This study describes a method for optimizing selective stimulus parameters for multi-contact peripheral electrodes. Overlap between pairs of contacts is quantified by the deviation in their combined response from linear addition of their individual responses. Mathematical models are fit to recruitment and overlap data, and a cost function is defined to maximize recruitment and minimize overlap between all contacts. Results are presented for two four-contact nerve-cuff electrodes stimulating bilateral femoral nerves of one human subject with spinal cord injury. Knee extension moments between 11.6 and 17.2 Nm are achieved through two contacts of each nerve-cuff with less than 10% overlap between each pair of contacts. These results suggest that optimization can provide an automated means of determining stimulus parameters to achieve strong, selective muscle contractions through multi-contact peripheral nerve electrodes.
Comparative methods for RNA secondary structure prediction use evolutionary information from RNA alignments to increase prediction accuracy. The model is often described in terms of stochastic context-free grammars (SCFGs), which generate a probability distribution over secondary structures. It is, however, unclear how this probability distribution changes as a function of the input alignment. As prediction programs typically only return a single secondary structure, better characterisation of the underlying probability space of RNA secondary structures is of great interest. In this work, we show how to efficiently compute the information entropy of the probability distribution over RNA secondary structures produced for RNA alignments by a phylo-SCFG, and implement it for the PPfold model. We also discuss interpretations and applications of this quantity, including how it can clarify reasons for low prediction reliability scores. PPfold and its source code are available from http://birc.au.dk/software/ppfold/.
Aberrant activation of the hedgehog (Hh) signaling pathway is implicated widely in both pediatric and adult malignancies. Inactivation of the Hh regulator PTCH is responsible for the Gorlin cancer predisposition syndrome. The spectrum of tumors found in Gorlin Syndrome includes basal cell carcinoma, medulloblastoma, and rarely, rhabdomyosarcoma (RMS). A previous report utilizing in situ hybridization has provided initial evidence for the expression of Hh targets GLI1 and PTCH in RMS tumors.
To investigate the role of Hh pathway signaling in pediatric rhabdomyosarcoma (RMS) and undifferentiated sarcoma (US) tumors, the expression of Hh pathway targets GLI1 and PTCH was measured. RNA was extracted from archival human tumor specimens collected from pediatric patients enrolled on Intergroup Rhabdomyosarcoma Study III and IV, and subjected to quantitative reverse transcriptase-polymerase chain reaction.
Expression of GLI1 with or without PTCH was detected in substantial subsets of embryonal RMS (ERMS) and US tumors but only rarely in alveolar RMS tumors. Neither PTCH mutations nor activating SMO mutations were detected in ERMS tumors with high GLI1 expression. Microarray analysis demonstrated relative overexpression of downstream Hh targets in ERMS tumors with high or intermediate GLI1 expression. Unlike a recent report, Hh pathway activity in ERMS tumors did not correlate with a unique clinical phenotype.
Our findings support a role for Hh pathway activation in the genesis of a subset of ERMS and US tumors. Hh signaling may represent a novel therapeutic target in affected tumors.
Rhabdomyosarcoma; Undifferentiated sarcoma; Gorlin’s syndrome; GLI; Hedgehog
Foreign body-type multinucleated giant cells (FBGC), formed by macrophage fusion, are a prominent cell type on implanted biomaterials, although the roles they play at these and other sites of chronic inflammation are not understood. Why lymphocytes are present in this scenario and the effects of fusing macrophages/FBGC on subsequent lymphocyte responses are also unclear. To address the physiological significance of FBGC in this regard, we employed our in vitro system of interleukin (IL)-4-induced human monocyte-derived macrophage fusion/FBGC formation. Initially, we pursued the identities of lymphocyte co-stimulatory molecules on fusing macrophages/FBGC. In addition, we further compared the FBGC phenotype to that currently associated with osteoclasts and dendritic cells using recognized markers. Immunoblotting of cell lysates and immunochemistry of macrophages/FBGC in situ, revealed that IL-4-induced macrophages/FBGC strongly express HLA-DR, CD98, B7-2 (CD86), and B7-H1 (PD-L1), but not B7-1 (CD80) or B7-H2 (B7RP-1). Furthermore, molecules currently recognized to be expressed on osteoclasts (calcitonin receptor, tartrate-resistant acid phosphatase, RANK) or dendritic cells (CD1a, CD40, CD83, CD95/fas) are undetectable. In contrast, fusing macrophages/FBGC strongly express the macrophage markers αX integrin (CD11c), CD68, and dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), whereas CD14 is completely down-modulated with IL-4-induced macrophage fusion. These novel data demonstrate that IL-4-induction of macrophage multinucleation/FBGC formation features the acquisition of a CD14-negative phenotypic profile which is distinguishable from that of dendritic cells and osteoclasts, yet potentially exhibits multiple capacities for lymphocyte interactions with resultant lymphocyte down-modulation.
