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1.  Myocardial T2 mapping reveals age- and sex-related differences in volunteers 
Background
T2 mapping indicates to be a sensitive method for detection of tissue oedema hidden beyond the detection limits of T2-weighted Cardiovascular Magnetic Resonance (CMR). However, due to variability of baseline T2 values in volunteers, reference values need to be defined. Therefore, the aim of the study was to investigate the effects of age and sex on quantitative T2 mapping with a turbo gradient-spin-echo (GRASE) sequence at 1.5 T. For that reason, we studied sensitivity issues as well as technical and biological effects on GRASE-derived myocardial T2 maps. Furthermore, intra- and interobserver variability were calculated using data from a large volunteer group.
Methods
GRASE-derived multiecho images were analysed using dedicated software. After sequence optimization, validation and sensitivity measurements were performed in muscle phantoms ex vivo and in vivo. The optimized parameters were used to analyse CMR images of 74 volunteers of mixed sex and a wide range of age with typical prevalence of hypertension and diabetes. Myocardial T2 values were analysed globally and according to the 17 segment model. Strain-encoded (SENC) imaging was additionally performed to investigate possible effects of myocardial strain on global or segmental T2 values.
Results
Ex vivo studies in muscle phantoms showed, that GRASE-derived T2 values were comparable to those acquired by a standard multiecho spinecho sequence but faster by a factor of 6. Besides that, T2 values reflected tissue water content. The in vivo measurements in volunteers revealed intra- and interobserver correlations with R2=0.91 and R2=0.94 as well as a coefficients of variation of 2.4% and 2.2%, respectively. While global T2 time significantly decreased towards the heart basis, female volunteers had significant higher T2 time irrespective of myocardial region. We found no correlation of segmental T2 values with maximal systolic, diastolic strain or heart rate. Interestingly, volunteers´ age was significantly correlated to T2 time while that was not the case for other coincident cardiovascular risk factors.
Conclusion
GRASE-derived T2 maps are highly reproducible. However, female sex and aging with typical prevalence of hypertension and diabetes were accompanied by increased myocardial T2 values. Thus, sex and age must be considered as influence factors when using GRASE in a diagnostic manner.
Electronic supplementary material
The online version of this article (doi:10.1186/s12968-015-0118-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12968-015-0118-0
PMCID: PMC4318191  PMID: 25656484
Cardiovascular magnetic resonance; T2 mapping; Volunteer study; SENC
5.  The natural history of conducting and reporting clinical trials: interviews with trialists 
Trials  2015;16:16.
Background
To investigate the nature of the research process as a whole, factors that might influence the way in which research is carried out, and how researchers ultimately report their findings.
Methods
Semi-structured qualitative telephone interviews with authors of trials, identified from two sources: trials published since 2002 included in Cochrane systematic reviews selected for the ORBIT project; and trial reports randomly sampled from 14,758 indexed on PubMed over the 12-month period from August 2007 to July 2008.
Results
A total of 268 trials were identified for inclusion, 183 published since 2002 and included in the Cochrane systematic reviews selected for the ORBIT project and 85 randomly selected published trials indexed on PubMed. The response rate from researchers in the former group was 21% (38/183) and in the latter group was 25% (21/85). Overall, 59 trialists were interviewed from the two different sources. A number of major but related themes emerged regarding the conduct and reporting of trials: establishment of the research question; identification of outcome variables; use of and adherence to the study protocol; conduct of the research; reporting and publishing of findings. Our results reveal that, although a substantial proportion of trialists identify outcome variables based on their clinical experience and knowing experts in the field, there can be insufficient reference to previous research in the planning of a new trial. We have revealed problems with trial recruitment: not reaching the target sample size, over-estimation of recruitment potential and recruiting clinicians not being in equipoise. We found a wide variation in the completeness of protocols, in terms of detailing study rationale, outlining the proposed methods, trial organisation and ethical considerations.
Conclusion
Our results confirm that the conduct and reporting of some trials can be inadequate. Interviews with researchers identified aspects of clinical research that can be especially challenging: establishing appropriate and relevant outcome variables to measure, use of and adherence to the study protocol, recruiting of study participants and reporting and publishing the study findings. Our trialists considered the prestige and impact factors of academic journals to be the most important criteria for selecting those to which they would submit manuscripts.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0536-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-014-0536-6
PMCID: PMC4322554  PMID: 25619208
Qualitative; Interviews; Trialists; Research reporting; Recruitment; Trial protocols; Equipoise
6.  Plasmid-mediated quinolone resistance 
Microbiology spectrum  2014;2(2):10.1128/microbiolspec.PLAS-0006-2013.
