Search

Summary Background Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). Methods NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov , NCT02508532 . Findings Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2–25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2–24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3–4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76–95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30–400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). Interpretation Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. Funding Blueprint Medicines.

Understanding why and how elaborated traits evolve remains a fascination and a challenge. Darwin proposed both male-male competition and female mate choice as explanations for elaboration because such traits are often mediators of social interactions that govern access to mates. Although we have robust evolutionary quantitative genetic models for how mate choice can lead to runaway evolution, we lack an equivalent framework for understanding how male-male competition can drive extreme elaboration of traits. Here, we integrate the logic of optimality models into the quantitative genetic framework of interacting phenotypes to fill this gap. We assume that males modulate their aggression based on the relative size of a trait that signals willingness and ability to fight and identify conditions where the signal undergoes rapid and exponential evolution. Males receive fitness benefits from winning contests, but they may accrue fitness costs due to threats imposed by their opponent. This cost leads to a force of social selection that accelerates as the signaling trait is elaborated, which may cause runaway evolution of the signal. Even when a runaway is checked by natural selection, we find that signaling traits evolving by male-male competition can be elaborated well beyond their naturally selected optimum. Our model identifies simple conditions generating feedback between the behavioral and morphological traits mediating male-male competition, providing clear testable predictions. We conclude that, like the well-characterized case of female mate choice, male-male competition can provide a coevolving source of selection that can drive a runaway process resulting in evolution of elaborate traits. Significance It has long been appreciated that female mate choice can drive elaboration of male displays, but it has been less clear whether contests between males may lead to similar elaboration. To address this fundamental question, we use a genetic model evolution via male-male competition. We find that when a male trait is an honest indicator of aggression, it generates selection on itself by altering the social environment. This process can cause the strength of selection to increase as the trait becomes more elaborate, which can lead to runaway evolution. Our results show that the key unifying feature of runaway sexual selection by both male-male competition and female mate choice is an evolving source of selection provided by the social environment.

Genomic imprinting creates a difference in how maternal and paternal gene copies contribute to quantitative genetic variation and evolutionary change. To fully understand these impacts, O’Brien and Wolf develop a definitive extension to the classic.... Genomic imprinting shapes the genotype–phenotype relationship by creating an asymmetry between the influences of paternally and maternally inherited gene copies. Consequently, imprinting can impact heritable and nonheritable variation, resemblance of relatives, and evolutionary dynamics. Although previous analyses have identified some of the quantitative genetic consequences of imprinting, we lack a framework that cleanly separates the influence of imprinting from other components of variation, particularly dominance. Here we apply a simple orthogonal genetic model to evaluate the roles of genetic (additive and dominance) and epigenetic (imprinting) effects. Imprinting increases the resemblance of relatives who share the expressed allele, and therefore increases variance among families of full or half-siblings. However, only part of this increased variance is heritable and contributes to selection responses. When selection is within, or among, families sharing only a single parent (half-siblings), which is common in selective breeding programs, imprinting can alter overall responses. Selection is more efficient when it acts among families sharing the expressed parent, or within families sharing the parent with lower expression. Imprinting also affects responses to sex-specific selection. When selection is on the sex whose gene copy has lower expression, the response is diminished or delayed the next generation, although the long-term response is unaffected. Our findings have significant implications for understanding patterns of variation, interpretation of short-term selection responses, and the efficacy of selective breeding programs, demonstrating the importance of considering the independent influence of genomic imprinting in quantitative genetics.

Rituximab is a chimeric anti-CD20 monoclonal antibody that is an effective therapy for multiple sclerosis. Rituximab has been associated with the development of serum sickness (type III hypersensitivity) characterized by arthralgia, fever, and rash during the treatment of other conditions, such as rheumatoid arthritis. Here we describe serum sickness associated with rituximab in multiple sclerosis patients and discuss both the management of serum sickness itself and implications for utilizing alternative anti-CD20 monoclonal antibodies for disease management in this patient population.

Activation and repression of Notch target genes is mediated by transcription factor CSL, known as Suppressor of Hairless (Su(H)) in Drosophila and CBF1 or RBPJ in human. CSL associates either with co-activator Notch or with co-repressors such as Drosophila Hairless. The nuclear translocation of transcription factor CSL relies on co-factor association, both in mammals and in Drosophila. The Drosophila CSL orthologue Su(H) requires Hairless for repressor complex formation. Based on its role in transcriptional silencing, H protein would be expected to be strictly nuclear. However, H protein is also cytosolic, which may relate to its role in the stabilization and nuclear translocation of Su(H) protein. Here, we investigate the function of the predicted nuclear localization signals (NLS 1–3) and single nuclear export signal (NES) of co-repressor Hairless using GFP-fusion proteins, reporter assays and in vivo analyses using Hairless wild type and shuttling-defective Hairless mutants. We identify NLS3 and NES to be critical for Hairless function. In fact, H⁎NLS3 mutant flies match H null mutants, whereas H⁎NLS3⁎NES double mutants display weaker phenotypes in agreement with a crucial role for NES in H export. As expected for a transcriptional repressor, Notch target genes are deregulated in H⁎NLS3 mutant cells, demonstrating nuclear requirement for its activity. Importantly, we reveal that Su(H) protein strictly follows Hairless protein localization. Together, we propose that shuttling between the nucleo-cytoplasmic compartments provides the possibility to fine tune the regulation of Notch target gene expression by balancing of Su(H) protein availability for Notch activation.

Purpose To determine whether altered sodium (Na(+)) and chloride (Cl(-)) homeostasis can be visualized in periodic paralyses by using 7-T sodium 23 ((23)Na) and chlorine 35 ((35)Cl) magnetic resonance (MR) imaging. Materials and Methods Institutional review board approval and informed consent of all participants were obtained. (23)Na (repetition time msec/echo time msec, 160/0.35) and (35)Cl (40/0.6) MR imaging of both lower legs was performed with a 7-T whole-body system in patients with genetically confirmed hypokalemic periodic paralysis (Cav1.1-R1239H mutation, n = 5; Cav1.1-R528H mutation, n = 8) and Andersen-Tawil syndrome (n = 3) and in 16 healthy volunteers. Additionally, each participant underwent 3-T proton MR imaging on the same day by using T1-weighted, short-tau inversion-recovery, and Dixon-type sequences. Muscle edema was assessed on short-tau inversion-recovery images, fatty degeneration was assessed on T1-weighted images, and muscular fat fraction was quantified with Dixon-type imaging. Na(+) and Cl(-) were quantified in the soleus muscle by using three phantoms that contained 10-, 20-, and 30-mmol/L NaCl solution and 5% agarose gel as a reference. Parametric data for all subpopulations were tested by using one-way analysis of variance with the Dunnett test, and correlations were assessed with the Spearman rank correlation coefficient. Results Median muscular (23)Na concentration was higher in patients with Cav1.1-R1239H (34.7 mmol/L, P < .001), Cav1.1-R528H (32.0 mmol/L, P < .001), and Kir2.1 (24.3 mmol/L, P = .035) mutations than in healthy volunteers (19.9 mmol/L). Median muscular normalized (35)Cl signal intensity was higher in patients with Cav1.1-R1239H (27.6, P < .001) and Cav1.1-R528H (23.6, P < .001) than in healthy volunteers (12.6), but not in patients with the Kir2.1 mutation (14.3, P = .517). When compared with volunteers, patients with Cav1.1-R1239H and Cav1.1-R528H showed increased muscular edema (P < .001 and P = .003, respectively) and muscle fat fraction (P < .001 and P = .017, respectively). Conclusion With 7-T MR imaging, changes of Na(+) and Cl(-) homeostasis can be visualized in periodic paralyses and are most pronounced in the severe phenotype Cav1.1-R1239H, with up to daily paralytic episodes. (©) RSNA, 2016 An earlier incorrect version of this article appeared online. This article was corrected on April 18, 2016.

