Evaluation of the rearfoot component (module 3) of the ACFAS scoring scale.
The American College of Foot and Ankle Surgeons (ACFAS) scoring scale modules 3 and 4 have not been validated or tested against other validated instruments widely used in medical and surgical research and practice. The purpose of the present study was to evaluate the rearfoot component (module 3) of the ACFAS scoring system by assessing its correlation against well-established instruments. A modified ACFAS scale (mACFAS), Medical Outcomes Study 36-item short form (SF-36), version 2 (SF-36v2), and the short form of the International Physical Activity Questionnaire (IPAQ) were administered to subjects enrolled in our ongoing longitudinal cohort flatfoot study. Eighty-six patients were evaluated. The mACFAS correlated moderately to highly with the SF-36v2 physical component score and moderately with the mental component score and IPAQ. When divided into higher arched, lower arched, and rectus foot groups, the mACFAS correlated more strongly with the SF-36v2 and correlated with the IPAQ in the lower arched population. The results of the present study are promising for the rearfoot component of the ACFAS scoring scale, especially in the evaluation of the lower arched foot type. Future research should evaluate the disease- and symptom-specific validity, responsiveness, and reproducibility of the mACFAS.


Epigenome-wide DNA methylation analysis implicates neuronal and inflammatory signaling pathways in adult murine hepatic tumorigenesis following perinatal exposure to bisphenol A.
Developmental exposure to the endocrine-active compound bisphenol A (BPA) has been linked to epigenotoxic and potential carcinogenic effects in rodent liver, prostate, and mammary glands. A dose-dependent increase in hepatic tumors in 10-month mice perinatally exposed to one of three doses of BPA (50 ng, 50 µg, or 50 mg BPA/kg chow) was previously reported. These tumors represent early-onset disease and lack classical sexual dimorphism in incidence. Here, adult epigenome-wide liver DNA methylation profiles to identify gene promoters associated with perinatal BPA exposure and disease in 10-month mice with and without liver tumors were investigated. Mice with hepatic tumors showed 12,822 (1.8%) probes with differential methylation as compared with non-tumor animals, of which 8,656 (67.5%) were hypomethylated. A significant enrichment of differential methylation in Gene Ontology (GO) terms and biological processes related to morphogenesis and development, and epigenomic alteration were observed. Pathway enrichment revealed a predominance of hypermethylated neuronal signaling pathways linked to energy regulation and metabolic function, supporting metabolic consequences in the liver via BPA-induced disruption of neuronal signaling pathways. Hypothesis-driven pathway analysis revealed mouse and human genes linked to BPA exposure related to intracellular Jak/STAT and MAPK signaling pathways. Taken together, these findings are indicators of the relevance of the hepatic tumor phenotype seen in BPA-exposed mice to human health. This work demonstrated that epigenome-wide discovery experiments in animal models were effective tools for identification and understanding of paralagous epimutations salient to human disease. Environ. Mol. Mutagen. 57:435-446, 2016. © 2016 Wiley Periodicals, Inc.


A New Algorithm and Theory for Penalized Regression-based Clustering.
Clustering is unsupervised and exploratory in nature. Yet, it can be performed through penalized regression with grouping pursuit, as demonstrated in Pan et al. (2013). In this paper, we develop a more efficient algorithm for scalable computation and a new theory of clustering consistency for the method. This algorithm, called DC-ADMM, combines difference of convex (DC) programming with the alternating direction method of multipliers (ADMM). This algorithm is shown to be more computationally efficient than the quadratic penalty based algorithm of Pan et al. (2013) because of the former's closed-form updating formulas. Numerically, we compare the DC-ADMM algorithm with the quadratic penalty algorithm to demonstrate its utility and scalability. Theoretically, we establish a finite-sample mis-clustering error bound for penalized regression based clustering with the L 0 constrained regularization in a general setting. On this ground, we provide conditions for clustering consistency of the penalized clustering method. As an end product, we put R package prclust implementing PRclust with various loss and grouping penalty functions available on GitHub and CRAN.


