Clinical evidence of interaction between itraconazole and nonnucleoside reverse transcriptase inhibitors in HIV-infected patients with disseminated histoplasmosis.

BACKGROUND: Itraconazole is the preferred drug for chronic maintenance therapy in HIV-infected patients with disseminated histoplasmosis. Unfortunately, few clinical data exist confirming a presumed interaction between itraconazole and nonnucleoside reverse transcriptase inhibitors (NNRTIs). OBJECTIVE: To determine whether serum itraconazole concentrations are affected by the type of antiretroviral therapy (NNRTI or protease inhibitor [PI]) being taken concomitantly. METHODS: This retrospective cohort identified patients on antiretroviral therapy and itraconazole for disseminated histoplasmosis between January 2003 and December 2006 at a large HIV clinic in Houston, TX. Available laboratory values were abstracted from medical records. RESULTS: Thirteen itraconazole concentrations from 10 patients were available for analysis: 7 patients were on concomitant PIs, 4 on concomitant NNRTIs, and 2 on antiretroviral regimens containing both PIs and NNRTIs. Six of the itraconazole concentrations during concomitant PI treatment were therapeutic (>1.0 microg/mL), in contrast with none in patients taking an NNRTI. All patients taking concomitant NNRTIs had undetectable serum itraconazole concentrations (<0.05 microg/mL). Two patients switched from NNRTI-based to PI-based antiretroviral regimens and subsequently reached therapeutic itraconazole concentrations. Although limited by small sample size, this study provides the largest clinical data among HIV-infected patients demonstrating that coadministration of an NNRTI and itraconazole results in significant decreases in itraconazole blood concentrations, likely by inducing the CYP3A4 enzyme system. CONCLUSIONS: Itraconazole concentrations should be monitored in patients taking concomitant NNRTIs. PI-based highly active antiretroviral therapy (HAART) may be preferred over NNRTI-based HAART when itraconazole is used to treat HIV-infected patients with disseminated histoplasmosis.

Evaluation of cross-protection by immunization with an experimental trivalent companion animal periodontitis vaccine in the mouse periodontitis model.

Companion animal periodontal disease is one of the most prevalent diseases seen by veterinarians. The goal of this study was to evaluate the vaccine performance of a trivalent canine periodontitis vaccine in the mouse oral challenge model of periodontitis. Mice vaccinated subcutaneously with an inactivated, whole-cell vaccine preparation of Porphyromonas denticanis, Porphyromonas gulae, and Porphyromonas salivosa displayed significantly reduced alveolar bone loss in response to heterologous and cross-species challenges as compared to sham vaccinated animals. Based on the results of these studies, a periodontitis vaccine may be a useful tool in preventing the initiation and progression of periodontitis caused by the most commonly isolated pigmenting anaerobic bacteria in animals.

Transfer of Bacteroides splanchnicus to Odoribacter gen. nov. as Odoribacter splanchnicus comb. nov., and description of Odoribacter denticanis sp. nov., isolated from the crevicular spaces of canine periodontitis patients.

Numerous novel anaerobic bacteria were isolated from the crevicular spaces of dogs with periodontitis. The phenotypic characteristics of these bacterial isolates indicated that they were similar to members of the genus Porphyromonas. However, comparison of the 16S rRNA gene sequences of the isolates indicated that they were related to members of the Bacteroides splanchnicus subgroup. A representative of the novel isolates, strain B106(T), induced alveolar bone loss in a mouse model of experimental periodontal disease. Based on biochemical, morphological, molecular phylogenetic, and pathogenic evidence, it is proposed that the taxonomic subgroup containing these novel isolates and B. splanchnicus should be classified in a new genus, Odoribacter gen. nov., within the family 'Porphyromonadaceae'. In addition, it is proposed that B. splanchnicus should be reclassified as Odoribacter splanchnicus comb. nov., and that the newly identified isolates should be classified as representing Odoribacter denticanis sp. nov., the type strain of which is B106(T) (=ATCC PTA-3625(T)=CNCM I-3225(T)).

An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor-dependent signals.