The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer’s disease (AD). Apolipoprotein E ɛ4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD.

We aimed to evaluate the sensitivity and specificity of 8 biochemical scanning tools in signalling the presence of unmeasured anions. We used blood gas and biochemical data from 15 patients during and after cardio-pulmonary bypass. Sampling time-points were pre-bypass (T1), 2 min post equilibration with priming fluid containing acetate and gluconate anions (T2), late bypass (T3) and 4 h after surgery (T4). We calculated the anion gap (AG), albumin—corrected anion gap (AGc), whole blood base excess (BE) gap, plasma BE gap, standard BE gap and the strong ion gap (SIG), plus 2 new indices—the unmeasured ion index (UIX) and unmeasured plasma anions according to the interstitial, plasma and erythrocyte acid–base model (IPEua). Total measured plasma concentrations of acetate and gluconate [XA] were proxies for unmeasured plasma anions. [XA] values (mmol/L) were 1.41 (0.87) at T1, 11.73 (3.28) at T2, 4.80 (1.49) at T3 and 1.36 (0.73) at T4. Corresponding [albumin] values (g/L) were 32.3 (2.0), 19.8 (2.6), 21.3 (2.5) and 29.1 (2.3) respectively. Only the AG failed to increase significantly at T2 in response to a mean [XA] surge of >10 mEq/L. At an [XA] threshold of 6 mEq/L, areas under receiver –operator characteristic curves in rank order were IPEua and UIX (0.88 and 0.87 respectively), SIG (0.81), AGc (0.79), standard BE gap (0.77), plasma BE gap (0.71), BE gap (0.70) and AG (0.59). Similar ranking hierarchies applied to positive and negative predictive values. We conclude that during acute hemodilution UIX and IPEua are superior to the anion gap (with and without albumin correction) and 4 other indices as scanning tools for unmeasured anions.

Objective: To assess the emergency preparedness knowledge, behaviors, and training needs of families of children with developmental disabilities (DD). Design: An online survey. Participants: A sample of 314 self-selecting US parents/guardians of children with DD, aged birth-21 years. Main outcome measures: 1) Preparedness self-assessment; 2) self-report regarding the extent to which families followed 11 specific preparedness action steps derived from publicly available preparedness guides; and 3) parent training and support needs. Results: Although most participants assessed themselves to be somewhat to moderately well prepared, even those who reported being “very well prepared” had taken fewer than half of 11 recommended action steps. Most participants expressed a need for preparedness support; virtually all the respondents felt that training was either important or very important. Conclusions: Children with disabilities are known to be particularly vulnerable to negative disaster impacts. Overall, parents in this study appeared under-prepared to meet family disaster needs, although they recognized its importance. The results suggest opportunities and methods for public health and safety planning, education and outreach to parents of children with DD who would benefit from targeted training such as information and skill building to develop effective family preparedness plans and connections to local emergency management and responders.

Exercise may be beneficial for individuals in substance use disorder (SUD) treatment given the higher rates of both medical and psychiatric comorbidity, namely mood and anxiety disorders, compared to the general population. Gender and/or racial/ethnic differences in health benefits and response to prescribed exercise have been reported and may have implications for designing exercise interventions in SUD programs. METHOD: Data are from the National Drug Abuse Treatment Clinical Trials Network (NIDA/CTN) Stimulant Reduction Intervention using Dosed Exercise (STRIDE) trial. Gender differences across racial/ethnic groups in physiological responses and stimulant withdrawal severity across time were analyzed using linear mixed effects models. RESULTS: Males completed significantly more exercise sessions than females and were more adherent to the prescribed exercise dose of 12 Kcal/Kg/Week. Controlling for age, race/ethnicity, treatment group and stimulant withdrawal severity, there was a significant gender by time interaction for body mass index (BMI) (p < 0.001), waist circumference (p < 0.001) and heart rate measured prior to exercise sessions (p < 0.01). For females, body mass index (BMI) and waist circumference increased over time while for males BMI and waist circumference stayed unchanged or slightly decreased with time. Heart rate over time significantly increased for females at a higher rate than in males. Stimulant withdrawal severity was similar in males and females at baseline but males exhibited a significant decrease over time while females did not. Although baseline differences were observed, there were no time by race/ethnicity differences in physiologic responses. DISCUSSION: Gender differences in response to exercise may have implications for developing gender specific exercise interventions in SUD programs.

Surgical resection is the main curative modality for non-small cell lung cancer (NSCLC), but variation in the quality of care contributes to suboptimal survival rates. Improving surgical outcomes by eliminating quality deficits is a key strategy for improving population-level lung cancer survival. We evaluated the long-term survival effect of providing direct feedback on institutional performance in a population-based cohort.The Mid-South Quality of Surgical Resection cohort includes all NSCLC resections at 11 hospitals in four contiguous Dartmouth Hospital Referral Regions in Arkansas, Mississippi, and Tennessee. We evaluated resections from 2004 to 2013, before and after onset of a benchmarked performance feedback campaign to surgery and pathology teams in 2009.We evaluated 2,206 patients: 56% preintervention (pre-era) and 44% postintervention (post-era). Preoperative positron emission tomography/computed tomography (46% vs 82%, p0.0001), brain scans (6% vs 21%, p0.0001), and bronchoscopy (8% vs 27%, p0.0001) were more frequently used in the post-era. Patients had 5-year survival of 47% (44% to 50%) in the pre-era compared with 53% (50% to 56%) in the post-era (p = 0.0028). The post-era had an adjusted hazard ratio of 0.85 (95% confidence interval [CI], 0.75 to 0.97; p = 0.0158) compared with the pre-era. This differed by extent of resection (p = 0.0113): compared with the pre-era, the post-era adjusted hazard ratio was 0.49 (95% CI, 0.33 to 0.72) in pneumonectomy, 0.91 (95% CI, 0.79 to 1.05) in lobectomy/bilobectomy, and 0.85 (95% CI, 0.63 to 1.15) in segmentectomy/wedge resections.Overall survival after surgical resection improved significantly in a high lung cancer mortality region of the United States. Reasons may include better selection of patients for pneumonectomy and more thorough staging.

The objective of this prospective, randomised study was to examine the impact of a multi-angle needle guide for ultrasound-guided, in-plane, central venous catheter placement in the subclavian vein. One hundred and sixty patients were randomly allocated to two groups, freehand or needle-guided, and then 159 catheterisations were analysed. Cannulation of the first examined access site was successful in 96.9% of cases with no significant difference between groups. There were three arterial punctures and no other severe injuries. Catheter misplacements did not differ between the groups. Higher success rates within the first and second attempts in the needle-guided group were observed (p = 0.041 and p = 0.019, respectively). Use of the needle guide reduced the access time from a median (IQR [range]) of 30 (18-76 [6-1409]) s to 16 (10-30 [4-295]) s; p = 0.0001, and increased needle visibility from 31.8% (9.7%-52.2% [0-96.67]) to 86.2% (62.5%-100% [0-100]); p < 0.0001. A multi-angle needle guide significantly improved aligning the needle and ultrasound plane compared with the freehand technique when cannulating the subclavian vein. Use of the guide resulted in faster access times and increased success at the first and second attempts.

Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor–antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics. Mol Cancer Ther; 14(7); 1625–36. ©2015 AACR.

Background: Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide–mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function. Methods: We conducted a case-control analysis (n ¼ 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n ¼ 1048) or task-evoked reactivity to emotional stimuli (n ¼ 103) in healthy individuals. Results: Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio ¼ 1.32, gene-wise corrected p ¼ .011) and rs10875995 (odds ratio ¼ 1.26, gene-wise corrected p ¼ .046). The association appeared to be stronger when early-onset (age # 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p ¼ .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p ¼ .0048). Conclusions: Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.

