Lung nodule malignancy classification with weakly supervised explanation generation.
Purpose: Explainable AI aims to build systems that not only give high performance but also are able to provide insights that drive the decision making. However, deriving this explanation is often dependent on fully annotated (class label and local annotation) data, which are not readily available in the medical domain. Approach: This paper addresses the above-mentioned aspects and presents an innovative approach to classifying a lung nodule in a CT volume as malignant or benign, and generating a morphologically meaningful explanation for the decision in the form of attributes such as nodule margin, sphericity, and spiculation. A deep learning architecture that is trained using a multi-phase training regime is proposed. The nodule class label (benign/malignant) is learned with full supervision and is guided by semantic attributes that are learned in a weakly supervised manner. Results: Results of an extensive evaluation of the proposed system on the LIDC-IDRI dataset show good performance compared with state-of-the-art, fully supervised methods. The proposed model is able to label nodules (after full supervision) with an accuracy of 89.1% and an area under curve of 0.91 and to provide eight attributes scores as an explanation, which is learned from a much smaller training set. The proposed system's potential to be integrated with a sub-optimal nodule detection system was also tested, and our system handled 95% of false positive or random regions in the input well by labeling them as benign, which underscores its robustness. Conclusions: The proposed approach offers a way to address computer-aided diagnosis system design under the constraint of sparse availability of fully annotated images.


Risk Factors for Cervical Pain in F-15C Pilots.
Many fighter pilots report cervical pain during their careers. Etiology likely relates to +Gz exposure, physical positioning with maneuvers, and varying load associated with headgear. We evaluated whether selected risk factors predicted cervical pain in this population. An Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant, controlled crossover study of the use of home cervical traction was undertaken with 20 male F-15C pilots. We recorded pilot age (mean 38 yr, range 34-49), total high-G hours (2338 h, range 1038-4645), and previous neck problems and measured cervical range of motion. For 12 wk, pilots logged pre- and postflight pain, whether the Joint Helmet Mounted Cueing System (JHMCS) was employed, maximum +Gz experienced, and sortie duration. Pain with and without JHMCS was compared using paired t-tests and correlations assessed with Pearson or Spearman coefficients. Mean flight-related pain increased by 0.73 on the numerical rating scale with JHMCS and 0.52 without. Neck extension coupled with JHMCS use correlated negatively with increased pain (r = -0.551). Higher numbers of previously reported neck problems correlated with pain when using JHMCS (r = 0.629). Age, maximum +Gz per sortie, total high-Gz hours flown, and hours per sortie did not correlate. To our knowledge, this is the first prospective evaluation of risk factors for fighter pilots' cervical pain. Neck pain was significantly worse with JHMCS use and with flexed posture or history of prior neck problems combined with JHMCS use. This information will help guide countermeasure development for high-G pilots.Chumbley EM, Stolfi A, McEachen JC. Risk factors for cervical pain in F-15C pilots. Aerosp Med Hum Perform. 2017; 88(11):1000-1007.


N-Octanoyl Dopamine for Donor Treatment in a Brain-death Model of Kidney and Heart Transplantation.
This study investigated the potential use of N-octanoyl dopamine (NOD) in donor management to ameliorate the damage caused by brain death and ischemia-reperfusion injury in a rat model of kidney and heart transplantation. Brain-dead Fisher rats were treated for 6 hours with either saline or saline plus NOD. Orthotopic kidney and heterotopic heart transplantation were performed in different Lewis recipient rats. The right donor kidneys were stored for biochemical analysis. Blood samples were taken from the donor and on several days after transplantation from the recipient. All grafts were harvested after 7 days. There was no effect on donor heart rate and blood pressure under NOD treatment. The release of lactate dehydrogenase (LDH) during brain death was reduced in the NOD group. The right kidneys from NOD-preconditioned animals revealed diminished expression of the proinflammatory cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, there was no difference in renal infiltration with ED1 (CD68) or major histocompatibility complex (MHC) class II-positive cells. Recipients receiving a renal allograft from NOD-treated donors had a significantly better renal function at day 1 after transplantation. Banff-grading after 7 days showed significantly reduced scores for tubulitis and vasculitis in the grafts of these recipients. In the heart allograft recipients, lower plasma LDH levels were observed. Donor preconditioning with NOD leads to better graft function and reduced acute rejection in untreated renal allograft recipients without displaying adverse effects on heart allografts.


Aggregate size and architecture determine microbial activity balance for one-stage partial nitritation and anammox.
Aerobic ammonium-oxidizing bacteria (AerAOB) and anoxic ammonium-oxidizing bacteria (AnAOB) cooperate in partial nitritation/anammox systems to remove ammonium from wastewater. In this process, large granular microbial aggregates enhance the performance, but little is known about granulation so far. In this study, three suspended-growth oxygen-limited autotrophic nitrification-denitrification (OLAND) reactors with different inoculation and operation (mixing and aeration) conditions, designated reactors A, B, and C, were used. The test objectives were (i) to quantify the AerAOB and AnAOB abundance and the activity balance for the different aggregate sizes and (ii) to relate aggregate morphology, size distribution, and architecture putatively to the inoculation and operation of the three reactors. A nitrite accumulation rate ratio (NARR) was defined as the net aerobic nitrite production rate divided by the anoxic nitrite consumption rate. The smallest reactor A, B, and C aggregates were nitrite sources (NARR, >1.7). Large reactor A and C aggregates were granules capable of autonomous nitrogen removal (NARR, 0.6 to 1.1) with internal AnAOB zones surrounded by an AerAOB rim. Around 50% of the autotrophic space in these granules consisted of AerAOB- and AnAOB-specific extracellular polymeric substances. Large reactor B aggregates were thin film-like nitrite sinks (NARR, <0.5) in which AnAOB were not shielded by an AerAOB layer. Voids and channels occupied 13 to 17% of the anoxic zone of AnAOB-rich aggregates (reactors B and C). The hypothesized granulation pathways include granule replication by division and budding and are driven by growth and/or decay based on species-specific physiology and by hydrodynamic shear and mixing.


The association of ADORA2A and ADORA2B polymorphisms with the risk and severity of chronic heart failure: a case-control study of a northern Chinese population.
The causes of chronic heart failure (CHF) and its progression are likely to be due to complex genetic factors. Adenosine receptors A2A and A2B (ADORA2A and ADORA2B, respectively) play an important role in cardio-protection. Therefore, polymorphisms in the genes encoding those receptors may affect the risk and severity of CHF. This study was a case-control comparative investigation of 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls. Four common single-nucleotide polymorphisms (SNPs) of ADORA2A (rs2236625, rs2236624, rs4822489, and rs5751876) and one SNP of ADORA2B (rs7208480) were genotyped and an association between SNPs and clinical outcomes was evaluated. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. The rs4822489 was significantly associated with the severity of CHF after adjustment for traditional cardiovascular risk factors (p = 0.040, OR = 1.912, 95% CI = 1.029-3.550). However, the five SNPs as well as the haplotypes were not found to be associated with CHF susceptibility. The findings of this study suggest that rs4822489 may contribute to the severity of CHF in the northern Chinese. However, further studies performed in larger populations and aimed at better defining the role of this gene are required.


Transformation Invariant Control of Voxel-Wise False Discovery Rate.
Multiple testing for statistical maps remains a critical and challenging problem in brain mapping. Since the false discovery rate (FDR) criterion was introduced to the neuroimaging community a decade ago, many variations have been proposed, mainly to enhance detection power. However, a fundamental geometrical property known as transformation invariance has not been adequately addressed, especially for the voxel-wise FDR. Correction of multiple testing applied after spatial transformation is not necessarily equivalent to transformation applied after correction in the original space. Without the invariance property, assigning different testing spaces will yield different results. We find that normalized residuals of linear models with Gaussian noises are uniformly distributed on a unit high-dimensional sphere, independent of t-statistics and F-statistics. By defining volumetric measure in the hyper-spherical space mapped by normalized residuals, instead of the image's Euclidean space, we can achieve invariant control of the FDR under diffeomorphic transformation. This hyper-spherical measure also reflects intrinsic "volume of randomness" in signals. Experiments with synthetic, semi-synthetic and real images demonstrate that our method significantly reduces FDR inconsistency introduced by the choice of testing spaces.


The 2016 Revision of ISO 1 - Standard Reference Temperature for the Specification of Geometrical and Dimensional Properties.
This paper discusses the changes in the 2016 (third edition) of International Standard ISO 1. While the value of the standard reference temperature remains unchanged at 20 °C, the important definitions for the "reference temperature" and "standard reference temperature," absent in prior editions, are now defined, with the latter exclusively reserved for the assignment of the internationally agreed upon temperature of 20 °C. The scope of the revised Standard has been carefully refined and made more explicit. This, together with other clarifications and improvements, has eliminated the ambiguities associated with specifications at non-standard reference temperatures and allows, if needed, different reference temperatures to be associated with different properties of a workpiece. The relationship between ISO 1 and dimensional measurements is also discussed and clarified. In this paper, we discuss the motivation for these changes and present several issues debated during the revision process for the benefit of future standards committees that might study this topic.


Leaf surface factors of transgenic Bt cotton associated with the feeding behaviors of cotton aphids: a case study on non-target effects.
The present paper reports case study results of the risk assessment of transgenic Bt cotton on a non-target pest, cotton aphid, Aphis gossypii. Several types of techniques, i.e., electrical penetration graph (EPG), light and electron microscopy, bioassays and chemical analysis, were applied to investigate physical and chemical leaf factors of 2 transgenic Bt cotton lines (GK12 and GK19) and their parental non-Bt cotton line (Simian3) associated with searching and feeding behaviors of cotton aphids on leaves or leaf extracts of cotton plants. EPG results showed that there were some differences among behaviors of cotton aphids on 2 Bt cotton and 1 non-Bt cotton lines. Cotton aphids performed similarly to leaf surface extracts from 3 cotton lines; and leaf surface chemicals, mainly volatiles and waxes, were almost identical in the components and concentrations among the cotton lines. However, three cotton lines were quite different from each other in the densities of certain kinds of covering trichomes. Therefore, the relationships between the physical characteristics and the searching behaviors of cotton aphids on the three cotton lines were constructed as the regression equations. Glandular trichomes and covering trichomes with 5 branches influenced the cotton aphids' searching behaviors effectively; and other trichomes with other branches affected aphids in varying ways. These results demonstrated that leaf surface physical factors of transgenic Bt cotton lines different from their parental non-Bt line could affect the penetration behaviors of non-target cotton aphids. Cotton aphids penetrate and feed more easily on two Bt cotton lines than on the non-Bt cotton line.


