Immunity and age: living in the past?

Increasing age is associated with a decreasing ability to mediate effective immune responses to newly encountered antigens. It is generally believed that this reflects the age-associated decline in the number, repertoire and function of available naive T cells. Here, we propose that naive T cells become increasingly irrelevant to the immune system, and that responses to newly encountered antigens are progressively dominated by cross-reactive memory T cells as the individual ages. In addition, we propose that the majority, if not all, of the response to newly encountered antigens in the elderly is mediated by cross-reactive memory T cells. This predicts highly stochastic responses to new infections that should vary between individuals, and has important implications for vaccination strategies in the elderly.     

Physiological blushing in social anxiety disorder patients with and without blushing complaints: Two subtypes?

This study investigates whether social anxiety disorder (SAD) patients with blushing complaints show heightened physiological blushing and arousability in social situations than SAD patients without blushing complaints and healthy controls. SAD blushers (n = 32), SAD non-blushers (n = 34), and healthy controls (n = 25) conducted two social tasks. The physiological responses cheek and forehead blood flow, cheek temperature, and skin conductance were recorded, as well as confederates-observed blushing. The SAD blushers showed more physiological blushing (cheek temperature and blood flow) than SAD non-blushers and observers detected this difference. This finding was also present in comparison to the controls, except for blood flow. For blood flow SAD blushers and controls did not differ but SAD non-blushers showed a ‘suppressed response’: a smaller cheek blood flow increase during the interaction and no recovery compared to the other groups. Furthermore, on skin conductance no differences between groups were observed. Discussed is to what extent SAD blushers and SAD non-blushers represent two qualitative distinct subgroups of SAD.     

Racial and ethnic harassment and discrimination: in the eye of the beholder?

The nature, rate, and higher-order relationships among facets of racial/ethnic harassment (REH) and discrimination (RED) were examined across five racial/ethnic groups in a sample of 5,000 US military personnel. Using a hierarchical, multigroup confirmatory factor analysis approach, results suggest that the nature of REH and RED do not differ by race, with behavioral items equally representing REH and RED across the different groups. Further, higher-order relationships among the facets of REH and RED do not vary across race, with a single second-order factor accounting for the relationships. This single factor is theorized to represent a root intergroup prejudice that leads to harassment and discrimination. However, as anticipated, individuals from minority groups generally reported higher levels of REH and RED once measurement equivalence has been established. Together, the results suggest that both intergroup prejudice (which is multidirectional) and racism (which originates in powerful groups against other groups) are operating in REH and RED experiences.     

Heat-shock proteins and the γδ T cell response in virus infections: Implications for autoimmunity

Conclusions Macrophages expressing hsp65 mRNA⁺ and TcR mRNA⁺ lymphocytes are found at high frequency late in the course of the pneumonia induced in mice by human influenza A viruses. The numbers of the two populations increase in parallel, after the time that infectious virus has been cleared from the lung. The range of TcR genes that are detected is consistent with, although not exclusive to, the pattern found by others for hybridoma cell lines that are reactive to hsp65. Secondary infection (in the absence of neutralizing antibody) greatly enhances both the rapidity and the magnitude of this T cell response for mice that are primed with a different type A influenza virus, but not with an influenza B virus. This could be taken to indicate that the initial infection has induced the generation of influenza A virus-specific T cell memory. However, when the primed T cells are depleted from such mice by treatment with mAb to CD4 and CD8, the accumulation of both the hsp65 mRNA⁺ macrophages and the TcR mRNA⁺ lymphocytes is greatly decreased.The results are consistent with the following hypothesis, which is highly speculative and based on limited data. The T cell response that mediates virus clearance induces high levels of hsp65 expression in macrophages, which in turn stimulates the involvement of hsp65-reactive T cells. Lymphokines/cytokines secreted by these T cells then function to maintain macrophage activation, and to retain these macrophages in the respiratory tract after the time that the virus has been eliminated and the T cells are no longer being stimulated. This serves to provide a nonspecific cover to protect the damaged lung from secondary bacterial infection during the process of tissue repair. If this model is correct, any virus-specific T cell response is likely to promote a local hsp65⁺ macrophage/ T cell circuit. Although normally a protective mechanism, such interactions could potentially exacerbate autoreactivity if occurring in sites (e. g., the joint) where inflammatory cells may not be readily cleared by normal, physiological processes.     

Transthyretin and Alzheimer's disease: where in the brain?