To implement chlorine 35 ((35)Cl) magnetic resonance (MR) at a 7-T whole-body MR system and evaluate its feasibility for imaging humans.All examinations were performed with ethical review board approval; written informed consent was obtained from all volunteers. Seven examinations each of brain and muscle in healthy volunteers and four examinations of patients were performed. Two patients with histologically confirmed glioblastoma multiforme underwent brain imaging. (35)Cl MR and (35)Cl inversion-recovery (IR) MR were performed. Two patients with genetically confirmed hypokalemic periodic paralysis underwent calf muscle imaging. Seven multiecho sequences (acquisition time, 5 minutes; voxel dimension, 11 mm(3)) were applied to determine transverse relaxation time as affected by magnetic field heterogeneity (T2*) and chlorine concentration. (35)Cl and sodium 23 ((23)Na) MR were conducted with a 7-T whole-body MR system. (35)Cl longitudinal relaxation time (T1) and T2* of healthy human brain and muscle were determined with a three-dimensional density-adapted-projection reconstruction technique to achieve short echo times and high signal-to-noise ratio (SNR) efficiency. A nonlinear least squares routine and mono- (T1) and biexponential (T2*) models were used for curve fitting.Phantom imaging revealed 15-fold lower SNR and much shorter relaxation times for (35)Cl than (23)Na. In vivo T2* was biexponential and extremely short. Monoexponential fits of T1 revealed 9.2 and 4.0 milliseconds ± 0.7 (standard deviation) for brain and muscle, respectively. In glioblastoma tissue, increased Cl(-) concentrations and increased Cl(-) IR signal intensities were detected. Voxel dimension and acquisition time, respectively, were 6 mm(3) and 9 minutes 45 seconds ((35)Cl MR) and 10 mm(3) and 10 minutes ((35)Cl IR MR). In patients with hypokalemic periodic paralysis versus healthy volunteers, Cl(-) and Na(+) concentrations were increased. Cl(-) concentration of muscle could be determined (voxel size, 11 mm(3); total acquisition time, 35 minutes).MR at 7 T enables in vivo imaging of (35)Cl in human brain and muscle in clinically feasible acquisition times (10-35 minutes) and voxel volumes (0.2-1.3 cm(3)). Pathophysiological changes of Cl(-) homeostasis due to cancer or muscular ion channel disease can be visualized.

The epigenetic phenomenon of genomic imprinting has motivated the development of numerous theories for its evolutionary origins and genomic distribution. In this review, we examine the three theories that have best withstood theoretical and empirical scrutiny. These are: Haig and colleagues' kinship theory; Day and Bonduriansky's sexual antagonism theory; and Wolf and Hager's maternal-offspring coadaptation theory. These theories have fundamentally different perspectives on the adaptive significance of imprinting. The kinship theory views imprinting as a mechanism to change gene dosage, with imprinting evolving because of the differential effect that gene dosage has on the fitness of matrilineal and patrilineal relatives. The sexual antagonism and maternal-offspring coadaptation theories view genomic imprinting as a mechanism to modify the resemblance of an individual to its two parents, with imprinting evolving to increase the probability of expressing the fitter of the two alleles at a locus. In an effort to stimulate further empirical work on the topic, we carefully detail the logic and assumptions of all three theories, clarify the specific predictions of each and suggest tests to discriminate between these alternative theories for why particular genes are imprinted.

Numerous evolutionary theories have been developed to explain the epigenetic phenomenon of genomic imprinting. Here, we explore a subset of theories wherein non-additive genetic interactions can favour imprinting. In the simplest genic interaction--the case of underdominance--imprinting can be favoured to hide effectively low-fitness heterozygous genotypes; however, as there is no asymmetry between maternally and paternally inherited alleles in this model, other means of enforcing monoallelic expression may be more plausible evolutionary outcomes than genomic imprinting. By contrast, more successful interaction models of imprinting rely on an asymmetry between the maternally and paternally inherited alleles at a locus that favours the silencing of one allele as a means of coordinating the expression of high-fitness allelic combinations. For example, with interactions between autosomal loci, imprinting functionally preserves high-fitness genotypes that were favoured by selection in the previous generation. In this scenario, once a focal locus becomes imprinted, selection at interacting loci favours a matching imprint. Uniparental transmission generates similar asymmetries for sex chromosomes and cytoplasmic factors interacting with autosomal loci, with selection favouring the expression of either maternal or paternally derived autosomal alleles depending on the pattern of transmission of the uniparentally inherited factor. In a final class of models, asymmetries arise when genes expressed in offspring interact with genes expressed in one of its parents. Under such a scenario, a locus evolves to have imprinted expression in offspring to coordinate the interaction with its parent's genome. We illustrate these models and explore key links and differences using a unified framework.

In this article, we discuss decision making during labor and delivery, specifically focusing on decision making around offering women a trial of labor after cesarean section (TOLAC). Many have discussed how humans are notoriously bad at assessing risks and how we often distort the nature of various risks surrounding childbirth. We will build on this discussion by showing that physicians make decisions around TOLAC not only based on distortions of risk, but also based on personal values (i.e. what level of risk are you comfortable with or what types of risks are you willing to take) rather than medical data (or at least medical data alone). As a result of this, we will further suggest that the party who is best epistemically situated to make decisions about TOLAC is the woman herself.

Surgery is the most important curative treatment modality for patients with early-stage non-small cell lung cancer (NSCLC). We examined the pattern of surgical resection for NSCLC in a high incidence and mortality region of the United States over a 10-year period (2004-2013) in the context of a regional surgical quality improvement initiative. We abstracted patient-level data on all resections at 11 hospitals in 4 contiguous Dartmouth Hospital Referral Regions in North Mississippi, East Arkansas, and West Tennessee. Surgical quality measures focused on intraoperative practice, with emphasis on pathologic nodal staging. We used descriptive statistics and trend analyses to assess changes in practice over time. To measure the effect of an ongoing regional quality improvement intervention with a lymph node specimen collection kit, we used period effect analysis to compare trends between the preintervention and postintervention periods. Of 2566 patients, 18% had no preoperative biopsy, only 15% had a preoperative invasive staging test, and 11% underwent mediastinoscopy. The rate of resections with no mediastinal lymph nodes examined decreased from 48%-32% (P0.0001), whereas the rate of resections examining 3 or more mediastinal stations increased from 5%-49% (P0.0001). There was a significant period effect in the increase in the number of N1, mediastinal, and total lymph nodes examined (all P0.0001). A quality improvement intervention including a lymph node specimen collection kit shows early signs of having a significant positive effect on pathologic nodal examination in this population-based cohort. However, gaps in surgical quality remain.

The purpose of this study was to determine functional and subjective results of patients who received arthroscopic debridement for their TFCC Palmer 1B lesions and to compare their results with those of arthroscopic suture repair. Between March 2007 and August 2011, 36 patients were diagnosed with Palmer type 1B tears and underwent arthroscopic debridement. 31 patients (15 males and 16 females) were followed up for an average of 26.7 months (±17.4 months) postoperatively. Their average age was 36.7 years (±12.7 years). Follow-up included the determination of range of motion (ROM), grip strength, pain, and wrist scores (modified Mayo wrist score (MMWS), Disabilities of the Arm, Shoulder and Hand questionnaire (DASH score)). Postoperative ROM averaged 99.2 % for the extension/flexion arc, 95.5 % for the radial/ulnar deviation arc, and 99.4 % for the pronation/supination arc of motion when compared with the contralateral wrist. The MMWS was rated excellent in 48 % of patients, good in 39 %, fair in 13 %, and poor in 0 %. The average DASH score was 17.02 (±14.92). There was a significant reduction in pain. The grip strength was 96.7 % (±15.8), pulp-to-pulp pinch 101.9 % (±17.4), and the ulnar variance −0.12 ± 1.69 mm. Arthroscopic debridement of Palmer type 1B lesions in stable DRUJ yields satisfactory to excellent results. Our study showed similar results compared with the studies of arthroscopic suture repair with shorter postoperative care and fewer complications.

