Over the last century, intakes of omega-6 (ω-6) fatty acids in Western diets have dramatically increased, while omega-3 (ω-3) intakes have fallen. Resulting ω-6/ω-3 intake ratios have risen to nutritionally undesirable levels, generally 10 to 15, compared to a possible optimal ratio near 2.3. We report results of the first large-scale, nationwide study of fatty acids in U.S. organic and conventional milk. Averaged over 12 months, organic milk contained 25% less ω-6 fatty acids and 62% more ω-3 fatty acids than conventional milk, yielding a 2.5-fold higher ω-6/ω-3 ratio in conventional compared to organic milk (5.77 vs. 2.28). All individual ω-3 fatty acid concentrations were higher in organic milk—α-linolenic acid (by 60%), eicosapentaenoic acid (32%), and docosapentaenoic acid (19%)—as was the concentration of conjugated linoleic acid (18%). We report mostly moderate regional and seasonal variability in milk fatty acid profiles. Hypothetical diets of adult women were modeled to assess milk fatty-acid-driven differences in overall dietary ω-6/ω-3 ratios. Diets varied according to three choices: high instead of moderate dairy consumption; organic vs. conventional dairy products; and reduced vs. typical consumption of ω-6 fatty acids. The three choices together would decrease the ω-6/ω-3 ratio among adult women by ∼80% of the total decrease needed to reach a target ratio of 2.3, with relative impact “switch to low ω-6 foods” > “switch to organic dairy products” ≈ “increase consumption of conventional dairy products.” Based on recommended servings of dairy products and seafoods, dairy products supply far more α-linolenic acid than seafoods, about one-third as much eicosapentaenoic acid, and slightly more docosapentaenoic acid, but negligible docosahexaenoic acid. We conclude that consumers have viable options to reduce average ω-6/ω-3 intake ratios, thereby reducing or eliminating probable risk factors for a wide range of developmental and chronic health problems.
The Accreditation Council for Graduate Medical Education (ACGME) introduced the Outcome Project in July 2001 to improve the quality of resident education through competency-based learning. The purpose of this systematic review is to determine and explore the perceptions of program directors regarding challenges to implementing the ACGME Outcome Project.
We used the PubMed and Web of Science databases and bibliographies for English-language articles published between January 1, 2001, and February 17, 2012. Studies were included if they described program directors' opinions on (1) barriers encountered when attempting to implement ACGME competency-based education, and (2) assessment methods that each residency program was using to implement competency-based education. Articles meeting the inclusion criteria were screened by 2 researchers. The grading criterion was created by the authors and used to assess the quality of each study.
The survey-based data reported the opinions of 1076 program directors. Barriers that were encountered include: (1) lack of time; (2) lack of faculty support; (3) resistance of residents to the Outcome Project; (4) insufficient funding; (5) perceived low priority for the Outcome Project; (6) inadequate salary incentive; and (7) inadequate knowledge of the competencies. Of the 6 competencies, those pertaining to patient care and medical knowledge received the most responses from program directors and were given highest priority.
The reviewed literature revealed that time and financial constraints were the most important barriers encountered when implementing the ACGME Outcome Project.
Type III secretion systems are used by many Gram-negative pathogens to directly deliver effector proteins into the cytoplasm of host cells. To accomplish this, bacteria secrete translocator proteins that form a pore in the host-cell membrane through which the effector proteins are then introduced into the host cell. Evidence from multiple systems indicates that the pore-forming translocator proteins are exported before effectors, but how this secretion hierarchy is established is unclear. Here we used the P. aeruginosa translocator protein PopD as a model to identify its export signals. The amino-terminal secretion signal and chaperone, PcrH, are required for export under all conditions. Two novel signals in PopD, one proximal to the chaperone-binding site and one at the very C-terminus of the protein, are required for export of PopD before effector proteins. These novel export signals establish the translocator-effector secretion hierarchy, which in turn, is critical for the delivery of effectors into host cells.
T3SS; secretion signal; PopB
The recent identification of nonprimate hepaciviruses in dogs and then in horses prompted us to look for pegiviruses (GB virus-like viruses) in these species. Although none were detected in canines, we found widespread natural infection of horses by a novel pegivirus. Unique genomic features and phylogenetic analyses confirmed that the tentatively named equine pegivirus (EPgV) represents a novel species within the Pegivirus genus. We also determined that EPgV causes persistent viremia whereas its clinical significance is undetermined.