Summary
Three mechanisms for plasmid-mediated quinolone resistance (PMQR) have been discovered since 1998. Plasmid genes qnrA, qnrB, qnrC, qnrD, qnrS, and qnrVC code for proteins of the pentapeptide repeat family that protects DNA gyrase and topoisomerase IV from quinolone inhibition. The qnr genes appear to have been acquired from chromosomal genes in aquatic bacteria, are usually associated with mobilizing or transposable elements on plasmids, and are often incorporated into sul1-type integrons. The second plasmid-mediated mechanism involves acetylation of quinolones with an appropriate amino nitrogen target by a variant of the common aminoglycoside acetyltransferase AAC(6′)-Ib. The third mechanism is enhanced efflux produced by plasmid genes for pumps QepAB and OqxAB. PMQR has been found in clinical and environmental isolates around the world and appears to be spreading. The plasmid-mediated mechanisms provide only low-level resistance that by itself does not exceed the clinical breakpoint for susceptibility but nonetheless facilitates selection of higher-level resistance and makes infection by pathogens containing PMQR harder to treat.
doi:10.1128/microbiolspec.PLAS-0006-2013
PMCID: PMC4288778  PMID: 25584197
7.  The Role of Reminding in the Effects of Spaced Repetitions on Cued Recall: Sufficient but not Necessary 
Three experiments examined the role of study-phase retrieval (reminding) in the effects of spaced repetitions on cued recall. Remindings were brought under task control to evaluate their effects. Participants studied two lists of word pairs containing three item types: single items that appeared once in List 2, within-list repetitions that appeared twice in List 2, and between-list repetitions that appeared once in List 1 and once in List 2. Our primary interest was in performance on between-list repetitions. Detection of between-list repetitions was encouraged in an n-back condition by instructing participants to indicate when a presented item was a repetition of any preceding item, including items presented in List 1. In contrast, detection of between-list repetitions was discouraged in a within-list back condition by instructing participants only to indicate repetitions occurring in List 2. Cued recall of between-list repetitions was enhanced when instructions encouraged detection of List 1 presentations. These results accord with those from prior experiments showing a role of study-phase retrieval in effects of spacing repetitions. Past experiments have relied on conditionalized data to draw conclusions, producing the possibility that performance benefits merely reflected effects of item selection. By bringing effects under task control, we avoided that problem. Our results provide evidence that reminding resulting from retrieval of earlier presentations plays a role in the effects of spaced repetitions on cued recall. However, our results also reveal that such retrievals are not necessary to produce an effect of spacing repetitions.
doi:10.1037/a0034055
PMCID: PMC4032790  PMID: 23937236
cognitive control; reminding; repetition effects; spacing effects; study-phase retrieval
8.  In Memoriam: Robert C. Moellering, Jr. 
doi:10.1128/AAC.03199-14
PMCID: PMC4068561  PMID: 24798286
9.  Protective effect of CMV reactivation on relapse after allogeneic hematopoietic cell transplantation in AML patients is influenced by their conditioning regimen 
Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with reduced risk of relapse in patients with acute myeloid leukemia (AML). However the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Out of these 264 patients, 206 received myeloablative (MA) and 58 received reduced intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P= .01) and multivariate analyses (hazard ratio of 0.5246, P= .006), however CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies, however they suggest that this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant.
doi:10.1016/j.bbmt.2013.10.003
PMCID: PMC4029772  PMID: 24120526
10.  Early Mortality and Primary Causes of Death in Mothers of Children with Intellectual Disability or Autism Spectrum Disorder: A Retrospective Cohort Study 
PLoS ONE  2014;9(12):e113430.
Introduction
Mothers of children with intellectual disability or autism spectrum disorder (ASD) have poorer health than other mothers. Yet no research has explored whether this poorer health is reflected in mortality rates or whether certain causes of death are more likely. We aimed to calculate the hazard ratios for death and for the primary causes of death in mothers of children with intellectual disability or ASD compared to other mothers.