Transthyretin (TTR), a carrier protein for thyroxine and retinol in plasma and cerebrospinal fluid (CSF), has been shown to bind the amyloid beta peptide. Accordingly, TTR has been suggested to protect against amyloid beta deposition, a key pathological feature in Alzheimer's disease (AD). Supporting this view are the reduced TTR levels found in CSF of patients with AD, as well as reports of altered TTR expression in the cortex and hippocampus of AD rodent models. Importantly, early characterization of TTR distribution revealed the choroid plexus as the site of TTR synthesis within the brain. To resolve this controversy we used precise laser microdissection technology to assay for TTR mRNA expression. Our results clearly demonstrate that TTR is not produced in the brain parenchyma of wild-type mice nor in two different transgenic mouse models of AD, suggesting that contamination by choroid plexus contributed to the recent results indicating TTR production in various brain regions. The relevance of TTR to AD should now take into consideration TTR production by the choroid plexus and its ability, in the CSF, to sequester the amyloid beta peptide.     

Implications of structural variations in the human sacrum: why is an anatomical classification crucial?

Purpose

An array of diversity in sacral anatomy including lumbosacral transitional variations is commonly found in the general population. These anatomical variations involve alterations in number of sacral segments, auricular surface area, and neural arch dimensions and are associated with biomechanical, surgical and obstetric implications.

Methods

The present study reports screening >300 dried human sacral specimens and grouping them based on the common variations observed specifically in context of the number of sacral segments, position of the auricular surfaces, and type of the neural arch components.

Results

Screening and grouping of the samples presented a five-group classification and coding system that incorporates specific structural characteristic in a sacrum.

Conclusion

The grouping and coding system developed in this study classifies variabilities associated with sacral anatomy along a common-to-rare anatomical spectrum that may provide handy information needed in a clinical, biomechanical, obstetric or medico-legal context.

     

Friendly and dangerous signals: is the tissue in control?

In their own defense, tissues send a panoply of signals that initiate immunity and guide the choice of effector class. T(H)1-T(H)2 and T(reg) is far too simple a representation of the breathtaking variety of the resulting responses.     

Deletions spanning the neurofibromatosis type 1 gene: Implications for genotype-phenotype correlations in neurofibromatosis type 1?

Neurofibromatosis type 1 (NF1) is an autosomal-dominant disorder characterized by abnormalities of tissues predominantly derived from the neural crest. Symptoms are highly variable and severity cannot be predicted, even within families. DNA of 84 unrelated patients with NF1, unselected for clinical features or severity, were screened with intragenic polymorphic repeat markers and by Southern analysis with cDNA probes. Deletions of the entire gene were detected in five patients from four unrelated families. Their phenotype resembled that of five previously reported patients with deletions, including intellectual impairment and dysmorphic features, but without an excessive number of dermal neurofibromas. This report supports the hypothesis that large deletions spanning the entire NF1 gene may lead to a specific phenotype. Hum Mutat 9:458–464, 1997 © 1997 Wiley-Liss, Inc.     

Bone biology and physiology: Implications for novel osteoblastic osteosarcoma treatments?

Healthy bone undergoes a continuous cycle of bone resorption by osteoclasts and formation by osteoblasts. These processes are in turn regulated by developmental sequences involved in differentiation of bone marrow puripotent mesenchymal cells into osteoblasts and mononuclear hemaotpoitic stem cells into osteoclasts. A variety of growth factors and receptors are involved in these maturation sequences. Osteoblast proliferation and inhibition, for example, are highly dependent not only on such factors as bone morphogenic protein and core binding factor a1 (CBFa1), but on intracellular levels of calcium and cAMP. Therefore, agents that affect concentrations of these two compounds may hypothetically play a role in osteoblastic osteosarcoma treatment. Osteoblast proliferation is also under neural control; in particular, the activity of the N-methyl-d-aspartate (NMDA) and alpha adrenergic 1 receptors. Antagonists to these receptors may also hypothetically play a role in osteoblastic osteosarcoma therapy. This article reviews the basic science supporting the putative roles of common, relatively safe but disparate agents-ranging from caffeine and theophylline to dextromethorphan and econazole-in the potential treatment of osteoblastic osteosarcoma.     

Cytokine and anti-cytokine therapy in asthma: ready for the clinic?

