Pathophysiology of nAChRs: Limbic circuits and related disorders.

Human epidemiological studies have identified links between nicotine intake and stress disorders, including anxiety, depression and PTSD. Here we review the clinical evidence for activation and desensitization of nicotinic acetylcholine receptors (nAChRs) relevant to affective disorders. We go on to describe clinical and preclinical pharmacological studies suggesting that nAChR function may be involved in the etiology of anxiety and depressive disorders, may be relevant targets for medication development, and may contribute to the antidepressant efficacy of non-nicotinic therapeutics. We then review what is known about nAChR function in a subset of limbic system areas (amygdala, hippocampus and prefrontal cortex), and how this contributes to stress-relevant behaviors in preclinical models that may be relevant to human affective disorders. Taken together, the preclinical and clinical literature point to a clear role for ACh signaling through nAChRs in regulation of behavioral responses to stress. Disruption of nAChR homeostasis is likely to contribute to the psychopathology observed in anxiety and depressive disorders. Targeting specific nAChRs may therefore be a strategy for medication development to treat these disorders or to augment the efficacy of current therapeutics.

Detection of CD8+ T cell responses to human papillomavirus type 16 antigens in women using imiquimod as a treatment for high-grade vulval intraepithelial neoplasia.

OBJECTIVES: To investigate CD8+ T cell reactivity to human papillomavirus (HPV) 16 antigens in patients with high-grade vulval intraepithelial neoplasia (VIN) before, during and after treatment with 5% imiquimod cream. METHODS: CD8-enriched responder cell populations were obtained from 10 patients with high-grade VIN using imiquimod cream as a treatment. Overlapping synthetic peptides covering the entire primary sequences of the HPV16 E6, E7 and E4 proteins were used to screen for CD8+ T cell responses using an ELISPOT assay of interferon (IFN)-gamma release. RESULTS: Reactivity to the proteins was detected in all patients on at least one occasion. With the exception of one patient, CD8+ T cell reactivity generally increased at some stage during treatment. The magnitude and specificities of responses changed over the treatment period. This was particularly noticeable in response to peptides derived from the E4 protein. CD8+ T cell reactivity to HPV16 E7 appeared to be dominant amongst women with high-grade VIN. The magnitude and specificity of response had no correlation with clinical response to imiquimod. CONCLUSIONS: HPV16 specific CD8+ T cell activity was detected in patients with high-grade VIN. Imiquimod use appeared to increase the magnitude of the response and broaden the specificity of response in some patients. Despite the presence of these CD8+ T cells, the disease state persisted; therefore, a role for HPV-specific cytotoxic T cells (CTLs) in VIN resolution remains unproven.

Telecolposcopy - a feasibility study in primary care.

Organized cervical screening has reduced the incidence of invasive cervical cancer, but this has resulted in large numbers of women requiring investigation. We have investigated the negative predictive value of colposcopy and used telemedicine to develop a secondary screening technique for use in primary care. A video-colposcope was used to record video-clips, which were subsequently transmitted to a specialist for interpretation. The gold standard for the comparison was the opinion of the colposcopist who examined the women in the hospital colposcopy clinic. Eighty-one out of 97 women were studied by both techniques. Using a diagnosis of normal or abnormal, telecolposcopy had a sensitivity of 88.9% and a specificity of 93.3%. There was very good agreement between the telecolposcopy screener and the colposcopist (Cohen s kappa statistic = 0.70). Furthermore, telecolposcopy screening did not grade any cases of colposcopic high-grade cervical intraepithelial neoplasia as normal. The pilot study has established the validity of diagnosing from transmitted computerized video-clips.

Effect of nurse colposcopists on a hospital-based service.

The number of colposcopies performed annually in the UK is increasing. Nurse colposcopists have been introduced by many units to cope with this workload. The small amount of evidence to support the introduction of nurse colposcopists suggests that nurses are viable alternative providers of colposcopy. This study compares the performance of nurse colposcopists with that of doctors.

The effects of 5% imiquimod cream on high-grade vulval intraepithelial neoplasia.

OBJECTIVES: The aim of this study was to investigate the effects of topical 5% Imiquimod (3M Pharmaceuticals, St. Paul, Minnessota) on high-grade vulval intraepithelial neoplasia (VIN). METHODS: A prospective uncontrolled observational study was performed. Fifteen patients with histologically confirmed VIN 3 were asked to self-administer 5% Imiquimod cream to their vulval lesions up to three times weekly for 16 weeks. Review was conducted at 1, 2, 3, 4, 6, and 9 months postrecruitment. Lesions were photodocumented and at 4 months any areas demonstrating a clinical response were biopsied. RESULTS: Of 15 patients recruited, 4 demonstrated a clinical improvement in their disease, 3 of whom had negative biopsies posttreatment. Local side effects limited the frequency of application such that 7 patients applied the cream once weekly, 6 twice weekly, and 2 three times weekly. CONCLUSIONS: 5% Imiquimod cream appears to have an effect when used on high-grade VIN. The frequency of application was limited by local side effects which may have reduced the clinical responses seen. Measures to alleviate local side effects may allow more aggressive use of Imiquimod and lead to improved responses.