Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial

Context  Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. Objective  To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder. Design, Setting, and Participants  Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. Interventions  Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. Main Outcome Measures  Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. Results  Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P = .001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P = .02) and CBT alone (P = .01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P = .01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone, 60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%-52%); and placebo, 34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P = .02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. Conclusion  The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder.      

Immunosuppression use in renal transplantation from Asian transplant centers: a preliminary report from the Asian Transplant Registry

Since the first renal transplant (RTx) in 1956 in Asia in Japan, over 100,000 RTx have been performed in over 300 centers across the region. A survey was conducted to evaluate immunosuppression (IS) use among Asian RTx. Briefly, directors of RTx centers were surveyed regarding IS use for RTx performed at their centers in 2001 for (1) induction therapy, (2) maintenance IS therapy at hospital discharge, (3) antirejection treatment (REJ) to 1 year post-RTx, and (4) maintenance IS therapy to 1 year post-RTx. Categories and types of IS included in the survey were polyclonal antilymphocyte antibodies (PAB), OKT3, IL2 receptor antibodies (IL2RAb), corticosteroids (CS), cyclosporine (CyA), tacrolimus (Tac), azathioprine (Aza), mycophenolate mofetil (MMF), Mizoribine (Miz), Sirolimus (Sir), and other agents. Though only 17 RTx centers in Asia responded to the survey, a wide variation in IS use was demonstrated. In the 334 living and 85 cadavericRTx among whom actual usage was reported, induction therapy was used in only 18.4% of Asian RTx (14.1%, IL2RAb; 4.3%, PAB), in contrast to the 59.3% reported as using induction IS among RTx from the UNOS database in the same year. For maintenance therapy at hospital discharge, 87.1% of Asian RTx received CyA-based IS while only 12.4% received Tac-based therapy. This is in contrast to the 55.3% use of Tac for new RTx in the United States. Generic CyA has widespread use in Asia with over 29.9% on CyA using generic versus the Neoral formulation. Azathioprine is still the predominant antimetabolite in use in Asian RTx, with MMF being used in only 33.6% of patients, in contrast to its 77% usage in the United States. Usage of Tac and MMF for maintenance therapy was significantly higher among cadavericRTx (P < .005). Corticosteroids were used in 51.1% of REJ episodes while PAB or OKT3 were used in 31.9% and 17% of REJ episodes, respectively. As these results may be skewed due to participation of few centers in the survey, greater participation will ensure more accurate evaluation of immunosuppression use in Asia for de novo RTx.     

Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression

BACKGROUND: Cyclosporine (CsA) is a substrate for the MDR-1 gene product P-glycoprotein (P-gp). CsA efficacy may be modulated by lymphocyte P-gp expression levels. In this study, CsA inhibition of lymphocyte proliferation in whole-blood cultures ex vivo has been related to (1) lymphocyte P-gp expression and (2) the C3435T polymorphism in the MDR-1 gene, which has been reported to alter P-gp function. METHODS: In 30 renal-transplant recipients taking CsA monotherapy, P-gp expression was measured by flow cytometry. Whole-blood samples were stimulated with purified protein derivative (PPD) and phytohemagglutinin (PHA). CsA resistance ex vivo was defined as less than 10% reduction in proliferation with either PPD or PHA at 2 hours compared with 0 hours. RESULTS: CsA resistance was associated with greater P-gp expression using either PPD (median expression, resistant 1.89 vs. sensitive 0.96, P =0.02) or PHA (1.66 vs. 0.96, respectively, P =0.02). Whole-blood CsA levels in resistant and sensitive patients were similar. The C3435T polymorphism did not affect inhibition of proliferation by CsA (P >0.05 for all between genotype group comparisons). CONCLUSIONS: Our results indicate that lymphocyte P-gp expression determines the degree of inhibition of proliferation by CsA ex vivo; whether this also affects CsA effectiveness in vivo and therefore graft survival requires further study.     

Racial and center differences in hemodialysis adequacy in children treated at pediatric centers: a North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) report

This study assessed hemodialysis adequacy in pediatric centers. Monthly adequacy data were requested in NAPRTCS enrollees on hemodialysis for at least 6 mo. Data forms were returned for 147 children from 32 centers. Data are presented for the 138 children (57% boys, 45% black) that were dialyzed 3 times/wk, representing 2282 patient-months of follow-up. Pre- and postdialysis BUN levels were reported in all children. Kt/V values were reported in 76 children; however, sufficient data were obtained to calculate Kt/V in 129 children. On average, 14.9 Kt/V and 15.2 urea reduction ratio (URR) values were calculated per child. Aggregate dialysis dose was defined as adequate if Kt/V was >1.2 in at least 75% of calculated Kt/V measures within a subject. Mean +/- SD age was 11.3 +/- 3.7 yr (median, 12.0 yr). Hemodialysis dose was variable within subjects (median CV%: URR 8.2, Kt/V 16.9). Aggregate dialysis dose was adequate in 70% of subjects. Multivariate logistic regression showed male gender (OR, 0.41; 95% CI, 0.16 to 0.98), black race (OR, 0.28; 95% CI, 0.11 to 0.67), larger body surface area (fourth versus first quartile: OR, 0.22; 95% CI, 0.05 to 0.80), and absence of reported Kt/V at the treating center (OR, 0.26; 95% CI, 0.10 to 0.62) were significant predictors of inadequate dialysis dose. Age, renal diagnosis, and center size were not associated with adequacy. Racial and gender disparities in hemodialysis dose existed among children at specialized academic pediatric centers and a substantial proportion received inadequate hemodialysis.     