Methods
The study population comprised all mothers of live-born children in Western Australia from 1983–2005. We accessed state-wide databases which enabled us to link socio-demographic details, birth dates, diagnoses of intellectual disability or ASD in the children and dates and causes of death for all mothers who had died prior to 2011. Using Cox Regression with death by any cause and death by each of the three primary causes as the event of interest, we calculated hazard ratios for death for mothers of children intellectual disability or ASD compared to other mothers.
Results and Discussion
During the study period, mothers of children with intellectual disability or ASD had more than twice the risk of death. Mothers of children with intellectual disability were 40% more likely to die of cancer; 150% more likely to die of cardiovascular disease and nearly 200% more likely to die from misadventure than other mothers. Due to small numbers, only hazard ratios for cancer were calculated for mothers of children with ASD. These mothers were about 50% more likely to die from cancer than other mothers. Possible causes and implications of our results are discussed.
Conclusion
Similar studies, pooling data from registries elsewhere, would improve our understanding of factors increasing the mortality of mothers of children with intellectual disability or ASD. This would allow the implementation of informed services and interventions to improve these mothers' longevity.
doi:10.1371/journal.pone.0113430
PMCID: PMC4275172  PMID: 25535971
11.  The Application of the Open Pharmacological Concepts Triple Store (Open PHACTS) to Support Drug Discovery Research 
PLoS ONE  2014;9(12):e115460.
Integration of open access, curated, high-quality information from multiple disciplines in the Life and Biomedical Sciences provides a holistic understanding of the domain. Additionally, the effective linking of diverse data sources can unearth hidden relationships and guide potential research strategies. However, given the lack of consistency between descriptors and identifiers used in different resources and the absence of a simple mechanism to link them, gathering and combining relevant, comprehensive information from diverse databases remains a challenge. The Open Pharmacological Concepts Triple Store (Open PHACTS) is an Innovative Medicines Initiative project that uses semantic web technology approaches to enable scientists to easily access and process data from multiple sources to solve real-world drug discovery problems. The project draws together sources of publicly-available pharmacological, physicochemical and biomolecular data, represents it in a stable infrastructure and provides well-defined information exploration and retrieval methods. Here, we highlight the utility of this platform in conjunction with workflow tools to solve pharmacological research questions that require interoperability between target, compound, and pathway data. Use cases presented herein cover 1) the comprehensive identification of chemical matter for a dopamine receptor drug discovery program 2) the identification of compounds active against all targets in the Epidermal growth factor receptor (ErbB) signaling pathway that have a relevance to disease and 3) the evaluation of established targets in the Vitamin D metabolism pathway to aid novel Vitamin D analogue design. The example workflows presented illustrate how the Open PHACTS Discovery Platform can be used to exploit existing knowledge and generate new hypotheses in the process of drug discovery.
doi:10.1371/journal.pone.0115460
PMCID: PMC4270790  PMID: 25522365
12.  Growth and metastasis of B16-F10 melanoma cells is not critically dependent on host CD73 expression in mice 
BMC Cancer  2014;14(1):898.
Background
Recent studies have suggested that adenosine generated by ecto-5′-nucleotidase (CD73) in the tumor microenvironment plays a major role in promoting tumor growth by suppressing the immune response and stimulating angiogenesis via A2A and A2B receptors. However, adenosine has also been reported to inhibit tumor growth acting via A1 and A3 receptors. Therefore the aim of this study was to clarify the role of host CD73, which catalyzes the extracellular hydrolysis of AMP to adenosine, on tumor growth and metastasis of B16-F10 melanoma cells.
Methods
CD73 and alkaline phosphatase (AP) activity of B16-F10 melanoma cells were measured by HPLC. Tumor cells were injected either subcutaneously or intradermally in WT and CD73−/− mice and tumor growth was monitored by MRI at 9.4 T. Immune cell subpopulations within tumors were assessed by FACS after enzymatic digestion. An endothelium specific CD73−/− was created using Tie2-Cre+ mice and CD73flox/flox (loxP) mice. Chimeric mice lacking CD73−/− on hematopoietic cells was generated by bone marrow transplantation. Lung metastatic spread was measured after intravenous B16-F10 application.
Results
B16-F10 cells showed very little CD73 and negligible AP activity. Neither complete loss of host CD73 nor specific knockout of CD73 on endothelial cells or hematopoietic cells affected tumor growth after subcutaneous or intradermal tumor cell application. Only peritumoral edema formation was significantly attenuated in global CD73−/− mice in the intradermal model. Immune cell composition revealed no differences in the different transgenic mice models. Also lung metastasis after intravenous B16-F10 injection was not altered in CD73−/− mice.
