Patient perspectives on the Poole PCT cancer genetics service

Focussing on the primary care aspects of the Kenilworth model, the Poole Primary Care Trust (PCT) cancer genetics service has aimed to develop a high quality primary care-led service for the assessment and counselling of people concerned about their genetic risk of cancer. The service has been available through General Practitioner (GP) surgeries within the PCT since early 2006, and is delivered by Community Cancer Nurses as part of their role to provide proactive care and support to cancer patients, their families and the local population. Acting as a point of reference for cancer genetics at each practice, the nurses have supplied basic education to both health professionals and lay staff about the aims of the service and the genetic risk of cancer. Feedback from service users is one of the key elements of the Poole evaluation. This article is based on the views of some of the first patients referred. The patients consulted one of the cancer nurses between June and December 2006, and were interviewed by a researcher about their experience. The interviews focussed on the psychosocial aspects of the patients’ experiences, which are less accessible through quantitative methods. The patients were encouraged to talk specifically and generally about their experiences, and described some of the feelings and emotions from the time of their referral onwards.     

Seizures following picornavirus infection

Purpose : We demonstrate the establishment and characterization of a novel virus infection-induced seizure model in C57BL/6 mice.
Methods: C57BL/6 mice were infected with Theiler's murine encephalomyelitis virus (TMEV) or mock infected. Mice were followed for seizures, weight change, body temperature, motor function (righting reflex, rotorod) and neurological manifestations (inflammation [perivascular cuffing], pyknotic neurons, transforming growth factor [TGF]-β expression).
Results: C57BL/6 mice are susceptible to seizures induced by TMEV infection. Approximately 50% of C57BL/6 mice develop transient afebrile seizures. Motor function and coordination are impaired in seized mice. Pyramidal neuron pyknosis and TGF-β expression correlate with seizure activity in the hippocampus.
Discussion: The characterization of this model will enable the investigation of viral and immune contributions in the central nervous system to the development of seizure disorders in humans.     

Comparative preclinical activity of the folate-targeted Vinca alkaloid conjugates EC140 and EC145

EC140 is a water soluble folate conjugate of desacetylvinblastine monohydrazide (DAVLBH), which is constructed with an endosome-cleavable acyl hydrazone bond. This agent has proven to be active and specific against well established, subcutaneous folate receptor (FR)-positive tumors in multiple animal models. Recent structure-activity and optimization studies have yielded a disulfide bond-containing counterpart to EC140, herein referred to as EC145. This new conjugate was found to retain high affinity for FR-positive cells, and it produced specific, dose-responsive activity in vitro. Comparative in vivo efficacy tests confirmed that, like EC140, EC145 displays activity against both syngeneic and xenograft tumor models. However, EC145 was found to be more active and better tolerated than EC140; hence, more durable complete responses were consistently observed in EC145-treated tumor-bearing animals. Furthermore, EC145 was not found to be active against a FR-negative tumor model. Additional preclinical studies are therefore warranted to better understand EC145's breadth of activity against FR-positive tumors.     

CD4/CD8 double negative pagetoid reticulosis: a case report and literature review

Pagetoid reticulosis is an indolent primary cutaneous T‐cell lymphoma. It typically presents as a solitary and slowly growing patch or plaque on the extremity, histologically characterized by an acanthotic epidermis infiltrated with atypical lymphocytes. Here, we present histological, immunophenotypical and molecular findings of a 29‐year‐old Jamaican man with bilateral wrist plaques. Histology showed marked acanthosis, hyperkeratosis and an intraepidermal infiltration consisting of large atypical lymphocytes. Immunohistochemical stains showed CD3 and CD5 positive T cells with significant loss of CD7, double negative CD4 and CD8 and strong positive CD30. Molecular analysis showed a monoclonal T‐cell receptor (TCR) gamma gene rearrangement. Review of the literature confirms that the immunophenotype of pagetoid reticulosis is variable with decreasing frequency of CD8+ cytotoxic/suppressor T cell, CD4+ helper T cell and least commonly CD4/CD8 double negative phenotypes. Although CD4/CD8 double negative phenotype appears to be associated with higher proliferation index, it does not appear to confer prognostic significance. Mourtzinos N, Puri PK, Guanghua W, Liu M‐L. CD4/CD8 double negative pagetoid reticulosis: a case report and literature review.     

Comparison of PC and iPad administrations of the Cogstate Brief Battery in the Mayo Clinic Study of Aging: Assessing cross-modality equivalence of computerized neuropsychological tests

Objective: Computerized neuropsychological assessments are increasingly used in clinical practice, population studies of cognitive aging and clinical trial enrichment. Subtle, but significant, performance differences have been demonstrated across different modes of test administration and require further investigation.

Method: Participants included cognitively unimpaired adults aged 50 and older from the Mayo Clinic Study of Aging who completed the Cogstate Brief Battery and Cogstate’s Groton Maze Learning Test (GMLT) on an iPad or a personal computer (PC) in the clinic. Mode of administration differences and test–retest reliability coefficients were examined across 3 cohorts: a demographically matched test–retest cohort completing PC and iPad administrations the same day (N?=?168); a test naïve cohort comparing baseline PC (n?=?1820) and iPad (n?=605) performance; and a demographically matched longitudinal cohort completing 3 Cogstate visits over 15 months on either the PC (n?=63) or iPad (n?=63).

