to twelve months orientation before integration into the local final year class. It is common for these students to experience academic difficulty on their return. Frequently this is viewed merely as a matter of a knowledge deficit. Discussion We argue that the problem arises from a fundamental divergence in the outcomes of the Cuban and South African medical curricula, each of which is designed with a particular healthcare system in mind. Using the discrepancy theory of identity proposed by Higgins in 1987, we discuss the challenges experienced by the returning Nelson Mandela Fidel Castro Medical Collaboration students in terms of a potential crisis of identity and suggest interventions which may prove valuable in promoting academic success and successful integration. Conclusions Though providing additional training to address the gap in skills and knowledge in returning students is an important part of their successful reintegration, this could be insufficient on its own and must be complemented by a range of measures designed to ameliorate the discrepancies in identity which arise from the transition from one educational model to another

Defragmenting resource management on the southeast arm of Lake Malawi : case of fisheries

The Southeast Arm of Lake Malawi catchment has a wide range of natural resources that require prudent management for sustainability and maximisation of benefits. The current management practice is government sector based, with individual Departments and Ministries using their own policies, legislations and management approaches, yet dealing with the same composite resource and user communities. This has resulted in fragmentation of management leading to the lack of alignment between formal and informal institutions, and competition for power and authority for management. Fragmentation is also leading to loss of resource rent. This paper analyses how and why management is fragmented in the Southeast Arm of Lake Malawi catchment and suggests how management could be defragmented, with special interest on fisheries. Activities with high negative impacts on fisheries include: overfishing; soil erosion resulting in siltation and turbidity of the lake; chemical and organic pollution; loss of access to land and beaches; and habitat loss. There is need for a better and more holistic understanding of how human activities represent both livelihood benefits and a threat to sustainability of natural resources in order to find ways for balancing these two aspects. We suggest that to increase the efficacy of management of Lake Malawi’s Southeast Arm will require ‘defragmented decentralization’, an approach whereby devolution of authority and responsibility are ceded to the district and local levels, respectively

Fisheries co-management institutions in Southern Africa: A hierarchical analysis of perceptions of effectiveness

A random sample attitude survey concluded a ten-year research effort on fisheries co-management that was carried out in Malawi, Mozambique and Zambia. The survey responses were analyzed using a two-level hierarchical model that allowed conclusions about village-level institutions to be based on individual-level survey responses. The present paper describes the surveys background, methodology, and conclusions. Three of these conclusions are very clear from the survey results. The first is that co-management that is more responsive to the community is more effective. The second is that co-management institutions made up mainly of fishers are more effective than ones that incorporate a broad range of stakeholders. The third is that local conservation efforts being seen as making a positive contribution to village life is unrelated to their being seen as rule enforcement mechanisms