Purpose In clinical day-to-day life, grip strength, key pinch, and range of motion (ROM) serve to objectively evaluate treatment outcomes on wrist interventions. The goals of this study were to generate normative values of wrist function including the parameters of grip strength, key pinch, wrist ROM, and Disabilities of the Arm, Shoulder, and Hand (DASH) scores in a healthy, working population, and to investigate the influence of age, sex, body weight and height, handedness, and work strain. Methods We clinically examined 750 volunteer working subjects (363 women and 387 men, all white). We divided subjects into 2 groups depending on whether their labor involved high or low manual strain. We recorded participants' height, weight, grip strength, pinch strength, and wrist ROM. Each participant filled out a DASH questionnaire. Results Grip strength and pinch strength showed a maximum at between 30 and 49 years of age. In men, body mass index, body height, and weight all correlated with grip strength and pinch grip. Whereas women exhibited greater grip strength on the right side, men showed nonsignificant greater grip strength on the left side. Wrist ROM was greatest for ages ranging between 18 and 29 years. The average DASH value for all male subjects was significantly less than that of female subjects. In a healthy working population, the DASH score increased yearly by an average of 0.2 points in men and 0.3 points in women. Conclusions This study showed that in a healthy working population, people 30 to 49 years of age had the highest grip strength and pinch strength. Age positively correlated with the DASH score and inversely related to wrist ROM. Persons employed in jobs with high manual strain presented with lower wrist ROM and higher DASH scores. Clinical relevance These data help to objectively evaluate wrist function and the effectiveness of therapeutic interventions.

The objective of this study was to examine the influence of anthropometric data, occupational manual strain, DASH (disability of arm, shoulder and hand) score and range of motion (ROM) on grip strength and key pinch. An additional goal was to develop models that enable the prediction of hand strength using the aforementioned parameters. Normative data generated from a healthy working population (n = 750) served as basis for the statistical analysis. Prediction models for hand strength were developed using multivariate regression analysis. Gender, body weight and height, BMI and extension ROM correlate positively, age and DASH score, however, correlate negatively with grip strength and key pinch. Occupational manual strain has no influence on hand strength. The predictive power of the developed models was 68.4 % for grip strength and 57.1 % for key pinch. The developed models enable the prediction of hand strength using easily obtainable data points. The models will have application in clinical practice, physiological studies, medical evidence and rehab decisions.

To assess the presence and persistence of muscular edema and increased myoplasmic sodium (Na(+)) concentration in Duchenne muscular dystrophy (DMD). We examined eight DMD patients (mean age 9.5 ± 5.4 years) and eight volunteers (mean age 9.5 ± 3.2 years) with 3-tesla proton ((1)H) and (23)Na density-adapted 3D-radial MR sequences. Seven DMD patients were re-examined about 7 months later without change of therapy. The eighth DMD patient was re-examined after 5 and 11 months under medication with eplerenone. We quantified muscle edema on STIR images with background noise as reference and fatty degeneration on T1-weighted images using subcutaneous fat as reference. Na(+) was quantified by a muscular tissue Na(+) concentration (TSC) sequence employing a reference containing 51.3 mM Na(+) with 5 % agarose. With an inversion-recovery (IR) sequence, we determined mainly the myoplasmic Na(+). The normalized muscular (23)Na IR signal intensity was higher in DMD than in volunteers (n = 8, 0.75 ± 0.07 vs. 0.50 ± 0.05, p < 0.001) and persisted at second measurement (n = 7, 1st 0.75 ± 0.07, 2nd 0.73 ± 0.06, p = 0.50). When compared to volunteers (25.6 ± 2.0 mmol/l), TSC was markedly increased in DMD (38.0 ± 5.9 mmol/l, p < 0.001) and remained constant (n = 7, 1st 37.9 ± 6.4 mmol/l, 2nd 37.0 ± 4.0 mmol/l, p = 0.49). Muscular edema (15.6 ± 3.5 vs. 6.9 ± 0.7, p < 0.001) and fat content (0.48 ± 0.08 vs. 0.38 ± 0.01, p = 0.003) were elevated in DMD when compared to volunteers. This could also be confirmed during follow-up (n = 7, p = 0.91, p = 0.12). Eplerenone slightly improved muscle strength and reduced muscular sodium and edema. The permanent muscular Na(+) overload in all DMD patients is likely osmotically relevant and responsible for the persisting, mainly intracellular muscle edema that may contribute to the progressive muscle degeneration.

The purpose of this retrospective study was to identify the postoperative complications and disorders associated with open trigger finger release. Factors that were investigated by this study included demographic details, the number of digits affected, BMI, level of manual strain, trauma, received systemic medication, hand dominance, pre-treatment with steroid injection, and concomitant diseases.One hundred and three patients, who underwent open release surgery for 117 trigger fingers and thumbs, were followed up until complete resolution of all complaints. Patients' age, BMI, hand dominance, occupational manual strain, and previous medical history regarding trigger finger or thumb were obtained. Associated conditions and medical treatment, trauma, and previous hand surgical interventions were included as well. Details regarding duration of complaints, ROM, visual analogue pain scale, swelling, recurrence of the disease following previous surgical release, and persistence of complaints following corticosteroid injection were examined.The dominant hand was not significantly more frequently affected than the non-dominant hand. Occupation also did not influence the incidence of trigger digit. Patients with systemic steroid therapy had a significantly shorter duration of postoperative symptoms with a mean duration of 29.3 days (range, 28-31 days ± 1.3). Significantly less postoperative swelling was noticed in patients with a pre-surgical steroid injection. The mean duration of symptoms before and after surgery was significantly shorter for a trigger thumb than for trigger finger.Open trigger digit release constitutes an adequate low-risk surgical procedure for treatment of trigger digit. In this study, we could show that the incidence of this disease is not significantly correlated with the manual strain, trauma, BMI, hand dominance or concomitant diseases like diabetes mellitus, rheumatoid arthritis, renal insufficiency, and hypothyroidism. Additionally, this study illustrates the importance of a careful postoperative follow-up treatment to avoid potential persistent functional limitations.

Purpose To analyze functional and subjective outcomes of patients with posttraumatic dorsal instability of the distal radioulnar joint (DRUJ) treated by a dorsal capsular imbrication. Methods We reviewed 11 patients (7 men and 4 women) with posttraumatic instability of the DRUJ who were treated by a capsular imbrication. The patients ranged in age from 18 to 48 years (average, 33 y). The duration of symptoms before surgery ranged from 3 weeks to 6 months (average, 5 mo). We evaluated subjective outcome measurements such as the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, questions regarding symptoms of pain and instability, and overall satisfaction. Objective outcome measurements were physical examination, standard radiographs, and a review of any surgical complications. Patients were asked whether they experienced wrist tenderness with applied pressure, swelling, scar sensitivity, or pain. We determined functional outcome using the Modified Mayo Wrist Score including range of motion and grip strength. The score was used to evaluate the surgical technique and enable comparison with other surgical methods used to treat instability of the DRUJ. Results After surgery, the total mean DASH score was 15 points. Range of motion, grip strength, pain, and overall function resulted in a mean Modified Mayo Wrist Score of 88 points, and therefore a good functional outcome. Three patients were noted to have persistent mild DRUJ instability on the stress test but did not have symptoms. The only intraoperative or postoperative complications observed were transient paresthesias on the ulnar side of the hand. Conclusions Capsular imbrication for posttraumatic instability of the DRUJ is a highly effective procedure with few complications and good functional and subjective results even in cases with concomitant healed fractures of the radius or ulnar styloid. Type of study/level of evidence Therapeutic IV.