IL-17 and its receptor are founding members of a novel family of inflammatory cytokines. IL-17 plays a pathogenic role in rheumatoid arthritis (RA)-associated bone destruction. However, IL-17 is also an important regulator of host defense through granulopoiesis and neutrophil trafficking. Therefore, the role of IL-17 in pathogen-initiated bone loss was not obvious. The most common form of infection-induced bone destruction occurs in periodontal disease (PD). In addition to causing significant morbidity, PD is a risk factor for atherosclerotic heart disease and chronic obstructive pulmonary disease (COPD). Similar to RA, bone destruction in PD is caused by the immune response. However, neutrophils provide critical antimicrobial defense against periodontal organisms. Since IL-17 is bone destructive in RA but a key regulator of neutrophils, we examined its role in inflammatory bone loss induced by the oral pathogen Porphyromonas gingivalis in IL-17RA-deficient mice. These mice showed enhanced periodontal bone destruction, suggesting a bone-protective role for IL-17, reminiscent of a neutrophil deficiency. Although IL-17RA-deficient neutrophils functioned normally ex vivo, IL-17RA knock-out (IL-17RA(KO)) mice exhibited reduced serum chemokine levels and concomitantly reduced neutrophil migration to bone. Consistently, CXCR2(KO) mice were highly susceptible to alveolar bone loss; interestingly, these mice also suggested a role for chemokines in maintaining normal bone homeostasis. These results indicate a nonredundant role for IL-17 in mediating host defense via neutrophil mobilization.

Temporal and postural variation of 12-lead high-frequency QRS electrocardiographic signals in asymptomatic individuals.

Because changes in the 12-lead high-frequency QRS electrocardiogram (HF QRS ECG) more sensitively identify myocardial ischemia than do changes in the ST segments of the conventional ECG, it is important that changes in HF QRS signals that are merely physiological be distinguishable from those that are potentially pathological. We therefore studied the temporal variation of HF QRS measures such as root mean square (RMS) voltage and the presence vs absence of reduced amplitude zones (RAZs) in 107 asymptomatic individuals in the supine position during a brief period of ECG monitoring. In addition, to ascertain the effects of posture on the 12-lead HF QRS ECG, we collected additional seated data from 25 of these individuals and estimated the fifth and 95th percentile of the percent relative change between the supine and seated measurements. In all cases, variation of HF QRS parameters decreased as the number of beats in the signal average increased. For example, in the supine position, the 95th percentile of the percent relative change between consecutive within-lead measurements of RMS voltage for a 50-beat signal average was 12.3% but decreased to 11.7%, 11.2%, and 10.7% for 75, 100, and 150 beat signal averages, respectively (P < .01). After transition from the supine to the seated upright position, changes in some measures of HF QRS were statistically significant, with RMS voltage decreasing significantly in lead V3 and with the number of RAZs lost in the 12-lead HF QRS ECG significantly exceeding the number of RAZs gained. We conclude that most measures of HF QRS ECG are sufficiently stable for routine continuous monitoring.

Evaluation of a monovalent companion animal periodontal disease vaccine in an experimental mouse periodontitis model.

Periodontal disease in companion animals is clinically similar to that of human periodontal disease. Despite the usage of veterinary procedures and antibiotic therapy, the disease still remains as one of the most highly prevalent disorders seen by veterinarians. The goal of this study was to evaluate the immunogenic properties and vaccine performance of a monovalent canine periodontal disease vaccine in the mouse oral challenge model of periodontitis. Mice vaccinated subcutaneously with inactivated, whole-cell bacterin preparations of Porphyromonas gulae displayed both high titers of anti-P. gulae specific antibodies and significantly reduced alveolar bone loss in response to homologous, heterologous, and cross-species challenge. Based on the results of these studies, a periodontal disease vaccine may be a useful tool in preventing the progression of periodontitis in animals.

Pigmented-anaerobic bacteria associated with canine periodontitis.

The etiology of human periodontal disease has been the focus of considerable research, yet relatively little is known about the causative agents of companion animal periodontitis. In humans, Porphyromonas gingivalis, a black-pigmented anaerobic bacteria (BPAB), has been implicated as the primary periopathogen. It has been demonstrated that BPAB are also found in companion animal periodontal pockets. While some animal BPAB have been individually identified, a study to identify the most frequently isolated subgingival BPAB has not been completed using genetic tools. The objective of this work was to identify the types and relative frequencies of pigmented anaerobic bacteria found in the periodontal pockets of dogs. Porphyromonas salivosa, Porphyromonas denticanis (a novel species) and Porphyromonas gulae were found to be the most frequently isolated BPAB associated with canine periodontitis.