Results: Results showed a small but statistically significant and consistent finding for faster performance on PC relative to iPad for several Cogstate Brief Battery measures. Measures of accuracy generally did not differ or differences were very small. The GMLT showed faster performance and higher total errors on iPad. Most Cogstate variables showed no difference in the rate of change across PC and iPad administrations.

Conclusions: There are small, but significant, differences in performance when giving the same cognitive tests on a PC or an iPad. Future studies are needed to better understand if these small differences impact the clinical interpretation of results and research outcomes.     

Activities of Murine Peripheral Blood Lymphocytes Provide Immune Correlates That Predict Francisella tularensis Vaccine Efficacy

We previously identified potential correlates of vaccine-induced protection against Francisella tularensis using murine splenocytes and further demonstrated that the relative levels of gene expression varied significantly between tissues. In contrast to splenocytes, peripheral blood leukocytes (PBLs) represent a means to bridge vaccine efficacy in animal models to that in humans. Here we take advantage of this easily accessible source of immune cells to investigate cell-mediated immune responses against tularemia, whose sporadic incidence makes clinical trials of vaccines difficult. Using PBLs from mice vaccinated with F. tularensis Live Vaccine Strain (LVS) and related attenuated strains, we combined the control of in vitroFrancisella replication within macrophages with gene expression analyses. The in vitro functions of PBLs, particularly the control of intramacrophage LVS replication, reflected the hierarchy of in vivo protection conferred by LVS-derived vaccines. Moreover, several genes previously identified by the evaluation of splenocytes were also found to be differentially expressed in immune PBLs. In addition, more extensive screening identified additional potential correlates of protection. Finally, expression of selected genes in mouse PBLs obtained shortly after vaccination, without ex vivo restimulation, was different among vaccine groups, suggesting a potential tool to monitor efficacious vaccine-induced immune responses against F. tularensis. Our studies demonstrate that murine PBLs can be used productively to identify potential correlates of protection against F. tularensis and to expand and refine a comprehensive set of protective correlates.     

Topical application of the anti-microbial chemical triclosan induces immunomodulatory responses through the S100A8/A9-TLR4 pathway

The anti-microbial compound triclosan is incorporated into numerous consumer products and is detectable in the urine of 75% of the general United States population. Recent epidemiological studies report positive associations with urinary triclosan levels and allergic disease. Although not sensitizing, earlier studies previously found that repeated topical application of triclosan augments the allergic response to ovalbumin (OVA) though a thymic stromal lymphopoietin (TSLP) pathway in mice. In the present study, early immunological effects following triclosan exposure were further evaluated following topical application in a murine model. These investigations revealed abundant expression of S100A8/A9, which reportedly acts as an endogenous ligand for Toll-like Receptor 4 (TLR4), in skin tissues and in infiltrating leukocytes during topical application of 0.75–3.0% triclosan. Expression of Tlr4 along with Tlr1, Tlr2 and Tlr6 increased in skin tissues over time with triclosan exposure; high levels of TLR4 were expressed on skin-infiltrating leukocytes. In vivo antibody blockade of the TLR4/MD-2 receptor complex impaired local inflammatory responses after four days, as evidenced by decreased Il6, Tnfα, S100a8, S100a9, Tlr1, Tlr2, Tlr4 and Tlr6 expression in the skin and decreased lymph node cellularity and production of IL-4 and IL-13 by lymph node T-cells. After nine days of triclosan exposure with TLR4/MD-2 blockade, impaired T-helper cell type 2 (T_H2) cytokine responses were sustained, but other early effects on skin and lymph node cellularity were lost; this suggested alternative ligands/receptors compensated for the loss of TLR4 signaling. Taken together, these data suggest the S100A8/A9-TLR4 pathway plays an early role in augmenting immunomodulatory responses with triclosan exposure and support a role for the innate immune system in chemical adjuvancy.     

Patient knowledge and beliefs as barriers to extending cervical cancer screening intervals in Federally Qualified Health Centers

Objective

Despite guidelines recommending cervical cancer screening intervals be extended beyond one year, clinical practice has been slow to change. Patient preferences are a potential barrier. In the Centers for Disease Control's Cervical Cancer (Cx3) Study at Federally Qualified Health Centers (FQHCs) across Illinois, we surveyed patients about screening practices, and assessed beliefs regarding lengthening screening intervals.

Method

We analyzed data from 984 low income women in the Cx3 Study (2009–2011). Participants completed a survey assessing health history, knowledge about Pap testing, beliefs and intentions about extending screening intervals, and demographics.

Results

The majority reported annual Pap testing (61%), while only 24% reported a 2–3 year screening interval (recommendation at time of survey). Misunderstandings about the Pap test were prevalent, with over half believing it screened for vaginal, yeast, and sexually transmitted infections (58%–72%). Unfavorable beliefs about extending screening intervals were common. The majority (57%) indicated that they would not wait 3 years to be screened if their physician recommended it, and intentions were associated with knowledge about Pap testing.

Conclusion

Most women reported annual cervical cancer screening, and intended to resist longer screening intervals. Patients' lack of knowledge and unfavorable beliefs may serve as barriers to extending screening intervals.