Purpose Traumatic and degenerative disc lesions cause ulnar-sided wrist pain. To date, anatomical investigations of cadaver triangular fibrocartilage discs examining the innervation of the triangular fibrocartilage complex have found no evidence of nerve fibers in the healthy disc. In this study, we immunohistologically investigated biopsies from patients with either central traumatic or degenerative disc lesions, to determine the existence of nerve fibers. We hypothesized that an ingrowth of nerve fibers causes ulnar-sided wrist pain associated with traumatic and degenerative disc lesions. Methods We included 32 patients with a traumatic Palmer 1A lesion and 17 patients with a degenerative Palmer 2C lesion in the study. We obtained a biopsy of each patient and stained the specimen with protein gene product 9.5 for nerve fiber detection. Results There were no nerve fibers in either traumatic or degenerative disc lesions. In addition, the marginal areas of the biopsies showed no evidence of nerve fibers. Conclusions Traumatic and degenerative disc lesions show no ingrowth of nerve fibers. Clinical relevance The ulnar-sided pain associated with traumatic and degenerative disc lesions must have other, currently unknown causes.

Variations in diabetic phenotypes are caused by complex interactions of genetic effects, environmental factors, and the interplay between the two. We tease apart these complex interactions by examining genome-wide genetic and epigenetic effects on diabetes-related traits among different sex, diet, and sex-by-diet cohorts in a Mus musculus model. We conducted a genome-wide scan for quantitative trait loci that affect serum glucose and insulin levels and response to glucose stress in an F(16) Advanced Intercross Line of the LG/J and SM/J intercross (Wustl:LG,SM-G16). Half of each sibship was fed a high-fat diet and half was fed a relatively low-fat diet. Context-dependent genetic (additive and dominance) and epigenetic (parent-of-origin imprinting) effects were characterized by partitioning animals into sex, diet, and sex-by-diet cohorts. We found that different cohorts often have unique genetic effects at the same loci, and that genetic signals can be masked or erroneously assigned to specific cohorts if they are not considered individually. Our data demonstrate that the effects of genes on complex trait variation are highly context-dependent and that the same genomic sequence can affect traits differently depending on an individual's sex and/or dietary environment. Our results have important implications for studies of complex traits in humans.

Previous studies on the LG,SM advanced intercross line have identified approximately 40 quantitative trait loci (QTL) for long -bone (humerus, ulna, femur, and tibia) lengths. In this study, long-bone-length QTL were fine-mapped in the F(34) generation (n = 1424) of the LG,SM advanced intercross. Environmental effects were assessed by dividing the population by sex between high-fat and low-fat diets, producing eight sex/diet cohorts. We identified 145 individual bone-length QTL comprising 45 pleiotropic QTL; 69 replicated QTL from previous studies, 35 were new traits significant at previously identified loci, and 41 were novel QTL. Many QTL affected only a subset of the population based on sex and/or diet. Eight of ten known skeletal growth genes were upregulated in 3-week-old LG/J male proximal tibial growth plates relative to SM/J. The sequences of parental strains LG/J and SM/J indicated the presence of over half a million polymorphisms in the confidence intervals of these 45 QTL. We examined 526 polymorphisms and found that 97 represented radical changes to amino acid composition while 40 were predicted to be deleterious to protein function. Additional experimentation is required to understand how changes in gene regulation or protein function can alter the genetic architecture and interact with the environment to produce phenotypic variation.

Postbariatric plastic surgery is considered to be a high-risk procedure, which entails such frequent minor complications as postoperative seroma, bleeding and wound dehiscence. These occur with a high incidence, especially, following postbariatric abdominal dermolipectomy. In order to reduce these complication rates, a new type of dressing with wide abdominal topical negative pressure (TNP) application was applied. We performed abdominal dermolipectomy in 23 obese patients. The average body mass index was 32.8 kg/m(2), and the median age of the patients was 42.9 years. Ten patients received conventional standard dressings (control group I), whereas the other 13 patients received a wide TNP dressing including the ventral and lateral trunk (negative pressure group II). Postoperative exudate volumes were collected, tallied and documented for each group separately until all drains could be removed. The conventionally treated control group (I) showed a significantly higher postoperative secretion volume compared with the negative pressure group (II). In addition, the average time to postoperative final drain removal was significantly lower in the negative pressure group (II) compared with the control group (I). The results indicate that widely applied external TNP wound dressing on the ventral and lateral trunk following postbariatric abdominal dermolipectomy leads to a significant reduction in exudate formation, enables early drain removal and thus, decreases length of hospitalization.

The aim of this study was to analyse various gene expression profiles of muscle tissue during normoxia, ischaemia and after reperfusion in human muscle free flaps, to gain an understanding of the occurring regulatory, inflammatory and apoptotic processes on a cellular and molecular basis. Eleven Caucasian patients with soft tissue defects needing coverage with microsurgical free muscle flaps were included in this study. In all patients, the muscle samples were taken from free myocutaneous flaps. The first sample was taken before induction of ischaemia in normoxia (I), another one after ischaemia (II), and the last one was taken after reperfusion (III). The samples were analysed using DNA-microarray, real-time-quantitative-PCR and immunohistochemistry. DNA-microarray analysis detected multiple, differentially regulated genes when comparing the different groups (I–III) with statistical significance. Comparing ischaemia (II) versus normoxia (I) educed 13 genes and comparing reperfusion (III) versus ischaemia (II) educed 19 genes. The comparison of reperfusion (III) versus normoxia (I) yielded 100 differentially regulated genes. Real-time-quantitative-PCR confirmed the results of the DNA-microarrays for a subset of four genes (CASP8, IL8, PLAUR and S100A8). This study shows that ischaemia and reperfusion induces alterations on the gene expression level in human muscle free flaps. Data may suggest that the four genes CASP8, IL8, PLAUR and S100A8 are of great importance in this context. We could not confirm the DNA-microarry and real-time-quantitative-PCR results on the protein level. Finally, these findings correspond with the surgeon’s clinical experience that the accepted times of ischaemia, generally up to 90 min., are not sufficient to induce pathophysiological processes, which can ultimately lead to flap loss. When inflammatory and apoptotic proteins are expressed at high levels, flap damage might occur and flap loss is likely. The sole expression on mRNA level might explain why flap loss is unlikely.

Purpose Degenerative articular disk perforations of the triangular fibrocartilage (TFC) of the wrist could result from chronic loading of the ulnocarpal joint. Apoptosis played a crucial role in fibrocartilage cell loss, and the purpose of this study was to clarify which apoptotic pathway was involved in the development of degenerative disk lesions. We also investigated whether ulna length played an etiologic role in the occurrence of fibrocartilage cell loss. Methods Included in the study were 17 patients with degenerative articular disk tears of the TFC (Palmer type 2C). After arthroscopic debridement of the TFC, histologic sections were examined to assess the presence of apoptosis. Apoptosis was determined by use of caspase 3, caspase 8, and caspase 9 immunohistochemistry. Furthermore, Fas ligand and BID (BH3 interacting domain death) agonist were applied for immunohistochemical analysis. Results Cells positive for caspase 3, caspase 8, caspase 9, Fas ligand, and BID were found in all specimens. The number of cells positive for caspase 3 and BID was significantly increased in specimens from patients with an ulna-positive variance. In contrast, for cells positive for caspase 8, caspase 9, and Fas ligand, no significant difference was found between specimens from patients with an ulna-positive variance and those from patients with an ulna-neutral/ulna-negative variance. Conclusions The extrinsic and intrinsic apoptotic pathways are involved in the development of degenerative disk lesions. Fibrocartilage cell loss occurs mainly through the intrinsic apoptotic pathway. The accumulation of apoptotic cells is not significantly different between the 3 zones of the TFC. It could be verified that ulna length is correlated with fibrocartilage cell loss. Clinical Relevance Ulnar shortening is a valuable treatment option for degenerative TFC lesions. Knowledge of the specific apoptotic pathway that is causing degenerative disk lesions is critical in selecting the appropriate and most beneficial therapeutic treatment to halt further cell loss and the degeneration of the TFC.