Biocompatibility; chronic inflammation; lymphocyte; macrophage; multinucleated giant cell
To investigate the dosimetric impact of point A definitions on both conventional point A plans and MRI-guided conformal high-dose-rate (HDR) brachytherapy plans.
Material and methods
Fifty-five HDR plans of 36 patients with FIGO stage I to IV cervical cancer were retrospectively studied; these included 30 conventional treatments and 25 conformal plans. Two different point A definitions were explored: the revised Manchester point A and the new point A as recommended by the American Brachytherapy Society. Conventional plans were produced by varying only the point A definition and the normalized isodose lines. Conformal plans were retrospectively generated per GEC-ESTRO recommendations based upon 3.0 Tesla MRI data.
Small yet significant variations were found in point A locations (mean: 0.5 cm, maximum: 2.1 cm, p < 0.001). The use of a new point A caused minimal dose variation for both conventional and conformal plans. Conventional plans normalized to the new point A generated up to 12% (avg. 1-3%) higher overall dose in terms of higher total reference air kerma than plans normalized to other points. Dosimetric changes due to point A definitions were up to 11-12% (avg. less than 2%) on target volumes or organs-at-risk.
For both conventional and conformal plans, the new point A definition leads to smaller variations caused during implant and/or differences in patient anatomy. Using the new point A is expected to produce more consistent brachytherapy plans and improve outcome analysis.
brachytherapy; cervical cancer; high-dose-rate brachytherapy; MRI-guided; point A
Eastern Equine Encephalitis virus (EEEV) is an alphavirus with high pathogenicity in both humans and horses. Florida continues to have the highest occurrence of human cases in the USA, with four fatalities recorded in 2010. Unlike other states, Florida supports year-round EEEV transmission. This research uses GIS to examine spatial patterns of documented horse cases during 2005–2010 in order to understand the relationships between habitat and transmission intensity of EEEV in Florida.
Cumulative incidence rates of EEE in horses were calculated for each county. Two cluster analyses were performed using density-based spatial clustering of applications with noise (DBSCAN). The first analysis was based on regional clustering while the second focused on local clustering. Ecological associations of EEEV were examined using compositional analysis and Euclidean distance analysis to determine if the proportion or proximity of certain habitats played a role in transmission.
The DBSCAN algorithm identified five distinct regional spatial clusters that contained 360 of the 438 horse cases. The local clustering resulted in 18 separate clusters containing 105 of the 438 cases. Both the compositional analysis and Euclidean distance analysis indicated that the top five habitats positively associated with horse cases were rural residential areas, crop and pastureland, upland hardwood forests, vegetated non-forested wetlands, and tree plantations.
This study demonstrates that in Florida tree plantations are a focus for epizootic transmission of EEEV. It appears both the abundance and proximity of tree plantations are factors associated with increased risk of EEE in horses and therefore humans. This association helps to explain why there is are spatially distinct differences in the amount of EEE horse cases across Florida.
Eastern equine encephalitis; GIS; Spatial epidemiology; Compositional analysis; Euclidean distance
To describe use of the ACR/EULAR (AE) rheumatoid arthritis (RA) remission criteria in clinical practice.