The cost of clinically significant urinary storage symptoms for community dwelling adults in the UK

OBJECTIVES: To estimate the cost of clinically significant urinary storage symptoms (CSUSS), including costs borne by the National Health Service (NHS) and individuals, in terms of the use of goods and services in community-dwelling adults. SUBJECTS AND METHODS: The subjects were community-dwelling adults aged >/= 40 years and living in Leicestershire. The prevalence of CSUSS was estimated using a postal questionnaire with a randomly selected sample of 23 182 respondents. The costs associated with CSUSS were estimated using home interviews with 613 cases with and 523 subjects without CSUSS. Cases were defined on the basis of urinary symptoms of leakage, urgency, frequency and nocturia. Willingness-to-pay was used to measure intangible costs as an indicator of the value of alleviating symptoms. RESULTS: The estimated total annual cost to the NHS for treating CSUSS cases in community-dwelling adults was pound 536 million at 1999/2000 prices ( pound 303 million and pound 233 million for men and women, respectively). The total value of costs borne by individuals was estimated to be pound 207 million ( pound 29 million and pound 178 million for men and women, respectively). This gives total annual costs related to the use of services of pound 743 million. There were large intangible costs borne by individuals estimated to be pound 669 million ( pound 301 and pound 368 million for men and women) for the UK in terms of willingness-to-pay. CONCLUSIONS: The costs of CSUSS in the community amounted to approximately 1.1% of overall NHS spending for 1999/2000. Personally borne and intangible costs are also large and important components of the costs of CSUSS. There are large gender differences in the proportion of costs borne by the NHS, i.e. 91% of male and 57% of female costs.     

VEGF receptors on chronic lymphocytic leukemia (CLL) B cells interact with STAT 1 and 3: implication for apoptosis resistance.

We have previously shown that chronic lymphocytic leukemia (CLL) B cells secrete vascular endothelial growth factor (VEGF) in vitro, have constitutively active VEGF receptors R1 and R2, and respond to exogenous VEGF by specifically upregulating Mcl-1 and XIAP in association with decreased cell death. We found that epigallocatechin (EGCG) decreases VEGF receptor phosphorylation and induces apoptosis in CLL B cells. The mechanism(s) by which VEGF receptor activation increases Mcl-1 and XIAP and promotes survival remains unknown. To further define the signaling pathway mediating VEGF induction of antiapoptotic proteins in CLL B-cells, we investigated downstream effects of VEGF-VEGF receptor binding on the STAT signaling pathway. We find that CLL B cells abundantly express cytoplasmic serine phosphorylated (p)-STAT-1 and p-STAT-3, VEGF-R1/2 are physically associated with p-STAT-1 and p-STAT-3, and p-STAT-3 (but not p-STAT-1) is found in the CLL nucleus. VEGF receptor ligation selectively induces activation and perinuclear translocation of STAT 3 through receptor-mediated endocytosis. The inhibition of VEGF receptor activation with either tyrosine kinase inhibitors or VEGF neutralizing antibodies inhibit VEGF receptor phosphorylation, decrease p-STAT-3 (serine 727), Mcl-1, and induces cell death in CLL B cells. Thus, a VEGF-VEGF receptor pathway in CLL B cells can be linked to activation of STAT proteins that are able to enhance their apoptotic resistance.     

Glanzmann's thrombasthenia: identification of 19 new mutations in 30 patients

Glanzmann's thrombasthenia (GT) is a genetically heterogeneous autosomal recessive syndrome associated with a bleeding tendency. To elucidate molecular basis of GT we have screened for mutations 30 GT patients. On the whole, 21 different candidate causal mutations, 17 in the alphaIIb and 4 in the beta3 gene have been found. Only two (alphaIIb Pro145Ala and IVS3(-3)-418del) have been previously reported. Nine mutations (42.9%) were likely to produce truncated proteins, whereas the remaining 12 were missense mutations that affected highly conserved residues in alphaIIb and beta3 genes. Six mutations were found in different patients suggesting a possible founder effect. The wide spectrum of expressivity, ranging from mild to severe also among patients carrying the same mutations, provided evidence for a role of different loci or circumstantial factors. In conclusion, we have identified a spectrum of unreported mutations that may be of value to unravel the role of specific regions of alphaIIb and beta3 genes.