In vitro induction of benzo(a)pyrene diol epoxide-DNA adducts in peripheral lymphocytes as a susceptibility marker for human lung cancer.
Given the same exposure, DNA adduct profiles can be considered as a phenotypic marker for carcinogen metabolism and DNA repair, which may reflect individual susceptibility to chemical carcinogenesis. Based on this notion, we have established a straightforward assay that measures induced DNA adducts in peripheral lymphocytes exposed in vitro to a model carcinogen, benzo(a)pyrene diol epoxide (BPDE) by 32P-postlabeling. To test the hypothesis that the levels of induced DNA adducts are a predictor for cancer risk, we conducted a pilot study of 21 lung cancer patients and 41 healthy frequency-matched controls. We found that the peripheral lymphocytes of cancer patients tended to accumulate higher levels of BPDE-DNA adducts than controls did (mean +/- SE of relative adduct labeling x 10(7) value; 59.6 +/- 12.0 versus 39.4 +/- 6.1 for cases and controls, respectively; P = 0.09). Using the tertile relative adduct labeling value of controls (10 adducts/10(7) nucleotides) as the cutoff point, 18 of 21 cases and 23 of 41 controls distributed above this level (odds ratio, 4.7; 95% confidence interval, 1.2-18.5). In logistic regression analysis, the level of induced adduct was an independent risk factor (odds ratio, 6.4; 95% confidence interval, 1.3-29.4) after adjustment for the potential confounding factors, i.e., age, sex, ethnicity, and smoking. Stratified analyses showed that greater differences in DNA adduct levels induced by BPDE between cases and controls were observed in individuals younger than 65 years and in nonsmokers. Despite the small sample size, the significant association between the level of BPDE-induced DNA adducts and risk for lung cancer suggests that this assay is a promising method for further investigations.


Evaluation of Equivalent Flexural Strength for Complete Removable Dentures Made of Zirconia-Impregnated PMMA Nanocomposites.
High-impact (HI) polymethyl methacrylate (PMMA), obtained from modification of conventional PMMA, is commonly used in prosthodontics as a denture base material for improved impact resistance. However, it suffers from poor flexural strength properties. The aim of this study was to investigate the flexural strength of complete removable dentures made of HI heat-polymerised PMMA resin reinforced with zirconia nanoparticles at two different concentrations. The effect of fatigue loading on the flexural strength behaviour of the dentures was also investigated. A total of 30 denture specimens were fabricated from PMMA with different concentrations of zirconia nanoparticles: 0 (control), 3, and 5 wt.%. Ten specimens in each group were divided into two subgroups, with five specimens in each, to conduct both flexural strength and fatigue loading test of each of the subgroups. Fatigue loading was applied on the dentures using a mastication simulator and equivalent flexural strength was calculated with data from bending tests with and without fatigue cyclic loading. One-way analysis of variance (ANOVA) of the test data was conducted with the Bonferroni significant difference post-hoc test at a preset alpha value of 0.05. Paired t-test was employed to identify any difference between the specimens with and without the application of fatigue loading. The fractured surface of the denture specimens was examined with a scanning electron microscope (SEM). The bending tests demonstrated that the mean equivalent flexural strength of reinforced HI PMMA denture specimens with 5 wt.% zirconia nanoparticles increased significantly (134.9 ± 13.9 MPa) compared to the control group (0 wt.%) (106.3 ± 21.3 MPa) without any fatigue loading. The mean strength of the dentures with PMMA +3 wt.% zirconia also increased, but not significantly. Although the mean strength of all specimen groups subjected to fatigue loading slightly decreased compared to that of the specimen groups without any fatigue cyclic loading, this was not statistically significant. Denture specimens made of HI heat-polymerised PMMA reinforced with 5 wt.% zirconia nanoparticles had significantly improved equivalent flexural strength compared to that made of pure PMMA when the specimens were not subjected to any prior fatigue cyclic loading. In addition, the application of fatigue cyclic loading did not significantly improve the equivalent flexural strengths of all denture specimen groups. Within the limitations of this study, it can be concluded that the use of zirconia-impregnated PMMA in the manufacture of dentures does not result in any significant improvement for clinical application.