Asthma is a common disease with an increasing prevalence worldwide. Up to 10% of these patients have asthma that is refractory to current therapy. This group have a disproportionate use of health care resources attributed to asthma, have significant morbidity and mortality and therefore represent an unmet clinical need. Asthma is a complex heterogeneous condition that is characterized by typical symptoms and disordered airway physiology set against a background of airway inflammation and remodelling. The inflammatory process underlying asthma is co‐ordinated by a cytokine network. Modulating this network with biological therapy presents a new paradigm for asthma treatment. Clinical trials undertaken to date have underscored the complexity of the inflammatory profile and its relationship to the clinical features of the disease and have raised the importance of safety considerations related to these novel therapies. T helper type 2 cytokine blockade remains the most promising strategy, with anti‐interleukin‐5 reducing asthma exacerbations. Although anti‐cytokine therapy is not yet ready for the clinic, the long‐awaited possibility of new treatments for severe asthma is moving ever closer.     

Indian Hospitals and Government in the?Colonial?Andes

This article examines the reception of the early modern hospital among the indigenous people of the Andes under Spanish colonial rule. During the period covered by this study (sixteenth to mid-eighteenth centuries), the hospital was conceived primarily as a manifestation of the sovereign’s paternalistic concern for his subjects’ spiritual well being. Hospitals in the Spanish American colonies were organised along racial lines, and those catering to Indians were meant to complement the missionary endeavour. Besides establishing hospitals in the main urban centres, Spanish colonial legislation instituted hospitals for Indians in provincial towns and in small rural jurisdictions throughout the Peruvian viceroyalty. Indian hospitals often met with the suspicion and even hostility of their supposed beneficiaries, especially indigenous rulers. By conceptualising the Indian hospital as a tool of colonial government, this article investigates the reasons behind its negative reception, the work of adaptation that allowed a few of them to thrive, and the eventual failure of most of these institutions. Keywords and phrases : Hospital, Andes, Peru, Colonial, Government, PoorIn 1567, during his inspection visit to the province of Chucuito, the Spanish official Garci Diez de San Miguel questioned the local ethnic authorities about the conditions of the population under their oversight. The responses repeatedly referred to the numerous and growing payments of tribute and labour that the indigenous people of the province were obliged to provide to the Church, the colonial authorities, and the Spaniards who had settled in the region. The purpose of the inspection visit was to assess the resources of the province, compile the information necessary to set the rate of tribute, and facilitate the speedier and more abundant flow of its population’s contributions in labour, silver, and products to the benefit of the Crown. The voracious colonial extractive programme would be accompanied by measures that would assert the position of the king as protector of the Indians and patron of their evangelisation. Diez de San Miguel asked the curacas (chieftains of indigenous lineage groups) if they thought that a hospital where poor Indians could be treated should be established in the province. While some expressed their agreement, others replied that ‘there was no need for a hospital’. ¹ How should the curacas’ refusal be understood? The rejection of an institution that at least in theory should benefit them seems baffling, although it could be interpreted as a sign of opposition to the colonial order that was attempting to take root. Since in subsequent years hospitals were established not only in this province but also in the rest of the viceroyalty, this article proposes to examine why and how this policy came about and how it was received.As an extensive literature shows, the institution of the hospital was not originally created to address the problem of health, but rather that of poverty. ² Its point of departure and ultimate objectives were fundamentally concerned with spiritual affairs. ³ The hospital offered hospitality to pilgrims and the homeless, and sheltered those who, ill or near death, had urgent need of assistance and guidance to save their souls. The hospital was not a homogeneous institution; under this name were grouped establishments and collective actions that had a number of distinct purposes and rationales for assistance. ⁴ Their motivation was not disinterested, since it began with the premise that good works would receive divine recompense. Exported to the New World, the institution conserved some of these features, but changed its character, inasmuch as its promoters sought to express a bond between the Crown and its subjects as firm as the one between God and his faithful. In their objectives and operation, urban hospitals sought to foreground the role of health, and even that of doctors. I argue that, due to the political implications of these measures as well as for practical reasons, these objectives were difficult to attain. Because it had political and religious ends, and was, moreover, a space where distinct levels of authority and different, even discrepant visions of assistance to the poor and of the form in which it should be administered were articulated, the Indian hospital offers a privileged vantage point from which to observe the methods and institutions of government. Studying the conditions in which hospitals for Indians were established and administered allows us to approach a field of conflict and negotiation where matters of religion, subsistence, and governance overlapped. Using judicial and administrative sources produced by civil and church governments, I focus on hospitals located outside of the viceregal capital between the sixteenth and eighteenth centuries. ⁵