The symptoms of bipolar disorder affect and are affected by the functioning of family environments. Little is known, however, about the stability of family functioning among youth with bipolar disorder as they cycle in and out of mood episodes. This study examined family functioning and its relationship to symptoms of adolescent bipolar disorder, using longitudinal measures of family cohesion, adaptability and conflict. Parent and adolescent-reported symptom and family functioning data were collected from 58 families of adolescents with bipolar disorder (mean age =14.48 + 1.60; 33 female, 25 male) who participated in a 2-year randomized trial of family-focused treatment for adolescents (FFT-A). Cohesion and adaptability scores did not significantly change over the course of the study. Parent-reported conflict prior to psychosocial treatment moderated the treatment responses of families, such that high-conflict families participating in FFT-A demonstrated greater reductions in conflict over time than low-conflict families. Moreover, adolescent mania symptoms improved more rapidly in low-conflict than in high-conflict families. For all respondents, cohesion, adaptability, and conflict were longitudinally correlated with adolescents’ depression scores. Finally, decreases in parent-reported conflict also predicted decreases in adolescents’ manic symptoms over the 2-year study. Findings suggest that family cohesion, adaptability, and conflict may be useful predictors of the course of adolescent mood symptoms. Family conflict may be an important target for family intervention in early-onset bipolar disorder.
cohesion; conflict; adaptability; expressed emotion
The Ca2+ binding properties of the FHC-associated cardiac troponin C (cTnC) mutation L29Q were examined in isolated cTnC, troponin complexes, reconstituted thin filament preparations, and skinned cardiomyocytes. While higher Ca2+ binding affinity was apparent for the L29Q mutant in isolated cTnC, this phenomenon was not observed in the cTn complex. At the level of the thin filament in the presence of phosphomimetic TnI, L29Q cTnC further reduced the Ca2+ affinity by 27% in the steady-state measurement and increased the Ca2+ dissociation rate by 20% in the kinetic studies. Molecular dynamics simulations suggest that L29Q destabilizes the conformation of cNTnC in the presence of phosphomimetic cTnI and potentially modulates the Ca2+ sensitivity due to the changes of the opening/closing equilibrium of cNTnC. In the skinned cardiomyocyte preparation, L29Q cTnC increased Ca2+ sensitivity in a highly sarcomere length (SL)-dependent manner. The well-established reduction of Ca2+ sensitivity by phosphomimetic cTnI was diminished by 68% in the presence of the mutation and it also depressed the SL-dependent increase in myofilament Ca2+ sensitivity. This might result from its modified interaction with cTnI which altered the feedback effects of cross-bridges on the L29Q cTnC-cTnI-Tm complex. This study demonstrates that the L29Q mutation alters the contractility and the functional effects of the phosphomimetic cTnI in both thin filament and single skinned cardiomyocytes and importantly that this effect is highly sarcomere length dependent.
Many believe that electronic medical record systems hold promise for improving the quality of health care services. The body of research on this topic is still in the early stages, however, in part because of the challenge of measuring the capabilities of electronic medical record systems. The purpose of this study was to identify classes of Electronic Medical Record (EMR) system sophistication in hospitals as well as hospital characteristics associated with the sophistication categories. The data used were from the American Hospital Association (AHA) and the Health Information Management and Systems Society (HIMSS). The sample included acute care hospitals in the United States with 50 beds or more. We used latent class analysis to identify the sophistication classes and logistic regression to identify relationships between these classes and hospital characteristics. Our study identifies cumulative categories of EMR sophistication: ancillary-based, ancillary/data aggregation, and ancillary-to-bedside. Rural hospital EMRs are likely to be ancillary-based, while hospitals in a network are likely to have either ancillary-based or ancillary-to-bedside EMRs. Future research should explore the effect of network membership on EMR system development.