Inconsistent reports of sexual intercourse among South African high school students.
This study aims to describe patterns of inconsistent reports of sexual intercourse among a sample of South African adolescents. Consistency of reported lifetime sexual intercourse was assessed using five semiannual waves of data. Odds ratios related inconsistent reporting to demographic variables and potential indicators of general and risk-behavior-specific reliability problems. Of the sexually active participants in the sample, nearly 40% reported being virgins after sexual activity had been reported at an earlier assessment. Inconsistent reporting could not be predicted by gender or race or by general indicators of poor reliability (inconsistent reporting of gender and birth year). However individuals with inconsistent reports of sexual intercourse were more likely to be inconsistent reporters of substance use. These results suggest that researchers need to undertake efforts to deal specifically with inconsistent risk behavior data. These may include modification of data collection procedures and use of statistical methodologies that can account for response inconsistencies.


FGF7 Over Expression is an Independent Prognosticator in Patients with Urothelial Carcinoma of the Upper Urinary Tract and Bladder.
Urothelial carcinoma of the bladder and upper tract is the most common tumor type in the urinary tract but its molecular pathogenesis and survival determinants remain obscure. By data mining a published transcriptomic database of bladder urothelial carcinoma (GSE31684) we identified FGF7 as the most significant gene up-regulated during urothelial carcinoma progression. We then used our well characterized urothelial carcinoma cohort to analyze FGF7 transcript and protein expression, and its clinicopathological significance. We performed real-time reverse transcriptase-polymerase chain reaction assay to determine the FGF7 transcript level in 30 fresh samples each of upper tract and bladder urothelial carcinoma. Immunohistochemistry evaluated by H-score was used to determine FGF7 protein expression in 340 upper tract and 295 bladder urothelial carcinomas. Transcript and protein expression were correlated with clinicopathological features. We further evaluated the prognostic significance of FGF7 protein expression for disease specific and metastasis-free survival. An increased FGF7 transcript level was associated with higher pT stage in upper tract and bladder urothelial carcinoma (p = 0.003 and <0.001, respectively). In the upper tract and bladder carcinoma groups FGF7 protein over expression was also significantly associated with advanced pT status (each p <0.001), lymph node metastasis (p = 0.002 and <0.001), high histological grade (p = 0.019 and <0.001), vascular invasion (each p <0.001), perineural invasion (p = 0.002 and 0.021) and frequent mitoses (p = 0.002 and 0.042, respectively). FGF7 over expression predicted dismal disease specific and metastasis-free survival on univariate and multivariate analysis. Our study shows that FGF7 over expression is associated with advanced clinical features in patients with upper tract and bladder urothelial carcinoma, justifying its potential prognostic value for urothelial carcinoma.


Effective COVID-19 Control: A Comparative Analysis of the Stringency and Timeliness of Government Responses in Asia.
Many governments in East and Southeast Asia responded promptly and effectively at the onset of the COVID-19 pandemic. Synthesizing and analyzing these responses is vital for disease control evidence-based policymaking. An extensive review of COVID-19 control measures was conducted in selected Asian countries and subregions, including Mainland China, Hong Kong, Taiwan, South Korea, Singapore, Japan, and Vietnam from 1 January to 30 May 2020. Control measures were categorized into administrative, public health, and health system measures. To evaluate the stringency and timeliness of responses, we developed two indices: the Initial Response Index (IRI) and the Modified Stringency Index (MSI), which builds on the Oxford COVID-19 Government Response Tracker (OxCGRT). Comprehensive administrative, public health, and health system control measures were implemented at the onset of the outbreak. Despite variations in package components, the stringency of control measures across the study sites increased with the acceleration of the outbreak, with public health control measures implemented the most stringently. Variations in daily average MSI scores are observed, with Mainland China scoring the highest (74.2), followed by Singapore (67.4), Vietnam (66.8), Hong Kong (66.2), South Korea (62.3), Taiwan (52.1), and Japan (50.3). Variations in IRI scores depicting timeliness were higher: Hong Kong, Taiwan, Vietnam, and Singapore acted faster (IRI > 50.0), while Japan (42.4) and Mainland China (4.2) followed. Timely setting of stringency of the control measures, especially public health measures, at dynamically high levels is key to optimally controlling outbreaks.


Identification of novel regulators of atonal expression in the developing Drosophila retina.
Atonal is a Drosophila proneural protein required for the proper formation of the R8 photoreceptor cell, the founding photoreceptor cell in the developing retina. Proper expression and refinement of the Atonal protein is essential for the proper formation of the Drosophila adult eye. In vertebrates, expression of transcription factors orthologous to Drosophila Atonal (MATH5/Atoh7, XATH5, and ATH5) and their progressive restriction are also involved in specifying the retinal ganglion cell, the founding neural cell type in the mammalian retina. Thus, identifying factors that are involved in regulating the expression of Atonal during development are important to fully understand how retinal neurogenesis is accomplished. We have performed a chemical mutagenesis screen for autosomal dominant enhancers of a loss-of-function atonal eye phenotype. We report here the identification of five genes required for proper Atonal expression, three of which are novel regulators of Atonal expression in the Drosophila retina. We characterize the role of the daughterless, kismet, and roughened eye genes on atonal transcriptional regulation in the developing retina and show that each gene regulates atonal transcription differently within the context of retinal development. Our results provide additional insights into the regulation of Atonal expression in the developing Drosophila retina.


Contraceptive Procedures in Internal Medicine Clinics and Resident Education: a Qualitative Study of Implementation Methods, Barriers, and Facilitators.
Long-acting reversible contraceptives (LARCs) such as intrauterine devices (IUDs) and implants are highly effective and increasingly popular. Internal Medicine (IM) clinics and residency curricula do not routinely include LARCs, which can limit patient access to these methods. In response, internists are integrating LARCs into IM practices and residency training. This study examines the approaches, facilitators, and barriers reported by IM faculty to incorporating LARCs into IM clinics and resident education. We interviewed faculty who were prior or current LARC providers and/or teachers in 15 IM departments nationally. Each had implemented or attempted to implement LARC training for residents in their IM practice. Semi-structured interviews were used. Eligible participants were a convenience sample of clinicians identified as key informants at each institution. We used inductive thematic coding analysis to identify themes in the transcribed interviews. Fourteen respondents currently offered LARCs in their clinic and 12 were teaching these procedures to residents. LARC integration into IM clinics occurred in 3 models: (1) a dedicated procedure or women's health clinic, (2) integration into existing IM clinical sessions, or (3) an interdisciplinary IM and family medicine or gynecology clinic. Balancing clinical and educational priorities was a common theme, with chosen LARC model(s) reflecting the desired priority balance at a given institution. Most programs incorporated a mix of educational modalities, with opportunities based upon resident interest and desired educational goals. Facilitators and barriers related to clinical (equipment, workflow), educational (curriculum, outcomes), or process considerations (procedural volume, credentialing). Participants reported that support from multiple stakeholders including patients, residents, leadership, and other departments was necessary for success. The model for integration of LARCs into IM clinics and resident education depends upon the clinical resources, patient needs, stakeholder support, and educational goals of the program.


Modeling extended lactation curves of dairy cattle: a biological basis for the multiphasic approach.
Objectives of this study are to describe the biological basis for multiphasic milk production and to propose a new empirical model for the lactation curve. To illustrate this model, we used data on 3573 first-lactation Holsteins having lactations of various lengths (285, 345, 405, 465, and 525 d) and with various days open (45, 105, 165, 225, and 285 d). The model describes an increasing first phase of milk yield and a series of decreasing phases of yield. The increasing phase, described by an increasing logistic function of time, is associated with increase in number of active mammary gland cells and increase in yield per cell. The decreasing phases, described by three decreasing logistic functions of time, are associated with decreases in cell number due to apoptosis and in yield per cell due to pregnancy. The new model is [equation: see text] where yDIM is milk yield at each day in milk (DIM), a1 is upper level for the increasing first phase, and p2, p3, and p4 = (1 - p2 - p3) are proportions of a1 for the decreasing second, third, and fourth phases; b's are proportional to duration of each phase; and c's are time of maximum increase or decrease. Nonlinear regression was used to fit average milk yield for each of nine datasets, four with 180 d carried calf and five with 240 d carried calf. Average results indicated that for the first phase, upper level of milk yield was about 22 kg. Duration was about 120 d, centered on time of maximum increase, which was about 11 d before calving. For the second phase (first phase of apoptosis), decrease in yield was relatively large (about 20%) and duration was relatively long (about 375 d). Time of maximum decrease was about 107 d after calving. For the third phase (pregnancy), decrease in yield was relatively small (about 6%) and duration was relatively short (about 200 d). Time of maximum decrease was about 300 d after calving. For each additional day open, time of maximum decrease increased about 1 d. For the fourth phase (second phase of apoptosis), decrease in yield was relatively large (about 74%) and duration was relatively long (about 765 d). Duration for the lactation length of 525 d was exceptionally long. Time of maximum decrease was about 382 d after calving. For each additional day of lactation, duration increased about 5.4 d and day of maximum decrease increased about 0.82 d. We believe that it is possible to model empirically standard and extended lactation curves of dairy cows, based on biological theory and predicated on the multiphasic approach. Further research to understand better the biology of extended lactations, using the proposed multiphasic model, should use planned extended lactations that are at least 525 d in milk and have at least 240 d carried calf.


Diversification of importin-α isoforms in cellular trafficking and disease states.
The human genome encodes seven isoforms of importin α which are grouped into three subfamilies known as α1, α2 and α3. All isoforms share a fundamentally conserved architecture that consists of an N-terminal, autoinhibitory, importin-β-binding (IBB) domain and a C-terminal Arm (Armadillo)-core that associates with nuclear localization signal (NLS) cargoes. Despite striking similarity in amino acid sequence and 3D structure, importin-α isoforms display remarkable substrate specificity in vivo. In the present review, we look at key differences among importin-α isoforms and provide a comprehensive inventory of known viral and cellular cargoes that have been shown to associate preferentially with specific isoforms. We illustrate how the diversification of the adaptor importin α into seven isoforms expands the dynamic range and regulatory control of nucleocytoplasmic transport, offering unexpected opportunities for pharmacological intervention. The emerging view of importin α is that of a key signalling molecule, with isoforms that confer preferential nuclear entry and spatiotemporal specificity on viral and cellular cargoes directly linked to human diseases.