Conclusions
CD73 expression on host cells, particularly on endothelial and hematopoietic cells, does not modulate tumor growth and metastatic spread of B16-F10 melanoma cells most likely because of insufficient adenosine formation by the tumor itself.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-898) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-898
PMCID: PMC4265456  PMID: 25465225
CD73; B16-F10 melanoma; Adenosine; Immune system; Tumor; Mice
13.  Risk factors and clinical characteristics of patients with qnr-positive Klebsiella pneumoniae bacteraemia 
Journal of Antimicrobial Chemotherapy  2013;68(12):2907-2914.
Objectives
Plasmid-mediated quinolone resistance (PMQR) caused by qnr genes has been known for 15 years. Information about global distribution and prevalence of qnr genes is abundant, but clinical information concerning infections produced by these isolates and risk factors for their acquisition is limited.
Methods
Klebsiella pneumoniae blood isolates (n = 227) from a 1 year prospective cohort of patients in Taiwan were studied. MICs of quinolones were determined for all isolates, and multiplex PCR for the presence of PMQR genes and DNA gyrase mutations was applied to all 24 isolates with ciprofloxacin MICs ≥0.12 mg/L and a control group of 72 isolates with MICs ≤0.06 mg/L.
Results
All qnr isolates were in the group with ciprofloxacin MICs ≥0.12 mg/L, constituting 9.4% of tested isolates and 3.9% (qnrB 2.6% and qnrS 1.3%) of total isolates. aac(6′)-Ib-cr and qepA were not found. Risk factors for qnr included nosocomial infection, bedridden status, surgery within 3 months, non-K1/K2 serotypes and prior antimicrobial use. Ciprofloxacin MIC ≥0.12 mg/L was associated with prior quinolone use; in contrast, prior cephalosporin use was more closely linked to the presence of qnr. Fourteen-day mortality was similar in patients infected with qnr-positive versus qnr-negative isolates, but there was a trend for increased in-hospital mortality in patients infected with qnr-positive isolates.
Conclusions
In K. pneumoniae blood isolates collected at a hospital in Taiwan, the overall prevalence of qnr genes was 3.9%. Prior quinolone use was linked to increased ciprofloxacin MIC, but not with the prevalence of qnr, which was most strongly linked to exposure to other antimicrobials, especially cephalosporins.
doi:10.1093/jac/dkt295
PMCID: PMC3820109  PMID: 23956373
K. pneumoniae; PMQR; resistance
14.  One-bone forearm procedure for Hajdu–Cheney syndrome: a case report 
Hand (New York, N.Y.)  2013;8(4):479-482.
One-bone forearm surgery is generally regarded as one of the last available salvage procedures that could be used to treat patients with longitudinal forearm instability secondary to a congenital, oncologic, or a post-traumatic etiology. We performed this procedure on a 23-year-old patient with longitudinal forearm instability secondary to Hajdu–Cheney syndrome, which is a rare genetic disorder characterized by generalized ligamentous laxity, skeletal dysplasia, acro-osteolysis, and generalized osteoporosis. The patient developed shoulder pain secondary to overuse 28 months following treatment, and was managed conservatively. Eight years after surgery, the patient had not undergone any additional procedures, had no pain, reported a Quick Disabilities of the Arm Shoulder and Hand score of 21, and was completely satisfied with treatment. Although OBF procedure is a radical first-line salvage option, in unique circumstances and appropriate patient selection, it may provide acceptable, durable, and predictable results.
doi:10.1007/s11552-013-9542-5
PMCID: PMC3840764  PMID: 24426971
15.  The DNA Double-Strand Break Response Is Abnormal in Myeloblasts From Patients With Therapy-Related Acute Myeloid Leukemia 
Leukemia  2013;28(6):1242-1251.