Electronic Medical Records; Electronic Health Records; Hospitals; Diffusion of Innovation
Using novel murine models of claudin-low and basal-like breast cancer, we tested the hypothesis that diet-induced obesity (DIO) and calorie restriction (CR) differentially modulate progression of these aggressive breast cancer subtypes. For model development, we characterized two cell lines, “mesenchymal (M)-Wnt” and “epithelial (E)-Wnt,” derived from MMTV-Wnt-1 transgenic mouse mammary tumors. M-Wnt, relative to E-Wnt, cells were tumor-initiating cell (TIC)-enriched (62% vs 2.4% CD44high/CD24low), and displayed enhanced aldefluor-positivity, epithelial-to-mesenchymal transition (EMT) marker expression, mammosphere-forming ability, migration, invasion, and tumorigenicity (p<0.001, each parameter). M-Wnt and E-Wnt cells clustered with claudin-low and basal-like breast tumors, respectively, in gene expression profiles, and recapitulated these tumors when orthotopically transplanted into ovariectomized C57BL/6 mice. To assess the effects of energy balance interventions on tumor progression and EMT, mice were administered DIO, control or CR diets for 8 weeks before orthotopic transplantation of M-Wnt or E-Wnt cells (for each cell line, n=20 mice/diet), and continued on their diets for 6 weeks while tumor growth was monitored. Relative to control, DIO enhanced M-Wnt (p=0.01), but not E-Wnt, tumor progression; upregulated EMT- and TIC-associated markers including N-cadherin, fibronectin, TGFβ, SNAIL, FOXC2, and Oct4 (p<0.05, each); and increased intratumoral adipocytes. Conversely, CR suppressed M-Wnt and E-Wnt tumor progression (p<0.02, each) and inhibited EMT and intratumoral adipocyte accumulation. Thus dietary energy balance interventions differentially modulate EMT and progression of claudin-low and basal-like tumors. EMT pathway components may represent targets for breaking the obesity-breast cancer link, particularly for preventing and/or controlling TIC-enriched subtypes such as claudin-low breast cancer.
basal-like breast cancer; claudin-low breast cancer; diet; epithelial-to-mesenchymal transition; mice
We evaluate novel magnetic resonance imaging (MRI) and positron emission tomography (PET) quantitative imaging biomarkers and associated multimodality, serial-time-point analysis methodologies, with the ultimate aim of providing clinically feasible, predictive measures for early assessment of response to cancer therapy. A focus of this work is method development and an investigation of the relationship between the information content of the two modalities. Imaging studies were conducted on subjects who were enrolled in glioblastoma multiforme (GBM) therapeutic clinical trials. Data were acquired, analyzed and displayed using methods that could be adapted for clinical use. Subjects underwent dynamic [18F]fluorothymidine (F-18 FLT) PET, sodium (23Na) MRI and 3-T structural MRI scans at baseline (before initiation of therapy), at an early time point after beginning therapy and at a late follow-up time point after therapy. Sodium MRI and F-18 FLT PET images were registered to the structural MRI. F-18 FLT PET tracer distribution volumes and sodium MRI concentrations were calculated on a voxel-wise basis to address the heterogeneity of tumor physiology. Changes in, and differences between, these quantities as a function of scan timing were tracked.
While both modalities independently show a change in tissue status as a function of scan time point, results illustrate that the two modalities may provide complementary information regarding tumor progression and response. Additionally, tumor status changes were found to vary in different regions of tumor. The degree to which these methods are useful for GBM therapy response assessment and particularly for differentiating true progression from pseudoprogression requires additional patient data and correlation of these imaging biomarker changes with clinical outcome.
Gleoblastoma Multiforme; Therapy Response assessment; Sodium MRI; FLT PET
Although the tuberculin skin test (TST) is frequently used to aid in the diagnosis of tuberculosis (TB) disease and to identify persons with latent TB infection, it is an imperfect test and approximately 10–25% of persons with microbiologically confirmed TB disease have a negative TST. Previous studies have suggested that persons with a negative TST are more likely to present with severe TB disease and have an increased rate of TB-related death.
We analyzed culture-confirmed TB cases captured in US TB surveillance data from 1993 to 2008 and performed multivariate logistic regression analysis to determine the association between TST result and death.
Of 284,866 cases of TB reported in the US, 58,180 persons were eligible for inclusion in the analysis and 3,270 of those persons died after initiating TB treatment. Persons with a negative TST accounted for only 14% of the eligible cases but accounted for 42% of the deaths. Persons with a TST≥15 mm had 67% lower odds of death than persons with a negative TST (adjusted odds ratio 0.33, 95% confidence interval 0.30–0.36).