A novel c.3636-4 A>G mutation in the CCDC88C plays a causative role in familial spinocerebellar ataxia.
Spinocerebellar ataxia (SCA) is an autosomal dominant genetic disease characterized by cerebellar neurological deficits. Specifically, its primary clinical manifestation is ataxia accompanied by peripheral nerve damage. A total of 48 causative genes of SCA have been identified. This study aimed to identify causative genes of autosomal dominant SCA in a four-generation Chinese kindred comprised of eight affected individuals. Genomic DNA samples were extracted from the pedigree members, and genomic whole-exome sequencing (WES) was performed, followed by bidirectional Sanger sequencing, and minigene assays to identify mutation sites. A novel pathogenic heterozygous mutation in the splice region of the coiled-coil domain containing the 88C (CCDC88C) gene (NM_001080414:c.3636-4 A>G) was identified in four affected members. The minigene assay results indicated that this mutation leads to the insertion of CAG bases (c.3636-1_3636-3 insCAG). CCDC88C gene mutation leads to SCA40 (OMIM:616053), which is a rare subtype of SCA without symptoms during childhood. Our findings further demonstrated the role of the CCDC88C gene in SCA and indicated that the c.3636-4 A>G (NM_001080414) variant of CCDC88C is causative for a later-onset phenotype of SCA40. Our findings enrich the mutation spectrum of CCDC88C gene and provide a theoretical basis for the genetic counseling of SCA40.


Role of CCR2 in the Development of Streptozotocin-Treated Diabetic Cardiomyopathy.
CCR2 has been proven to play an important role in diabetes. However, the role of CCR2 in diabetic cardiomyopathy has not been examined. In this study, we investigated the effects of cardiac CCR2 on diabetic cardiomyopathy. We created a model of streptozotocin (STZ)-induced diabetic cardiomyopathy. Expression of CCR2 was upregulated in the hearts of STZ-induced diabetic mice. CCR2 knockout significantly improved STZ-induced cardiac dysfunction and fibrosis. Moreover, deletion of CCR2 inhibited STZ-induced apoptosis and the production of STZ-induced reactive oxygen species in the heart. CCR2 knockout resulted in M2 polarization in hearts of STZ-treated mice. Treatment with a CCR2 inhibitor reversed hyperglycemia-induced cardiac dysfunction in db/db mice. These results suggest that CCR2-induced inflammation and oxidative stress in the heart are involved in the development of diabetic cardiomyopathy and that CCR2 could be a novel target for therapy.


Leukocytoclastic vasculitis in children: clinical characteristics, subtypes, causes and direct immunofluorescence findings of 56 biopsy-confirmed cases.
Leukocytoclastic vasculitis (LCV) in children is a complex group of conditions. This study presents the demographics, clinical features, direct immunofluorescence (DIF) results and suspected aetiologies of 56 biopsy-confirmed cases of leukocytoclastic vasculitis in children. Retrospective review of 56 children seen at Mayo Clinic in Rochester, Minnesota, from 1993 to 2013 with clinical features and cutaneous biopsy consistent with LCV. Twenty-seven (48%) cases were found to be due to IgA vasculitis (Henoch-Schonlein purpura). The remaining cases were found to be due to cutaneous small-vessel vasculitis (n = 19, 34%), urticarial vasculitis (n = 5, 9%), ANCA-associated vasculitis (n = 4, 7%) and acute haemorrhagic oedema of infancy (n = 1, 2%). IgA vasculitis was found to be associated with abdominal pain (P = 0.008), whereas the non-IgA vasculitis group was associated with headache (P = 0.052). Children with IgA vasculitis had palpable purpura (P = <0.001), petechia (P = 0.057), vesicles (P = 0.009) and involvement of the buttock (P = 0.004) more frequently than the non-IgA vasculitis group. On DIF, perivascular IgA was positive in IgA vasculitis compared to non-IgA vasculitis cases (P = <0.001), the other conjugates were similar between the two groups. The most common subtype of biopsy-confirmed LCV in children is IgA vasculitis. Clinical features, exam characteristics and DIF results can be helpful in determining the subtype of cutaneous vasculitis in children.


Suicidal erythrocyte death, eryptosis, as a novel mechanism in heart failure-associated anaemia.
Suicidal death of erythrocytes (eryptosis) is characterized by cell shrinkage and exposure of phosphatidylserine (PS) residues at the cell surface. Excessive eryptosis may lead to anaemia. We aimed to study the role of eryptosis in heart failure (HF)-associated anaemia. We measured eryptosis in rodent models of HF. Typical measures of eryptosis including PS-exposure, increased intracellular Ca(2+) levels, and decreased cell volume were determined by flow cytometry. Transgenic REN2 rats displayed mild anaemia which was associated with a two-fold increase in erythrocyte PS-exposure when compared with Sprague Dawley (SD) control rats (P < 0.01). Upon stimulation with eryptotic triggers such as oxidative stress, hyperosmotic shock and energy depletion, eryptosis was more prominent in REN2 as shown by increased PS-exposure, cytosolic Ca(2+) influx, and cell shrinkage (P < 0.05 vs. SD). Increasing cytosolic Ca(2+) levels resulted in a stronger increase in PS-exposure in REN2 erythrocytes (P < 0.01 vs. SD). Accordingly, inhibition of Ca(2+) entry blunted the increased PS-exposure upon oxidative stress. The REN2 rats had significantly higher reticulocytes (REN2: 10.6 ± 2.3%; SD: 5.4 ± 0.1%; P < 0.05) and erythrocyte turnover was increased, indicated by increased clearance of eryptotic erythrocytes. Eryptosis was also increased in a rat model of hypertensive cardiac remodelling (uninephrectomized rats implanted with deoxycorticosterone acetate pellets), in mice after transverse aortic constriction, as well as in a small proof-of-concept study in human HF patients. Eryptosis is increased during HF development and could contribute to HF-associated anaemia. Eryptosis may therefore become a novel target for therapy in HF-associated anaemia.


Management factors affecting stereotypies and body condition score in nonracing horses in Prince Edward Island.
In North America, there are few representative data about the effects of management practices on equine welfare. In a randomized survey of 312 nonracing horses in Prince Edward Island (response rate 68.4%), owners completed a pretested questionnaire and a veterinarian examined each horse. Regression analyses identified factors affecting 2 welfare markers: body condition score (BCS) and stereotypic behavior. Horses' BCSs were high (mean 5.7, on a 9-point scale) and were associated with sex (males had lower BCSs than females; P < 0.001) and examination date (P = 0.052). Prevalences of crib biting, wind sucking, and weaving were 3.8%, 3.8%, and 4.8%, respectively. Age (OR = 1.07, P = 0.08) and hours worked weekly (OR = 1.12, P = 0.03) were risk factors for weaving. Straw bedding (OR = 0.3, P = 0.03), daily hours at pasture (OR = 0.94, P = 0.02), and horse type (drafts and miniatures had a lower risk than light horses; P = 0.12) reduced the risk of horses showing oral stereotypies. Some of these results contradict those of other studies perhaps because of populations concerned.


alpha -galactosylceramide-activated Valpha 14 natural killer T cells mediate protection against murine malaria.
Natural killer T (NKT) cells are a unique population of lymphocytes that coexpress a semiinvariant T cell and natural killer cell receptors, which are particularly abundant in the liver. To investigate the possible effect of these cells on the development of the liver stages of malaria parasites, a glycolipid, alpha-galactosylceramide (alpha-GalCer), known to selectively activate Valpha14 NKT cells in the context of CD1d molecules, was administered to sporozoite-inoculated mice. The administration of alpha-GalCer resulted in rapid, strong antimalaria activity, inhibiting the development of the intrahepatocytic stages of the rodent malaria parasites Plasmodium yoelii and Plasmodium berghei. The antimalaria activity mediated by alpha-GalCer is stage-specific, since the course of blood-stage-induced infection was not inhibited by administration of this glycolipid. Furthermore, it was determined that IFN-gamma is essential for the antimalaria activity mediated by the glycolipid. Taken together, our results provide the clear evidence that NKT cells can mediate protection against an intracellular microbial infection.


Patterns of gendered risk factors and associations with intimate partner violence and low educational attainment among adolescent girls and young women in Lesotho: A latent class analysis.
Globally, adolescent girls and young women (AGYW) are disproportionately impacted by economic, demographic, and social factors associated with a wide range of negative outcomes. The objective of this study was to use latent class analysis (LCA) to identify groupings of AGYW in Lesotho based on patterns of gendered risk factors, and to assess the association between the identified groupings and intimate partner violence (IPV) and low educational attainment. Data were from the 2018 Lesotho Violence Against Children and Youth Survey. AGYW reported gendered risk factors: teen pregnancy, child marriage, intergenerational sex, early sexual debut, being HIV positive, transactional sex, endorsement of one or more negative traditional gender norms, and one or more norms supportive of violence against women. LCA identified latent classes of eight gendered risk factors. Multivariable logistic regression assessed associations between latent classes and IPV victimization and low educational attainment. A three-class solution was selected, and classes were named as: Low Risk class, Behavioral Risk class, and Attitudinal Risk class. Odds of low educational attainment and IPV were higher in the Attitudinal Risk class than the Low Risk class. Odds of low educational attainment and IPV were higher in the Behavioral Risk class than the Low Risk class and the Attitudinal Risk class. In Lesotho, gendered risk factors form distinct classes that have variable associations with low educational attainment and IPV. LCA can be an important approach to better understand the complicated relationship gendered risk factors have with each other and with certain outcomes, to further elucidate the influence that gender has on the health of AGYW and to provide more targeted prevention programming.


