Insights into lysosomal cobalamin trafficking: lessons learned from cblF disease

Vitamin B₁₂ (cobalamin) is essential in animals and humans for metabolism of methylmalonic acid, for the remethylation of homocysteine to methionine and, consequently, for all S-adenosylmethionine-dependent methylation reactions, including DNA synthesis. In man, cobalamin deficiency leads to anemia and neurologic and cognitive impairment. In the cblF inborn error of vitamin B₁₂ metabolism, free vitamin accumulates in lysosomes and cannot be converted to cofactors for mitochondrial methylmalonyl-CoA mutase and cytosolic methionine synthase. Recent work has shown that this defect is caused by mutations in the lysosomal membrane protein LMBD1, which shows significant homology to lipocalin membrane receptors, thereby indicating that LMBD1 is a lysosomal membrane exporter for cobalamin.     

HIV vaccine research in Thailand: lessons learned

Thailand is the only country that has conducted two Phase III efficacy trials and ten other Phase I/II studies using various HIV-1 vaccine constructs. This outstanding record is the result of strong efforts and commitment among various partners, including policy makers, regulators, researchers and foreign collaborators. Recently, it has become apparent that hardly any new HIV/AIDS candidate vaccines are in the pipeline reaching the stage of clinical testing, especially a candidate vaccine that is suitable for Thailand and the surrounding region. However, many lessons learned can be utilized or modified for other vaccine trials, particularly vaccines against other infectious diseases prevalent in developing countries.     

SARS: lessons learned from other coronaviruses

The identification of a new coronavirus as the etiological agent of severe acute respiratory syndrome (SARS) has evoked much new interest in the molecular biology and pathogenesis of coronaviruses. This review summarizes present knowledge on coronavirus molecular biology and pathogenesis with particular emphasis on mouse hepatitis virus (MHV). MHV, a member of coronavirus group 2, is a natural pathogen of the mouse; MHV infection of the mouse is considered one of the best models for the study of demyelinating disease, such as multiple sclerosis, in humans. As a result of the SARS epidemic, coronaviruses can now be considered as emerging pathogens. Future research on SARS needs to be based on all the knowledge that coronavirologists have generated over more than 30 years of research.     

Ethical conflicts in translational genetic research: lessons learned from the eMERGE-III experience

PurposeThe Electronic Medical Records and Genomics (eMERGE) Consortium integrated biorepository-based research with electronic health records (EHR) to return results from large-scale genetic tests to participants and uploaded those data into the EHR. This article explores the ethical issues investigators encountered in that process.MethodsWe conducted in-depth, semistructured interviews with study personnel of the eMERGE-III Consortium sites that returned results.ResultsWe discuss major ethical issues that arose while attempting to return research results from the eMERGE Consortium to individual participants. These included difficulties recontacting those participants who had not explicitly consented to such and disclosing results to many participants with insufficient infrastructure and staff. Investigators reported being driven by a supererogatory clinical impulse.ConclusionAll these issues ultimately derive from ethical conflicts inherent to translational work being done at the interface of research and clinical care. A critical rethinking of this divide is important, but infrastructural support for such work is necessary for an ethically sound rollout of large-scale genetic testing.     

HIT: lessons learned

The peculiar pathogenesis of heparin-induced thrombocytopenia (HIT), involving a "self" antigen-platelet factor 4 (PF4) bound to heparin-and resulting antibody-mediated platelet activation, is a model for thrombosis triggered by drug-induced autoimmunity. The high probability of forming an immune response to heparin, and the highly-variable clinical significance of a positive laboratory test-depending on the type of assay and the magnitude of a given positive test result-provides lessons regarding appropriate interpretation of diagnostic laboratory testing in the context of pretest probability. The relatively high risk of inducing microvascular thrombosis due to coumarin-induced vitamin K antagonism attests to the dangers of a compromised protein C natural anticoagulant system in the setting of a hypercoagulability state such as HIT. Unusual immunologic features of HIT, such as the dissociation between immunogenicity (induction of immune response) and cross-reactivity (capacity to form the antigens recognized by HIT antibodies)of the implicated polysaccharide anticoagulants, and the generally rapid formation and disappearance of anti-PF4/heparin antibodies, suggest that further lessons regarding HIT immunopathogenesis remain to be learned.     

Immunity against cancer: lessons learned from melanoma

Most major advances in human cancer immunology and immunotherapy have come from studies in melanoma. We are beginning to understand the immune repertoire of T cells and antibodies that are active against melanoma, with recent glimpses of the CD4(+) T cell repertoire. The view of what the immune system can see is extending to mutations and parts of the genome that are normally invisible.     

Cytokine reporter mice in immunological research: perspectives and lessons learned

Cytokines are soluble messenger molecules with important regulatory functions throughout the immune system. 'Cytokine reporter' strains express marker molecules under control of elements from cytokine genes allowing for easy identification of their cellular sources. Such systems are well-accepted tools for research of cytokine function. The value of these strains lies in the ability to perform experiments relying on identification and isolation of live cytokine-expressing cells, provided that the reporter faithfully reflects the proper cytokine mRNA and protein production. As more diverse cell subsets are defined by their cytokine expression, the field has adapted with the generation of more sophisticated strains. In this review we summarize the evolution of cytokine detection methods and give examples of knowledge gained using cytokine reporter mice for cell types expressing interferon-γ and interleukin-4, -10 and -17. We also discuss current options for generating such reporter strains and their potential pitfalls.     

