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The microbial basis of inflammatory bowel diseases
Sushila R. Dalal, Eugene B. Chang
Sushila R. Dalal, Eugene B. Chang
Published August 1, 2014
Citation Information: J Clin Invest. 2014. https://doi.org/10.1172/JCI72330.
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The microbial basis of inflammatory bowel diseases

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Abstract

Inflammatory bowel diseases (IBD) are chronic, progressive diseases characterized by aberrant immune responses to environmental and gut microbial triggers in genetically susceptible hosts. Clinical, genetic, and experimental data support the role of gut microbes in causing and sustaining these diseases. Our understanding of IBD has changed dramatically as the result of advances in cultivation-independent approaches and computational platforms for the analysis of large data sets. However, investigations relevant to clinical observations and the natural history of the diseases will be essential for the development of microbial, genetic, and biological metrics that may be used to individualize assessment of risk and improve clinical outcomes in IBD.

Authors

Sushila R. Dalal, Eugene B. Chang

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Clostridium difficile and the microbiota
Anna M. Seekatz, Vincent B. Young
Anna M. Seekatz, Vincent B. Young
Published July 18, 2014
Citation Information: J Clin Invest. 2014. https://doi.org/10.1172/JCI72336.
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Clostridium difficile and the microbiota

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Abstract

Clostridium difficile infection (CDI) is the leading health care–associated illness. Both human and animal models have demonstrated the importance of the gut microbiota’s capability of providing colonization resistance against C. difficile. Risk factors for disease development include antibiotic use, which disrupts the gut microbiota, leading to the loss of colonization resistance and subsequent CDI. Identification of the specific microbes capable of restoring this function remains elusive. Future studies directed at how microbial communities influence the metabolic environment may help elucidate the role of the microbiota in disease development. These findings will improve current biotherapeutics for patients with CDI, particularly those with recurrent disease.

Authors

Anna M. Seekatz, Vincent B. Young

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Deciphering the tête-à-tête between the microbiota and the immune system
Neeraj K. Surana, Dennis L. Kasper
Neeraj K. Surana, Dennis L. Kasper
Published July 18, 2014
Citation Information: J Clin Invest. 2014. https://doi.org/10.1172/JCI72332.
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Deciphering the tête-à-tête between the microbiota and the immune system

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Abstract

The past decade has witnessed an explosion in studies — both clinical and basic science — examining the relationship between the microbiota and human health, and it is now clear that the effects of commensal organisms are much broader than previously believed. Among the microbiota’s major contributions to host physiology is regulation of the development and maintenance of the immune system. There are now a handful of examples of intestinal commensal bacteria with defined immunomodulatory properties, but our mechanistic understanding of how microbes influence the immune system is still in its infancy. Nevertheless, several themes have emerged that provide a framework for appreciating microbe-induced immunoregulation. In this Review, we discuss the current state of knowledge regarding the role of the intestinal microbiota in immunologic development, highlighting mechanistic principles that can guide future work.

Authors

Neeraj K. Surana, Dennis L. Kasper

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Mechanisms of vancomycin resistance in Staphylococcus aureus
Susana Gardete, Alexander Tomasz
Susana Gardete, Alexander Tomasz
Published July 1, 2014
Citation Information: J Clin Invest. 2014;124(7):2836-2840. https://doi.org/10.1172/JCI68834.
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Mechanisms of vancomycin resistance in Staphylococcus aureus

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Abstract

Vancomycin is a glycopeptide antibiotic used for the treatment of Gram-positive bacterial infections. Traditionally, it has been used as a drug of last resort; however, clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) strains with decreased susceptibility to vancomycin (vancomycin intermediate-resistant S. aureus [VISA]) and more recently with high-level vancomycin resistance (vancomycin-resistant S. aureus [VRSA]) have been described in the clinical literature. The rare VRSA strains carry transposon Tn1546, acquired from vancomycin-resistant Enterococcus faecalis, which is known to alter cell wall structure and metabolism, but the resistance mechanisms in VISA isolates are less well defined. Herein, we review selected mechanistic aspects of resistance in VISA and summarize biochemical studies on cell wall synthesis in a VRSA strain. Finally, we recapitulate a model that integrates common mechanistic features of VRSA and VISA strains and is consistent with the mode of action of vancomycin.

Authors

Susana Gardete, Alexander Tomasz

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Uterine NK cells: active regulators at the maternal-fetal interface
Ashley Moffett, Francesco Colucci
Ashley Moffett, Francesco Colucci
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(5):1872-1879. https://doi.org/10.1172/JCI68107.
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Uterine NK cells: active regulators at the maternal-fetal interface

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Abstract

Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternal-fetal immune mechanism that regulates placentation.