Central nervous system infection in a pediatric population in West Java.
Central nervous system (CNS) viral infections are critical causes of morbidity and mortality in children; however, comprehensive data on etiology is lacking in developing countries such as Indonesia. To study the etiology of CNS infections in a pediatric population, 50 children admitted to two hospitals in Bandung, West Java, during 2017-2018 were enrolled in a CNS infection study. Cerebrospinal fluid and serum specimens were tested using molecular, serological, and virus isolation platforms for a number of viral and bacteriological agents. Causal pathogens were identified in 10 out of 50 (20%) and included cytomegalovirus (n = 4), Streptococcus pneumoniae (n = 2), tuberculosis (n = 2), Salmonella serotype Typhi (n = 1) and dengue virus (n = 1). Our study highlights the importance of using a wide range of molecular and serological detection methods to identify CNS pathogens, as well as the challenges of establishing the etiology of CNS infections in pediatric populations of countries with limited laboratory capacity.


Preserved specific anti-viral T-cell response but associated with decreased lupus activity in SLE patients with cytomegalovirus infection.
SLE is an autoimmune disease characterized by aberrant autoantibody production and immune dysfunctions. Whether the anti-CMV immunity is impaired in SLE patients is poorly understood. We investigated the specific anti-viral T-cell response in SLE patients with CMV infection and its possible impacts on clinical manifestations in lupus. CD28 null T-cell percentages were measured by flow cytometry in 89 SLE patients and 58 healthy controls. A specific anti-CMV CD8 T-cell response was assessed ex vivo by the production of intracellular cytokines in response to CMV phosphoprotein 65 (pp65) by flow cytometry. Clinical manifestations and immune parameters were analysed in SLE patients according to their CMV serostatus. CD28 null T cells were significantly expanded in SLE patients. When the anti-CMV pp65 CD8 polyfunctional T cell response was analysed, as defined by production of at least three of four functional cytokines or effectors (intracellular IFN-γ, IL-2, TNF-α and surface CD107a), the results demonstrated that it was not impaired in SLE patients. In contrast, when comparing clinical manifestations, there were lower anti-ds-DNA levels and decreased SLEDAI in SLE patients with CMV infection. Furthermore, the expansion of CD4+CD28 null T cells was negatively associated with anti-ds-DNA levels and SLEDAI in these lupus patients. In SLE patients with CMV infection, the specific anti-CMV CD8 T-cell response is preserved but is associated with decreased disease activity and lower anti-DNA levels among these patients, suggesting CMV infection may mitigate lupus activity.


Understanding the delivery of a Canadian-based after-school STEM program: a case study.
Due to the rising demands for a Canadian workforce with science, technology, engineering, and math (STEM)-related education, there is a need to increase youth engagement in STEM education and programming. Research, however, has shown that youth residing in low-income communities are disproportionately affected by psychosocial barriers, which often inhibit meaningful engagement in STEM programming. Visions of Science Network for Learning (VoSNL) was designed and implemented to address these existing barriers. VoSNL is a charitable organization in Southern Ontario, Canada, that provides weekly community-based STEM programming to low-income and marginalized youth during out-of-school time. VoSNL programming is delivered directly within the community and is free-of-charge for all youth in order to minimize barriers of physical and financial accessibility. The purpose of this report was to provide a detailed description of a core program within VoSNL-Community Science Clubs-and summarize the findings of a process evaluation, specifically the successes and challenges of implementing a community-based, out-of-school STEM program. Program successes are outlined along with the challenges that have been identified through program implementation. Successes include (a) delivering the program within a community context, (b) opportunities for consistent engagement, and (c) establishing positive youth-staff relationships. Challenges include (a) navigating community-based issues, (b) conducting outreach and promotion, and (c) accommodating a wide age range of youth. Further, lessons learned from an evaluation of program implementation are also discussed. This report provides one of the first program descriptions and process evaluations of a community-based, youth-focused STEM program within a Canadian context. The findings in this report have helped to improve the delivery and evaluation of the VoSNL program and may act as a catalyst for program expansion to reach more youth in marginalized communities. Further, the findings can also provide a strong framework for programmers interested in implementing STEM youth programming in a community context, assist in the replication of similar models in other locations, and enhance STEM learning amongst youth.


Influence of health insurance status on childhood cancer treatment outcomes in Kenya.
Survival of childhood cancer in high-income countries is approximately 80%, whereas in low-income countries, it is less than 10%. Limited access to health insurance in low-income settings may contribute to poor survival rates. This study evaluates the influence of health insurance status on childhood cancer treatment in a Kenyan academic hospital. This was a retrospective study. All children diagnosed with a malignancy from 2010 until 2012 were included. Data on treatment outcomes and health insurance status at diagnosis were abstracted from patient charts. Of 280 patients, 34% abandoned treatment, 19% died, and 18% had progressive or relapsed disease resulting in 29% event-free survival. The majority of patients (65%) did not have health insurance at diagnosis. Treatment results differed significantly between patients with different health insurance status at diagnosis; 37% of uninsured versus 28% of insured patients abandoned treatment, and 24% of uninsured versus 37% of insured patients had event-free survival. The event-free survival estimate was significantly higher for patients with health insurance at diagnosis compared with those without (P = 0.004). Of patients without health insurance at diagnosis, 77% enrolled during treatment. Among those patients who later enrolled in health insurance, frequency of progressive or relapsed disease and deaths was significantly lower (P = 0.013, P < 0.001, respectively), while the event-free survival estimate was significantly higher (P < 0.001) compared with those who never enrolled. Childhood cancer event-free survival was 29% at a Kenyan hospital. Children without health insurance had significant lower chance of event-free survival. Childhood cancer treatment outcomes could be ameliorated by strategies that prevent treatment abandonment and improve access to health insurance.


Genomic insights into the vulnerability of sympatric whitefish species flocks.
The erosion of habitat heterogeneity can reduce species diversity directly but can also lead to the loss of distinctiveness of sympatric species through speciation reversal. We know little about changes in genomic differentiation during the early stages of these processes, which can be mediated by anthropogenic perturbation. Here, we analyse three sympatric whitefish species (Coregonus spp) sampled across two neighbouring and connected Swiss pre-alpine lakes, which have been differentially affected by anthropogenic eutrophication. Our data set comprises 16,173 loci genotyped across 138 whitefish using restriction-site associated DNA sequencing (RADseq). Our analysis suggests that in each of the two lakes, the population of a different, but ecologically similar, whitefish species declined following a recent period of eutrophication. Genomic signatures consistent with hybridization are more pronounced in the more severely impacted lake. Comparisons between sympatric pairs of whitefish species with contrasting ecology, where one is shallow benthic and the other one more profundal pelagic, reveal genomic differentiation that is largely correlated along the genome, while differentiation is uncorrelated between pairs of allopatric provenance with similar ecology. We identify four genomic loci that provide evidence of parallel divergent adaptation between the shallow benthic species and the two different more profundal species. Functional annotations available for two of those loci are consistent with divergent ecological adaptation. Our genomic analysis indicates the action of divergent natural selection between sympatric whitefish species in pre-alpine lakes and reveals the vulnerability of these species to anthropogenic alterations of the environment and associated adaptive landscape.


Microbes to the Rescue - Exploring the Chemistry of Microbial Communication and Using it to Protect Plant Health.
Plants are densely colonized by diverse microbial communities. These microbes, which provide important benefit to their host supporting its growth and health, interact with each other and with their host plant by exchanging chemical signals, among which volatile organic compounds (VOCs). This review presents some of our current research lines in the field of microbial VOCs, including their bioactivities on both plants and plant pathogens, and the abiotic and biotic factors influencing their emission. Understanding how VOCs emission is regulated in plant-associated microbes is one of the major challenges for both fundamental and translational aspects of this research field.


Hypersensitive response to Potato virus Y in potato cultivar Sárpo Mira is conferred by the Ny-Smira gene located on the long arm of chromosome IX.
Potato virus Y (PVY, Potyvirus) is the fifth most important plant virus worldwide in terms of economic and scientific impact. It infects members of the family Solanaceae and causes losses in potato, tomato, tobacco, pepper and petunia production. In potato and its wild relatives, two types of resistance genes against PVY have been identified. While Ry genes confer symptomless extreme resistance, Ny genes cause a hypersensitive response visible as local necrosis that may also be able to prevent the virus from spreading under certain environmental conditions. The potato cultivar Sárpo Mira originates from Hungary and is highly resistant to PVY, although the source of this resistance remains unknown. We show that cv. Sárpo Mira reacts with a hypersensitive response leading to necrosis after PVYNTN infection in detached leaf, whole plant and grafting assays. The hypersensitivity to PVYNTN segregated amongst 140 individuals of tetraploid progeny of cvs. Sárpo Mira × Maris Piper in a 1:1 ratio, indicating that it was conferred by a single, dominant gene in simplex. Moreover, we identified five DNA markers linked to this trait and located the underlying locus (Ny-Smira) to the long arm of potato chromosome IX. This position corresponds to the location of the Rychc and Ny-1 genes for PVY resistance. A simple PCR marker, located 1 cM from the Ny-Smira gene, can be recommended for selection of PVY-resistant progeny of cv. Sárpo Mira.


Alcohol acyl transferase 1 links two distinct volatile pathways that produce esters and phenylpropenes in apple fruit.
Fruit accumulate a diverse set of volatiles including esters and phenylpropenes. Volatile esters are synthesised via fatty acid degradation or from amino acid precursors, with the final step being catalysed by alcohol acyl transferases (AATs). Phenylpropenes are produced as a side branch of the general phenylpropanoid pathway. Major quantitative trait loci (QTLs) on apple (Malus × domestica) linkage group (LG)2 for production of the phenylpropene estragole and volatile esters (including 2-methylbutyl acetate and hexyl acetate) both co-located with the MdAAT1 gene. MdAAT1 has previously been shown to be required for volatile ester production in apple (Plant J., 2014, https://doi.org/10.1111/tpj.12518), and here we show it is also required to produce p-hydroxycinnamyl acetates that serve as substrates for a bifunctional chavicol/eugenol synthase (MdoPhR5) in ripe apple fruit. Fruit from transgenic 'Royal Gala' MdAAT1 knockdown lines produced significantly reduced phenylpropene levels, whilst manipulation of the phenylpropanoid pathway using MdCHS (chalcone synthase) knockout and MdMYB10 over-expression lines increased phenylpropene production. Transient expression of MdAAT1, MdoPhR5 and MdoOMT1 (O-methyltransferase) genes reconstituted the apple pathway to estragole production in tobacco. AATs from ripe strawberry (SAAT1) and tomato (SlAAT1) fruit can also utilise p-coumaryl and coniferyl alcohols, indicating that ripening-related AATs are likely to link volatile ester and phenylpropene production in many different fruit.