Toward cultural competence in cancer genetic counseling and genetics education: lessons learned from Chinese-Australians.

PURPOSE: In societies such as Australia with a strong multicultural makeup, culturally determined attitudes to genetics, testing, and counseling may be incompatible with current genetics service provision. METHODS: An ethnographic investigation using purposive sampling to increase subject diversity was used to explore the range of beliefs about kinship and inheritance using Chinese-Australians as a case. Participants comprised a sample of 15 Chinese-Australians who had been recruited through several community-based organizations. RESULTS: The level of acculturation does not correlate with holding beliefs about inheritance, kinship, and causes of hereditary cancer that are based on "Western" biomedical or traditional concepts. Mismatch between beliefs may exist within families that can impact participation in cancer genetic testing. Family history taking that underpins the surveillance, management, and referral to genetic counseling where there is a strong family history of breast, ovarian, or colorectal cancer can also be impacted unless recognition is made of the patrilineal concept of kinship prevalent in this Chinese-Australian community. CONCLUSION: This community-based study confirmed and validated views and beliefs on inheritance and kinship and inherited cancer attributed to senior family members by Chinese-Australians who attended cancer genetic counseling. Barriers to communication can occur where there may be incompatibility within the family between "Western" and traditional beliefs. The findings were used to develop strategies for culturally competent cancer genetic counseling with Australian-Chinese patients. These include nonjudgmental incorporation of their belief systems into the genetic counseling process and avoidance of stereotyping. They have also influenced the development of genetics education materials to optimize family history taking.     

Molecular pathogenesis of lymphangioleiomyomatosis: lessons learned from orphans

Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials.     

Immunity to intestinal pathogens: lessons learned from Salmonella

Salmonella are a common source of food- or water-borne infection and cause a wide range of clinical disease in human and animal hosts. Salmonella are relatively easy to culture and manipulate in a laboratory setting, and the infection of laboratory animals induces robust innate and adaptive immune responses. Thus, immunologists have frequently turned to Salmonella infection models to expand understanding of host immunity to intestinal pathogens. In this review, I summarize current knowledge of innate and adaptive immunity to Salmonella and highlight features of this response that have emerged from recent studies. These include the heterogeneity of the antigen-specific T-cell response to intestinal infection, the prominence of microbial mechanisms to impede T- and B-cell responses, and the contribution of non-cognate pathways for elicitation of T-cell effector functions. Together, these different issues challenge an overly simplistic view of host–pathogen interaction during mucosal infection, but also allow deeper insight into the real-world dynamic of protective immunity to intestinal pathogens.     

Integrating diversity and fostering interdependence: Ecological lessons learned about refugee participation in multiethnic communities

Communities in the United States are becoming increasingly diverse, in part, because of the continual resettlement of refugees and immigrants from around the world. The promotion of refugees' well‐being and integration depends upon how our communities value diversity and provide opportunities for meaningful involvement. However, refugees often face challenges to such involvement. An ecological perspective suggests that it is important to consider not only the characteristics of individuals but also to examine the extent to which particular settings are able to facilitate the participation of community members. The purpose of this study was to understand the participation experiences of 54 Hmong refugees living in multiethnic housing developments. Interviews revealed that while Hmong residents valued participation highly, most were excluded from meaningful avenues of participation because of multiple barriers, including language differences, time constraints, and discrimination. No supports to address these barriers existed in their communities. It is important to understand and build individuals' capacities to participate and communities' capacities to promote involvement, integrate diversity, and foster interdependence. Participation is fundamental to the process of enabling refugees to become an integral part of their new communities and is a potential way for them to regain a sense of control over their lives and the decisions that affect them. © 2002 Wiley Periodicals, Inc.     

Evaluating recovery from anorexia nervosa and bulimia nervosa: integrating lessons learned from research and clinical practice.

The aims of this article are to critically examine the conceptualization and measurement of recovery, within the eating disorder outcome literature, and suggest possible ways of developing the clinical utility of outcome research. First, definitions and measures of recovery operationalized in outcome studies are critically reviewed, highlighting the variety of definitions and measures used in outcome research. Two important caveats in the outcome literature are identified: absence of clients' views on their recovery from outcome evaluations and dissociation of outcome research from negotiated interpersonal and organizational meanings of recovery. These caveats form the focus of the second section of the article. A need for greater integration between research and clinical perspectives on recovery is identified, and the final section of the article suggests several proposals for enhancing current research on recovery from eating disorders. These proposals particularly advocate development of methods and measures that can accommodate diversity of clients' experiences of recovery, while remaining informative to both researchers and clinicians.     

Innate immunity against moulds: lessons learned from invertebrate models

The emergence over the past two decades of invasive mycoses as a significant problem in immunocompromised patients underscores the importance of deciphering innate immunity against filamentous fungi. However, the complexity and cost of traditionally used mammalian model hosts presents a bottleneck that has limited the rate of advances in this field. In contrast, invertebrate model hosts have several important advantages, including simple immune systems, genetic tractability, and amenity to high-throughput experiments. The application of these models to studies of host-pathogen interactions is contingent on two tenets: (1) host innate defenses are preserved across widely disparate taxa, and (2) similar fungal virulence factors are operative in insects and in mammals. Validation of these principles paved the way for the use of invertebrates as facile models for studying invasive mould infections. These studies have helped shape our understanding of human pattern recognition receptors, phagocytic cell function and antimicrobial proteins, and their roles in host defense against filamentous fungi.