A negative TST is associated with an increased risk of death among persons with culture-confirmed TB disease, even after adjustment for HIV status, site of TB disease, sputum smear AFB status, drug susceptibility, age, sex, and origin of birth. In addition to indicating risk of developing disease, the TST may also be a marker for increased risk of death.
Due to the heterogeneous nature of breast cancer and the widespread use of single-gene studies, there is limited knowledge of multi-gene, locus-specific DNA methylation patterns in relation to molecular subtype and clinical features. We, therefore, quantified DNA methylation of 70 candidate gene loci in 140 breast tumors and matched normal tissues and determined associations with gene expression and tumor subtype. Using Sequenom’s EpiTYPER platform, approximately 1,200 CpGs were interrogated and revealed six DNA methylation patterns in breast tumors relative to matched normal tissue. Differential methylation of several gene loci was observed within all molecular subtypes, while other patterns were subtype-dependent. Methylation of numerous gene loci was inversely correlated with gene expression, and in some cases, this correlation was only observed within specific breast tumor subtypes. Our findings were validated on a larger set of tumors and matched adjacent normal tissue from The Cancer Genome Atlas dataset, which utilized methylation data derived from both Illumina Infinium 27 and 450 k arrays. These findings highlight the need to control for subtype when interpreting DNA methylation results, and the importance of interrogating multiple CpGs across varied gene regions.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-013-2738-0) contains supplementary material, which is available to authorized users.
Epigenetic; Methylation; Breast cancer; Illumina; BRCA1; Basal-like
We investigated the impact of cognitive behavioral therapy and mindfulness training (CBT/MT) on attentional task performance in incarcerated adolescents. Attention is a cognitive system necessary for managing cognitive demands and regulating emotions. Yet persistent and intensive demands, such as those experienced during high-stress intervals like incarceration and the events leading to incarceration, may deplete attention resulting in cognitive failures, emotional disturbances, and impulsive behavior. We hypothesized that CBT/MT may mitigate these deleterious effects of high stress and protect against degradation in attention over the high-stress interval of incarceration. Using a quasi-experimental, group randomized controlled trial design, we randomly assigned dormitories of incarcerated youth, ages 16–18, to a CBT/MT intervention (youth n = 147) or an active control intervention (youth n = 117). Both arms received approximately 750 min of intervention in a small-group setting over a 3–5 week period. Youth in the CBT/MT arm also logged the amount of out-of-session time spent practicing MT exercises. The Attention Network Test was used to index attentional task performance at baseline and 4 months post-baseline. Overall, task performance degraded over time in all participants. The magnitude of performance degradation was significantly less in the CBT/MT vs. control arm. Further, within the CBT/MT arm, performance degraded over time in those with no outside-of-class practice time, but remained stable over time in those who practiced mindfulness exercises outside of the session meetings. Thus, these findings suggest that sufficient CBT/MT practice may protect against functional attentional impairments associated with high-stress intervals.
adolescent development; incarcerated adolescents; detained adolescents; stress; attention; mindfulness meditation
We present a mathematical and a computational framework for the modelling of cell motility. The cell membrane is represented by an evolving surface, with the movement of the cell determined by the interaction of various forces that act normal to the surface. We consider external forces such as those that may arise owing to inhomogeneities in the medium and a pressure that constrains the enclosed volume, as well as internal forces that arise from the reaction of the cells' surface to stretching and bending. We also consider a protrusive force associated with a reaction–diffusion system (RDS) posed on the cell membrane, with cell polarization modelled by this surface RDS. The computational method is based on an evolving surface finite-element method. The general method can account for the large deformations that arise in cell motility and allows the simulation of cell migration in three dimensions. We illustrate applications of the proposed modelling framework and numerical method by reporting on numerical simulations of a model for eukaryotic chemotaxis and a model for the persistent movement of keratocytes in two and three space dimensions. Movies of the simulated cells can be obtained from http://homepages.warwick.ac.uk/∼maskae/CV_Warwick/Chemotaxis.html.
cell motility; chemotaxis; surface finite elements; reaction–diffusion systems
Sublingual buprenorphine/naloxone (Bup/Nx) is approved for addiction treatment and may be useful for pain management, particularly in opioid-treated pain patients with nonadherence behaviors. The transition of opioid-treated pain patients to buprenorphine carries the risk of precipitated withdrawal and increased pain. This study convened pain and addiction specialists to develop and pilot a clinical protocol for safe transitioning to Bup/Nx.