Mothers can determine which genotypes of offspring they will produce through selective abortion or selective implantation. This process can, at some loci, favour matching between maternal and offspring genotype whereas at other loci mismatching may be favoured (e.g. MHC, HLA). Genomic imprinting generally renders gene expression monoallelic and could thus be adaptive at loci where matching or mismatching is beneficial. This hypothesis, however, remains unexplored despite evidence that loci known to play a role in genetic compatibility may be imprinted. We develop a simple model demonstrating that, when matching is beneficial, imprinting with maternal expression is adaptive because the incompatible paternal allele is not detected, protecting offspring from selective abortion. Conversely, when mismatching is beneficial, imprinting with paternal expression is adaptive because the maternal genotype is more able to identify the presence of a foreign allele in offspring. Thus, imprinting may act as a genomic 'cloaking device' during critical periods in development when selective abortion is possible.

Degenerative articular disc perforations of the triangular fibrocartilage (TFC) of the wrist are characterized by fibrocartilage cell loss and are often associated with ulna-plus situations. Apoptosis has been found to play a crucial role in fibrocartilage cell loss, however, the molecular mechanism and mediators are still poorly understood. The purpose of this study was to identify receptors to apoptosis in degenerative disc lesions. Included in the study were 17 patients with degenerative articular disc tears of the TFC (Palmer type 2C). Following arthroscopic debridement of the TFC, histological sections were examined to assess the presence of apoptosis. Apoptosis was determined using TRAIL and death receptor DR4 agonists for immunohistochemical analyses. The number of cells positive for apoptosis was then correlated with ulna length. Cells positive for TRAIL and DR4 were found in all specimens. The number of cells positive for TRAIL was significantly increased in specimens of patients with an ulna positive variance (P = 0.040). However, DR4 was not significantly increased in ulna plus (P > 0.05). Both, TRAIL and DR4 positive cells were found to be evenly distributed throughout each specimen. There was no accumulation of any type of cells in any particular zone of the biopsies. This is the first study that shows that TFCC cells express TRAIL and DR4, which suggests that apoptosis, as well as, mechanical trauma are involved in the development of disc perforation. The TRAIL/DR4 receptor system is a molecular mediator of apoptosis induction in TFC cells and therefore plays a role in cell loss in degenerative disc lesions.

Genomic imprinting, where the effects of alleles depend on their parent-of-origin, can be an important component of the genetic architecture of complex traits. Although there has been a rapidly increasing number of studies of genetic architecture that have examined imprinting effects, none have examined whether imprinting effects depend on genetic background. Such effects are critical for the evolution of genomic imprinting because they allow the imprinting state of a locus to evolve as a function of genetic background. Here we develop a two-locus model of epistasis that includes epistatic interactions involving imprinting effects and apply this model to scan the mouse genome for loci that modulate the imprinting effects of quantitative trait loci (QTL). The inclusion of imprinting leads to nine orthogonal forms of epistasis, five of which do not appear in the usual two-locus decomposition of epistasis. Each form represents a change in the imprinting status of one locus across different classes of genotypes at the other locus. Our genome scan identified two different locus pairs that show complex patterns of epistasis, where the imprinting effect at one locus changes across genetic backgrounds at the other locus. Thus, our model provides a framework for the detection of genetic background-dependent imprinting effects that should provide insights into the background dependence and evolution of genomic imprinting. Our application of the model to a genome scan supports this assertion by identifying pairs of loci that show reciprocal changes in their imprinting status as the background provided by the other locus changes.

The interaction between maternally provided environment and offspring genotype is a major determinant of offspring development and fitness in many organisms. Recent research has demonstrated that not only genetic effects, but also epigenetic effects may be subject to modifications by the maternal environment. Genomic imprinting resulting in parent-of-origin-dependent gene expression is among the best studied of epigenetic effects. However, very little is known about the degree to which genomic imprinting effects can be modulated by the maternally provided environment, which has important implications for phenotypic plasticity. In this study, we investigated this unresolved question using a cross-fostering design in which mouse pups were nursed by either their own or an unrelated mother. We scanned the entire genome to search for quantitative trait loci whose effects depend on cross-fostering and detected 10 of such loci. Of the 10 loci, 4 showed imprinting by cross-foster interactions. In most cases, the interaction effect was due to the presence of an effect in either cross-fostered or non-cross-fostered animals. Our results demonstrate that genomic imprinting effects may often be modified by the maternal environment and that such interactions can impact key fitness-related traits suggesting a greater plasticity of genomic imprinting than previously assumed.

The central zone of the triangular fibrocartilage complex (TFCC) of the wrist is thought to be avascular and is generally considered to lack any healing potential. The purpose of this study was to investigate, if cartilage cells of degenerative disc lesions possess any healing or proliferation potential and whether ulna length plays a significant role in the proliferation process. Cells positive for proliferating cell nuclear antigen (PCNA) were found in all specimens. Specimens of patients with ulna positive variance showed a decreased number of PCNA positive cells than specimens of patients with either negative or neutral ulna variance. We found that cartilage cells of Palmer type 2C lesions undergo mitotic cell division, thus exhibiting proliferation capability. It could not be shown that ulnar length is significantly correlated with the number of PCNA positive cells.

Maternal effects can play an important role in a diversity of ecological and evolutionary processes such as population dynamics, phenotypic plasticity, niche construction, life-history evolution and the evolutionary response to selection. However, although maternal effects were defined by quantitative geneticists well over half a century ago, there remains some confusion over exactly what phenomena should be characterized as maternal effects and, more importantly, why it matters and how they are defined. We suggest a definition of maternal effects as thecausalinfluence of the maternal genotype or phenotype on the offspring phenotype. This definition differs from some definitions in that it treats maternal effects as a phenomenon, not as a statistical construct. The causal link to maternal genotype or phenotype is the critical component of this definition providing the link between maternal effects and evolutionary and ecological processes. We show why phenomena such as maternal cytoplasmic inheritance and genomic imprinting are distinct genetically from and have different evolutionary consequences than true maternal effects. We also argue that one should consider cases where the maternal effect is conditional on offspring genotype as a class of maternal effects.

Purpose The objective of this retrospective study was to determine functional and subjective outcomes of patients with Palmer type 1B tears repaired arthroscopically and to investigate whether clinical outcomes are related to ulna length. Methods Forty-six patients with arthroscopic repair of Palmer type 1B tears were reviewed. There were 23 males and 23 females. The average age was 34 years (range, 10 to 58 yrs). The average follow-up was 11 months (range, 6 to 23 mos), and the delay to surgery was 9.7 months. All patients suffered ulnar-sided wrist pain and were diagnosed with Palmer type 1B tears. The tear was repaired arthroscopically with an inside-outside suture technique. The range of motion (ROM), grip strength, pain, wrist score (modified Mayo wrist score), Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH) score, and ulna length (static and dynamic) were evaluated. Results There was a reduction in pain and an improvement in grip strength. Postoperative ROM averaged 128° ± 23° for the extension/flexion arc, 41° ± 11° for the radial/ulnar deviation arc, and 171° ± 19° for the pronation/supination arc of motion. However, no relation could be found between ulna length and clinical outcome. The modified Mayo wrist score was rated excellent in 22% of patients, good in 41%, fair in 27%, and poor in 10%. The average DASH score was 21.70 ± 17.17 (range, 0 to 58.33). Conclusions Arthroscopic repair of Palmer type 1B tears yields satisfactory results. Sixty-three percent of patients achieved good to excellent results, experienced increased ROM, grip strength, and pain relief. Ulnar neutral or positive variance is not a contraindication for suture repair and does not require simultaneous ulna shortening when repairing the triangular fibrocartilage complex arthroscopically. A delay to surgery did not affect clinical outcome. Level of Evidence Level IV, therapeutic case series.