The complex chromosomal aberrations found in therapy related acute myeloid leukemia (t-AML) suggest that the DNA double strand break (DSB) response may be altered. In this study we examined the DNA DSB response of primary bone marrow cells from t-AML patients and performed next-generation sequencing of 37 canonical homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA repair genes, and a subset of DNA damage response genes using tumor and paired normal DNA obtained from t-AML patients. Our results suggest that the majority of t-AML patients (11 of 15) have tumor cell-intrinsic, functional dysregulation of their DSB response. Distinct patterns of abnormal DNA damage response in myeloblasts correlated with acquired genetic alterations in TP53 and the presence of inferred chromothripsis. Furthermore, the presence of trisomy 8 in tumor cells was associated with persistently elevated levels of DSBs. Although tumor-acquired point mutations or small indels in canonical HR and NHEJ genes do not appear to be a dominant means by which t-AML leukemogenesis occurs, our functional studies suggest that an abnormal response to DNA damage is a common finding in t-AML.
doi:10.1038/leu.2013.368
PMCID: PMC4047198  PMID: 24304937
therapy-related AML; DNA damage; DNA repair; Trisomy 8
17.  Flow cytometry based enrichment for cell shape mutants identifies multiple genes that influence Helicobacter pylori morphology 
Molecular microbiology  2013;90(4):10.1111/mmi.12405.
Summary
The helical cell shape of Helicobacter pylori is highly conserved and contributes to its ability to swim through and colonize the viscous gastric mucus layer. A multi-faceted peptidoglycan (PG) modification program involving four recently characterized peptidases and two accessory proteins is essential for maintaining H. pylori's helicity. To expedite identification of additional shape-determining genes, we employed flow cytometry with fluorescence-activated cell sorting (FACS) to enrich a transposon library for bacterial cells with altered light scattering profiles that correlate with perturbed cell morphology. After a single round of sorting, 15% of our clones exhibited a stable cell shape defect, reflecting 37-fold enrichment. Sorted clones with straight rod morphology contained insertions in known PG peptidases, as well as an insertion in csd6, which we demonstrated has LD-carboxypeptidase activity and cleaves monomeric tetrapeptides in the PG sacculus, yielding tripeptides. Other mutants had only slight changes in helicity due to insertions in genes encoding MviN/MurJ, a protein possibly involved in initiating PG synthesis, and the hypothetical protein HPG27_782. Our findings demonstrate FACS robustly detects perturbations of bacterial cell shape and identify additional PG peptide modifications associated with helical cell shape in H. pylori.
doi:10.1111/mmi.12405
PMCID: PMC3844677  PMID: 24112477
Helicobacter pylori; cell shape; cell wall
18.  Tackling antibiotic resistance 
Nature reviews. Microbiology  2011;9(12):894-896.
The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable, but can nevertheless be controlled and must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of thirty scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, May 16-18, 2011. From these discussions emerged a priority list of steps that need to be taken to resolve this global crisis.
doi:10.1038/nrmicro2693
PMCID: PMC4206945  PMID: 22048738
19.  Day occupation is associated with psychopathology for adolescents and young adults with Down syndrome 
BMC Psychiatry  2014;14(1):266.
Background
Young adults with Down syndrome experience increased rates of emotional and behavioural problems compared with the general population. Most adolescents with Down syndrome living in Western Australia participate in sheltered employment as their main day occupation. Relationship between day occupation and changes in behaviour has not been examined. Therefore, the aim of this research was to explore any relationship between post school day occupations and changes in the young person’s behaviour.
Methods
The Down syndrome Needs Opinion Wishes database was used for case ascertainment of young adults aged 15 to 32 years with Down syndrome. Families of 118 young people in this population-based database completed questionnaires in 2004, 2009 and 2011. The questionnaires addressed both young person characteristics such as age, gender, presence of impairments, behaviour, functioning in activities of daily living, and family characteristics such as income and family functioning. Post-school day occupations in which the young people were participating included open and sheltered employment, training and day recreation programs. Change in behaviour of young adults who remained in the same post-school day occupation from 2009 to 2011 (n = 103) were examined in a linear regression model adjusting for confounding variables including age, gender, prior functioning and behaviour in 2004 and family income.
Results
In comparison to those young adults attending open employment from 2009 to 2011, those attending day recreation programs were reported to experience worsening in behaviour both in the unadjusted (effect size −0.14, 95% CI −0.24, −0.05) and adjusted models (effect size −0.15, 95% CI −0.29, −0.01).
Conclusions
We found that the behaviour of those participating in open employment improved compared to those attending other day occupations. Further examination of the direction of this association is required.
doi:10.1186/s12888-014-0266-z
PMCID: PMC4190345  PMID: 25274152
Intellectual disability; Down syndrome; Participation; Employment; Psychopathology; Behaviour
20.  Influence of the Environment on Participation in Social Roles for Young Adults with Down Syndrome 
PLoS ONE  2014;9(9):e108413.
