Studying sex and gender differences in pain and analgesia: a consensus report

In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"     

Evaluating thin compression paddles for mammographically compatible ultrasound

We are developing a combined digital mammography/3D ultrasound system to improve detection and/or characterization of breast lesions. Ultrasound scanning through a mammographic paddle could significantly reduce signal level, degrade beam focusing and create reverberations. Thus, appropriate paddle choice is essential for accurate sonographic lesion detection and assessment with this system. In this study, we characterized ultrasound image quality through paddles of varying materials (lexan, polyurethane, TPX, mylar) and thicknesses (0.25 to 2.5 mm). Analytical experiments focused on lexan and TPX, which preliminary results demonstrated were most competitive. Spatial and contrast resolution, side-lobe and range lobe levels, contrast and signal strength were compared with no-paddle images. When the beamforming of the system was corrected to account for imaging through the paddle, the TPX 2.5 mm paddle performed the best. Test objects imaged through this paddle demonstrated < or = 15% reduction in spatial resolution, < or = 7.5 dB signal loss, < or = 3 dB contrast loss and range lobe levels > or = 35 dB below signal maximum over 4 cm. TPX paddles <2.5 mm could also be used with this system, depending on imaging goals. In 10 human subjects with cysts, small CNR losses were observed but were determined to be statistically insignificant. Radiologists concluded that 75% of cysts in through-paddle scans were at least as detectable as in their corresponding direct-contact scans.     

Patient preference for triptan formulations: a prospective study with zolmitriptan

OBJECTIVES: To investigate patterns of patient preference for 3 formulations of zolmitriptan, in a primary care study utilizing a naturalistic longitudinal design. BACKGROUND: Although differences in efficacy between individual triptans tend to be small, migraine patients show clear preferences for individual triptans and formulations. The groups of patients suitable for the different triptan formulations, and the reasons underlying individual preferences, are not clearly understood. METHODS: Migraine patients entered a prospective, randomized, open, crossover, longitudinal design study, with patients receiving zolmitriptan formulations according to UK prescribing recommendations. Patients na?ve to zolmitriptan received zolmitriptan 2.5-mg film-coated tablets or 2.5-mg Orally Disintegrating Tablets (ODT) for 1 month, before being crossed over to receive the alternative formulation for Month 2. All patients then received zolmitriptan nasal spray 5 mg for Month 3. Patients could then choose the formulation(s) of their choice for a further 7 months. Patients recorded their preferences for individual formulations, the reasons for their preferences, and also the headache-related disability (measured by the Migraine Disability Assessment [MIDAS] score) at clinic visits. Primary endpoints were the individual preferences and changes in MIDAS scores. Adverse events were also recorded. RESULTS: Forty-eight patients took part in the study. At baseline, most patients expressed a preference for conventional tablets. After 4 months, 46.9% of patients preferred zolmitriptan ODT, 43.8% zolmitriptan nasal spray, and 6.3% the conventional tablet. The most common reasons given for preferring conventional tablets were personal reasons: for zolmitriptan ODT, convenience and, to a lesser extent, speed of onset: for zolmitriptan nasal spray, speed of onset, and overall efficacy. MIDAS scores decreased significantly following treatment with zolmitriptan. Zolmitriptan was well tolerated. CONCLUSIONS: Patient experience of newer zolmitriptan formulations influenced a change in preference away from conventional tablets. Speed and efficacy were the key drivers of preference for zolmitriptan nasal spray, while convenience mostly drove preference for the ODT formulation. Open, longitudinal, naturalistic studies may, allowing for biases, sometimes be an appropriate way of conducting migraine studies in primary care.     

Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid

To maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. In this regard, the gut is home to a large number of regulatory T (T reg) cells, including the Foxp3(+) T reg cell. Therefore, we hypothesized that the gut environment preferentially supports extrathymic T reg cell development. We show that peripheral conversion of CD4(+) T cells to T reg cells occurs primarily in gut-associated lymphoid tissue (GALT) after oral exposure to antigen and in a lymphopenic environment. Dendritic cells (DCs) purified from the lamina propria (Lp; LpDCs) of the small intestine were found to promote a high level of T reg cell conversion relative to lymphoid organ-derived DCs. This enhanced conversion by LpDCs was dependent on TGF-beta and retinoic acid (RA), which is a vitamin A metabolite highly expressed in GALT. Together, these data demonstrate that the intestinal immune system has evolved a self-contained strategy to promote T reg cell neoconversion.     