A pilot study to validate modification of the Duke University Severity of Illness scale to measure a family's burden of illness.
Measurement of burden of illness is rarely undertaken in general practice, although a specific tool [Duke University Severity of Illness DUSOI scale] has been incorporated in the International Classification in Primary Care. This measures the burden of illness in an individual at a point in time. There has not been any measure of the burden of illness in families. Such an instrument would allow measurement of the impact of events on the health of families. This pilot study aimed to modify the DUSOI to measure a family's burden of illness and to validate any changes. The DUSOI was modified to measure the mean burden of illness in a family over a 1 year period. The changes were then subject to a validation process using convenient samples of patients from the author's multidoctor practice in Australia. Reliability was examined by the test-re-test method. Inter-rater reliability could not be assessed. Responsiveness was measured by measuring changes in score in the years before and after four events: counselling for a minor mental health problem; referral to a psychiatrist; diagnosis and treatment of breast cancer; and the occurrence of an acute myocardial infarction. The modifications made to the DUSOI have not altered the face or content validity of the original instrument. Construct validity and test-re-test reliability were satisfactory. Inter-rater reliability was not tested, but the original single patient score showed levels lower than are desirable. Responsiveness varied significantly. Families where a member was referred to a psychiatrist showed a decrease in burden after referral, while families where a member suffered an infarct showed a large increase. The other family groups did not show any change. A Family DUSOI will be of value in research when validated for individual conditions.


Interstitial pneumonia induced by bleomycin treatment is exacerbated in Angptl2-deficient mice.
Angiopoietin-like protein 2 (ANGPTL2) is a chronic inflammatory mediator that, when deregulated, is associated with various pathologies. However, little is known about its activity in lung. To assess a possible lung function, we generated a rabbit monoclonal antibody that specifically recognizes mouse ANGPTL2 and then evaluated protein expression in mouse lung tissue. We observed abundant ANGPTL2 expression in both alveolar epithelial type I and type II cells and in resident alveolar macrophages under normal conditions. To assess ANGPTL2 function, we compared lung phenotypes in Angptl2 knockout (KO) and wild-type mice but observed no overt changes. We then generated a bleomycin-induced interstitial pneumonia model using wild-type and Angptl2 KO mice. Bleomycin-treated wild-type mice showed specifically upregulated ANGPTL2 expression in areas of severe fibrosing interstitial pneumonia, while Angptl2 KO mice developed more severe lung fibrosis than did comparably treated wild-type mice. Lung fibrosis seen following bone marrow transplant was comparable in wild-type or Angptl2 KO mice treated with bleomycin, suggesting that Angptl2 loss in myeloid cells does not underlie fibrotic phenotypes. We conclude that Angptl2 deficiency in lung epithelial cells and resident alveolar macrophages causes severe lung fibrosis seen following bleomycin treatment, suggesting that ANGPTL2 derived from these cell types plays a protective role against fibrosis in lung.


Follicular lymphoma (FL): Immunological tolerance theory in FL.
The ultimate cause of follicular lymphoma (FL) remains unknown. Remarkably, almost nothing is known about immunological tolerance mechanisms that might contribute to FL development. Immunological tolerance mechanisms, like other stimuli, also induce persistent changes of B cell receptors that induce genetic instability and molecular aberrations promoting the development of a neoplasm. Using the same method as Burnet, we provide a new perspective taking advantage of the comparison of a normal linear B cell differentiation process and FL development within the framework of clonal selection theory. We propose that FL is a malignancy of cells that acquire both translocation t(14;18) and self-BCR, inducing them to proliferate and mature, resistant to negative selection. Additional genetic damage induced by non-apoptotic tolerance mechanisms, such as receptor editing, may transform a self-reactive B cell with t(14;18) into an FL. The result of tolerogenic mechanisms and genetic aberrations is the survival of FL B cell clones with similar markers and homogenous gene expression signatures despite the different stages of maturation at which the molecular damage occurs. To antagonize further growth advantage due to self-antigen recognition and chronic activation of tolerance mechanisms in the apoptosis-resistant background of FL B cells, inhibitors of BCR signaling may be promising therapeutic options.


Robust stereo matching using adaptive normalized cross-correlation.
A majority of the existing stereo matching algorithms assume that the corresponding color values are similar to each other. However, it is not so in practice as image color values are often affected by various radiometric factors such as illumination direction, illuminant color, and imaging device changes. For this reason, the raw color recorded by a camera should not be relied on completely, and the assumption of color consistency does not hold good between stereo images in real scenes. Therefore, the performance of most conventional stereo matching algorithms can be severely degraded under the radiometric variations. In this paper, we present a new stereo matching measure that is insensitive to radiometric variations between left and right images. Unlike most stereo matching measures, we use the color formation model explicitly in our framework and propose a new measure, called the Adaptive Normalized Cross-Correlation (ANCC), for a robust and accurate correspondence measure. The advantage of our method is that it is robust to lighting geometry, illuminant color, and camera parameter changes between left and right images, and does not suffer from the fattening effect unlike conventional Normalized Cross-Correlation (NCC). Experimental results show that our method outperforms other state-of-the-art stereo methods under severely different radiometric conditions between stereo images.