We examined remission in the US Veterans Affairs RA (VARA) registry of 1,341 patients (91% men) with 9,700 visits and a community rheumatology practice (ARCK) of 1,168 patients (28% men) with 6,362 visits. We studied cross-sectional and cumulative probabilities, agreement among various remission criteria, and aspects of reliability using Boolean definitions and CDAI and SDAI methods proposed by AE.
By AE definition for community practice (swollen and tender joints ≤1, patient global ≤1), cross-sectional remission was 7.5% (6.4, 8.7) for ARCK and 8.9% (7.9, 9.9) for VARA. Cumulative or remission at any observation was 18.0% (ARCK) and 24.4% (VARA) over a mean of 2.2 years. Addition of ESR or CRP to criteria reduced remission to 5.0-6.2%, and use of CDAI/SDAI increased proportions to 6.9-10.1%. 1.8%-4.6% of patients met remission criteria at ≥2 visits. Agreement between criteria definitions was good by Kappa and Jaccard measures. Among patients in remission, the probability of a remission lasting 2 years was 6.0%-14.1%. Among all patients the probability of a remission lasting 2 years was <3%. Remission and examination results varied substantially among physicians by multilevel analyses.
Cross-sectional remission occurs at 5.0%-10.1%, with cumulative remission 2-3 times greater. Long-term remissions are rare. Problems with reliability and agreement limit criteria usefulness in the individual patient. However, the criteria can be an effective method for measuring clinical status and treatment effect in groups of patients in the community.
Rheumatoid arthritis; Remission; Reliability
RNA secondary structure prediction, or folding, is a classic problem in bioinformatics: given a sequence of nucleotides, the aim is to predict the base pairs formed in its three dimensional conformation. The inverse problem of designing a sequence folding into a particular target structure has only more recently received notable interest. With a growing appreciation and understanding of the functional and structural properties of RNA motifs, and a growing interest in utilising biomolecules in nano-scale designs, the interest in the inverse RNA folding problem is bound to increase. However, whereas the RNA folding problem from an algorithmic viewpoint has an elegant and efficient solution, the inverse RNA folding problem appears to be hard.
In this paper we present a genetic algorithm approach to solve the inverse folding problem. The main aims of the development was to address the hitherto mostly ignored extension of solving the inverse folding problem, the multi-target inverse folding problem, while simultaneously designing a method with superior performance when measured on the quality of designed sequences. The genetic algorithm has been implemented as a Python program called Frnakenstein. It was benchmarked against four existing methods and several data sets totalling 769 real and predicted single structure targets, and on 292 two structure targets. It performed as well as or better at finding sequences which folded in silico into the target structure than all existing methods, without the heavy bias towards CG base pairs that was observed for all other top performing methods. On the two structure targets it also performed well, generating a perfect design for about 80% of the targets.
Our method illustrates that successful designs for the inverse RNA folding problem does not necessarily have to rely on heavy biases in base pair and unpaired base distributions. The design problem seems to become more difficult on larger structures when the target structures are real structures, while no deterioration was observed for predicted structures. Design for two structure targets is considerably more difficult, but far from impossible, demonstrating the feasibility of automated design of artificial riboswitches. The Python implementation is available at
RNA; Inverse folding; Genetic algorithm; Riboswitch
Neuroimaging studies involving human subjects raise a range of ethics issues. Many of these issues are heightened in the context of neuroimaging research involving persons with mental health disorders. There has been growing interest in these issues among legal scholars, philosophers, social scientists, and as well as neuroimagers over the last decade. Less clear, however, is the extent to which members of the neuroimaging community are engaged with these issues when they undertake their research and report results. In this study, we analyze the peer-reviewed review literature involving fMRI as applied to the study of mental health disorders. Our hypothesis is that, due to the critical orientation of reviews, and the vulnerability of mental health population, the penetrance of neuroethics will be higher in the review literature in this area than it is in the primary fMRI research literature more generally. We find that while authors of reviews do focus a great deal of attention on the methodological limitations of the studies they discussed, contrary to our hypothesis, they do not frame concerns in ethical terms despite their ethical significance. We argue that an ethics lens on such discussion would increase the knowledge-value of this scholarly work.
