Our results suggest that ondansetron (particularly the 4 microg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality. JAMA. 2000;284:963-971

No abstract

ABSTRACT. Using the best-fitting multiple logistic regression equation, a 100-point increase in pAkt staining resulted in a 160% increase in the odds of being a PSA failure. There was decreased staining for pERK in PSA failures versus non-failures: a 100-point decrease resulted in an 80% increase in the odds of being a PSA failure. Each of these effects assumed the other biomarker was held constant. The area under the receiver-operating characteristic curve for these two biomarkers predicting PSA failure was 0.84, indicating excellent discrimination between PSA failure and non-failure cases. These data indicate that increased pAkt, alone or together with decreased pERK, is an important predictor of probability of PSA failure. However, pERK alone was not a significant predictor of PSA failure.

To study the effectiveness of adenoidectomy and of the placement of tympanostomy tubes in the treatment of chronic otitis media with effusion, we randomly assigned 578 children, aged four through eight years, to receive bilateral myringotomy and no additional treatment (Group 1), placement of tympanostomy tubes (Group 2), adenoidectomy (Group 3), or adenoidectomy and placement of tympanostomy tubes (Group 4). The 491 children who underwent one of these treatments were examined at six-week intervals for up to two years. The mean time spent with effusion of any type in either ear over the two-year follow-up in the four groups was 51, 36, 31, and 27 weeks, respectively (P less than 0.0001), comparing Group 1 with each of the other groups. Hearing was equivalent in Groups 2, 3, and 4, and was significantly better than in Group 1. The most frequent sequela, purulent otorrhea, occurred one or more times in 22, 29, 11, and 24 percent of the subjects in Groups 1, 2, 3, and 4, respectively (P less than 0.001). Adenoidectomy plus bilateral myringotomy lowered the overall post-treatment morbidity (as measured by hearing acuity in the most severely affected ear [P = 0.0174] and the number of surgical retreatments required [P = 0.009]) more than did tympanostomy tubes alone and to the same degree as did adenoidectomy and tympanostomy tubes. We conclude that adenoidectomy should be considered when surgical therapy is indicated in children four to eight years old who are severely affected by chronic otitis media with effusion.

No abstract

Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes SLCO1B1, SLCO1B3, and MDR1. Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC 0-24 ] of 40.2 versus 40.9 g ⅐ h/ml; P ‫؍‬ 0.9). However, in multivariable analyses, the rifampin AUC 0-24 was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC 0-24 was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC 0-24 was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 g ⅐ h/ml; P ‫؍‬ 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC 0-24 values was observed, but the mean values of the AUC 0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.

Purpose: We previously showed that nuclear localization of the actin-binding protein, filamin A (FlnA), corresponded to hormone-dependence in prostate cancer. Intact FlnA (280 kDa, cytoplasmic) cleaved to a 90 kDa fragment which translocated to the nucleus in hormone-naI« ve cells, whereas in hormone-refractory cells, FlnA was phosphorylated, preventing its cleavage and nuclear translocation. We have examined whether FlnA localization determines a propensity to metastasis in advanced androgen-independent prostate cancer. Experimental Design: We examined, by immunohistochemistry, FlnA localization in paraffinembedded human prostate tissue representing different stages of progression. Results were correlated with in vitro studies in a cell model of prostate cancer. Results: Nuclear FlnA was significantly higher in benign prostate (0.6612 F 0.5888), prostatic intraepithelial neoplasia (PIN; 0.6024 F 0.4620), and clinically localized cancers (0.69134 F 0.5686) compared with metastatic prostate cancers (0.3719 F 0.4992, P = 0.0007). Cytoplasmic FlnA increased from benign prostate (0.0833 F 0.2677), PIN (0.1409 F 0.2293), localized cancers (0.3008 F 0.3762, P = 0.0150), to metastases (0.7632 F 0.4414, P < 0.00001). Logistic regression of metastatic versus nonmetastatic tissue yielded the area under the receiver operating curve as 0.67 for nuclear-FlnA, 0.79 for cytoplasmic-FlnA, and 0.82 for both, indicating that metastasis correlates with cytoplasmic to nuclear translocation. In vitro studies showed that cytoplasmic localization of FlnA induced cell invasion whereas nuclear translocation of the protein inhibited it. FlnA dephosphorylation with the protein kinaseA inhibitor H-89 facilitated FlnA nuclear translocation, resulting in decreased invasiveness and AR transcriptional activity, and induced sensitivity to androgen withdrawal in hormone-refractory cells. Conclusions:The data presented in this study indicate that in prostate cancer, metastasis correlates with cytoplasmic localization of FlnA and may be prevented by cleavage and subsequent nuclear translocation of this protein.Filamins are a family of cytoskeletal proteins that organize filamentous actin into networks and stress fibers (1). Filamin A (FlnA) is a 280 kDa non -muscle actin binding protein, the appropriate function of which is essential for development (2, 3). FlnA dimerization forms a V-shaped flexible structure which can induce high-angle orthogonal branching and efficiently gather actin filaments into a three-dimensional gel in vitro by cross-linking actin filaments at the leading edge of migrating cells. Hence, filamins are essential for mammalian cell locomotion, anchoring of transmembrane proteins including integrins, and also act as interfaces for protein-protein interaction (4). More than 30 proteins of great functional diversity are known to interact with filamins which function as a signaling scaffold by connecting and coordinating a large variety of cellular processes (4).In prostate cancer, a role for FlnA was identified in prost...

The lack of a generally accepted case definition for multiple chemical sensitivity (MCS) and the absence of a standardized approach for measuring salient aspects of chemical sensitivity that would permit cross-comparison of findings by different investigators have hindered progress in this area. Based upon findings from an earlier study of 112 persons with self-reported chemical sensitivity who attributed their chemical sensitivity to a well-defined exposure event, we developed an instrument with self-rating scales to assess Symptom Severity, Chemical (Inhalant) Intolerances, Other Intolerances (e.g., foods, medications, alcohol), Life Impact, and Masking (a measure of ongoing chemical exposures). When administered to four patient groups and controls, the scales showed good reliability and validity overall (n = 421) and in each group. Used together, the scales provided sensitivity of 92% and specificity of 95% in differentiating chemically sensitive persons from controls. Our results support use of these scales individually or collectively for a variety of applications including the selection of chemically sensitive subjects and controls for research, assessment of chemical sensitivity in various study populations, cross-comparison of groups studied by different investigators, pre- and post-assessment of therapeutic interventions, clinical evaluation of complex patients who report intolerances, and teaching medical residents and students how to evaluate patients for chemical sensitivity and MCS.