Nucleotide sequence of the thrB gene of E. coli, and its two adjacent regions; the thrAB and thrBC junctions.
We have sequenced a DNA fragment containing the Escherichia coli thrA-thrB junction, the complete thrB gene and the thrB-thrC junction. The intergenic sequence thrA and thrB is only one base pair. The coding region for homoserine kinase is 927 base pairs long. It is followed by 114 base pair segment in an open reading frame predicting that thrC begins just after non-sense codon of thrB. The presence at the end of thrA and of thrB of sequences that can pair with the 3' end of the 16 S ribosomal RNA suggests that reinitiation of translation occurs at the end of the two genes. The deduced aminoacid sequence for homoserine kinase shows no striking homology with aspartokinase I homoserine dehydrogenase I.


Relative brain displacement and deformation during constrained mild frontal head impact.
This study describes the measurement of fields of relative displacement between the brain and the skull in vivo by tagged magnetic resonance imaging and digital image analysis. Motion of the brain relative to the skull occurs during normal activity, but if the head undergoes high accelerations, the resulting large and rapid deformation of neuronal and axonal tissue can lead to long-term disability or death. Mathematical modelling and computer simulation of acceleration-induced traumatic brain injury promise to illuminate the mechanisms of axonal and neuronal pathology, but numerical studies require knowledge of boundary conditions at the brain-skull interface, material properties and experimental data for validation. The current study provides a dense set of displacement measurements in the human brain during mild frontal skull impact constrained to the sagittal plane. Although head motion is dominated by translation, these data show that the brain rotates relative to the skull. For these mild events, characterized by linear decelerations near 1.5g (g = 9.81 m s⁻²) and angular accelerations of 120-140 rad s⁻², relative brain-skull displacements of 2-3 mm are typical; regions of smaller displacements reflect the tethering effects of brain-skull connections. Strain fields exhibit significant areas with maximal principal strains of 5 per cent or greater. These displacement and strain fields illuminate the skull-brain boundary conditions, and can be used to validate simulations of brain biomechanics.


Reconstructing the TIR Side of the Myddosome: a Paradigm for TIR-TIR Interactions.
Members of the Toll-like receptor and interleukin-1 (IL-1) receptor families all signal via Toll/IL-1R (TIR) domain-driven assemblies with adaptors such as MyD88. We here combine the mammalian two-hybrid system MAPPIT and saturation mutagenesis to complement and extend crystallographic and nuclear magnetic resonance data, and reveal how TIR domains interact. We fully delineate the interaction sites on the MyD88 TIR domain for homo-oligomerization and for interaction with Mal and TLR4. Interactions between three sites drive MyD88 homo-oligomerization. The BB-loop interacts with the αE-helix, explaining how BB-loop mimetics inhibit MyD88 signaling. The αC'-helix interacts symmetrically. The MyD88 TIR domains thus assemble into a left-handed helix, compatible with the Myddosome death domain crystal structure. This assembly explains activation of MyD88 by Mal and by an oncogenic mutation, and regulation by phosphorylation. These findings provide a paradigm for the interaction of mammalian TIR domains.


On the multi-reference nature of plutonium oxides: PuO22+, PuO2, PuO3 and PuO2(OH)2.
Actinide-containing complexes present formidable challenges for electronic structure methods due to the large number of degenerate or quasi-degenerate electronic states arising from partially occupied 5f and 6d shells. Conventional multi-reference methods can treat active spaces that are often at the upper limit of what is required for a proper treatment of species with complex electronic structures, leaving no room for verifying their suitability. In this work we address the issue of properly defining the active spaces in such calculations, and introduce a protocol to determine optimal active spaces based on the use of the Density Matrix Renormalization Group algorithm and concepts of quantum information theory. We apply the protocol to elucidate the electronic structure and bonding mechanism of volatile plutonium oxides (PuO3 and PuO2(OH)2), species associated with nuclear safety issues for which little is known about the electronic structure and energetics. We show how, within a scalar relativistic framework, orbital-pair correlations can be used to guide the definition of optimal active spaces which provide an accurate description of static/non-dynamic electron correlation, as well as to analyse the chemical bonding beyond a simple orbital model. From this bonding analysis we are able to show that the addition of oxo- or hydroxo-groups to the plutonium dioxide species considerably changes the π-bonding mechanism with respect to the bare triatomics, resulting in bent structures with a considerable multi-reference character.