Quantitative real-time polymerase chain reaction (qRT-PCR) is the most important tool in measuring levels of gene expression due to its accuracy, specificity, and sensitivity. However, the accuracy of qRT-PCR analysis strongly depends on transcript normalization using stably expressed reference genes. The aim of this study was to find internal reference genes for qRT-PCR analysis in various experimental conditions for seed, adventitious underground bud, and other organs of leafy spurge. Eleven candidate reference genes (BAM4, PU1, TRP-like, FRO1, ORE9, BAM1, SEU, ARF2, KAPP, ZTL, and MPK4) were selected from among 171 genes based on expression stabilities during seed germination and bud growth. The other ten candidate reference genes were selected from three different sources: (1) 3 stably expressed leafy spurge genes (60S, bZIP21, and MD-100) identified from the analyses of leafy spurge microarray data; (2) 3 orthologs of Arabidopsis “general purpose” traditional reference genes (GAPDH_1, GAPDH_2, and UBC); and (3) 4 orthologs of Arabidopsis stably expressed genes (UBC9, SAND, PTB, and F-box) identified from Affymetrix ATH1 whole-genome GeneChip studies. The expression stabilities of these 21 genes were ranked based on the CT values of 72 samples using four different computation programs including geNorm, Normfinder, BestKeeper, and the comparative ΔCT method. Our analyses revealed SAND, PTB, ORE9, and ARF2 to be the most appropriate reference genes for accurate normalization of gene expression data. Since SAND and PTB were obtained from 4 orthologs of Arabidopsis, while ORE9 and ARF2 were selected from 171 leafy spurge genes, it was more efficient to identify good reference genes from the orthologs of other plant species that were known to be stably expressed than that of randomly testing endogenous genes. Nevertheless, the two newly identified leafy spurge genes, ORE9 and ARF2, can serve as orthologous candidates in the search for reference genes from other plant species.
Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, occurs less commonly in infants. Historically, poorer outcomes have been seen for infants diagnosed with RMS than for older children.
We analyzed the characteristics, treatment administered, outcomes, and patterns of failure for infants < 1 year of age with non-metastatic RMS who were treated with multimodal therapy on Intergroup Rhabdomyosarcoma Study (IRS) protocols IRS-IV, D9602, and D9803.
Seventy-six infants with non-metastatic RMS were treated on the 3 protocols from 1991 to 2005. Median age was 7.4 months (range 0.1–12 months). Tumor histology included embryonal (57%), alveolar (21%), and undifferentiated sarcoma/other (22%). Parameningeal primary site was less common in this infant cohort (3%) than for all patients treated on IRS-IV (25%). Estimated 5-year failure-free survival and overall survival (95% confidence intervals) are 57% (44%, 67%) and 76% (65%, 85%) for infants compared to 81% (79%, 83%) and 87% (85%, 89%) for ages 1–9 years. Twenty-three of 32 infants with treatment failure had local recurrence/progression with (n=3) or without (n=20) distant failure. The overall local failure rate was 30%. Median time to treatment failure was 13 months. FFS was worse for infants with Group III tumors and for those who received less than protocol recommended radiation therapy.
Infants with RMS appear to have worse outcomes than older patients, in part due to high rates of local failure. Concerns regarding morbidity in infants and reluctance to perform aggressive local control measures may lead to higher rates of local failure.
pediatric; sarcoma; infant; radiotherapy; rhabdomyosarcoma
To evaluate the incidence and prognostic factors for regional failure, with attention to in-transit pathways of spread, in children with non-metastatic rhabdomyosarcoma (RMS) of the extremity.
