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Audrey Anna Bolyard Merideth L. Kelley Jennifer E. Below Michael J. Bamshad Kathryn M. Bofferding Joshua D. Smith Kati Buckingham Laurence A. Boxer Julia Skokowa Karl Welte Deborah A. Nickerson Gail P. Jarvik David C. Dale for the UW Center for Mendelian Genomics 《Human mutation》2014,35(7):824-827
Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30% of cases remains unknown. We report a five‐generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1. 相似文献
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Li Z Huang H Li Y Jiang X Chen P Arnovitz S Radmacher MD Maharry K Elkahloun A Yang X He C He M Zhang Z Dohner K Neilly MB Price C Lussier YA Zhang Y Larson RA Le Beau MM Caligiuri MA Bullinger L Valk PJ Delwel R Lowenberg B Liu PP Marcucci G Bloomfield CD Rowley JD Chen J 《Blood》2012,119(10):2314-2324
Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. 相似文献
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Thorsten Suess Cornelius Remschmidt Susanne B Schink Brunhilde Schweiger Andreas Nitsche Kati Schroeder Joerg Doellinger Jeanette Milde Walter Haas Irina Koehler Gérard Krause Udo Buchholz 《BMC infectious diseases》2012,12(1):1-16
Background
Previous controlled studies on the effect of non-pharmaceutical interventions (NPI) - namely the use of facemasks and intensified hand hygiene - in preventing household transmission of influenza have not produced definitive results. We aimed to investigate efficacy, acceptability, and tolerability of NPI in households with influenza index patients.Methods
We conducted a cluster randomized controlled trial during the pandemic season 2009/10 and the ensuing influenza season 2010/11. We included households with an influenza positive index case in the absence of further respiratory illness within the preceding 14 days. Study arms were wearing a facemask and practicing intensified hand hygiene (MH group), wearing facemasks only (M group) and none of the two (control group). Main outcome measure was laboratory confirmed influenza infection in a household contact. We used daily questionnaires to examine adherence and tolerability of the interventions.Results
We recruited 84 households (30 control, 26 M and 28 MH households) with 82, 69 and 67 household contacts, respectively. In 2009/10 all 41 index cases had a influenza A (H1N1) pdm09 infection, in 2010/11 24 had an A (H1N1) pdm09 and 20 had a B infection. The total secondary attack rate was 16% (35/218). In intention-to-treat analysis there was no statistically significant effect of the M and MH interventions on secondary infections. When analysing only households where intervention was implemented within 36 h after symptom onset of the index case, secondary infection in the pooled M and MH groups was significantly lower compared to the control group (adjusted odds ratio 0.16, 95% CI, 0.03-0.92). In a per-protocol analysis odds ratios were significantly reduced among participants of the M group (adjusted odds ratio, 0.30, 95% CI, 0.10-0.94). With the exception of MH index cases in 2010/11 adherence was good for adults and children, contacts and index cases.Conclusions
Results suggest that household transmission of influenza can be reduced by the use of NPI, such as facemasks and intensified hand hygiene, when implemented early and used diligently. Concerns about acceptability and tolerability of the interventions should not be a reason against their recommendation.Trial registration
The study was registered with ClinicalTrials.gov (Identifier NCT00833885). 相似文献29.
ABSTRACTBackground: Emotive adjectives are used in everyday conversations to express opinions and feelings and make evaluations (e.g., “interesting”, “intelligent”). It has been reported that people with aphasia have difficulty using emotive language and that they would like this to be targeted in therapy. However, the literature provides little guidance whether it is possible to improve production of emotive adjectives.Aims: Our aim was to test the hypothesis that a treatment technique that has been found to be effective in improving noun and verb retrieval (Repetition in the Presence of a Picture) would be effective in improving production of emotive adjectives.Methods & Procedures: This study involved GEC, a 66-year-old English-speaking man who presented with non-fluent aphasia including frequent word-finding difficulties and impaired production of emotive adjectives following a left-hemisphere stroke. Treatment was carried out using a single-subject multiple-baseline design consisting of two treatment periods each of 2 weeks preceded by four baseline measurements, with one within-treatment measurement and three post-treatment measurements (immediately, 1-week, and 11 weeks after the end of the treatment programme). The treatment comprised weekly meetings with the therapist and computer-presented, self-paced, home-practice using to treat 72 emotive adjectives (36 positive and 36 negative adjectives) associated with 24 pictures.Outcomes & Results: GEC’s ability to produce treated adjectives for treated pictures significantly improved. The effect was maintained for the positive items with maintenance for negative items close to significant. However, these item-specific effects of treatment did not generalise: No significant improvement was observed in producing new, untreated labels for the treated pictures. Nor was GEC able to use treated labels with pictures other than those with which they were treated. In addition, GEC’s performance in a connected speech task remained unchanged. These results indicate that the treatment effects were not only item-specific but also task-specific.Conclusions: This study provides the first demonstration that emotive adjective retrieval may be improved using a treatment method similar to that commonly used for treating nouns and verbs. This result was achieved after only 2 weeks of practice at home with a computer including sparse meetings with a therapist and targeting only single-word production of adjectives. While there was no evidence of generalisation across items or tasks, this study encourages further exploration of the topic. This should include replication across participants and the inclusion of more natural conversational tasks in the treatment to facilitate transfer. 相似文献
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Mönkkönen KS Aflatoonian R Lee KF Yeung WS Tsao SW Laitinen JT Tuckerman EM Li TC Fazeli A 《Human reproduction (Oxford, England)》2007,22(5):1224-1230
BACKGROUND: Heterotrimeric G proteins take part in membrane-mediated cell signalling and have a role in hormonal regulation. This study clarifies the expression and localization of the G protein subunit G alpha(i2) in the human endometrium and Fallopian tube and changes in G alpha(i2) expression in human endometrium during the menstrual cycle. METHODS: The expression of G alpha(i2) was identified by Polymerase chain reaction (PCR), and localization confirmed by immunostaining. Cyclic changes in G alpha(i2) expression during the menstrual cycle were evaluated by quantitative real-time PCR. RESULTS: We found G alpha(i2) to be expressed in human endometrium, Fallopian tube tissue and in primary cultures of Fallopian tube epithelial cells. Our studies revealed enriched localization of G alpha(i2) in Fallopian tube cilia and in endometrial glands. We showed that G alpha(i2) expression in human endometrium changes significantly during the menstrual cycle, with a higher level in the secretory versus proliferative and menstrual phases (P < 0.05). CONCLUSIONS: G alpha(i2) is specifically localized in human Fallopian tube epithelial cells, particularly in the cilia, and is likely to have a cilia-specific role in reproduction. Significantly variable expression of G alpha(i2) during the menstrual cycle suggests G alpha(i2) might be under hormonal regulation in the female reproductive tract in vivo. 相似文献