Macrophages and infertility: enhancement of human macrophage-mediated sperm killing by antisperm antibodies

The mechanism by which antisperm antibodies inhibit fertility is not completely understood. Macrophages may play a role in mediating infertility by interacting with sperm and destroying gametes. Experiments were conducted evaluating the effect of antisperm antibody on the phagocytosis and lysis of sperm by human peritoneal macrophages in vitro. Sperm from a fertile man treated with sera from normal men and women or medium alone had 5 to 280 molecules of IgG/sperm, as determined by a 125I-labeled anti-human IgG monoclonal antibody assay. By contrast, sperm treated with sera containing antisperm antibodies had 310 to 1240 molecules of IgG/sperm. Peritoneal macrophages harvested from infertile women with tubal/adhesive problems mediated phagocytosis and lysis of 111In-labeled sperm which was enhanced by treatment of the sperm with sera containing antisperm antibodies (39.0% +/- 1.5% versus 76.3% +/- 3.2% phagocytosis, and 3.3% +/- 0.3% versus 23.3% +/- 2.3% lysis of sperm [control versus antibody-treated]). The likelihood of fertilization in couples with antisperm antibody may be determined not only by the antibody but also by the presence of genital tract macrophages capable of destroying the antibody-coated sperm.     

Evaluation of Preoperative Therapy for Pancreatic Cancer Using a Prognostic Nomogram

Background Theoretical benefits of preoperative chemoradiation therapy (preop CRT) for pancreatic cancer include improved efficacy, resectability, and patient selection. The goal of this study was to evaluate the applicability of a nomogram, which was developed for patients undergoing resection without preop CRT and which incorporates several post-resection pathological factors, to a population of patients who received preop CRT prior to resection.Methods From 1994 to 2004, 82 patients with biopsy-proven, radiographically localized adenocarcinoma of the pancreatic head underwent preop CRT followed by pancreaticoduodenectomy (PD); 50 concurrent patients underwent PD without preop CRT. Mean nomogram-predicted disease-specific survival (DSS) rates were compared with observed DSS rates from the time of resection.Results Despite having more locally advanced tumors on initial staging (21 vs. 8%; P < .05), patients who received preop CRT had smaller resected tumors (mean 2.3 vs. 3.1 cm; P < .01), were less likely to have T3 tumors (54 vs. 80%, P < .01), were less likely to have positive lymph nodes (29 vs. 58%, P < .01), and had fewer positive lymph nodes (mean .4 vs. 1.9, P < .01), all factors that imply treatment effect and favorably impact on nomogram-predicted DSS. Observed DSS was similar to predicted DSS in both groups.Conclusions The similarity in observed and predicted DSS following resection in patients who received preop CRT suggests that the effects of preop CRT—whether treatment, selection, or no effect—are reflected by the nomogram. The ability of the nomogram to evaluate the effects of preop CRT on survival is limited by the potential effects of preop CRT on factors within the nomogram.     

Smoked cocaine discrimination in humans: effects of gabapentin

Gamma-aminobutyric acid (GABA) agonists, such as the GABA analogue, gabapentin, may provide new avenues for pharmacological treatment of cocaine dependence. The purpose of this study was to develop a smoked cocaine drug discrimination procedure in humans to test the effects of gabapentin maintenance on the discriminative stimulus, subjective, cognitive and cardiovascular effects of smoked cocaine. Eight male, nontreatment-seeking, cocaine-dependent volunteers, residing on an inpatient research unit for 47 days completed a within-subjects, counter-balanced design. Participants learned to discriminate between cocaine (25 mg) and placebo, and once the criterion for discrimination was met, smoked cocaine dose-effect functions (0, 6, 12, 25 and 50 mg) were determined under three gabapentin maintenance conditions (0, 600 and 1200 mg/day po). The highest dose of gabapentin tested (1200 mg/day) decreased the discriminative stimulus effects of cocaine (6 mg), decreased cocaine craving by 41-53% following cocaine administration (6 and 12 mg), and increased heart rate following either placebo or cocaine (12 mg) administration. Gabapentin did not significantly affect psychomotor task performance or the subjective effects of cocaine. Although the direction of gabapentin's effects was appropriate for a potential treatment medication, i.e., a decrease in cocaine-elicited craving and a decrease in cocaine's discriminative stimulus effects, these effects were limited to low doses of cocaine. The results suggest gabapentin may not produce effects sufficiently robust to be clinically useful, at least at this dose regimen.     