White matter integrity in alcohol-naive youth with a family history of alcohol use disorders.
Understanding pre-existing neural vulnerabilities found in youth who are family history positive (FHP) for alcohol use disorders could help inform preventative interventions created to delay initiation age and escalation of heavy drinking. The goal of this study was to compare indices of white matter integrity using diffusion tensor imaging (DTI) between FHP and family history negative (FHN) youth using a sample of 94 alcohol-naive adolescents and to examine if differences were associated with global and domain-specific cognitive functioning. Participants were 48 FHP and 46 FHN demographically matched, healthy, substance-naive 12- to 14-year-olds (54% female) recruited from local middle schools. Participants completed a neuropsychological test battery and magnetic resonance imaging session, including DTI. FHP youth had higher fractional anisotropy and axial diffusivity, and lower radial and mean diffusivity, than FHN youth in 19 clusters spanning projection, association and interhemispheric white matter tracts. Findings were replicated after controlling for age, gender, socio-economic status, grade and pubertal development. Groups did not differ significantly on global or domain-specific neuropsychological test scores. FHP teens showed higher white matter integrity, but similar cognitive functioning, to FHN youth. More mature neural features could be related to more precocious behaviors, such as substance use initiation, in FHP youth. Future research exploring white matter maturation before and after substance use initiation will help elucidate the neurodevelopmental trajectories in youth at risk for substance use disorders, to inform preventive efforts and better understand the sequelae of adolescent alcohol and drug use.


Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1.
The three-dimensional structure of stromal cell-derived factor-1 (SDF-1) was determined by NMR spectroscopy. SDF-1 is a monomer with a disordered N-terminal region (residues 1-8), and differs from other chemokines in the packing of the hydrophobic core and surface charge distribution. Results with analogs showed that the N-terminal eight residues formed an important receptor binding site; however, only Lys-1 and Pro-2 were directly involved in receptor activation. Modification to Lys-1 and/or Pro-2 resulted in loss of activity, but generated potent SDF-1 antagonists. Residues 12-17 of the loop region, which we term the RFFESH motif, unlike the N-terminal region, were well defined in the SDF-1 structure. The RFFESH formed a receptor binding site, which we propose to be an important initial docking site of SDF-1 with its receptor. The ability of the SDF-1 analogs to block HIV-1 entry via CXCR4, which is a HIV-1 coreceptor for the virus in addition to being the receptor for SDF-1, correlated with their affinity for CXCR4. Activation of the receptor is not required for HIV-1 inhibition.


Syntheses of the plant auxin conjugate 2-O-(indole-3-acetyl)-myo-inositol IAInos.
The plant hormone conjugate 2-O-(indole-3-acetyl)-myo-inositol (IAInos) has been selectively prepared for the first time by two routes from myo-inositol. One of the syntheses depended upon the construction of the 3-indoleacetyl group by a Fischer indole synthesis on an unreactive axial hydroxyl group, while the other via a direct acylation of the equatorially orientated hydroxy group created by conformational constraint of the cyclohexane ring. The latter synthesis produced IAInos in 5 steps and 29% overall yield.


Native California soils are selective reservoirs for multidrug-resistant bacteria.
Soil bacteria can exhibit extensive antibiotic resistomes and act as reservoirs of important antibiotic resistance traits. However, the geographic sources and evolutionary drivers of resistance traits are poorly understood in these natural settings. We investigated the prevalence, spatial structure and evolutionary drivers of multidrug resistance in natural populations of Bradyrhizobium, a cosmopolitan bacterial lineage that thrives in soil and aquatic systems as well as in plant and human hosts. We genotyped > 400 isolates from plant roots and soils across California and assayed 98 of them for resistance traits against 17 clinically relevant antibiotics. We investigated the geographic and phylogenetic structure of resistance traits, and analysed correlations of resistance with strain abundance, host infection capacity and in vitro fitness. We found: (i) multidrug resistance at all sites, (ii) subsets of resistance traits that are spatially structured and (iii) significant associations between resistance traits and increased strain abundance or host infection capacity. Our results highlight multiple selective factors that can result in the spread of resistance traits in native Bradyrhizobium populations.


Phase dynamics at microtubule ends: the coexistence of microtubule length changes and treadmilling.
The length dynamics both of microtubule-associated protein (MAP)-rich and MAP-depleted bovine brain microtubules were examined at polymer mass steady state. In both preparations, the microtubules exhibited length redistributions shortly after polymer mass steady state was attained. With time, however, both populations relaxed to a state in which no further changes in length distributions could be detected. Shearing the microtubules or diluting the microtubule suspensions transiently increased the extent to which microtubule length redistributions occurred, but again the microtubules relaxed to a state in which changes in the polymer length distributions were not detected. Under steady-state conditions of constant polymer mass and stable microtubule length distribution, both MAP-rich and MAP-depleted microtubules exhibited behavior consistent with treadmilling. MAPs strongly suppressed the magnitude of length redistributions and the steady-state treadmilling rates. These data indicate that the inherent tendency of microtubules in vitro is to relax to a steady state in which net changes in the microtubule length distributions are zero. If the basis of the observed length redistributions is the spontaneous loss and regain of GTP-tubulin ("GTP caps") at microtubule ends, then in order to account for stable length distributions the microtubule ends must reside in the capped state far longer than in the uncapped state, and uncapped microtubule ends must be rapidly recapped. The data suggest that microtubules in cells may have an inherent tendency to remain in the polymerized state, and that microtubule disassembly must be induced actively.


Measuring chronic health condition and disability as distinct concepts in national surveys of school-aged children in Canada: a comprehensive review with recommendations based on the ICD-10 and ICF.
With the aim of improving the measurement of child health and disability in survey research, this paper reviews the coverage of chronic health conditions and the domains of disability and related environmental factors as they are laid out in the ICD-10 and ICF, respectively, in national surveys of school-aged children conducted in Canada since 1980. Recommendations are made for future survey use and construction. Two reviewers independently examined each of the surveys. Coverage of chronic health conditions, the domains of disability, and environmental factors in survey questions was identified by mapping question content onto ICD-10 and ICF codes. The reviewers then compared their findings and came to a final consensus. Surveys vary in the range and depth of coverage of the ICD-10 and ICF chapters. Disability surveys and health surveys for persons aged 12 and over contain the most comprehensive lists of chronic conditions. Coverage of impairments is limited. Coverage of activity limitations and participation restrictions is most limited in the domains of personal care and domestic life. Environmental factors not covered include natural environmental changes, attitudes, and policies. Development of a comprehensive standard list of chronic health conditions based on the ICD-10 and development of standard survey measures of the domains of disability and environmental factors based on the ICF for use in surveys of school-aged children would facilitate an understanding of children's health and disability in the context of the current international health framework provided by the World Health Organization.


Assessment of sampling methods about level of mercury in fish.
Mercury (Hg) seriously affects some sensitive subgroups of population and the detection of Hg content in fish and fishery products is one of the most important activities aimed at controlling their safety. In fact, Regulation (EC) No 1881/2006 set maximum levels for certain contaminants in foodstuffs and Regulation (EC) No 333/2007 laid down the methods of sampling and analysis for their control in foodstuffs. As Hg content highly varies among different fish species depending on a variety of factors and even among members of the same population, sampling methods play a crucial role in the accuracy, precision and statistical significance of Hg determination. By the use of an analysis method independent probabilistic model, based on the axioms of Kolmogorov's probability theory, this paper aims to assess the relationship between sampling methods set by Regulation (EC) No 333/2007 and the probability to detect compliant or non-compliant outcomes of Hg in fish.


Raised plasma concentrations of alpha-defensins in patients with idiopathic pulmonary fibrosis.
Neutrophils are thought to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Human neutrophils contain antimicrobial and cytotoxic peptides in the azurophil granules which belong to a family of mammalian neutrophil peptides named alpha-defensins. A study was undertaken to investigate the role of alpha-defensins in the pathogenesis of IPF. The concentrations of alpha-defensins (human neutrophil peptides (HNPs) 1, 2, and 3) in plasma and bronchoalveolar lavage (BAL) fluid of 30 patients with IPF and 15 healthy subjects were measured by radioimmunoassay. The concentrations of alpha-defensins in plasma, but not in BAL fluid, were significantly higher in IPF patients than in controls. BAL fluid concentrations of interleukin (IL)-8 in patients with IPF, which were significantly higher than in controls, correlated with those of alpha-defensins. An inverse relationship was seen between plasma alpha-defensin levels and the arterial oxygen tension (PaO(2)) and pulmonary function (vital capacity (%VC), forced expiratory volume in 1 second (FEV(1)), and carbon monoxide transfer factor (%TLCO)) in patients with IPF. Plasma levels of alpha-defensins also correlated with the clinical course in IPF patients with an acute exacerbation. Immunohistochemically, positive staining was observed inside and outside neutrophils in the alveolar septa, especially in dense fibrotic areas. These findings suggest that alpha-defensins play an important role in the pathogenesis of IPF, and that the plasma alpha-defensin level may be a useful marker of disease severity and activity.


The tumor suppressor merlin is required for cell cycle exit, terminal differentiation, and cell polarity in the developing murine lens.
PURPOSE. Neurofibromatosis type 2 (NF2) is an autosomal-dominant CNS tumor syndrome that affects 1:25,000 children and young adults. More than 50% of NF2 patients also develop posterior subcapsular cataracts (PSCs). The authors deleted Nf2 from the lens to determine its role in fiber cell differentiation. METHODS. Nf2 was conditionally deleted from murine lenses using the LeCre transgene. Standard histology and immunohistochemical and immunofluorescent methods were used to analyze lens morphology and markers of cell cycle progression, differentiation, and cell junctions in wild-type and knockout lenses from embryonic day 10.5 through postnatal day 3. RESULTS. Fiber cells lacking Nf2 did not fully exit the cell cycle and continued to express epithelial cell markers, such as FoxE3 and E-cadherin, despite expressing the fiber cell marker Prox1. Many fiber cells lost their elongated morphology. Markers of apical-basal polarity, such as ZO-1, were mislocalized along the lateral and basal membranes of fiber cells. The lens vesicle failed to separate from the surface ectoderm, and prospective lens and corneal epithelial cells formed a multilayered mass of cells at the surface of the eye. Herniation of this membrane caused the fiber mass to erupt through the cornea. CONCLUSIONS. Nf2 is required for complete fiber cell terminal differentiation, maintenance of cell polarity, and separation of lens vesicle from corneal epithelium. Defects identified in fiber cell differentiation may explain the formation of PSCs in patients with NF2. The lens provides an assay system to identify pathways critical for fiber cell differentiation and to test therapies for the tumors that occur in patients with NF2.