Reversal of cognitive decline in Alzheimer's disease.
Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published [1]. The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4-, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer's disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.


Molecular basis of the light-driven switching of the photochromic fluorescent protein Padron.
Reversibly switchable fluorescent proteins can be repeatedly photoswitched between a fluorescent and a nonfluorescent state by irradiation with the light of two different wavelengths. The molecular basis of the switching process remains a controversial topic. Padron0.9 is a reversibly switchable fluorescent protein with "positive" switching characteristics, exhibiting excellent spectroscopic properties. Its chromophore is formed by the amino acids Cys-Tyr-Gly. We obtained high resolution x-ray structures of Padron0.9 in both the fluorescent and the nonfluorescent states and used the structural information for molecular dynamics simulations. We found that in Padron0.9 the chromophore undergoes a cis-trans isomerization upon photoswitching. The molecular dynamics simulations clarified the protonation states of the amino acid residues within the chromophore pocket that influence the protonation state of the chromophore. We conclude that a light driven cis-trans isomerization of the chromophore appears to be the fundamental switching mechanism in all photochromic fluorescent proteins known to date. Distinct absorption cross-sections for the switching wavelengths in the fluorescent and the nonfluorescent state are not essential for efficient photochromism in fluorescent proteins, although they may facilitate the switching process.


Depression in children and adolescents.
Depression may affect 2-8% of children and adolescents, with a peak incidence around puberty. It may be self-limiting, but about 40% of affected children experience a recurrent attack, a third of affected children will make a suicide attempt, and 3-4% will die from suicide. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmacological, psychological, combination, and complementary treatments for depression in children and adolescents? What are the effects of treatments for refractory depression in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: citalopram, cognitive behavioural therapy (CBT) (individual or group, to prevent relapse), escitalopram, electroconvulsive therapy, family therapy, fluoxetine (alone or with cognitive therapy or CBT), fluvoxamine, group therapeutic support (other than CBT), guided self-help, individual psychodynamic psychotherapy, interpersonal therapy, lithium, mirtazapine, monoamine oxidase inhibitors (MAOIs), omega-3 polyunsaturated fatty acids, paroxetine, sertraline (alone or with CBT), St John's Wort (Hypericum perforatum), tricyclic antidepressants, and venlafaxine.


Hereditary spherocytosis: Retrospective evaluation of 65 children.
Güngör A, Yaralı N, Fettah A, Ok-Bozkaya İ, Özbek N, Kara A. Hereditary spherocytosis: Retrospective evaluation of 65 children. Turk J Pediatr 2018; 60: 264-269. Hereditary spherocytosis (HS) is a common cause of congenital hemolytic anemia in Caucasians and it could be diagnosed at any age. The aim of this study is to examine the demographic characteristics, clinical features and laboratory findings of children with HS and their complications observed during follow up. Sixty-five patients, with hereditary spherocytosis between January 2008 and September 2013, were enrolled into this retrospective study. The age of patients at the time of diagnosis varied between 15 days and 17 years. The median age of patients at diagnosis was 48 months (IQR 2-78). The female/male ratio was 1.1. Forty-seven patients (72.3%) had a family history of HS. The patients were classified according to laboratory findings: 13 of them (20%) were diagnosed as mild HS, 36 (55.4%) as moderate HS and of 16 (24.6%) as severe HS. During follow-up, nine patients (13.8%) experienced an aplastic crisis. Megaloblastic crisis was not observed in any patient. Twenty patients (30.8%) had cholelithiasis. Splenectomy was performed in 20% of patients and the mean age for splenectomy was 8.3 years. Complications such as sepsis or thrombosis were not detected after splenectomy. Hereditary spherocytosis should be kept in mind in patients with anemia, jaundice and splenomegaly and the family history must be questioned. The most common complication was gallstone; even patients without severe hemolysis should be followed intermittently by abdominal ultrasonography in order to control the development of gallstone.