Intergroup Rhabdomyosarcoma Studies III, IV-Pilot, and IV enrolled 226 children with RMS of the extremity. Failure at in-transit (epitrochlear/brachial and popliteal) and proximal (axillary/infraclavicular and inguinal/femoral) nodes were evaluated. Median follow-up for surviving patients is 10.4 years.
Fifty-five (24%) of 226 children had clinical or pathologic evidence of either in-transit and/or proximal lymph node involvement (LNI) at diagnosis. The actuarial 5-year risk of regional failure is 12%. The prognostic factors for poor regional control are female gender and LNI at diagnosis. In the 116 patients with a distal extremity primary tumor, 5% had in-transit LNI at diagnosis. The estimated 5-year incidences of in-transit and proximal nodal failure are 12% and 8%, respectively. The in-transit failure rate is 0% in patients who received radiation therapy and/or underwent lymph node sampling of the in-transit nodal site, but 15% in those who did not (p=0.07), although 5-year EFS did not differ between these two groups (64% vs. 55%, p=0.47).
The high incidence of regional involvement necessitates aggressive identification and treatment of regional lymph nodes in RMS of the extremity. In patients with distal extremity tumors, in-transit failures are as common as failures in more proximal regional sites. Patients who undergo complete lymph node staging with appropriate radiotherapy to the in-transit nodal site, if indicated, are at a slightly lower risk of in-transit failure.
rhabdomyosarcoma; regional failure; in-transit nodes; radiation therapy; extremity
To establish occurrence, method of injury, length of stay (LOS), psychiatric diagnosis, rehabilitation outcome, and demographic data for those admitted to a Scottish Spinal Injuries Rehabilitation Unit as a consequence of deliberate self-harm (DSH).
A retrospective audit of case-notes and electronic databases of admissions and rehabilitation outcome in a spinal cord injury (SCI) unit where the mechanism of injury was (DSH).
Forty-six (44 having detailed data available) patients were identified with 95% of injuries resulting from falls. Thirty-six people had pre-existing mental health problems (82%) with 15 (34%) having this diagnosis established shortly after admission. Seventy-five per cent received follow-up from mental health services. Ninety-five per cent returned to their pre-injury (or similar) residence. LOS and functional independence measure (FIM) for the DSH group were compared with a non-DSH group. No differences were found in those with SCI. LOS was significantly longer in the patients with vertebral fracture and no neurological impairment (32 versus 22 days). Sixty-four per cent of those who had self-harmed had substance dependence problems. The predominance of falls (63%) occurred in a residential setting. Annual admissions due to individuals self-harming were stable across the studied period.
Spinal column fracture in the DSH group is predominantly caused by falls. High levels of mental health and substance abuse problems are noted necessitating formal mental health assessment and follow-up. DSH as a mechanism for injury appears to have a significant impact on LOS only if the patient has fracture without SCI. Immediate rehabilitation outcomes are similar to that of non-DSH group.
Spinal cord injuries; Rehabilitation; Self-injurious behaviour; Suicide
This study aimed to clarify whether infants and preschool children show susceptibility to contagious yawning, a well-known effect that has been demonstrated experimentally in older children and adults by exposing them to video sequences showing yawns. In a first study, parents kept a log of their child's yawns for a one week period. None of the log entries reported any contagious yawns by the children. Although less frequent than in older children and adults, spontaneous yawning by infants and preschoolers showed the typical morning, post-wakening peak, and an increase before bedtime in the evening. In an experimental study, infants and preschoolers watched a presentation that included many images of yawning and a repeated video clip of their own mother yawning, but there was no evidence of contagious yawning. The results suggest that, even when witnessing yawns by someone with whom they have a strong and positive emotional relationship, very young children do not show contagious yawning.
yawning; contagious yawning; infants; children; video; model
The applications of synthetic biology will involve the release of artificial life forms into the environment. These organisms will present unique safety challenges that need to be addressed by researchers and regulators to win public engagement and support.
