Multiple myeloma and pulmonary aspergillosis: dental treatment prior to chemotherapy and management of post extraction complications.

This case study discusses the dental management of a patient with a history of multiple myeloma and pulmonary aspergillosis, whom was referred to a hospital-based dental service for urgent dental review. The patient had received a dental assessment in primary care prior to commencement of chemotherapy and had four teeth extracted without complications. However, following the commencement of chemotherapy, he presented with a significant infection associated with two of his wisdom teeth resulting in extraction. Despite atraumatic extraction, the upper right wisdom tooth socket developed an oroantral fistula. A multidisciplinary team approach was required to enable effective patient management in this complex patient regarding myeloma, aspergillosis and the medications used including bisphosphonates and chemotherapy. It highlights the higher risk of oral complications that can arise in myelosuppressed patients and emphasises the need to identify potential sources of dental infection prior to the commencement of chemotherapy.

Granulomatosis with polyangiitis: potentially lethal gingival lesions presenting to the dentist.

Gingival pathology is a daily presentation, however a small number of systemic conditions can manifest similar to a common gingival condition and have fatal results. Dentist referred 56-year-old woman to Oral and Maxillofacial Surgery department with a 2-week medical history of gingival bleeding not responding to local measures. Biopsy showed eosinophilic infiltrate and vasculitis, and blood tests showed positive markers including cytoplasmic antineutrophil cytoplasmatic antibodies. Granulomatosis with polyangiitis is a rare disease affecting the respiratory tract, blood vessels and kidneys. Oral lesions are rarely the primary presenting feature. When left untreated, most cases are fatal within a year of diagnosis. The diagnosis can only be made when certain criteria are found, including granular oral lesions exhibiting an eosinophilic inflammatory infiltrate on biopsy. With 5% of cases showing intraoral lesions as the primary feature, it is essential that dentists have the knowledge of this rare disease to refer and not to treat as a common gingival condition.

Studies To Examine Potential Tolerability Differences between the 5-HT2C Receptor Selective Agonists Lorcaserin and CP-809101.

Lorcaserin (LOR) is a selective 5-HT2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of functional selectivity designed to examine signaling pathways activated by both drugs in CHO (Chinese hamster ovary) cells expressing h5-HT2C receptors failed to identify evidence for biased signaling differences between LOR and CP. Thus, both drugs showed similar profiles across PLC, PLA2, and ERK signaling pathways. In studies designed to examine pharmacokinetic differences between LOR and CP, while drug plasma levels correlated with increasing dose, CSF levels did not. CSF levels of LOR increased proportionally with dose; however CSF levels of CP plateaued from 6 to 12 mg/kg. Thus, the apparently improved tolerability of CP likely reflects a limit to CNS levels attained at relatively high doses.

Enduring attentional deficits in rats treated with a peripheral nerve injury.

The present study investigated the impact of a spared nerve injury (SNI) on the daily performance of rats tested in two instrumental conditioning procedures: the progressive ratio (PR) schedule of food reinforcement to study motivation for an appetitive stimulus, and the 5-choice serial reaction time task (5-CSRTT), a test of attention and reaction time. Separate groups of male, Sprague-Dawley rats of age 8-10 months were trained to asymptotic performance in either task, before undergoing either SNI or sham surgery. After a recovery period of 3-4 days the animals were run 5 days/week for 3 months in either task. Tests of responsivity to evoked tactile (Von Frey) and thermal (acetone) stimuli were also conducted over this period to check integrity of the model. Post SNI surgery, rats showed equivalent responding to sham controls for food available under a PR schedule throughout the test period, implying a similar level of motivation for a food reward. In contrast, a performance deficit emerged in SNI treated rats run in the 5-CSRTT, consistent with an attentional deficit. This deficit emerged during the second month post-surgery and was characterized by slower response speed, reduced accuracy and increased trial omissions. Both SNI groups showed equivalent hypersensitivity to evoked sensory stimuli compared to controls. Since attention based deficits have been reported in individuals with clinical forms of neuropathic pain, the present studies suggest a novel approach to study this phenomena and a means to study the effect of treatments against this cognitive endpoint.

Screening CT colonography: multicenter survey of patient experience, preference, and potential impact on adherence.

OBJECTIVE: Prior research indicates CT colonography (CTC) would be a cost-effective colorectal cancer (CRC) screening test if widespread availability were to increase overall CRC screening adherence rates. The primary aims of this multicenter study were to evaluate patient experience and satisfaction with CTC screening and compare preference against screening colonoscopy. MATERIALS AND METHODS: A 12-question survey instrument measuring pretest choice, experience, and satisfaction was given to a consecutive cohort of adults undergoing CTC screening in three disparate screening settings: university academic center, military medical center, and community practice. The study cohort was composed of individuals voluntarily participating in clinical CTC screening programs. RESULTS: A total of 1417 patients responded to the survey. The top reasons for choosing CTC for screening included "noninvasiveness" (68.0%), "avoidance of sedation/anesthesia" (63.1%), "ability to drive after the test" (49.2%), "avoidance of optical colonoscopy risks" (46.9%), and "identifying abnormalities outside the colon" (43.3%). Only 7.2% of patients reported pain during the CTC examination and only 2.5% reported greater than moderate discomfort. Of 441 patients who had experienced both CTC and optical colonoscopy, 77.1% preferred CTC and 13.8% preferred optical colonoscopy. Of all patients, 29.6% indicated that they may not have undergone optical colonoscopy screening if CTC were not available. Of all patients, 92.9% labeled their overall experience with CTC as "excellent" or "good," and 93.0% indicated they would choose CTC for their next screening. CONCLUSION: Respondents reported a very high satisfaction level with CTC, and those who had experienced both modalities indicated a preference for CTC over optical colonoscopy. These results suggest that CTC has the potential to increase adherence to CRC screening guidelines if widely available.