An evaluation of the reinforcing effects of memantine in cocaine-dependent humans

The purpose of this double-blind, outpatient study was to evaluate the reinforcing and subjective effects of the uncompetitive N-methyl-d-aspartate (NMDA) antagonist memantine in cocaine-dependent humans. Eight participants (two females, six males) completed this study which consisted of three blocks of seven sessions; each block tested a different dose of memantine. During the first two sessions of each block, participants "sampled" the memantine capsule (10, 20, or 30 mg) and the placebo capsule that were available for the next five sessions. During the five subsequent sessions, participants had an opportunity to self-administer either the active or placebo capsule. Memantine was not reinforcing and subjective-effects ratings were not altered as a function of dose. Results suggest that these doses of memantine do not have abuse liability in cocaine-dependent individuals.     

The effects of acute pretreatment with high-dose memantine on the cardiovascular and behavioral effects of cocaine in humans

This study examined the acute effects of pretreatment with high-dose memantine, an N-methyl-D-aspartate antagonist, on the effects of cocaine in humans. Six African American men completed this laboratory study, in which, following pretreatment with memantine (0 or 60 mg), they had 5 opportunities to smoke cocaine base (0, 12, 25, or 50 mg) or receive an alternative reinforcer ($5.00 merchandise voucher). Cocaine alone produced the well-documented dose-dependent increases in cardiovascular activity and ratings of positive mood. Maximal systolic blood pressure was elevated during memantine pretreatment days. Peak ratings of "I feel stimulated" and "I feel anxious" were also higher with memantine pretreatment. However, memantine pretreatment did not alter the choice to self-administer cocaine. These data suggest that memantine pretreatment may not be helpful in the treatment of cocaine dependence.     

Efficacy of a new, oral estradiol acetate formulation for relief of menopause symptoms

OBJECTIVE: To determine the efficacy of three doses of a new, oral formulation of estradiol acetate (EA) for alleviation of vasomotor and urogenital symptoms in postmenopausal women. DESIGN: Two separate 12-week studies were undertaken in postmenopausal women with moderate to severe vasomotor symptoms. In the first study, women were randomly assigned to EA 0.9 mg/day, EA 1.8 mg/day, or placebo (study 1; N = 293), and in the second study to oral EA 0.45 mg/day or placebo (study 2; N = 259). Women recorded the frequency and severity of vasomotor symptoms daily and urogenital symptoms weekly on diary cards. Investigators assessed signs of vaginal atrophy. RESULTS: Frequency of moderate to severe vasomotor symptoms decreased significantly versus placebo, starting at week 2 in the EA 1.8-mg group (P = 0.005), week 3 in the EA 0.9-mg group (P = 0.003), and week 6 in the EA 0.45-mg group (P < 0.05). At week 12, mean percent reduction from baseline in vasomotor-symptom frequency was 91%, 78%, and 61%, respectively. Vasomotor-symptom severity decreased significantly versus placebo, starting at weeks 2 and 3 with EA 1.8 mg and 0.9 mg, respectively, and at week 5 with EA 0.45 mg. Vaginal pH and maturation index improved significantly in all EA groups versus placebo, and some signs and symptoms of vaginal atrophy improved at the EA 0.9- and 1.8-mg doses. Side effects were mild to moderate and consistent with estrogen therapy. CONCLUSIONS: Oral EA at all doses was well tolerated and significantly reduced the frequency and severity of postmenopause symptoms versus placebo.