Absolute bioavailability of intranasal fluticasone furoate in healthy subjects

BACKGROUND: Fluticasone furoate (drug code GW685698) is an enhanced-affinity glucocorticoid that has been developed for the treatment of allergic rhinitis. OBJECTIVES: The objectives of this study were to estimate the absolute bioavailability of fluticasone furoate nasal spray and to describe the intranasal (IN) and IV pharmacokinetics of fluticasone furoate in healthy subjects. METHODS: This was a single-center, randomized, open label, 2-period crossover study. Healthy male and female subjects were randomized to receive supra-therapeutic doses of fluticasone furoate 880 microg IN qSh for 10 doses in 1 treatment period, and a single IV dose of 250 pg fluticasone furoate given as an infusion over 20 minutes in the other treatment period. Each treatment period was separated by a 4- to 5-day washout period. Blood sampling was carried out over 8 hours following the final IN dose and 24 hours following the IV dose to determine plasma fluticasone furoate concentrations. Plasma samples were analyzed for fluticasone furoate using online solid-phase extraction with high-performance liquid chromatography with tandem mass-spectrometric detection. The lower limit of quantification was 10 pg/mL. The sample size was based primarily on logistical considerations. Sample-size sensitivity was assessed by estimating the 90% CI for the absolute bioavailability of IN fluticasone furoate, based on different estimated bioavailabilities and within-subject SDs. The following pharmacokinetic parameters were derived: IN administration: AUC from time 0 to the end of the dosing interval (AUC(0-tau)), AUC(0-t), C(max), and T(max); IV administration: AUC(0-infinity), AUC(0-t), t(1/2), C(max), T(max), total systemic clearance, and volume of distribution at steady state. RESULTS: A total of 16 subjects were included in the study. Their mean age was 27.8 years (range, 19-45 years), and their mean body weight was 72.84 kg (range, 55.3-97.2 kg). The geometric mean AUC(0-tau) for 880 microg IN was 74.9 pg x mL/h and geometric mean AUC(0-infinity) for 250 microg IV was 4259 pg x mL/h. The geometric mean of the absolute bioavailability of fluticasone furoate nasal spray in these healthy subjects was 0.50% (90% CI, 0.34%-0.74%). The administration of large doses by the IN route did not elicit clinical concern. Three (19%) of 16 subjects reported adverse events (AEs) during the IN administration period, with 2 subjects experiencing dizziness and 1, toothache. Five (31%) subjects reported AEs during the IV administration period, with 3 subjects experiencing infusion-site or IV catheter-related events; 1 subject, dizziness; and 1 subject, headache. CONCLUSIONS: The geometric mean of the absolute bioavailability of fluticasone furoate 880 microg IN qSh for 10 doses in these healthy subjects was low--0.50%.     

Increased Parietal and Frontal Activation after Remission from Recurrent Major Depression: A Repeated fMRI Study

Nine patients with unipolar major depression were scanned with MRI twice over a 2-year period, and compared with 12 healthy control subjects. All patients fulfilled criteria for major depressive disorder, recurrent type, at first scanning. Level of depressive psychopathology was assessed by the Hamilton Depression Rating Scale. The participants had to work on a mental arithmetics/working memory task while in the MR scanner. The task consisted of single digits (1 to 9) that were shown to the participant, who had to add the numbers in successive pairs and press a response button when the sum was 10. Neuronal activation was recorded based on the BOLD contrast phenomenon in a functional MRI protocol. The results showed significant increase in activation for the patients in the inferior frontal gyrus and the superior and inferior parietal lobule at the second compared with the first MR scanning session. There were also significant correlations between the HDRS scores and neuronal activation which showed a negative correlation particularly in the inferior frontal and parietal lobe areas, which overlapped with similar areas activated in the healthy control participants. This may indicate normalization of brain activation in depressed patients as a function of time from an illness phase to a remission/recovery state.