Molecular epidemiologic identification of Escherichia coli genes that are potentially involved in movement of the organism from the intestinal tract to the vagina and bladder

A first step in urinary tract infection (UTI) pathogenesis in the otherwise healthy host is the movement of uropathogenic Escherichia coli from the intestinal tract to the urinary tract. We conducted a genomic subtraction to isolate genetic regions associated with this movement. A representative UTI isolate present in the rectum, vagina, and bladder of a woman with UTI was chosen as the tester; the driver was a phylogenetically distant rectal isolate (based on pulsed-field gel electrophoresis analysis) with a profile of uropathogenic virulence genes similar to that of the tester. Tester-specific regions identified by the subtraction were screened, using DNA dot blot hybridization, against a collection of 88 uropathogens isolated from the rectum, urine, and/or vagina of women with UTIs and 54 E. coli isolates from the same women that were found only in the rectum. Twelve genetic regions occurred more often in multisite isolates than in rectal site-only isolates. Eleven of these 12 genetic regions are homologous to regions in the sequenced uropathogenic E. coli CFT073 strain.     

Variants in candidate ALS modifier genes linked to Cu/Zn superoxide dismutase do not explain divergent survival phenotypes

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; approximately 25% are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. A4V ALS cases typically have a very short survival (1-1.5 years versus 3-5 years for other dominant SOD1 mutations). A recent study of A4V carriers identified a common haplotype around the SOD1 locus, suggesting the hypothesis that genetic variations within the haplotypic region might accelerate the course of A4V cases. By contrast, SOD1(D90A/D90A) ALS cases have a very slow progression (>10 years), raising the reciprocal hypothesis that modifier genes linked to SOD1 ameliorate the phenotype of recessively inherited SOD1(D90A/D90A) mutations. In the present study, DNA sequencing of four genes within the haplotypic region shared in A4V and D90A ALS patients revealed 15 novel variants, but none result in changes in amino acid sequences specifically associated with SOD1(D90A/D90A) or SOD1(A4V) ALS. We conclude that mutations within coding regions of genes around the SOD1 locus are not responsible for the more aggressive and more benign natures of the SOD1(A4V) and SOD1(D90A/D90A) mutations, respectively.     

Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS)

OBJECTIVE: To identify predictors and moderators of response to acute treatments among depressed adolescents (N = 439) randomly assigned to fluoxetine, cognitive-behavioral therapy (CBT), both fluoxetine and CBT, or clinical management with pill placebo in the Treatment for Adolescents With Depression Study (TADS). METHOD: Potential baseline predictors and moderators were identified by a literature review. The outcome measure was a week 12 predicted score derived from the Children's Depression Rating Scale-Revised (CDRS-R). For each candidate moderator or predictor, a general linear model was conducted to examine main and interactive effects of treatment and the candidate variable on the CDRS-R predicted scores. RESULTS: Adolescents who were younger, less chronically depressed, higher functioning, and less hopeless with less suicidal ideation, fewer melancholic features or comorbid diagnoses, and greater expectations for improvement were more likely to benefit acutely than their counterparts. Combined treatment, under no condition less effective than monotherapy, was more effective than fluoxetine for mild to moderate depression and for depression with high levels of cognitive distortion, but not for severe depression or depression with low levels of cognitive distortion. Adolescents from high-income families were as likely to benefit from CBT alone as from combined treatment. CONCLUSIONS: Younger and less severely impaired adolescents are likely to respond better to acute treatment than older, more impaired, or multiply comorbid adolescents. Family income level, cognitive distortions, and severity of depression may help clinicians to choose among acute interventions, but combined treatment proved robust in the presence of moderators.     

Relapse and recurrence in pediatric depression

Depression is a chronic illness in children and adolescents that often leads to long-term difficulties with recurrent episodes of depression. Standard treatment must continue beyond acute symptom reduction to a chronic disease management model, such as those used in pediatric asthma and diabetes. Within the chronic disease management model, treatment interventions are directed not only at the urgent or acute concern but also at the prevention of future problems. Lack of consistent efficacy in acute treatment studies has limited long-term prevention treatment research in pediatric depression. The impact of long-term treatments, both psychosocial and pharmacologic, is currently unknown.     

Blood loss and postoperative complications associated with transurethral resection of the prostate after pretreatment with dutasteride

OBJECTIVE: To determine whether pretreatment with dutasteride, a dual 5alpha-reductase inhibitor (5ARI), reduces surgical blood loss or postoperative complications in patients with benign prostatic hyperplasia (BPH) who undergo transurethral resection of the prostate (TURP). PATIENTS AND METHODS: This double-blind, randomized, placebo-controlled, multicentre study comprised 214 patients with BPH. Placebo was compared with dutasteride 0.5 mg/day 2 weeks before and after TURP, or 4 weeks before and 2 weeks after TURP. Surgical blood loss was measured using a haemoglobin photometer (HemoCue AB, Angelholm, Sweden) and postoperative adverse events were recorded. Microvessel density (MVD) was calculated by immunostaining and light microscopy of the prostatic chips. RESULTS: Although dutasteride reduced serum dihydrotestosterone (DHT) by 86-89% in 2-4 weeks, and intraprostatic DHT was approximately 10 times lower than in the placebo group, the (adjusted) mean haemoglobin (Hb) loss during surgery was 2.15-2.55 g Hb/g resectate with no significant difference in blood loss between the groups either during or after TURP. Clot retention occurred in 6-11% and urinary incontinence in 14-15% of patients during the 14 weeks after TURP, with no difference between the groups. The MVD at TURP was also similar for all groups. CONCLUSION: There were no significant reductions in blood loss during or after TURP or complications afterward with dutasteride compared with placebo, despite significant suppression of intraprostatic DHT. Blood loss and transfusion rates in the placebo group were lower than those previously reported in studies where there was a beneficial effect of a 5ARI, relative to placebo, on bleeding during TURP.     

Secondary evaluations of MTA 36-month outcomes: propensity score and growth mixture model analyses

OBJECTIVE: To evaluate two hypotheses: that self-selection bias contributed to lack of medication advantage at the 36-month assessment of the Multimodal Treatment Study of Children With ADHD (MTA) and that overall improvement over time obscured treatment effects in subgroups with different outcome trajectories. METHOD: Propensity score analyses, using baseline characteristics and severity of attention-deficit/hyperactivity disorder symptoms at follow-up, established five subgroups (quintiles) based on tendency to take medication at the 36-month assessment. Growth mixture model (GMM) analyses were performed to identify subgroups (classes) with different patterns of outcome over time. RESULTS: All five propensity subgroups showed initial advantage of medication that disappeared by the 36-month assessment. GMM analyses identified heterogeneity of trajectories over time and three classes: class 1 (34% of the MTA sample) with initial small improvement followed by gradual improvement that produced significant medication effects; class 2 (52%) with initial large improvement maintained for 3 years and overrepresentation of cases treated with the MTA Medication Algorithm; and class 3 (14%) with initial large improvement followed by deterioration. CONCLUSIONS: We failed to confirm the self-selection hypothesis. We found suggestive evidence of residual but not current benefits of assigned medication in class 2 and small current benefits of actual treatment with medication in class 1.