The protocol was revised three times based on outside expert review and pilot study observations. The pilot was conducted with a prospective cohort of 12 patients with moderate to severe chronic pain, who were receiving long-term opioid therapy with any full μ-agonist drug, and had exhibited one or more aberrant drug-related behaviors. Patients were followed up for 3 to 6 months with the expectation that they would experience few adverse events and report lower pain severity.
The three patients on the highest baseline opioid dose (equivalent to 303–450 mg of oral morphine) and the three on the lowest doses (≤20 mg) had early adverse events (AEs) when switched to Bup/Nx and did not complete the trial. Of the remaining six, one withdrew due to AEs; one responded well, then withdrew; and four completed a three-month trial. A mixed effects model controlling for dropouts found that average and worst pain significantly decreased after the switch to Bup/Nx (both p < .01).
Based on this experience, the protocol recommends Bup/Nx for pain only when baseline opioid doses are within bounds that reduce AEs at transition and incorporates dose flexibility to further reduce risks. This protocol warrants further testing.
Buprenorphine; chronic pain; treatment guidelines; opioid therapy; withdrawal
We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS mutant lung cancer cells.
Patients and Methods
We reviewed clinical data from patients whose lung cancers were identified at 6 institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. 6 NRAS mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e. EGFR, ALK, MET, IGF-1R, BRAF, PI3K and MEK).
Among 4562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45% to 0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS mutated lung tumors compared to KRAS-mutant NSCLCs (NRAS: 13% (4/30), KRAS: 66% (1772/2733), p<0.00000001). 5 of 6 NRAS mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested.
NRAS mutations define a distinct subset of lung cancers (~1%) with potential sensitivity to MEK inhibitors. While NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking.
NRAS mutation; EGFR mutation; KRAS mutation; lung cancer; non-small cell lung cancer; driver mutation; MEK inhibitor; erlotinib; gefitinib; crizotinib
BACKGROUND & AIMS
Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We carried out a 2-stage GWA study of liver fibrosis progression related to HCV infection.
We studied well-characterized HCV-infected patients of European descent who had liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of Metavir scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P-values<5×10−5 from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance.
In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients that received blood transfusions) were associated with fibrosis progression (Pcombined=8.9×10−9 and 1.1×10−9, respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (Pcombined=5.4×10−7), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages.
Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.
genetic analysis; risk factors; cirrhosis; liver disease
Five molecular subtypes (luminal A, luminal B, HER2-enriched, basal-like, and claudin-low) with clinical implications exist in breast cancer. Here, we evaluated the molecular and phenotypic relationships of (1) a large in vitro panel of human breast cancer cell lines (BCCLs), human mammary fibroblasts (HMFs), and human mammary epithelial cells (HMECs); (2) in vivo breast tumors; (3) normal breast cell subpopulations; (4) human embryonic stem cells (hESCs); and (5) bone marrow-derived mesenchymal stem cells (hMSC). First, by integrating genomic data of 337 breast tumor samples with 93 cell lines we were able to identify all the intrinsic tumor subtypes in the cell lines, except for luminal A. Secondly, we observed that the cell lines recapitulate the differentiation hierarchy detected in the normal mammary gland, with claudin-low BCCLs and HMFs cells showing a stromal phenotype, HMECs showing a mammary stem cell/bipotent progenitor phenotype, basal-like cells showing a luminal progenitor phenotype, and luminal B cell lines showing a mature luminal phenotype. Thirdly, we identified basal-like and highly migratory claudin-low subpopulations of cells within a subset of triple-negative BCCLs (SUM149PT, HCC1143, and HCC38). Interestingly, both subpopulations within SUM149PT were enriched for tumor-initiating cells, but the basal-like subpopulation grew tumors faster than the claudin-low subpopulation. Finally, claudin-low BCCLs resembled the phenotype of hMSCs, whereas hESCs cells showed an epithelial phenotype without basal or luminal differentiation. The results presented here help to improve our understanding of the wide range of breast cancer cell line models through the appropriate pairing of cell lines with relevant in vivo tumor and normal cell counterparts.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-013-2743-3) contains supplementary material, which is available to authorized users.