Background
The concept of disability is now understood as a result of the interaction between the individual, features related to impairment, and the physical and social environment. It is important to understand these environmental influences and how they affect social participation. The purpose of this study is to describe the social participation of young adults with Down syndrome and examine its relationship with the physical and social environment.
Methods
Families ascertained from the Down syndrome ‘Needs Opinion Wishes’ database completed questionnaires during 2011. The questionnaires contained two parts, young person characteristics and family characteristics. Young adults’ social participation was measured using the Assessment of Life Habits (LIFE-H) and the influences of environmental factors were measured by the Measure of the Quality of the Environment (MQE). The analysis involved descriptive statistics and linear and logistic regression.
Results
Overall, participation in daily activities was higher (mean 6.45) than in social roles (mean 5.17) (range 0 to 9). When the physical and/or social environment was reported as a facilitator, compared to being no influence or a barrier, participation in social roles was greater (coef 0.89, 95%CI 0.28, 1.52, coef 0.83, 95%CI 0.17, 1.49, respectively). The relationships between participation and both the physical (coef 0.60, 95% CI −0.40, 1.24) and social (coef 0.20, 95%CI −0.47, 0.87) environments were reduced when age, gender, behavior and functioning in ADL were taken into account.
Conclusion
We found that young adults’ participation in social roles was influenced more by the physical environment than by the social environment, providing a potentially modifiable avenue for intervention.
doi:10.1371/journal.pone.0108413
PMCID: PMC4178155  PMID: 25259577
21.  Toll-like Receptor 7 Rapidly Relaxes Human Airways 
Rationale: Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs.
Objectives: To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs.
Methods: Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs.
Measurements and Main Results: The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways.
Conclusions: TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.
doi:10.1164/rccm.201303-0442OC
PMCID: PMC3826186  PMID: 23924358
Toll-like receptor 7; imiquimod; nitric oxide; asthma; nerve
22.  Examining the efficacy and maintenance of contracture correction after collagenase clostridium histolyticum treatment for Dupuytren’s disease 
Hand (New York, N.Y.)  2013;8(3):261-266.
Background
This study examined the efficacy, complications, and contracture recurrence in patients who received injectable collagenase clostridium histolyticum (CCH) for Dupuytren’s-induced metacarpophalangeal (MP) and proximal interphalangeal (PIP) joint contractures.
Methods
A retrospective chart review at one center compared the degree of MP and PIP joint contracture pre-injection, post-cord rupture, and at final follow-up after a minimum duration of 6 months. Recurrence was defined as a 20 ° or greater increase in contracture above the minimum value achieved.
Results
Of 102 eligible patients, 48 patients (47 %) (31 males, 17 females) were available for review. 53 digits and 64 joints (46 MP joints and 18 PIP joints) were studied. The mean patient age was 66 years (range, 48–87 years) and mean follow-up duration was 15 months (range, 6 to 25 months). The mean MP joint contracture was 51 ± 20 ° at baseline, 4 ± 8 ° post-cord rupture, and 9 ± 15 ° at latest follow-up. The mean PIP joint contracture was 39 ± 23 ° at baseline, 14 ± 14 ° at cord rupture, and 29 ± 20 ° at latest follow-up. Of the 46 MP joints and 18 PIP joints, 11 MP (24 %) and 7 (39 %) PIP joints met the recurrence criteria. Of 102 patients, 1 patient had a small finger flexor tendon rupture.
Conclusions
Despite the dramatic initial reduction in contracture, recurrence developed in a high proportion of patients over the study period. While initially effective, CCH may not provide durable contracture reduction. However, CCH remains a viable nonsurgical treatment for Dupuytren’s disease.
doi:10.1007/s11552-013-9524-7
PMCID: PMC3745233  PMID: 24426932
Collagenase; Dupuytren’s disease; Recurrence
23.  One-stage Integra coverage for fingertip injuries 
Hand (New York, N.Y.)  2013;8(3):291-295.
Background
We hypothesize that one-stage Integra skin coverage is an effective treatment modality for the treatment of fingertip defects.