Many steps in nuclear RNA processing, surveillance and degradation require TRAMP, a complex containing the poly(A) polymerase Trf4p, the Zn-knuckle protein Air2p, and the RNA helicase Mtr4p. TRAMP polyadenylates RNAs designated for decay or trimming by the nuclear exosome. It has been unclear how polyadenylation by TRAMP differs from polyadenylation by conventional poly(A) polymerase, which produces poly(A) tails that stabilize RNAs. Using reconstituted S.cerevisiae TRAMP, we show that TRAMP inherently suppresses poly(A) addition after only 3–4 adenosines. This poly(A) tail length restriction is controlled by Mtr4p. The helicase detects the number of 3'-terminal adenosines and, over several adenylation steps, elicits precisely tuned adjustments of ATP affinities and rate constants for adenylation and TRAMP dissociation. Our data establish Mtr4p as critical regulator of polyadenylation by TRAMP and reveal that an RNA helicase can control the activity of another enzyme in a highly complex fashion and in response to features in RNA.
RNA helicase; TRAMP; Mtr4; RNP; polyadenylation; poly(A) polymerase
We examined the impact of gradual removal of hydroxyl groups from the A- and B-rings of ( –)-epicatechin gallate on antibacterial activity and oxacillin resistance attenuation of an epidemic strain of methicillin resistant Staphylococcus aureus. Removal of both hydroxyls from the B-ring effected a large reduction in oxacillin MIC (from 512 to 0.25 mg/mL at a concentration of 12.5 mg/L); further hydroxyl deletion of the A-ring reduced the oxacillin effect but increased intrinsic anti-staphylococcal activity
MRSA; ( –)-Epicatechin gallate analogues; β-Lactam antibiotics; Antibacterial chemotherapy; Antibiotic resistance
We analyzed the outcome of 47 patients with superficial facial rhabdomyosarcoma (RMS) treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-III, -IV-Pilot, and -IV.
We reviewed patients’ records. Clinico-pathologic features, treatment, and outcome were examined to identify prognostic factors.
Thirty-two patients were males; 35 patients were 1–9 years old at diagnosis. Tumor sites were buccal/cheek (N = 21), external nasal/nasolabial (N = 12), lip/chin (N = 9), and masseter (N = 5). Patients (46/47) had localized disease: 18 biopsy only (Group III), 17 microscopic residual tumor (Group II), and 11 complete resection without residual tumor (Group I). Eight-year estimated event-free survival (EFS) and overall survival (OAS) rates were 61% and 65%. Patients <12 months old had inferior EFS, 21%, compared to ~68% in older patients (P = 0.077). Eight-year EFS rates were 80% for females and 50% for males (P = 0.096). Eight-year EFS rates were 72% in 33 patients without regional lymph-nodal tumor and 39% in 14 patients with regional nodal tumor (P = 0.07). Eight-year EFS rates were 72% for 22 patients with embryonal RMS and 53% for 23 patients with alveolar RMS (P = 0.28). Location of the primary tumor was not significantly related to outcome.
Patients with superficial facial RMS often have localized, grossly resectable lesions at the time of presentation. Favorable prognostic factors include age >12 months, female gender, embryonal histology, and no lymph-nodal tumor.
childhood/adolescent superficial facial rhabdomyosarcoma; IRSG protocols
Stochastic Context–Free Grammars (SCFGs) were applied successfully to RNA secondary structure prediction in the early 90s, and used in combination with comparative methods in the late 90s. The set of SCFGs potentially useful for RNA secondary structure prediction is very large, but a few intuitively designed grammars have remained dominant. In this paper we investigate two automatic search techniques for effective grammars – exhaustive search for very compact grammars and an evolutionary algorithm to find larger grammars. We also examine whether grammar ambiguity is as problematic to structure prediction as has been previously suggested.
These search techniques were applied to predict RNA secondary structure on a maximal data set and revealed new and interesting grammars, though none are dramatically better than classic grammars. In general, results showed that many grammars with quite different structure could have very similar predictive ability. Many ambiguous grammars were found which were at least as effective as the best current unambiguous grammars.