Breast cancer; Cell lines; Intrinsic subtype; Stem cell; Tumor-initiating cell
Niemann-Pick disease type C (NP-C) is a rare, progressive, irreversible disease leading to disabling neurological manifestations and premature death. The estimated disease incidence is 1:120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. NP-C is characterised by visceral, neurological and psychiatric manifestations that are not specific to the disease and that can be found in other conditions. The aim of this review is to provide non-specialists with an expert-based, detailed description of NP-C signs and symptoms, including how they present in patients and how they can be assessed. Early disease detection should rely on seeking a combination of signs and symptoms, rather than isolated findings. Examples of combinations which are strongly suggestive of NP-C include: splenomegaly and vertical supranuclear gaze palsy (VSGP); splenomegaly and clumsiness; splenomegaly and schizophrenia-like psychosis; psychotic symptoms and cognitive decline; and ataxia with dystonia, dysarthria/dysphagia and cognitive decline. VSGP is a hallmark of NP-C and becomes highly specific of the disease when it occurs in combination with other manifestations (e.g. splenomegaly, ataxia). In young infants (<2 years), abnormal saccades may first manifest as slowing and shortening of upward saccades, long before gaze palsy onset. While visceral manifestations tend to predominate during the perinatal and infantile period (2 months–6 years of age), neurological and psychiatric involvement is more prominent during the juvenile/adult period (>6 years of age). Psychosis in NP-C is atypical and variably responsive to treatment. Progressive cognitive decline, which always occurs in patients with NP-C, manifests as memory and executive impairment in juvenile/adult patients. Disease prognosis mainly correlates with the age at onset of the neurological signs, with early-onset forms progressing faster. Therefore, a detailed and descriptive picture of NP-C signs and symptoms may help improve disease detection and early diagnosis, so that therapy with miglustat (Zavesca®), the only available treatment approved to date, can be started as soon as neurological symptoms appear, in order to slow disease progression.
Niemann-Pick disease type C; Lysosomal lipid storage disease; Splenomegaly; Ataxia; Dystonia; Vertical supranuclear gaze palsy; Gelastic cataplexy; Cognitive impairment; Diagnosis
To evaluate associations between neurodevelopment and exposure to surgery and anesthetic agents in children with single-suture craniosynostosis (SSC).
Young children with SSC have unexplained neurodevelopmental delays. The possible contributions of factors related to cranial vault surgery--including anesthesia--have not been previously examined.
Two anesthesiologists reviewed the surgical records of 89 infants (70 had complete data). Primary exposures were duration of surgery and anesthesia and total duration of inhaled anesthesia (at age 6 months on average). Outcomes were the cognitive and motor scores from the Bayley Scales of Infant Development-II and language scores from the Preschool Language Scale, 3rd edition, given at age 36 months. Linear regression using robust standard error estimates was performed, adjusting for age at surgery and suture site.
Anesthesia duration ranged from 155 to 547 minutes. For every 30-minute increase in anesthesia duration, the estimated average decrease in developmental test scores ranged from 1.1 to 2.9 (p ranged from <0.001 to 0.30). Similar, but weaker findings were observed with surgery duration and total duration of inhaled anesthesia. Inverse relations between exposure amounts and neurodevelopment were stronger in children with non-sagittal synostosis.
Average neurodevelopmental scores were lower among children experiencing longer surgeries and higher exposures to inhaled anesthesia. These associations may be due to anesthesia exposure, nonspecific effects of surgery, or unmeasured variables that correlate with surgery duration. Further study of potential causal mechanisms is warranted.
Human cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl ester mass from atheroprotective high-density lipoproteins to atherogenic low-density lipoproteins by an unknown mechanism. Delineating this mechanism would be an important step toward the rational design of new CETP inhibitors for treating cardiovascular diseases. Using EM, single-particle image processing and molecular dynamics simulation, we discovered that CETP bridges a ternary complex with its N-terminal β-barrel domain penetrating into high-density lipoproteins and its C-terminal domain interacting with low-density lipoprotein or very-low-density lipoprotein. In our mechanistic model, the CETP lipoprotein-interacting regions, which are highly mobile, form pores that connect to a hydrophobic central cavity, thereby forming a tunnel for transfer of neutral lipids from donor to acceptor lipoproteins. These new insights into CETP transfer provide a molecular basis for analyzing mechanisms for CETP inhibition.
