Group testing in mediation analysis

We consider the scenario where there is an exposure, multiple biologically defined sets of biomarkers, and an outcome. We propose a new two-step procedure that tests if any of the sets of biomarkers mediate the exposure/outcome relationship, while maintaining a prespecified familywise error rate. The first step of the proposed procedure is a screening step that removes all groups that are unlikely to be strongly associated with both the exposure and the outcome. The second step adapts recent advances in postselection inference to test if there are true mediators in each of the remaining candidate sets. We use simulation to show that this simple two-step procedure has higher statistical power to detect true mediating sets when compared with existing procedures. We then use our two-step procedure to identify a set of Lysine-related metabolites that potentially mediate the known relationship between increased body mass index and the increased risk of estrogen-receptor positive breast cancer in postmenopausal women.     

Differentiation of Motor Activity of Normally Active and Hyperactive Boys in Schools: Some Preliminary Results

All non-task-related body movements during school hours were listed in 11 normally active and 12 hyperactive boys. The mean number of movements was 48 +/- 7 per 45 minutes in the normal actives and 79 +/- 16 per 45 minutes in the hyperactives. The rather monotonous increment and decrement of motor activity during the 4-hr registration period was noticed only in hyperactive boys. These results could be a consequence of a circadian rhythm, as there was independence of type of school hours and of teacher personality. The cyclical level of activity in hyperactive boys was sometimes in the range of the normal actives.     

Prospective multicenter clinical trial of Uretex Sup for surgical treatment of stress urinary incontinence

AIM: To evaluate in a prospective multicenter study the efficacy and safety of the suburethral support Uretex (Sofradim, Trevoux, France) delivered by a suprapubic approach in the treatment of female stress urinary incontinence. METHODS: Between March 2002 and March 2003, 57 patients were treated for stress urinary incontinence with Uretex. Preoperative evaluation included urodynamic examination and questionnaires (symptoms and quality of life, Contilife). Forty patients had pure stress urinary incontinence and 17 mixed urinary incontinence. No associated procedure was performed. The objective cure rate was evaluated by clinical examination and pad-test, and the subjective cure rate was assessed through questionnaires at 1, 3 and 12 months. RESULTS: The mean follow-up was 13 months (range 11-24 months). During follow up, chronic urinary retention requiring a tape section occurred in one patient, and in another patient a delay of vaginal healing was followed by a sling exposure and resection at 4 months. No infection or urethral erosion was reported. The objective cure rate was 96.2%, and the subjective cure rate was 79.2%; four patients reported low leakage on stress and nine patients complained of urge incontinence (four de novo and five persistent). CONCLUSION: The suprapubic Uretex Sup procedure is a safe and effective treatment for women with stress urinary incontinence.     

Increased Radiosensitivity as an Indicator of Genes Conferring Breast Cancer Susceptibility

PURPOSE: This paper briefly summarizes the research on increased radiosensitivity in breast cancer patients measured by the micronucleus test (MNT) and its association to genetic variants in DNA repair genes. More preliminary data are presented on the distribution of chromosomes and chromosome fragments in micronuclei (MN) in order to gain more information on clastogenic and aneugenic effects and better understand the phenotype of increased radiosensitivity. MATERIAL AND METHODS: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. In four patients with high MN frequency (three cancer patients, one control) and four probands with low MN frequency, the presence of chromosome fragments or whole chromosomes in MN was determined by fluorescence in situ hybridization analysis for chromosomes 1, 7, and 17. RESULTS: An increased MN frequency in breast cancer patients compared to controls has consistently been reported with high significance. Higher MN frequencies were observed in 20-50% of breast cancer patients. Chromosomal fragments of chromosome 17, but not of chromosomes 1 and 7 were more frequent in the probands with high MN frequency than in those with low frequency (p = 0.045). CONCLUSION: The MNT detects a cellular phenotype common to a portion of sporadic breast cancer patients. This phenotype is very likely to be genetically determined. For the genetic dissection of breast cancer susceptibility this phenotype may turn out to be more efficient than breast cancer itself. Additional parameters which can be measured simultaneously with the MN frequency may be able to further enhance its usefulness.     

Expression of a 1,25-dihydroxyvitamin D3 membrane-associated rapid-response steroid binding protein during human tooth and bone development and biomineralization.