Overall the method of evolving SCFGs for RNA secondary structure prediction proved effective in finding many grammars that had strong predictive accuracy, as good or slightly better than those designed manually. Furthermore, several of the best grammars found were ambiguous, demonstrating that such grammars should not be disregarded.
ETOC: Our study reveals that ZO proteins in fully polarized cells regulate the assembly and contractility of the perijunctional actomyosin ring associated with the adherens junction.
The structure and function of both adherens (AJ) and tight (TJ) junctions are dependent on the cortical actin cytoskeleton. The zonula occludens (ZO)-1 and -2 proteins have context-dependent interactions with both junction types and bind directly to F-actin and other cytoskeletal proteins, suggesting ZO-1 and -2 might regulate cytoskeletal activity at cell junctions. To address this hypothesis, we generated stable Madin-Darby canine kidney cell lines depleted of both ZO-1 and -2. Both paracellular permeability and the localization of TJ proteins are disrupted in ZO-1/-2–depleted cells. In addition, immunocytochemistry and electron microscopy revealed a significant expansion of the perijunctional actomyosin ring associated with the AJ. These structural changes are accompanied by a recruitment of 1-phosphomyosin light chain and Rho kinase 1, contraction of the actomyosin ring, and expansion of the apical domain. Despite these changes in the apical cytoskeleton, there are no detectable changes in cell polarity, localization of AJ proteins, or the organization of the basal and lateral actin cytoskeleton. We conclude that ZO proteins are required not only for TJ assembly but also for regulating the organization and functional activity of the apical cytoskeleton, particularly the perijunctional actomyosin ring, and we speculate that these activities are relevant both to cellular organization and epithelial morphogenesis.
In this paper we examine imaging research involving first-episode schizophrenic treatment-naive individuals (FESTNIs) through a legal human rights lens; in particular, the lens of the Additional Protocol to the Convention on Human Rights and Biomedicine Concerning Biomedical Research. We identify a number of ethical and legal hot spots highlighted by the Protocol, and offer a series of recommendations designed to ensure the human rights compatibility of this research. Subsequently, we argue that the lack of reporting on design elements related to ethical concerns frustrates commitments at the heart of the human rights approach, namely, transparency and openness to international scrutiny. To redress this problem, we introduce two norms for the first time: ethical transparency, and ethical reproducibility. When concluding, we offer a set of reporting guidelines designed to operationalize these norms in the context of imaging research involving FESTNIs. Though we will not make this case here, we believe that parallel reporting guidelines should be incorporated into other areas of research involving human subjects.
Imaging; First-episode schizophrenic; Treatment-naive individuals; Additional protocol; Human rights and biomedicine
Patients with localized, grossly resected, or gross residual (orbital only) embryonal rhabdomyosarcoma (ERMS) had 5-year failure-free survival (FFS) rates of 83% and overall survival rates of 95% on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III/IV. IRSG D9602 protocol (1997 to 2004) objectives were to decrease toxicity in similar patients by reducing radiotherapy (RT) doses and eliminating cyclophosphamide for the lowest-risk patients.
Patients and Methods
Subgroup A patients (lowest risk, with ERMS, stage 1 group I/IIA, stage 1 group III orbit, stage 2 group I) received vincristine plus dactinomycin (VA). Subgroup B patients (ERMS, stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, stage 3 group I/II) received VA plus cyclophosphamide. Patients in group II/III received RT. Compared with IRS-IV, doses were reduced from 41.4 to 36 Gy for stage 1 group IIA patients and from 50 or 59 to 45 Gy for group III orbit patients.
Estimated 5-year FFS rates were 89% (95% CI, 84% to 92%) for subgroup A patients (n = 264) and 85% (95% CI, 74%, 91%) for subgroup B patients (n = 78); median follow-up: 5.1 years. Estimated 5-year FFS rates were 81% (95% CI, 68% to 90%) for patients with stage 1 group IIA tumors (n = 62) and 86% (95% CI, 76% to 92%) for patients with group III orbit tumors (n = 77).