Breast cancer is a collection of diseases with distinct molecular traits, prognosis, and therapeutic options. Luminal A breast cancer is the most heterogeneous, both molecularly and clinically. Using genomic data from over 1,000 Luminal A tumors from multiple studies, we analyzed the copy number and mutational landscape of this tumor subtype. This integrated analysis revealed four major subtypes defined by distinct copy-number and mutation profiles. We identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis. Aberrations of chromosomes 1, 8, and 16, together with PIK3CA, GATA3, AKT1, and MAP3K1 mutations drive the other subtypes. Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT. These rare alterations were the most prevalent in Luminal A tumors and may predict resistance to endocrine therapy. Our work provides for a further molecular stratification of Luminal A breast tumors, with potential direct clinical implications.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-013-2699-3) contains supplementary material, which is available to authorized users.
Luminal A breast cancer; Breast cancer genomics
The tuberculin skin test (TST) is used to test for latent tuberculosis (TB) infection and support the diagnosis of active TB. However, little is known about the relationship between the TST result and the clinical presentation of TB disease.
We analyzed US TB surveillance data, 1993–2010, and used multinomial logistic regression to calculate the association between TST result (0–4 mm [negative], 5–9 mm, 10–14 mm, and ≥ 15 mm) and clinical presentation of disease (miliary, combined pulmonary and extrapulmonary, extrapulmonary only, non-cavitary pulmonary, and cavitary pulmonary). For persons with pulmonary disease, multivariate logistic regression was used to calculate the odds of having acid-fast bacilli (AFB) positive sputum.
There were 64,238 persons with culture-confirmed TB included in the analysis, which was stratified by HIV status and birthplace (US- vs. foreign-born). Persons with a TST ≥ 15 mm were less likely to have miliary or combined pulmonary and extrapulmonary disease, but more likely to have cavitary pulmonary disease than non-cavitary pulmonary disease. Persons with non-cavitary pulmonary disease with a negative TST were significantly more likely to have AFB positive sputum.
Clinical presentation of TB disease differed according to TST result and persons with a negative TST were more likely to have disseminated disease (i.e., miliary or combined pulmonary and extrapulmonary). Further study of the TST result may improve our understanding of the host-pathogen relationship in TB disease.
Tuberculin test; Miliary tuberculosis; Pulmonary tuberculosis
The hepatitis C virus (HCV) NS2 protein has dual roles within the HCV life cycle. While well characterized as an autoprotease that cleaves the NS2/NS3 junction, NS2, primarily via its N-terminal region, is also involved in virion morphogenesis. In order to map the determinants necessary for infectious virus production and gain further insight into the multiple points at which NS2 may impact this process, a detailed mutational analysis of residues spanning amino acids (aa) 1 to 92 was performed. Initial block mutagenesis (5 or 7 amino acid residues) in both bicistronic and monocistronic HCV cell culture-based (HCVcc) genomes revealed that all but two blocks had various levels of impaired infectious virus production. None of these mutations affected RNA replication, indicating that the N-terminal region of NS2 is not required for NS2-3 processing and replicase assembly. Fine mapping identified 29 critical residues that, when mutated, yielded at least a 1 log decrease in infectious virus titers. These mutants were characterized further with respect to release of extracellular HCV RNA and core, intracellular infectivity, thermal stability of virus particles, and NS2 interactions. While the most severely debilitated mutants were impaired early in the assembly process, which is in agreement with previous reports, others targeted later steps of virus production, most notably egress. Thus, in addition to participating in early steps in virion assembly, this comprehensive mutagenesis study suggests yet another role for NS2 in later steps in virus production.
T cells are exhausted and overexpress inhibitory molecules in chronic hepatitis C virus (HCV) infection. It is unclear whether this is the cause or consequence of HCV persistence. By studying serial blood and liver samples of chimpanzees during acute infection, we demonstrate that the early expression of the memory precursor marker CD127 on HCV-specific T cells, but not the expression of inhibitory molecules on those T cells or their ligands in the liver, predicts the outcome of acute infection.