Methods
Nine patients who sustained fingertip injuries were treated with one-stage Integra coverage. In all cases, Integra was placed directly on bone. Static two-point discrimination and the Semmes–Weinstein Monofilament Test (SWMFT) were used to determine the sensations of the affected and opposite unaffected digit. The QuickDASH, Cold Intolerance Symptom Severity (CISS), visual analog scale (VAS), and a 0–10-point pain scale were administered to assess patient function, satisfaction, and pain levels.
Results
The mean age was 53.1 years (39–61). There were 8 males and 1 female. The average area covered was 2.3 cm2 (1.0–3.2). The mean follow-up duration was 16 months (8–46). The median QuickDASH, CISS score, VAS patient satisfaction, and 0–10 pain score were 9.1 (2.3–40.9), 18 (4–30), 10 (most satisfied) (7–10), and 0 (0–3), respectively. Five patients were evaluated for their digital sensory perception. The mean static two-point discrimination was 9.6 mm for the affected digit and 4.6 mm for the opposite unaffected digit. The median SWMFT was 4.31 for the affected digit and 3.61 for the opposite unaffected digit.
Conclusion
For small soft tissue and bone defects involving the fingertip, the use of Integra without further skin grafting appears to be effective, avoids the morbidity of the donor site, and avoids a second surgery. Despite mild sensory deficits, patients were satisfied with the results and fully functional during short-term follow-up.
doi:10.1007/s11552-013-9513-x
PMCID: PMC3745235  PMID: 24426936
Integra; Fingertip; Hand; Tissue reconstruction
24.  Hook of hamate fractures in competitive baseball players 
Hand (New York, N.Y.)  2013;8(3):302-307.
Background
Baseball players are susceptible to a number of specific upper extremity injuries secondary to batting, pitching, or fielding. Fractures of the hook of hamate have been known to occur in batters. The purpose of this study is to present our experience with the surgical management of hook of hamate fractures and their short-term impact on the playing capability of competitive baseball players.
Methods
A retrospective chart review was performed on patients with hook of hamate fractures between the years 2000 and 2012. The inclusion criteria were (1) hook of hamate fracture, (2) competitive baseball players, and (3) surgical treatment of the injury. Patient demographics, mechanism of injury, surgical treatment, and outcome were collected from the medical records. Information on return to play was collected from the Internet when applicable.
Results
There were seven male patients that underwent eight procedures. The mechanism of injury was attributed to batting in six cases and rogue pitches in two cases. All surgeries consisted of hamate hook excision and ulnar tunnel decompression. One patient had concomitant carpal tunnel release. The median time between surgery and return to play was 5.7 weeks (range, 4.3 to 10.4 weeks).
Conclusions
The mechanism of hook of hamate fractures in baseball players is predictable, most often developing secondary to repetitive swinging. This injury may occur at all levels of competition. Ulnar tunnel decompression with hook of hamate excision provides good outcomes, with minimal complications and early return to play.
doi:10.1007/s11552-013-9527-4
PMCID: PMC3745239  PMID: 24426938
Baseball; Fracture; Hook of hamate
25.  Mobility profile in Rett syndrome as determined by video analysis 
Neuropediatrics  2009;39(4):205-210.
This study used video supplemented by parent-report data to describe mobility in girls and women with Rett syndrome (n=99) and to investigate the effects of age, genotype, scoliosis and hand stereotypies on mobility. Most subjects were able to sit, slightly less than half were able to walk and a minority were able to transfer without assistance. Factor analysis enabled the calculation of general mobility and complex motor skills scores. General mobility declined with age and was poorer in those who had surgically treated scoliosis, but was not significantly related to the presence of conservatively managed scoliosis. Complex motor skills were better in those without scoliosis. Those who had a p.R133C, p.R294X, p.R306C or C terminal deletion mutation had better complex motor skills when younger than 13 years, and better general mobility and complex motor skills when 13 years or older. Neither set of motor skills scores was related to the frequency of hand stereotypies. The factor analysis and strong correlation between factor and WeeFIM scores supported the validity of the video assessment. Motor impairment is a fundamental but variable component of the Rett syndrome phenotype. General motor abilities declined with age whilst complex motor skills were more dependent on genotype. This information is useful for the clinician and family when planning support strategies and interventions.
doi:10.1055/s-0028-1104575
PMCID: PMC4122214  PMID: 19165708
Rett syndrome; gross motor function; mobility; MECP2 mutation; phenotype

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