PubMed Health⌕ Search

Biomedical subjects

Patricia Cristofaro

Publications and source records attributed to Patricia Cristofaro.

7 recordsLinked to original sources
PubMed2006

Engineering mucosal RNA interference in vivo.

Mucosal surfaces serve as a gateway to disease. Here, we demonstrate that RNA interference can be used to manipulate mucosal gene expression in vivo. Using a murine model, we show that direct application of liposome-complexed siRNA mediates gene-specific silencing in cervicovaginal and rectal mucosa. A single vaginal or rectal administration of siRNA targeting hematopoietic or somatic cell gene products reduced corresponding mRNA levels by up to 90%. Using a murine model of inflammatory bowel disease, we found that the rectal application of siRNA targeting TNF-alpha led to relative mucosal resistance to experimental colitis. Liposomal siRNA formulations proved nontoxic, did not elicit a nonspecific interferon response, and provide a means for genetic engineering of mucosal surfaces in vivo.

Animals↗
PubMed2006

Role of Toll-like receptors in infection and immunity: clinical implications.

The remarkable discovery of the Toll-like receptors (TLRs) over the past 5 years has opened up an entirely new era in the understanding of the molecular events that initiate the inflammatory response. These type 1 transmembrane receptors are expressed on a large number of immune cells as well as epithelial cells and play an essential role in the activation of the innate immune response to microbial pathogens. They impact on adaptive immune reactions and contribute to the initiation and maintenance of the inflammatory response to a multitude of potential microbial pathogens through recognition of pathogen-associated molecular patterns. TLRs also interact with a variety of endogenous human ligands and influence the activity of a wide range of tissues and cell processes. Among the common and important processes in which TLRs play a role are asthma, acute respiratory distress syndrome, cardiac ischaemia, coronary artery disease, ventricular remodelling, vascular collapse, inflammatory bowel disease, acute tubular necrosis, psoriasis, rheumatoid arthritis, pre-term birth, fertility, cancer angiogenesis and transplant rejection. From this strikingly diverse list, many important opportunities for disease modification through TLR manipulation can be imagined. Their role as potential targets for therapeutic intervention is just beginning to be appreciated, and the current status of these treatment strategies is reviewed in this article.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Penicillium marneffei infection in HIV-infected travelers.

Disseminated Penicillium marneffei infection is the third most common AIDS-defining illness in parts of Southeast Asia. A review of the literature now shows that penicilliosis may represent an emergent opportunistic infection in HIV-positive travelers to endemic regions as well.

Comment↗
PubMed2005

The activity of pathway-selective estrogen receptor ligands in experimental septic shock.

Estrogen receptors (ER) are widely expressed in multiple genital and nongenital tissues. Upon engagement of these receptors, multiple genes are affected in target tissues via estrogen response elements. Nonsteroidal pathway-selective ER ligands have recently been identified that inhibit NF-kappaB transcriptional activity and are devoid of conventional estrogenic activities on genital tissues. These pathway-selective ligands are potent anti-inflammatory agents in vivo and may prove to be of therapeutic utility in systemic inflammatory states. These pathway-selective ER ligands were tested in the murine listeriosis model, the neutropenic rat model, and the mouse cecal ligation and puncture model. WAY-204688 did not have any significant activity after systemic infection by Listeria monocytogenes. In the neutropenic rat model, WAY-204688 provided a significant survival benefit against an otherwise lethal challenge of Pseudomonas aeruginosa 12.4.4 compared with the control group (88% versus 25% survival; P < 0.05). Preservation of mucosal weight and prevention of histopathologic changes were observed with the administration of WAY-204688. Similar findings were observed in a cecal ligation and puncture model with WAY-204688 and a related compound WAY-169916. These results indicate that oral administration of these pathway-selective ER ligands preserved gastrointestinal barrier function and improve outcome in experimental models of systemic infection and inflammation. These agents may prove to be useful clinically as a novel treatment strategy for severe sepsis.

Administration, Oral↗
PubMed2004

Chloroquine enhances survival in Bacillus anthracis intoxication.

The intentional release of anthrax in the United States in 2001 resulted in 11 cases of inhalational disease, with an attendant mortality rate of 45%. Current therapeutic options for anthrax are limited; antimicrobials target only replicating organisms, thus allowing bacterial toxins to cause unchecked, devastating physiological derangements in the host. Novel approaches that target the cytotoxic effects of anthrax exotoxins are needed. Chloroquine (CQ), a commonly used antimalarial agent, endows anthrax-intoxicated murine peritoneal macrophages with a 50% and 35% marginal survival advantage at 2 and 4 h, respectively, over that of untreated control cells. The cell rescue is dose dependent and, at lower concentrations, results in delayed cell death. We subsequently studied the effect of CQ in BALB/c mice challenged with anthrax lethal toxin. CQ-treated mice demonstrated reduced tissue injury, as assessed by histopathological examination of the spleen and by peripheral blood differential cell count ratios. CQ significantly enhanced survival and may augment current treatment and prophylaxis options for this otherwise lethal infection.

Animals↗
PubMed2003

The Toll-like receptors and their role in septic shock.

The Toll-like receptors (TLRs) are a class of pattern recognition molecules with unique functions in the innate and the acquired immune systems. The innate immune response has evolved as the immediate host defence system in response to foreign structures and it also serves to prime the adaptive immune response. As such, the TLRs set the tone and pace of the inflammatory response that follows initial contact with a microbial pathogen over the course of the following minutes, hours and days. Sepsis, a leading cause of death in critically ill patients worldwide, is defined as 'the systemic inflammatory response syndrome that occurs during infection' [1]; that is, sepsis is the orchestration of the events controlled by the gene products triggered by signals transduced through the TLRs. Through analysis of the human genome, ten TLRs have been identified, and several of them have been characterised with respect to their associated ligands. Following engagement of the cognate ligand to the ectodomain of each TLR, the assembly of intracellular homo- or heterodimers or multimers induces cell signalling. The receptors are variably expressed on different types of cells, such as neutrophils, dendritic cells, lymphocytes, endothelial cells etc. and can be up- and downregulated, blocked or triggered by mimetic substances. By controlling or modifying TLR responses, the trajectory of the entire septic process may be modified. This review covers the events responsible for TLR activation in detail, with an emphasis on possible points of pharmacological intervention.

Animals↗