Multiple tandem copies of conserved gp41 epitopes incorporated in gag virus-like particles elicit systemic and mucosal antibodies in an optimized heterologous vector delivery regimen.

Induction of neutralizing antibodies to prevent HIV infection, especially at the mucosa, is a critical goal of future vaccines. In this study, we have designed chimeric HIV-gag virus-like particles (VLPs) that contain multiple copies of the two highly conserved gp41 membrane-proximal external region (MPER) epitopes, ELDKWA and NWFDIT, with the objective of generating high titers of MPER-specific antibodies. We have shown that the implementation of optimized vector design, delivery regimens and appropriate delivery methods is critical to significantly increase epitope-specific antibody titers. One goal of the methods that were tested and employed was to generate high levels of mucosal MPER-specific antibodies, as mucosal immune induction could play a key role in preventing HIV infection. We also tested a design strategy that incorporated multiple repeats of the MPER epitopes within gag, which significantly increased specific antibody titers, systemically and mucosally. This alternative design strategy and the implementation of optimized heterologous immunization regimens can serve to 'immuno-focus' and significantly increase epitope-specific titers.

Treatment of intravaginal HSV-2 infection in mice: a comparison of CpG oligodeoxynucleotides and resiquimod (R-848).

The mammalian innate immune system recognizes pathogens via a series of pattern-recognition receptors such as the toll-like receptors (TLR) that interact with pathogen-associated molecular patterns (PAMPs) and lead to the rapid activation of innate immune cells. In this study, we compared the efficacy of CpG ODN (a TLR9 agonist) and resiquimod (R-848; a TLR7/8 agonist) for topical immunoprophylaxis or immunotherapy of vaginal herpes simplex virus type 2 (HSV-2) infection in mice. Efficacy against HSV infection was observed with CpG ODN but less so with R-848, even after repeated administrations. Intravaginal (IVAG) administration of CpG ODN resulted in strong local but relatively weak systemic immune activation, as determined by levels of the chemokines IP-10, MIG and I-TAC in vaginal tissue and plasma, respectively. In contrast, IVAG administration of R-848 resulted in high levels of plasma IP-10, similar to those seen after parenteral administration, but overall, weaker or shorter-lived local immune responses than obtained with CpG ODN. These findings suggest that differences in biodistribution and sites of immune activation between CpG ODN and R-848 after IVAG delivery account for differences in efficacy, and demonstrate the need for local mucosal innate activation for protection against HSV-2.

Mucosal delivery of CpG oligodeoxynucleotides expands functional dendritic cells and macrophages in the vagina.

Antigen-presenting cells (APC) are specialized sentinel cells that sense pathogens within tissues and then activate appropriate immune effector cells in lymphoid organs. Recent evidence, however, suggests that APC can also induce effector cells in non-lymphoid organs. The purpose of this study was to determine the effect of intravaginal (IVAG) delivery of CpG-oligodeoxynucleotide (ODN) on expansion of resident genital APC. Our results show that delivery of CpG-ODN to the murine genital tract induced a rapid and significant, but transient expansion of genital APC in situ. As early as 12 hr post CpG-ODN delivery, we observed an enhanced level of F4/80+ major histocompatibility complex (MHC) class II-negative macrophages in the genital tissue. This was followed by increased levels of F4/80/MHC class II double-positive cells, as well as MHC class II, CD11c and CD86 triple-positive dendritic cells (DC) at 48 hr. Expanded APC levels at 48 hr post CpG-ODN resulted in increased ability of genital cells to induce an allogenic mixed leucocyte reaction. By 72 hr after CpG-ODN treatment, APC levels were not distinguishable from naive levels. Therefore, these results clearly show that administration of CpG-ODN to the genital tract induced a marked but transient enhancement of APC within the genital tissue, and that these APC appear to possess functional capacity. Furthermore, these results indicate that IVAG-CpG-ODN may be an important factor for the enhancement of local antigen presentation in the genital tract through increased DC numbers.

CD8+ T-cell-mediated cross-clade protection in the genital tract following intranasal immunization with inactivated human immunodeficiency virus antigen plus CpG oligodeoxynucleotides.