[Effects of vascular endothelial growth factor on differentiation and function of dendritic cells generated from CD34+ hematopoietic progenitor cells in vitro].
To investigate the effects of vascular endothelial growth factor (VEGF) on differentiation and function of dendritic cells derived from CD34+ hematopoietic progenitor cells. After isolation from umbilical cord blood with a high-gradient magnetic cell sorting system (MACS), the CD34+ cells were cultured with a cocktail cytokines for differentiating into dendritic cells (DC). The cells were stimulated by VEGF (25 ng/ml) either at the beginning or at day 9 of culture. Kinetics analysis of cell proliferation was performed during the process of cell culture, and the expression of DC differentiation antigens including CD1alpha, CD83, CD80, CD54 and HLA-DR was examined by flow cytometry. DC function was evaluated by the ability to induce proliferation of allogeneic T cells in mixed lymphocyte reaction (MLR) assay, and the production of IL-12 by ELISA. VEGF added at day 1 of culture induced an increase of total cell numbers by (1.51 +/- 0.23)-folds (P = 0.001). VEGF added at the initial but not the late stage of culture could dramatically down-regulate the expression of CD1a [(33.00 +/- 2.12)% vs (81.20 +/- 6.93)%], CD83 [(42.23 +/- 1.15)% vs (87.98 +/- 7.97)%], CD80 (42.93 +/- 1.32)% vs (94.53 +/- 0.87)%], and HLA-DR [(37.93 +/- 5.30)% vs (74.15 +/- 3.74)%], while obviously up-regulate the expression of CD14. Moreover, the inhibitory effect of VEGF on DC function was confirmed by a reduced ability to induce proliferation of allogeneic T cells and production of IL-12 (P < 0.01). VEGF could induce the expansion of hematopoietic progenitor cells and inhibit at the early stage their differentiation into mature DC.


Partitioning characteristics of perfluorooctane sulfonate between water and foods.
As a persistent, bioaccumulative, and toxic organic pollutant, perfluorooctane sulfonate (PFOS) has been found ubiquitously in the environment, including in tap water. For the first time, we studied PFOS sorption from water to foods (nine commonly consumed vegetables, three meats, and cereals) at two temperatures to estimate the daily intake of PFOS attributable to cooking and food preparation. The values of the food water-distribution coefficient (KF/W, l/kg) of PFOS ranged from 7 to 19 l/kg for most vegetables and from 19 to 38 l/kg for meats. Celery exhibited the highest affinity toward PFOS (KF/W=39.8±3.4 l/kg), whereas onions showed the lowest affinity toward PFOS (KF/W=1.1±0.4 l/kg). Adding table salt (sodium chloride) greatly increased PFOS sorption in most foods, except for celery and meats. The results indicate that human exposure to PFOS could result from the sorption of PFOS from water to food during food preparation, especially when using table salt. The average daily intake of PFOS through this route was estimated. Furthermore, raw and unprocessed foods (vegetables, meats, and cereals) bought from farmers' markets and grocery stores were basically free of PFOS and other long-chain perfluoroalkyl acids.


Electroencephalographic correlates of oral contraceptive use in psychiatric patients.
Previous studies have pointed to wake electroencephalographic changes associated with oral contraceptives. This investigation sought to determine if sleep EEG activation would show additional EEG-oral contraceptive relationships not previously suspected. With blind procedures, oral contraceptive and EEG data were collected on 110 adult women. Three age-equated comparison groups were formed: (1) never used pill (control); (2) previously used pill without side effects (asymptomatic); and (3) previously used pill with side effects (symptomatic). Analyses indicated a significant statistical relationship between paroxysmal EEGs and symptomatic pill use. No difference in paroxysmal EEG incidence existed between control and asymptomatic pill use groups. Among prior pill users, women with paroxysmal EEGs reported almost twice the side effect incidence (81.3%) as did women with normal EEGs (42.1%).


Contemporary failure aetiologies of the primary, posterior-stabilised total knee arthroplasty.
The number of revision total knee arthroplasties (TKA) that are performed is expected to increase. However, previous reports of the causes of failure after TKA are limited in that they report the causes at specific institutions, which are often dependent on referral patterns. Our aim was to report the most common indications for re-operations and revisions in a large series of posterior-stabilised TKAs undertaken at a single institution, excluding referrals from elsewhere, which may bias the causes of failure. A total of 5098 TKAs which were undertaken between 2000 and 2012 were included in the study. Re-operations, revisions with modular component exchange, and revisions with non-modular component replacement or removal were identified from the medical records. The mean follow-up was five years (two to 12). The Kaplan-Meier ten-year survival without a re-operation, modular component revision and non-modular component revision was 95.7%, 99.3% and 95.3%, respectively. The most common indications for a re-operation were: post-operative stiffness (58%), delayed wound healing (21%), and patellar clunk (11%). The indications for isolated modular component revision were acute periprosthetic joint infection (PJI) (64%) and instability (36%). The most common indications for non-modular component revision were chronic PJI (52%), aseptic loosening (17%), periprosthetic fracture (10%), and instability (10%). Post-operative stiffness remains the most common indication for re-operation after TKA. Infection is the most common indication for modular and non-modular component revision. Aseptic loosening was not an uncommon cause of failure, however, it was much less common than in national registry and non-registry data. Focusing on posterior-stabilised TKAs initially performed at our institution allowed for an accurate assessment of the causes of failure in a contemporary specialty practice. Cite this article: Bone Joint J 2017;99-B:647-52.


Neonatal Isoflurane Does Not Affect Sleep Architecture and Minimally Alters Neuronal Beta Oscillations in Adolescent Rats.
General anesthetics are neurotoxic to the developing rodent and primate brains leading to neurocognitive and socio-affective impairment later in life. In addition, sleep patterns are important predictors of cognitive outcomes. Yet, little is known about how anesthetics affect sleep-wake behaviors and their corresponding oscillations. Here we examine how neonatal general anesthesia affects sleep and wake behavior and associated neuronal oscillations. We exposed male and female rat pups to either 6 h of continuous isoflurane or sham anesthesia (compressed air) at the peak of their brain development (postnatal day 7). One cohort of animals was used to examine neurotoxic insult 2 h post-anesthesia exposure. At weaning age, a second cohort of rats was implanted with cortical electroencephalogram electrodes and allowed to recover. During adolescence, we measured sleep architecture (divided into wake, non-rapid eye movement, and rapid eye movement sleep) and electroencephalogram power spectra over a 24 h period. We found that exposure to neonatal isoflurane caused extensive neurotoxicity but did not disrupt sleep architecture in adolescent rats. However, these animals had a small but significant reduction in beta oscillations, specifically in the 12-20 Hz beta 1 range, associated with wake behavior. Furthermore, beta oscillations play a critical role in cortical development, cognitive processing, and homeostatic sleep drive. We speculate that dysregulation of beta oscillations may be implicated in cognitive and socio-affective outcomes associated with neonatal anesthesia.


Digital flexor sheath: repair and reconstruction of the annular pulleys and membranous sheath.
Rupture or transection of the digital pulley may necessitate repair or reconstruction to treat symptomatic flexor tendon bowstringing. When reconstruction is necessary, intrasynovial tendon grafts may provide superior gliding characteristics when compared with traditional extrasynovial tendon grafts. Lacerations of the membranous portion of the digital sheath and of noncritical annular pulleys usually do not require operative repair.


Accuracy of Digital Versus Conventional Periapical Radiographs to Detect Misfit at the Implant-Abutment Interface.
Misfit is a risk factor for rehabilitation with implants, and its detection is of fundamental importance to the success of treatment with implants. The use of appropriate radiographic imaging is key for a good prognosis. The aim of this study was to compare the efficacy of film and digital radiographs for the detection of misfit at the implant-abutment interface. Digital and conventional (manual and automatic processing) radiography was performed in seven test specimens, each one with a different vertical misfit between the abutment and the platform of the implant. Scanning electron microscopy was used to confirm the misfit and to measure it. Five dental radiologists independently and blindly evaluated the images. Cohen's kappa with linear weighting was calculated to determine interexaminer and intraexaminer concordance. Statistical analyses were performed using the Cochran's Q test and the receiver operating characteristic curve (ROC). Interexaminer analysis showed that the kappa value was equal to 0.74, whereas the average kappa value in the intraexaminer evaluation was 0.90. Digital imaging showed the largest area on the ROC graph, and conventional images with manual processing showed the smallest area. The images obtained through conventional radiography with both manual and automatic processing showed statistically significant differences from the measurement of the gold standard (P < .05). Digital imaging can be used to evaluate misfit at the implant-abutment interface. Conventional systems of radiographic imaging do not provide sufficient information to evaluate misfit at the implant-abutment interface.


SNF5 reexpression in malignant rhabdoid tumors regulates transcription of target genes by recruitment of SWI/SNF complexes and RNAPII to the transcription start site of their promoters.
Malignant rhabdoid tumor (MRT), a highly aggressive cancer of young children, displays inactivation or loss of the hSNF5/INI1/SMARCB1 gene, a core subunit of the SWI/SNF chromatin-remodeling complex, in primary tumors and cell lines. We have previously reported that reexpression of hSNF5 in some MRT cell lines causes a G1 arrest via p21(CIP1/WAF1) (p21) mRNA induction in a p53-independent manner. However, the mechanism(s) by which hSNF5 reexpression activates gene transcription remains unclear. We initially searched for other hSNF5 target genes by asking whether hSNF5 loss altered regulation of other consensus p53 target genes. Our studies show that hSNF5 regulates only a subset of p53 target genes, including p21 and NOXA, in MRT cell lines. We also show that hSNF5 reexpression modulates SWI/SNF complex levels at the transcription start site (TSS) at both loci and leads to activation of transcription initiation through recruitment of RNA polymerase II (RNAPII) accompanied by H3K4 and H3K36 modifications. Furthermore, our results show lower NOXA expression in MRT cell lines compared with other human tumor cell lines, suggesting that hSNF5 loss may alter the expression of this important apoptotic gene. Thus, one mechanism for MRT development after hSNF5 loss may rely on reduced chromatin-remodeling activity of the SWI/SNF complex at the TSS of critical gene promoters. Furthermore, because we observe growth inhibition after NOXA expression in MRT cells, the NOXA pathway may provide a novel target with clinical relevancy for treatment of this aggressive disease.


Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice.
Osterix (Osx or Sp7) is a zinc-finger-family transcriptional factor essential for osteoblast differentiation in mammals. The Osx-Cre mouse line (also known as Osx1-GFP::Cre) expresses GFP::Cre fusion protein from a BAC transgene containing the Osx regulatory sequence. The mouse strain was initially characterized during embryogenesis, and found to target mainly osteoblast-lineage cells. Because the strain has been increasingly used in postnatal studies, it is important to evaluate its targeting specificity in mice after birth. By crossing the Osx-Cre mouse with the R26-mT/mG reporter line and analyzing the progenies at two months of age, we find that Osx-Cre targets not only osteoblasts, osteocytes and hypertrophic chondrocytes as expected, but also stromal cells, adipocytes and perivascular cells in the bone marrow. The targeting of adipocytes and perivascular cells appears to be specific to those residing within the bone marrow, as the same cell types elsewhere are not targeted. Beyond the skeleton, Osx-Cre also targets the olfactory glomerular cells, and a subset of the gastric and intestinal epithelium. Thus, potential contributions from the non-osteoblast-lineage cells should be considered when Osx-Cre is used to study gene functions in postnatal mice.


Sub-lethal effects of herbicides penoxsulam, imazamox, fluridone and glyphosate on Delta Smelt (Hypomesus transpacificus).
Concerns regarding non-target toxicity of new herbicides used to control invasive aquatic weeds in the San Francisco Estuary led us to compare sub-lethal toxicity of four herbicides (penoxsulam, imazamox, fluridone, and glyphosate) on an endangered fish species Delta Smelt (Hypomesus transpacificus). We measured 17β-estradiol (E2) and glutathione (GSH) concentrations in liver, and acetylcholinesterase (AChE) activity in brain of female and male fish after 6 h of exposure to each of the four herbicides. Our results indicate that fluridone and glyphosate disrupted the E2 concentration and decreased glutathione concentration in liver, whereas penoxsulam, imazamox, and fluridone inhibited brain AChE activity. E2 concentrations were significantly increased in female and male fish exposed to 0.21 μM of fluridone and in male fish exposed to 0.46, 4.2, and 5300 μM of glyphosate. GSH concentrations decreased in males exposed to fluridone at 2.8 μM and higher, and glyphosate at 4.2 μM. AChE activity was significantly inhibited in both sexes exposed to penoxsulam, imazamox, and fluridone, and more pronounced inhibition was observed in females. The present study demonstrates the potential detrimental effects of these commonly used herbicides on Delta Smelt.


Digital Patient-Reported Outcome Measures for Monitoring of Patients on Cancer Treatment: Cross-sectional Questionnaire Study.
Oncology has been facing increasing outpatient activity associated with higher cancer incidence, better survival rates, and more treatment options. Innovative technological solutions could help deal with this increasing demand. Using digital patient-reported outcome measures (PROMs) to identify patients who need a face-to-face (FTF) appointment is a potential approach. This study aims to assess the feasibility of digital PROM questionnaires to enable remote symptom monitoring for patients undergoing cancer treatment and their ability to highlight the requirement for an FTF appointment. This study was performed at a tertiary oncology center between December 2018 and February 2019. The Common Terminology Criteria for Adverse Events were adapted into patient-friendly language to form the basis of treatment-specific digital questionnaires covering specific cancer drugs and radiotherapy treatments. These treatment-specific digital PROM questionnaires were scored by both patients and their clinicians during FTF appointments. Patients and clinicians did not see each other's scored PROMs. Agreement between patients and clinicians was assessed using descriptive statistics. Patient and staff feedback was also obtained. In total, 90 patients participated in the study across 10 different treatment pathways. By comparing paired patient and clinician responses, the sensitivity of the patient-completed questionnaires in correctly highlighting the need for FTF review was 94% (44/47), and all patients with severe or grade 3+ symptoms were identified (6/6, 100%). Patient-completed PROMs appropriately revealed that 29% (26/90) of the participating patients did not need FTF review based on their symptoms alone. Certain oncological treatment pathways, such as immunotherapy, were found to have a larger proportion of patients with minimal symptoms than others, such as conventional chemotherapy. Patient and staff feedback showed high approval of digital PROMs and their potential for use in remote monitoring. Digital PROM questionnaires can feasibly highlight the need for FTF review in oncology clinics for treatment. Their use with specific treatments could safely reduce the requirement for FTF care, and future work should evaluate their application in the remote monitoring of patients.


HLA-DM and invariant chain are expressed by thyroid follicular cells, enabling the expression of compact DR molecules.
Thyroid follicular cells (TFC) in Graves' disease (GD) hyperexpress HLA class I and express ectopic HLA class II molecules, probably as a consequence of cytokines produced by infiltrating T cells. This finding led us to postulate that TFC could act as antigen-presenting cells, and in this way be responsible for the induction and/or maintenance of the in situ autoimmune T cell response. Invariant chain (li) and HLA-DM molecules are implicated in the antigen processing and presentation by HLA class II molecules. We have investigated the expression of these molecules by TFC from GD glands. The results demonstrate that class II+ TFC from GD patients also express li and HLA-DM, and this expression is increased after IFN-gamma stimulation. The level of HLA-DM expression by TFC was low but sufficient to catalyze peptide loading into the HLA class II molecules and form stable HLA class II-peptide complexes expressed at the surface of TFC. These results have implications for the understanding of the possible role of HLA class II+ TFC in thyroid autoimmune disease.


Optimizing integrated imaging service delivery by tier in low-resource health systems.
Access to imaging diagnostics has been shown to result in accurate treatment, management, and optimal outcomes. Particularly in low-income and low-middle-income countries (LICs, LMICs), access is limited due to a lack of adequate resources. To achieve Sustainable Development Goal (SDG) 3, access to imaging services is critical at every tier of the health system. Optimizing imaging services in low-resource settings is best accomplished by prescriptive, integrated, and coordinated tiered service delivery that takes contextual factors into consideration. To our knowledge, this is the first recommendation for optimized, specific imaging care delivery by tier. A model for tier-based essential imaging services informs and guides policymakers as they set priorities and make budgetary decisions. In this paper, we recommend a framework for tiered imaging services essential to reduce the global burden of disease and attain universal health coverage (UHC). A lack of access to basic imaging services, even at the lowest tier of the health system, can no longer be justified by cost. Worldwide, affordable modalities of modern ultrasound and X-ray are becoming an accessible mainstay for the investigation of common conditions such as pregnancy, pneumonia, and fractures, and are safely performed and interpreted by qualified professionals. Finally, given the vast gap in access to imaging resources between LMICs and high-income countries (HICs), a scale-up of tiered imaging services in low-resource settings has the potential to reduce health disparities between, and within countries. As the access to appropriately integrated imaging services improves, UHC may be achieved.


Use of a constrained tripolar acetabular liner to treat intraoperative instability and postoperative dislocation after total hip arthroplasty: a review of our experience.
Constrained acetabular components have been used to treat certain cases of intraoperative instability and postoperative dislocation after total hip arthroplasty. We report our experience with a tripolar constrained component used in these situations since 1988. The outcomes of the cases where this component was used were analyzed for component failure, component loosening, and osteolysis. At average 10-year followup, for cases treated for intraoperative instability (2 cases) or postoperative dislocation (4 cases), the component failure rate was 6% (6 of 101 hips in 5 patients). For cases where the constrained liner was cemented into a fixed cementless acetabular shell, the failure rate was 7% (2 of 31 hips in 2 patients) at 3.9-year average followup. Use of a constrained liner was not associated with an increased osteolysis or aseptic loosening rate. This tripolar constrained acetabular liner provided total hip arthroplasty construct stability in most cases in which it was used for intraoperative instability or postoperative dislocation.


Knockdown of the germ cell factor Dead end induces multiple transcriptional changes in Atlantic cod (Gadus morhua) hatchlings.
The RNA binding protein Dead end (DnD) is essential for maintaining viable germ cells in vertebrates and silencing of the gene has been demonstrated to cause sterility in several mammalian and fish species. Here we investigated transcriptome changes in hatched larvae of Atlantic cod induced by DnD knockdown using morpholino oligonucleotides (MO) injected in two-cell embryos. Whereas no fluorescently labeled germ cells were shown in embryos coinjected with dnd MO and nanos3 3'UTR coupled to green fluorescent protein, DnD knockdown had no visible effect on the number and location of Vasa protein positive cells in larvae. However, quantitative real-time RT-PCR (qPCR) revealed decreased vasa, nanos3 and tudor domain containing protein 7 mRNA expression and genome-wide oligonucleotide microarray analyses indicated profound suppression of genes involved in development and regulation of the reproductive system. DnD morphants showed lowered expression of genes encoding proteins involved in lipid, retinoid, cholesterol and steroid metabolism, including those with roles in sex hormone metabolism. Biotransformation of lipophilic compounds appeared suppressed too, as evidenced by down-regulation of several key genes from the phases 1 and 2 detoxification pathways. Effects of DnD silencing were highly pleiotropic and consisted of endocrine and metabolic changes, massive induction of histones and suppression of diverse developmental processes, including erythropoiesis and formation of extracellular matrix. While transient inhibition of dnd mRNA translation did not block development of primordial germ cells until hatch, results suggested that ablation of DnD might have major indirect consequences, including suppression of reproductive functions.