The objective of this study was to determine functional and subjective outcomes of an ulnar shortening procedure elected by patients who experienced persistent ulno-carpal symptoms following arthroscopic suture repair of a Palmer type 1B lesion. All patients had a dynamic ulna positive variance.Five patients (3 males and 2 females) with arthroscopic repair of Palmer type 1B tears who subsequently underwent ulnar shortening were reviewed. At the time of the arthroscopic repair the patients' average age was 37 +/- 13 years (range 16-52 years). Average time to follow-up was 14 +/- 6 months (range 10-23 months). The average age was 38 +/- 14 years (range 17-53 years) when the ulnar shortening was performed. The second follow-up took place 7 +/- 2 months (range 5-9 months) after ulnar shortening. During the follow-ups, range of motion, grip strength, pain, Modified Mayo Wrist Score, DASH Score, and ulnar length were evaluated. Citing persistent ulno-carpal symptoms, the patients elected ulnar shortening an average of 17 +/- 7months (range 13-29 months) following the arthroscopic repair. Prior to ulnar shortening the average static ulnar variance was 0.2 +/- 1.3 mm (range -1 to 2 mm), the average dynamic ulnar variance was 1.4 +/- 0.5 mm (range 1 to 2 mm).Ulnar shortening brought about further reduction in pain after the arthroscopic repair of the triangular fibrocartilage complex (TFCC) had already reduced it. As measured by a visual analogue scale, the average value after ulnar shortening was 2.2 +/- 2.1 (range 0.7-5.0). The average static ulnar variance was -3.4 +/- 2 mm (range -5 to -1 mm). Patients were very satisfied with the results of the ulnar shortening and four out of five indicated that it had significantly improved their symptoms and they would elect ulnar shortening again. Postoperative range of motion as a percentage of the contralateral side averaged 90% for the extension/flexion arc, 80% for the radial/ulnar deviation arc, and 100% for the pronation/supination arc of motion. In addition, there was an improvement in grip strength. The Modified Mayo Wrist Score was rated excellent in three patients, and fair in two patients. The average DASH score was 22 +/- 22 (range 0-53).Patients who have a dynamic ulna positive variance and experience persistent ulno-carpal symptoms following arthroscopic suture repair of a Palmer type 1B lesion, benefit from an ulnar shortening procedure. Shortening the ulna can improve these patients' symptoms of pain, range of motion, and grip strength.

We present here a detailed study of the genetic contributions to adult body size and adiposity in the LG,SM advanced intercross line (AIL), an obesity model. This study represents a first step in fine-mapping obesity quantitative trait loci (QTLs) in an AIL. QTLs for adiposity in this model were previously isolated to chromosomes 1, 6, 7, 8, 9, 12, 13, and 18. This study focuses on heritable contributions and the genetic architecture of fatpad and organ weights. We analyzed both the F(2) and F(3) generations of the LG,SM AIL population single-nucleotide polymorphism (SNP) genotyped with a marker density of approximately 4 cM. We replicate 88% of the previously identified obesity QTLs and identify 13 new obesity QTLs. Nearly half of the single-trait QTLs were sex-specific. Several broad QTL regions were resolved into multiple, narrower peaks. The 113 single-trait QTLs for organs and body weight clustered into 27 pleiotropic loci. A large number of epistatic interactions are described which begin to elucidate potential interacting molecular networks. We present a relatively rapid means to obtain fine-mapping details from AILs using dense marker maps and consecutive generations. Analysis of the complex genetic architecture underlying fatpad and organ weights in this model may eventually help to elucidate not only heritable contributions to obesity but also common gene sets for obesity and its comorbidities.

Results of an ongoing prospective study of progeny of patients with adult-onset polycystic kidney disease using grey-scale ultrasound and high-dose nephrotomography are reported. Six asymptomatic subjects out of 17 at risk for polycystic kidney disease were found by ultrasonography to have multiple renal cysts; this included two unrelated children aged 18 months and 6 y who had normal high-dose nephrotomography. We suggest that ultrasonography may be the method of choice for presymptomatic detection of polycystic kidney disease. Serial studies of at-risk individuals by sonography will be useful in determining the earliest age of detection, the latest age of ultrasonography presentation, and in following the natural history of polycystic kidney disease.

Genomic imprinting results in the differential expression of genes, depending on which allele is inherited from the mother and which from the father. The effects of such differential gene expression are reflected in phenotypic differences between the reciprocal heterozygotes ( Aa vs. aA ). Although many imprinted genes have been identified and play a key role in development, little is known about the contribution of imprinting to quantitative variation in trait expression. Here, we examine this problem by mapping imprinting effects on adult body composition traits in the F 3 generation of an intercross between the Large (LG/J) and Small (SM/J) inbred mouse strains. We identified eight pleiotropic imprinted quantitative trait loci ( i QTL) located throughout the genome. Most i QTL are in novel locations that have not previously been associated with imprinting effects, but those on chromosomes 7, 12, and centromeric 18 lie in regions previously identified as containing imprinted genes. Our results show that the effects of genomic imprinting are relatively small, with reciprocal heterozygotes differing by ≈0.25 standard deviation units and the effects at each locus accounting for 1% to 4% of the phenotypic variance. We detected a variety of imprinting patterns, with paternal expression being the most common. These results indicate that genomic imprinting has small, but detectable, effects on the normal variation of complex traits in adults and is likely to be more common than usually thought.

Purpose: The purpose of this study was to investigate apoptosis in degenerative disc lesions (Palmer type IIC) and differentiate between patients with ulna-plus and ulna-neutral variance. Methods: Seventeen patients with degenerative tears (Palmer type IIC) in the articular disc of the triangular fibrocartilage were included in this study. The triangular fibrocartilage was debrided arthroscopically with a punch and the histologic sections were used to analyze necrosis and apoptosis. Apoptosis and necrosis was quantified by terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. Apoptotic cells were visualized by poly(ADP-ribose) polymerase (PARP) p85 immunohistochemistry. The number of apoptotic and necrotic cells was then correlated with ulnar length. Results: PARP- and TUNEL-positive cells were found in each patient. In addition, patients with an ulna plus variance showed a significantly increased number of apoptotic cells in comparison to patients with an ulna neutral variance. The distribution of the apoptosis-positive cells did not show any accumulation in the inner part of the specimen, but were evenly distributed. Conclusions: This study showed that patients with ulna plus present with significantly higher numbers of apoptotic cells in degenerative lesions in comparison to patients with ulna neutral. The apoptotic cells were evenly distributed throughout the entire specimen. Clinical Relevance The results of this study revealed that increased length of the ulna is related to increased cell death. Therefore, techniques that decrease the ulna variance would appear to be appropriate and would improve the clinical situation by preventing further cell death.

Epigenetic effects are increasingly recognized as an important source of variation in complex traits and have emerged as the focus of a rapidly expanding area of research. Principle among these effects is genomic imprinting, which has generally been examined in analyses of complex traits by testing for parent-of-origin-dependent effects of alleles. However, in most of these analyses maternal effects are confounded with genomic imprinting because they can produce the same patterns of phenotypic variation expected for various forms of imprinting. Distinguishing between the two is critical for genetic and evolutionary studies because they have entirely different patterns of gene expression and evolutionary dynamics. Using a simple single-locus model, we show that maternal genetic effects can result in patterns that mimic those expected under genomic imprinting. We further demonstrate how maternal effects and imprinting effects can be distinguished using genomic data from parents and offspring. The model results are applied to a genome scan for quantitative trait loci (QTL) affecting growth- and weight-related traits in mice to illustrate how maternal effects can mimic imprinting. This genome scan revealed five separate maternal-effect loci that caused a diversity of patterns mimicking those expected under various modes of genomic imprinting. These results demonstrate that the appearance of parent-of-origin-dependent effects (POEs) of alleles at a locus cannot be taken as direct evidence that the locus is imprinted. Moreover, they show that, in gene mapping studies, genetic data from both parents and offspring are required to successfully differentiate between imprinting and maternal effects as the cause of apparent parent-of-origin effects of alleles.