Human immunodeficiency virus (HIV) is a mucosally transmitted infection that rapidly targets and depletes CD4+ T cells in mucosal tissues and establishes a major reservoir for viral persistence in gut-associated lymphoid tissues. Therefore, vaccines designed to prevent HIV infections must induce potent and durable mucosal immune responses, especially in the genital tract. Here we investigated whether intranasal (i.n.) immunization with inactivated gp120-depleted HIV-1 antigen (Ag) plus CpG oligodeoxynucleotide (ODN) as an adjuvant induced local immune responses in the genital tract and cross-clade protection against intravaginal (IVAG) challenge. Lymphocytes isolated from the iliac lymph nodes (ILNs) and genital tracts of female mice i.n. immunized with HIV-1 Ag plus CpG showed significant HIV-specific proliferation and produced significantly higher levels of gamma interferon (IFN-gamma) and beta-chemokines than mice immunized with HIV-1 Ag alone or mixed with non-CpG ODN. CD8+ lymphocytes were dramatically increased in the genital tracts of mice immunized with HIV-1 Ag plus CpG, and protection following IVAG challenge with recombinant vaccinia viruses (rVVs) expressing HIV-1 gag was shown to be CD8 dependent. Finally, cross-clade protection was observed between clades A, C, and G but not B following IVAG challenge with rVVs expressing HIV-1 gag from different clades. These studies provide evidence that mucosal (i.n.) immunization induced strong local T-cell-mediated immune responses in the genital tract and cross-clade protection against IVAG challenge.

Toll-like receptor (TLR)-3, but not TLR4, agonist protects against genital herpes infection in the absence of inflammation seen with CpG DNA.

We previously demonstrated that delivery of CpG oligodeoxynucleotide (ODN) to vaginal mucosa induced an innate mucosal antiviral state that protected against intravaginal challenge with herpes simplex virus (HSV)-2. We report that mucosal, but not systemic, delivery of ligands for Toll-like receptor (TLR)-3, but not TLR4, induced protection against genital HSV-2 challenge that was not accompanied by the local inflammation and splenomegaly seen after treatment with CpG ODN. Surprisingly, TLR4 messenger (m) RNA expression was shown to be higher than that of TLR3 or TLR9 in murine genital mucosa. Similarly, murine RAW264.7 cells were shown to express more mRNA for TLR4 than TLR3 or TLR9, yet treatment of these cells with double-stranded RNA provided greater protection than lipopolysaccharide or CpG ODN. These results indicate that TLR3 ligand induces a more potent antiviral response than TLR4 and TLR9 ligands and may be a safer means of protecting against sexually transmitted viral infections.

Parameters of CpG oligodeoxynucleotide-induced protection against intravaginal HSV-2 challenge.

Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides within the context of certain flanking bases (CpG motifs) have been shown to induce potent innate and adaptive immune responses. Vaginal delivery of CpG ODN alone protects mice from vaginal herpes simplex virus type-2 (HSV-2) challenge. Here, we investigated the importance of timing of delivery, formulation, route and dose of vaginally administered CpG ODN in the prevention or treatment of intravaginal (IVAG) HSV-2 infection. Mice treated intravaginally with CpG ODN containing a phosphorothioate backbone 24 hours prior to IVAG HSV-2 challenge survived infection, showed minimal vaginal pathology, and had virtually no detectable virus in vaginal washes, when compared to mice treated with non-CpG ODN. Genital treatment of HSV-2 infected mice with CpG ODN 4 hours after infection resulted in increased survival and decreased pathology and vaginal virus titers, whereas treatment of infected mice with CpG ODN 24 and 72 hours after IVAG HSV-2 infection had no effect on disease progression. Both liquid and solid (delivered on a bio-erodible muco-adhesive film) formulations of CpG ODN were effective in protection against genital HSV-2 following vaginal delivery. Lastly, IVAG delivery of 10 micro g of CpG ODN protected as well as a 100 micro g dose.

Mucosal immunization with inactivated human immunodeficiency virus plus CpG oligodeoxynucleotides induces genital immune responses and protection against intravaginal challenge.

Vaccines capable of protecting against sexually transmitted infections, such as human immunodeficiency virus (HIV), will depend on the induction of potent long-lasting mucosal immune responses in the genital tract. We evaluated vaginal and systemic immune responses and protection from vaginal challenge elicited after intranasal immunization of mice with inactivated glycoprotien 120-depleted HIV-1 immunogen alone or in combination with immunostimulatory CpG oligodeoxynucleotides (ODNs). Mice immunized with HIV-1 immunogen plus CpG ODN had significantly enhanced levels of anti-protein 24 immunoglobulin (Ig) G and IgA antibodies in serum and vaginal washes and increased production of beta-chemokines and interferon-gamma, compared with mice immunized with HIV-1 immunogen alone or with control ODN. Furthermore, mice intranasally immunized with HIV-1 immunogen plus CpG were protected against intravaginal challenge with a recombinant vaccinia virus expressing HIV-1 gag. These results indicate that mucosal immunization with whole-killed HIV-1 plus CpG ODN may be an effective means of inducing local immunity and protection against genital infection.