SEQATOMS: a web tool for identifying missing regions in PDB in sequence context.
With over 46 000 proteins, the Protein Data Bank (PDB) is the most important database with structural information of biological macromolecules. PDB files contain sequence and coordinate information. Residues present in the sequence can be absent from the coordinate section, which means their position in space is unknown. Similarity searches are routinely carried out against sequences taken from PDB SEQRES. However, there no distinction is made between residues that have a known or unknown position in the 3D protein structure. We present a FASTA sequence database that is produced by combining the sequence and coordinate information. All residues absent from the PDB coordinate section are masked with lower-case letters, thereby providing a view of these residues in the context of the entire protein sequence, which facilitates inspecting 'missing' regions. We also provide a masked version of the CATH domain database. A user-friendly BLAST interface is available for similarity searching. In contrast to standard (stand-alone) BLAST output, which only contains upper-case letters, our output retains the lower-case letters of the masked regions. Thus, our server can be used to perform BLAST searching case-sensitively. Here, we have applied it to the study of missing regions in their sequence context. SEQATOMS is available at http://www.bioinformatics.nl/tools/seqatoms/.


DNA-free recombinant SV40 capsids protect mice from acute renal failure by inducing stress response, survival pathway and apoptotic arrest.
Viruses induce signaling and host defense during infection. Employing these natural trigger mechanisms to combat organ or tissue failure is hampered by harmful effects of most viruses. Here we demonstrate that SV40 empty capsids (Virus Like Particles-VLPs), with no DNA, induce host Hsp/c70 and Akt-1 survival pathways, key players in cellular survival mechanisms. We postulated that this signaling might protect against organ damage in vivo. Acute kidney injury (AKI) was chosen as target. AKI is critical, prevalent disorder in humans, caused by nephrotoxic agents, sepsis or ischemia, via apoptosis/necrosis of renal tubular cells, with high morbidity and mortality. Systemic administration of VLPs activated Akt-1 and upregulated Hsp/c70 in vivo. Experiments in mercury-induced AKI mouse model demonstrated that apoptosis, oxidative stress and toxic renal failure were significantly attenuated by pretreatment with capsids prior to the mercury insult. Survival rate increased from 12% to >60%, with wide dose response. This study demonstrates that SV40 VLPs, devoid of DNA, may potentially be used as prophylactic agent for AKI. We anticipate that these finding may be projected to a wide range of organ failure, using empty capsids of SV40 as well as other viruses.


Clinical characteristics and genetic profiles of young and adult patients with cholestatic liver disease.
heterozygous ABCB4, ABCB11 and ATP8B1 sequence variants were previously reported to be associated with low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis and biliary lithiasis. The present study aimed to identify the presence of sequence variations in genes responsible for Mendelian liver disorders in patients with cholestatic liver disease. targeted massive parallel sequencing of a panel of genes involved in bile acid homeostasis was performed in 105 young and adult patients with cholestatic liver disease in our laboratory for molecular diagnosis. The effects of novel variants were evaluated using bioinformatics prediction tools and the Protter and Phyre2 software programs were used to create 2D, 3D topology protein modeling. Genotype-phenotype correlation was established according to molecular analysis and clinical records. twenty novel heterozygous ABCB4 sequence variations, one heterozygous ABCB4 large intragenic deletion and only one novel missense variant in ABCB11 and ATP8B1 were identified. Interestingly, heterozygous and homozygous SLC4A2 missense variants were detected in patients with low phospholipid-associated cholelithiasis. Two patients harbored heterozygous GPBAR1 variants. Common variants such as homozygous ABCB11 p.Val444Ala and heterozygous ABCG8 p.Asp19His were also identified in 12 cases. forty-eight variants were identified in five genes including ABCB4, ABCB11, ATP8B1, SLC4A2 and GPBAR1, twenty-five of which were novel. This study expands the phenotypic and mutational spectrum in genes involved in bile acid homeostasis and highlights the genetic and phenotypic heterogeneity in patients with inherited liver disorders.


Fungi reduce preference and performance of insect herbivores on challenged plants.
Although insect herbivores and fungal pathogens frequently share the same individual host plant, we lack general insights in how fungal infection affects insect preference and performance. We addressed this question in a meta-analysis of 1,113 case studies gathered from 101 primary papers that compared preference or performance of insect herbivores on control vs. fungus challenged plants. Generally, insects preferred, and performed better on, not challenged plants, regardless of experimental conditions. Insect response to fungus infection significantly differed according to fungus lifestyle, insect feeding guild, and the spatial scale of the interaction (local/distant). Insect performance was reduced on plants challenged by biotrophic pathogens or endophytes but not by necrotrophic pathogens. For both chewing and piercing-sucking insects, performance was reduced on challenged plants when interactions occurred locally but not distantly. In plants challenged by biotrophic pathogens, both preference and performance of herbivores were negatively impacted, whereas infection by necrotrophic pathogens reduced herbivore preference more than performance and endophyte infection reduced only herbivore performance. Our study demonstrates that fungi could be important but hitherto overlooked drivers of plant-herbivore interactions, suggesting both direct and plant-mediated effects of fungi on insect's behavior and development.


Rational use of cetuximab in the treatment of advanced non-small cell lung cancer.
Lung cancer is the leading cause of mortality in the United States. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Most NSCLC patients present with loco-regionally advanced or metastatic disease where response rates are low and median overall survival approximates 8 to 10 months. Chemotherapy is the mainstay of treatment for NSCLC patients with metastatic disease. Epidermal growth factor receptor (EGFR) and family of receptors play a critical role in lung cancer tumorigenesis. Cetuximab, a monoclonal antibody that binds the EGFR, has demonstrated preclinical and clinical activity against NSCLC. This review focuses on the use of cetuximab in NSCLC.


Host cell mobilization for in situ tissue regeneration.
Although small, localized injuries can be healed through the body's normal reparative process, large traumatic injury overwhelms this system and may result in a deficit of functional recovery, despite the use of conventional reconstructive modalities. Cell-based approaches using tissue engineering and regenerative medicine techniques have offered new opportunities for treatment. Although the fundamental principles of cell-based therapies have been demonstrated clinically on multiple tissue systems, usually a donor tissue biopsy and ex vivo cell manipulation prior to implantation in vivo are necessary. The goal of the present study was to investigate whether host biologic resources and environmental conditions could be used for in situ tissue regeneration, which may eliminate the need for donor cell procurement and subsequent in vitro cell manipulation. To address this aim, we implanted a common biomaterial into mice and characterized the infiltrating cells to determine their regenerative potential. We showed that host cell infiltrates are not entirely comprised of inflammatory and fibroblast-like cells and the normal inflammatory process can be altered by incorporating anti-inflammatory agents that influence the formation of scar tissue. In addition, the infiltrating cells are capable of differentiating into multiple cell lineages, including osteogenic, myogenic, adipogenic, and endothelial lineages, if appropriate conditions are provided. These results suggest that it is possible to recruit a predominance of cells with multilineage potential into a biomaterial scaffold. Therefore, it may be possible to enrich the infiltrate with such cell types and control their fate, provided the proper substrate-mediated signaling can be imparted into the scaffold for in situ tissue regeneration.


Information sources and strategies of nutrition guidance used by primary care physicians.
We studied the nutrition information seeking behavior of primary care physicians (PCPs) and also PCPs' implementation of different strategies of nutrition guidance of patients. This was done by means of a questionnaire mailed to a nationwide random sample of 1000 PCPs in the Netherlands. The net response rate was 64%. The two most important nutrition information sources for PCPs were a dietitian (72% of respondents) and the literature (34% of respondents). Eighty-five percent of PCPs reported that they were actively involved in seeking nutrition information. For nutrition education of patients, PCPs gave personal information to patients, referred patients to a dietitian, and made publications available in the surgery. As preferred methods of obtaining nutrition information themselves, PCPs listed scientific journals, postgraduate nutrition education, congresses and study days, and publications. Determinants of nutrition information seeking behavior of PCPs as well as their implementation of different strategies of patient nutrition education were identified and discussed. PCPs were familiar with the body mass index, which is encouraging because treatment of overweight and obesity starts with a valid assessment. The findings in this study lead to a prudent positive conclusion about PCPs and nutrition information in practice. From this study and others it can be concluded that there are growing opportunities, challenges, and tools for PCPs to become more actively involved in nutrition guidance of patients.


Biology and treatment of chronic lymphocytic leukemia.
Major advances have occurred in our understanding of the biology, immunology, and opportunities for treatment of chronic lymphocytic leukemia (CLL) in recent times. Surface antigen analysis has helped us define classical CLL and differentiate it from variants such as marginal zone leukemia, mantle cell leukemia, and prolymphocytic leukemia. An important observation has been that the B-cells in indolent types of CLL, which do not require therapy, have undergone somatic hypermutation and function as memory B-lymphocytes whereas those more likely to progress have not undergone this process. Section I by Dr. Nicholas Chiorazzi encompasses emerging elements of the new biology of CLL and will address the types of somatic hypermutation that occur in CLL cells and their correlation with other parameters such as telomere length and ZAP70 status. In addition he addresses the concept of which cells are proliferating in CLL and how we can quantitate the proliferative thrust using novel methods. The interaction between these parameters is also explored. Section II by Dr. Thomas Kipps focuses on immune biology and immunotherapy of CLL and discusses new animal models in CLL, which can be exploited to increase understanding of the disease and create new opportunities for testing the interaction of the CLL cells with a variety of elements of the immune system. It is obvious that immunotherapy is emerging as a major therapeutic modality in chronic lymphocytic leukemia. Dr. Kipps addresses the present understanding of the immune status of CLL and the role of passive immunotherapy with monoclonal antibodies such as rituximab, alemtuzumab, and emerging new antibodies. In addition the interaction between the CLL cells and the immune system, which has been exploited in gene therapy with transfection of CLL cells by CD40 ligand, is discussed. In Section III, Dr. Michael Keating examines the question "Do we have the tools to cure CLL?" and focuses on the fact that we now have three distinct modalities, which are able to achieve high quality remissions with polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain in CLL. These modalities include initial chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, the use of alemtuzumab for marrow cytoreduction in minimal residual disease and allogeneic bone marrow transplants. The emergence of non-ablative marrow transplants in CLL has led to the broadening of the range of opportunities to treat older patients. The addition of rituximab to the chemotherapy preparative regimens appears to be a significant advance. The combination of our increased understanding of the biology, immune status, and therapy of CLL provides for the first time the opportunity for curative strategies.