Authors

Ashley Moffett, Francesco Colucci

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Emerging therapies for food allergy
Corinne A. Keet, Robert A. Wood
Corinne A. Keet, Robert A. Wood
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(5):1880-1886. https://doi.org/10.1172/JCI72061.
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Emerging therapies for food allergy

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Abstract

Food allergy is a common condition for which there are currently no approved treatments except avoidance of the allergenic food and treatment of accidental reactions. There are several potential treatments that are under active investigation in animal and human studies, but it is not yet clear what the best approach may be. Here, we review approaches that are currently in clinical trials, including oral, sublingual, and epicutaneous immunotherapy, immunotherapy combined with anti-IgE, and Chinese herbal medicine as well as approaches that are in preclinical or early clinical investigation, including modified protein immunotherapy, adjuvants, DNA vaccines, and helminth administration. We discuss the importance of fully exploring the risks and benefits of any treatment before it is taken to general clinical practice and the need for clarity about the goals of treatment.

Authors

Corinne A. Keet, Robert A. Wood

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Harnessing FOXP3+ regulatory T cells for transplantation tolerance
Herman Waldmann, … , Duncan Howie, Stephen Cobbold
Herman Waldmann, … , Duncan Howie, Stephen Cobbold
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(4):1439-1445. https://doi.org/10.1172/JCI67226.
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Harnessing FOXP3+ regulatory T cells for transplantation tolerance

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Abstract

Early demonstrations that mice could be tolerized to transplanted tissues with short courses of immunosuppressive therapy and that with regard to tolerance to self, CD4+FOXP3+ regulatory T cells (Tregs) appeared to play a critical role, have catalyzed strategies to harness FOXP3-dependent processes to control rejection in human transplantation. This review seeks to examine the scientific underpinning for this new approach to finesse immunosuppression.

Authors

Herman Waldmann, Robert Hilbrands, Duncan Howie, Stephen Cobbold

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Recent developments in the treatment of age-related macular degeneration
Frank G. Holz, … , Steffen Schmitz-Valckenberg, Monika Fleckenstein
Frank G. Holz, … , Steffen Schmitz-Valckenberg, Monika Fleckenstein
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(4):1430-1438. https://doi.org/10.1172/JCI71029.
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Recent developments in the treatment of age-related macular degeneration

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Abstract

Age-related macular degeneration (AMD) is a common cause of visual loss in the elderly, with increasing prevalence due to increasing life expectancy. While the introduction of anti-VEGF therapy has improved outcomes, there are still major unmet needs and gaps in the understanding of underlying biological processes. These include early, intermediate, and atrophic disease stages. Recent studies have assessed therapeutic approaches addressing various disease-associated pathways, including complement inhibitors. Drug-delivery aspects are also relevant, as many agents have to be administered repeatedly. Herein, relevant pathogenetic factors and underlying mechanisms as well as recent and potential therapeutic approaches are reviewed.

Authors

Frank G. Holz, Steffen Schmitz-Valckenberg, Monika Fleckenstein

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Multifocal epithelial tumors and field cancerization: stroma as a primary determinant
G. Paolo Dotto
G. Paolo Dotto
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(4):1446-1453. https://doi.org/10.1172/JCI72589.
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Multifocal epithelial tumors and field cancerization: stroma as a primary determinant

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Abstract

It is increasingly evident that cancer results from altered organ homeostasis rather than from deregulated control of single cells or groups of cells. This applies especially to epithelial cancer, the most common form of human solid tumors and a major cause of cancer lethality. In the vast majority of cases, in situ epithelial cancer lesions do not progress into malignancy, even if they harbor many of the genetic changes found in invasive and metastatic tumors. While changes in tumor stroma are frequently viewed as secondary to changes in the epithelium, recent evidence indicates that they can play a primary role in both cancer progression and initiation. These processes may explain the phenomenon of field cancerization, i.e., the occurrence of multifocal and recurrent epithelial tumors that are preceded by and associated with widespread changes of surrounding tissue or organ “fields.”

Authors

G. Paolo Dotto

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Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs
Herbert Y. Meltzer, Bryan L. Roth
Herbert Y. Meltzer, Bryan L. Roth
Published December 2, 2013
Citation Information: J Clin Invest. 2013;123(12):4986-4991. https://doi.org/10.1172/JCI70678.
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Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

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Abstract

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype–selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson’s disease psychosis, respectively.

Authors

Herbert Y. Meltzer, Bryan L. Roth

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