From June 2004 to April 2006, cosponsored by the U.S. Department of Health and Human Services and the Ad Council, the National Breastfeeding Awareness Campaign (NBAC) warned women that not breast-feeding put babies at risk for a variety of health problems. “You'd never take risks before your baby is born. Why start after?” asked televised public service announcements over images of pregnant women logrolling and riding a mechanical bull. The NBAC, and particularly its message of fear, neglected fundamental ethical principles regarding evidence quality, message framing, and cultural sensitivity in public health campaigns. The campaign was based on research that is inconsistent, lacks strong associations, and does not account for plausible confounding variables, such as the role of parental behavior, in various health outcomes. It capitalized on public misunderstanding of risk and risk assessment by portraying infant nutrition as a matter of safety versus danger and then creating spurious analogies. It also exploited deep-seated normative assumptions about the responsibility that mothers have to protect babies and children from harm and was insufficiently attentive to the psychological, socioeconomic, and political concerns of its intended audience. Critical analysis of the NBAC suggests that future health campaigns would benefit from more diverse review panels and from a greater focus on providing accurate risk information about probabilities and trade-offs in order to enable informed decision making.

The contribution that pleiotropic effects of individual loci make to covariation among traits is well understood theoretically and is becoming well documented empirically. However, little is known about the role of epistasis in determining patterns of covariation among traits. To address this problem we combine a quantitative trait locus (QTL) analysis with a two-locus model to assess the contribution of epistasis to the genetic architecture of variation and covariation of organ weights and limb bone lengths in a backcross population of mice created from the M16i and CAST/Ei strains. Significant epistasis was exhibited by 14 pairwise combinations of QTL for organ weights and 10 combinations of QTL for limb bone lengths, which contributed, on average, about 5% of the variation in organ weights and 8% in limb bone lengths beyond that of single-locus QTL effects. Epistatic pleiotropy was much more common in the limb bones (seven of 10 epistatic combinations affecting limb bone lengths were pleiotropic) than the organs (three of the 14 epistatic combinations affecting organ weights were pleiotropic). In both cases, epistatic pleiotropy was less common than single-locus pleiotropy. Epistatic pleiotropy accounted for an average of 6% of covariation among organ weights and 21% of covariation among limb bone lengths, which represented an average of one-fifth (for organ weights) and one-third (for limb bone lengths) of the total genetic covariance between traits. Thus, although epistatic pleiotropy made a smaller contribution than single-locus pleiotropy, it clearly made a significant contribution to the genetic architecture of variation/covariation.

OBJECTIVE To compare the effectiveness of 50 microg compared with 100 microg of repetitive misoprostol dosages administered sublingually for labor induction. METHODS Two hundred twelve women who presented with an indication for cervical ripening and labor induction were randomly assigned to 50 microg or 100 microg of misoprostol tablets administered sublingually with double masking of treatment group dose allocation. The primary outcome was the interval from start of induction to vaginal delivery. RESULTS Among the 203 evaluable participants, 102 were randomly assigned to the 50-microg group and 101 to the 100-microg group. The proportion of patients who delivered vaginally in less than 12 hours and less than 24 hours was significantly higher in the 100-microg group: 28% and 63% in the 100-microg group compared with 15% and 36% in the 50-microg group, respectively (P = .01 and P = .001). The incidence of tachysystole was significantly higher in the 100-microg group (P = .02). The incidence of hyperstimulation syndrome was higher in the 100-microg group, but not statistically significant (P = .46). With respect to the proportion of patients delivered after a single dose, mode of delivery, and perinatal outcome, no significant differences between treatment groups were observed. Regarding the need for oxytocin augmentation, 61% required augmentation in the 100-microg group compared with 81% in the 50-microg group (P = .002). CONCLUSION One hundred micrograms of sublingual misoprostol is more effective than 50 microg of sublingual misoprostol, but is associated with a higher incidence of tachysystole and uterine hyperstimulation syndrome. LEVEL OF EVIDENCE I.

Existing approaches to characterizing quantitative trait loci (QTL) utilize a paradigm explicitly focused on the direct effects of genes, where phenotypic variation among individuals is mapped onto genetic variation of those individuals. For many characters, however, the genotype of the mother via its maternal effect accounts for a considerable portion of the genetically based variation in progeny phenotypes. Thus the focus on direct effect QTL may result in an insufficient or misleading characterization of genetic architecture due to the omission of the potentially important source of genetic variance contributed by maternal effects. We analyze the relative contribution of direct and maternal effect (ME) QTL to early growth in mice using a three-generation intercross of the Small (SM/J) and Large (LG/J) inbred mouse lineages. Using interval mapping and composite interval mapping, direct effect (DE) QTL for early growth (change in body mass during the interval from week 1 to 2) were detected in the F(2) generation of the intercross (n = 510), where no maternal genetic effect variance is present (all individuals are progeny of genetically identical F(1) mothers). ME QTL were detected by treating the phenotypes of cross-fostered F(3) pups as a characteristic of their nurse-dam (n = 168 dams with cross-fostered progeny). Five DE QTL, significant at a chromosome wide level (alpha = 0.05), were detected, with two significant at a genome wide level. FourME QTL significant at the chromosome wide level were detected, with three significant at the genome wide level. A model containing only DE QTL accounted for 11.8% of phenotypic variance, while a model containing only ME QTL accounted for 31.5% of the among litter variance in growth. There was no evidence for pleiotropy of DE and ME loci since there was no overlap between loci detected in these two analyses. Epistasis between all pairs of loci was analyzed for both DEs and MEs. Ten pairs of loci showed significant epistasis for MEs (alpha = 0.05 corrected for multiple comparisons) while four pairs showed significant epistasis for DEs on early growth.

(68)Ga-DOTATOC-PET/CT is a well-established method for detecting and targeting the volume definition of meningiomas prior to radiotherapy. Moreover, there is evidence that this method is able to detect meningiomas with higher sensitivity than the goldstandard MRI. Since the hybrid PET/MRI scanner became available in the past few years, the next stage of development could consequently evolve by evaluating the feasibility of a hybrid PET/MRI scanner using (68)Ga-DOTATOC for detecting meningiomas.Fifteen patients received (68)Ga-DOTATOC-PET/CT (0.5 h post injection [p.i.]) followed by PET/MRI 2 hours p.i. Both investigations were analyzed separately and then compared with respect to image quality, detection of intracranial meningiomas, and radiotracer uptake values (RUVs). In addition, ratios between radiotracer uptake in meningiomas and pituitary glands were compared between both PET/CT and PET/MRI.Overall, 33 intracranial meningiomas were detected. All were visible with high contrast in both PET/CT and PET/MRI. (68)Ga-DOTATOC-PET/MRI provided flawless image quality without artefacts. Calculated RUV in meningiomas, as well as the ratios of RUVs in meningiomas to those of pituitary glands, were higher in PET/CT. As a result, meningiomas can be distinguished from pituitary glands better in early images.(68)Ga-DOTATOC-PET/MRI provided flawless image quality and presented an ideal combination of high sensitivity/specificity (PET) and the best possible morphological visualization of meningiomas (MRI). In addition, excellent detection of meningiomas is already possible at 0.5 hours p.i. Later images do not improve the distinction between pituitary gland and adjacent meningiomas. However, RUVs need to be carefully compared between both imaging modalities.