Five-year FFS and OS rates were similar to those observed in comparable IRS-III patients, including patients receiving reduced RT doses, but were lower than in comparable IRS-IV patients receiving VA plus cyclophosphamide. Five-year FFS rates were similar among subgroups A and B patients.
Epistatic interactions in which the phenotypic effect of an allele is conditional on its genetic background have been shown to play a central part in various evolutionary processes. In a previous study (J. B. Anderson et al., Curr. Biol. 20:1383-1388, 2010; J. R. Dettman, C. Sirjusingh, L. M. Kohn, and J. B. Anderson, Nature 447:585-588, 2007), beginning with a common ancestor, we identified three determinants of fitness as mutant alleles (each designated with the letter “e”) that arose in replicate Saccharomyces cerevisiae populations propagated in two different environments, a low-glucose and a high-salt environment. In a low-glucose environment, MDS3e and MKT1e interacted positively to confer a fitness advantage. Also, PMA1e from a high-salt environment interacted negatively with MKT1e in a low-glucose environment, an example of a Dobzhansky-Muller incompatibility that confers reproductive isolation. Here we showed that the negative interaction between PMA1e and MKT1e is mediated by alterations in intracellular pH, while the positive interaction between MDS3e and MKT1e is mediated by changes in gene expression affecting glucose transporter genes. We specifically addressed the evolutionary significance of the positive interaction by showing that the presence of the MDS3 mutation is a necessary condition for the spread and fixation of the new mutations at the identical site in MKT1. The expected mutations in MKT1 rose to high frequencies in two of three experimental populations carrying MDS3e but not in any of three populations carrying the ancestral allele. These data show how positive and negative epistasis can contribute to adaptation and reproductive isolation.
To determine event free survival (EFS) of children with Wilms tumor (WT) and metastatic liver disease at diagnosis.
Summary and Background data
We reviewed patients with stage IV Wilms tumor treated on National Wilms Tumor Study 4 and -5 to ascertain if they have a worse prognosis than other Stage IV disease.
742 patients (pts) with stage IV disease were assessed for EFS (95% confidence interval [CI]) at 5 years after diagnosis. Cohorts included those who underwent resection of the liver lesions compared with those who received only chemotherapy and radiotherapy (XRT).
Seven hundred and forty two patients with stage IV Wilms tumor were enrolled on NWTS-4 and 5, 111 of who had liver metastases. Of these, 96 had favorable histology disease and are the focus of this analysis. Twenty-two patients had a primary liver resection (wedge resection - 18 and lobectomy – 4). After chemotherapy and/or radiation, 13 patients underwent liver resection (wedge resection - 7, lobectomy - 5 and trisegmentectomy – 1). Seventy-one patients (67%) did not undergo surgery for their liver disease. In 14 patients the liver disease disappeared with chemotherapy only. Eighty-two patients received abdominal radiation. EFS for the patients with metastatic FH Wilms tumor was 75% (95% confidence interval [CI]: (71%, 78%), EFS by Stage IV category was: lung only 76% (95% CI: 72%, 80%)(513 patients); liver, not lung 76% (95% CI: 58%, 87%)(34 patients); liver and lung 70% (95% CI: 57%, 80%)(62 patients) and other sites 64% (95% CI: 42%, 79%)(25 patients). There were no significant differences among stage IV groups (p=0.60). EFS (95% CI) for the patients with primary resection of the liver metastases (22 patients) was 86% (63%, 95%) compared to 68% (56%, 78%) (p=0.09) for the 74 with no primary resection of liver metastases. There was no significant difference in EFS for patients with FH Wilms tumor treated with chemotherapy compared to that of patients treated with chemotherapy and radiation (p=0.63). The EFS (95% CI) for each of the subsets was; no abdominal radiation: 64% (34%, 83%); abdominal radiation, no boost: 77% (55%, 89%); abdominal radiation, boost: 72% (58%, 82%) (p=0.05).
Liver metastasis at diagnosis is not an adverse prognostic factor for stage IV metastatic FH WT.