Citations

ABSTRACT Introduction Studies of erectile dysfunction (ED) therapies typically assess erectile function end- points, although other treatment outcomes may also be of value to men and their partners. Aim To examine the treatment sensitivity of the Psychological and Interpersonal Relationship Scales (PAIRS) associated with the use of two phosphodiesterase type 5 (PDE5) inhibitors with different duration of action. Methods Men with ED were recruited from three clinical trials of tadalafil and sildenafil citrate to complete post-treatment questionnaires that included the PAIRS. In Study 1, the PAIRS was assessed after 6 months of open-label tadalafil (20 mg) treatment and after 2 months of real-world sildenafil use (25–100 mg). In studies 2 and 3, the PAIRS was assessed at the end of the trial assessment phase. In Study 2, men with a 6–24 week history of sildenafil use (25–100 mg) received 3 weeks of open-label sildenafil treatment (dosage at study entry), and then switched to 9 weeks of tadalafil treatment. In Study 3, a double-blind, crossover study, men were randomized to 12 weeks of either tadalafil (20 mg) or sildenafil (50 mg) treatment, followed by 12 weeks of the alternate treatment; PAIRS scores for the second treatment period were evaluated. Main Outcome Measure Treatment outcomes were assessed with the PAIRS, a new reliable and valid self-report measure of sexual self-confidence, spontaneity, and time concerns before sex. Results Significant mean differences were observed on all PAIRS domain scores associated with tadalafil and sildenafil treatment. Across studies, men had significantly higher sexual self-confidence and spontaneity scores, and lower time concerns scores in reference to tadalafil compared with their scores in reference to sildenafil. Conclusions Mean differences observed on PAIRS domains across studies support the sensitivity of the measure to differentiate between these two ED treatments.

Purpose To determine whether a response classification based on integration of fluorine-18–fluorodeoxyglucose positron emission tomography (FDG-PET) into the International Workshop Criteria (IWC) provides a more accurate response assessment than IWC alone in patients with non-Hodgkin's lymphoma (NHL). Patients and Methods Fifty-four patients with aggressive NHL who underwent FDG-PET and computed tomography 1 to 16 weeks after four to eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone were assessed for complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD) by the IWC and by integrated IWC and FDG-PET (IWC+PET). Progression-free survival (PFS) was also compared between IWC- and IWC+PET-assigned response designations. Results By IWC, 17 patients had a CR, seven had a CRu, 19 had a PR, nine had SD, and two had PD. In comparison, by IWC+PET, 35 patients had a CR, 12 had a PR, six had SD, one had PD, and zero had a CRu. In separate multivariate models, PFS was significantly shorter in patients with PR than in those with a CR using IWC (hazard ratio [HR], 8.9; P = .021) or IWC+PET (HR, 29.7; P = .0003). However, when the two classifications were included in the same multivariate model, only IWC+PET was a statistically significant independent predictor for PFS (P = .008 v P = .72 for IWC). In addition, when patients with a PR by IWC and a CR by IWC+PET were compared with those with a CR by IWC and a CR by IWC+PET, there was no significant difference in PFS (HR, 1.6; P = .72), indicating that IWC+PET identified a subset of IWC-PR patients with a more favorable prognosis. Conclusion Compared with IWC, the IWC+PET-based assessment provides a more accurate response classification in patients with aggressive NHL.

SummaryMechanisms that lead to induction of life-long immunity to measles virus (MV) are poorly understood. In the present study, we have assessed the activation, proliferation and cytokine secreting function of peripheral blood T cells from MV immune individuals. Expression of cell blastogenesis markers, such as increased forward light scatter and CD38 expression, peaked 5–7 days after infection of peripheral blood mononuclear cells (PBMC) with the live attenuated Edmonston strain of MV. Subset analysis revealed that both CD3– and CD3+ cells expressed activation markers but that the CD3+ T cells predominated late in the culture period corresponding to maximal proliferation and cell recovery. The majority of CD3+ T cells consisted of CD4+CD8– cells. IFN-γ and IL-4 production similarly showed optimal production late in culture. Depletion of CD4 cells prior to culture and MV stimulation completely abrogated both IFN-γ and IL-4 production, whereas depletion of CD8 cells did not diminish production, suggesting that CD4+CD8– T cells were principally involved in production of these cytokines. Finally, optimal IFN-γ production was elicited at high MV doses and IL-4 at much lower doses. These results suggest that among MV immune individuals, in vitro responses to measles are dominated by CD4+ T cells that, depending on antigen dose, primarily produce a Th1-like and, to a lesser extent, a Th1/Th2-mixed pattern of cytokine release.

ABSTRACT Signaling through Toll‐like receptor 4 (TLR4) is thought to initiate innate and adaptive immune responses. Signaling of TLR4 is usually studied using isolated cells, which are activated by subnanomolar concentrations of lipopolysaccharide (LPS). However, in normal tissues, cells bearing TLR4 reside in microenvironments containing large amounts of endogenous substances that can stimulate the receptor. We developed an in vitro model system using the human cell line HEK 293 and an in vivo model using mice that have normal or that lack TLR4 receptors to study how TLR4 functions in such microenvironments. Here we report that signaling through TLR4 is strongly inhibited by intact extracellular matrix and that inhibition is abrogated and endogenous agonist(s) are liberated when the matrix is degraded. Thus, release from inhibition rather than direct stimulation by agonists such as LPS is the critical first event by which TLR4 initiates immune responses.

Clinical Pharmacology & Therapeutics (2003) 73, P35–P35; doi:

Abstract The PAX8/PPARγ (PPFP) fusion-oncogene is moderately specific for follicular thyroid carcinomas (FTC). It remains unknown whether this can be translated into improved diagnosis, classification, or outcome prediction. We studied a cohort of well-characterized follicular adenomas (FA), FTC, and Hürthle cell carcinomas (HCC) from patients with complete clinical follow-up, to determine whether PPARγ immunohistochemistry (as a surrogate of PAX8/PPARγ expression) helps to distinguish FA from FTC and to assess its diagnostic accuracy as an adjunct to frozen section. We also correlated PPARγ staining with clinical outcomes to assess its role as a prognostic marker. PPARγ staining was more common in FTC (31 of 54; 57%) than in HCC (one of 23; 4%) or FA (four of 31; 13%) (P < 0.000001). Adjunctive use of PPARγ immunohistochemistry improved diagnostic sensitivity of intraoperative frozen section from 84% to 96% (P < 0.05) but reduced specificity from 100% to 90% (P < 0.05). PPARγ staining was associated with favorable prognostic indicators (female gender, better tumor differentiation, and lesser risk of metastases). PPARγ staining may be helpful in the differential diagnosis of FA, FTC, and HCC, particularly when diagnostic sensitivity of histomorphology is reduced (e.g. during intraoperative frozen section). PPARγ staining also shows an association with favorable prognosis and may have a role in risk stratification.