The calciotropic hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] has been established to control skeletal tissue formation and biomineralization via the regulation of gene expression. This action involves the well-characterized nuclear 1,25(OH)2D3 receptor. However, it has been recognized that several cellular responses to 1,25(OH)2D3 may not to be related to the exclusive nuclear receptor. Indeed, this secosteroid is able to generate rapid responses that have been proposed to be mediated by interactions of the ligand, which is a putative cell membrane-associated rapid-response steroid (MARRS) binding protein for 1,25(OH)2D3 [1,25D3-MARRS]. The nongenomic pathway of 1,25(OH)2D3 was studied here in detail by immunolocalization of the 1,25D3-MARRS during the specific context of human prenatal development. Western blotting with proteins extracted from 4 week- to 27-week-old embryos was performed, evidencing a 65-kDa molecular species recognized by antibody Ab 099 generated against synthetic peptides corresponding to the N terminus of the 1,25D3-MARRS from chick intestinal basolateral membranes. Based on this biochemical conservation of protein in the human species, the temporospatial expression patterns were established in the craniofacial skeleton at the same ages. Comparative analysis was performed in teeth and bones from early morphogenesis to terminal cell differentiation and extracellular biomineralization. The data show the potential implication of 1,25D3-MARRS in the heterogeneous cell population including ameloblasts, odontoblasts, osteoblasts, and osteoclasts. The epithelial-mesenchymal cascade related to odontogenesis was coincident with a sequence of up- and down-regulation of immunoreactive 1,25D3-MARRS. Biomineralization was associated with a striking up-regulation in the adjoining secretory cells in all tissues. Finally, osteoclasts appeared also to express the 1,25D3-MARRS during these early phases of bone modeling. Previously obtained data of the nuclear vitamin D receptor (VDR) expression and this study on 1,25D3-MARRS suggest the existence of cross-talk between the genomic and nongenomic pathways during human development.     

Alcohol, Osteoporosis, and Bone Regulating Hormones

The mechanism of the production of ethanol-associated osteopenia seems to be a direct effect of alcohol on bone cells and an indirect or modulating effect through mineral regulating hormones such as vitamin D metabolites, parathyroid hormone, and calcitonin. The modulating effects of these hormones on bone and mineral metabolism in acute and chronic alcohol consumption is discussed herein. Key Words: Alcohol, PTH, Calcitonin, Vitamin D, Bone.     

Sensory deafferentation fails to modify muscarinic receptor binding in raccoon somatosensory cortex

The characteristics and distribution of muscarinic acetylcholine (mACh) receptor binding in primary somatosensory (SI) cortex and the caudate nucleus of raccoons were studied using [3H]-QNB, a muscarinic antagonist. The binding characteristics were similar to reported values in rat and cat. Autoradiographs produced from tissue sections labeled with [3H]-QNB showed the distribution of mACh receptors in the forebrain of the raccoon. [3H]-QNB binding was highest in cerebral cortex, neostriatum and hippocampus. Within SI cortex, binding was high in layers I-III and VI and relatively low in layers IV and V. Autoradiographs obtained from animals that had undergone peripheral deafferentation of part of the forepaw revealed no changes in [3H]-QNB binding in the affected cortical region during the time that physiological reorganization is known to occur.     

Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial.

BACKGROUND: We tested whether transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. METHODS: In a double-blind, multisite study, 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted five times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3000 pulses/session, for 4-6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. RESULTS: Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well tolerated with a low dropout rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain. CONCLUSIONS: Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.     

Food allergy as a risk factor for asthma morbidity in adults.

BACKGROUND: The objective of this study was to evaluate the relationship between food allergy and asthma morbidity in adults. METHODS: We interviewed a cohort of persistent asthmatics from an inner-city clinic. Allergies to food were assessed by patient report of convincing symptoms of acute allergic reactions. Outcome variables included health resource utilization and medication use. RESULTS: The prevalence of allergy to fish, peanut, tree-nut, shellfish, and seed allergies were 3%, 3%, 3%, 13%, and 1%. Patients with allergies to > 1 food had increased asthma hospitalizations, ED visits, and use of oral steroids (p < 0.05 for all comparisons). Specifically, allergy to fish was associated with a greater risk of health resource utilization and increased frequency of oral steroid use (p < or = 0.03 for all comparisons). CONCLUSIONS: Self-reported allergy to foods was associated with worse outcomes, suggesting that food allergy may be a risk factor for increased asthma morbidity in adults.