Sensitivity analysis on parameters and processes affecting vapor intrusion risk.
A one-dimensional numerical model was developed and used to identify the key processes controlling vapor intrusion risks by means of a sensitivity analysis. The model simulates the fate of a dissolved volatile organic compound present below the ventilated crawl space of a house. In contrast to the vast majority of previous studies, this model accounts for vertical variation of soil water saturation and includes aerobic biodegradation. The attenuation factor (ratio between concentration in the crawl space and source concentration) and the characteristic time to approach maximum concentrations were calculated and compared for a variety of scenarios. These concepts allow an understanding of controlling mechanisms and aid in the identification of critical parameters to be collected for field situations. The relative distance of the source to the nearest gas-filled pores of the unsaturated zone is the most critical parameter because diffusive contaminant transport is significantly slower in water-filled pores than in gas-filled pores. Therefore, attenuation factors decrease and characteristic times increase with increasing relative distance of the contaminant dissolved source to the nearest gas diffusion front. Aerobic biodegradation may decrease the attenuation factor by up to three orders of magnitude. Moreover, the occurrence of water table oscillations is of importance. Dynamic processes leading to a retreating water table increase the attenuation factor by two orders of magnitude because of the enhanced gas phase diffusion.


Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis.
Inactivation of the tumor suppressor gene PTEN and overexpression of VEGF are two of the most common events observed in high-grade malignant gliomas. The purpose of this study was to determine whether PTEN controls VEGF expression in gliomas under normoxic conditions. Transfer of PTEN to human glioma cells resulted in the transduction of a functional PTEN protein as evidenced by the upregulation of p27 and modification of the phosphorylation status of Akt. Under normoxic conditions, enzyme-linked immunosorbent assay and Northern blot analyses showed downregulation of VEGF in PTEN-treated cells. Moreover, conditioned media from PTEN-treated glioma cells significantly diminished the ability of endothelial cells to grow and migrate. Western blot assays demonstrated that, in a normoxic environment, PTEN downregulates HIF-1 alpha. Finally, promoter activity assays showed that the VEGF promoter region containing the HIF-1alpha binding site is necessary and sufficient for PTEN-mediated downregulation of VEGF. Experiments with PI3-K inhibitors and kinase assays suggested that PI3-K is mediating the effect of PTEN on VEGF, and not the p42/p48 or p38 MAP kinases. These results indicate that restoration of PTEN function in gliomas may induce therapeutic effect by downregulating VEGF. Furthermore, this close functional relationship between PTEN and VEGF suggests that a better understanding of the transduction signal regulated by PTEN might enhance the knowledge of the cause and physiology of vascular and inflammatory diseases.


Certificate of need legislation and the dissemination of robotic surgery for prostate cancer.
The uncertainty about the incremental benefit of robotic prostatectomy and its higher associated costs makes it an ideal target for state based certificate of need laws, which have been enacted in several states. We studied the relationship between certificate of need laws and market level adoption of robotic prostatectomy. We used SEER (Surveillance, Epidemiology, and End Results)-Medicare data from 2003 through 2007 to identify men 66 years old or older treated with prostatectomy for prostate cancer. Using data from the American Health Planning Association, we categorized Health Service Areas according to the stringency of certificate of need regulations (ie low vs high stringency) presiding over that market. We assessed our outcomes (probability of adopting robotic prostatectomy and propensity for robotic prostatectomy use in adopting Health Service Areas) using Cox proportional hazards and Poisson regression models, respectively. Compared to low stringency markets, high stringency markets were more racially diverse (54% vs 15% nonwhite, p <0.01), and had similar population densities (886 vs 861 people per square mile, p = 0.97) and median incomes ($42,344 vs $39,770, p = 0.56). In general, both market types had an increase in the adoption and utilization of robotic prostatectomy. However, the probability of robotic prostatectomy adoption (p = 0.22) did not differ based on a market's certificate of need stringency and use was lower in high stringency markets (p <0.01). State based certificate of need regulations were ineffective in constraining robotic surgery adoption. Despite decreased use in high stringency markets, similar adoption rates suggest that other factors impact the diffusion of robotic prostatectomy.


How processing digital elevation models can affect simulated water budgets.
For regional models, the shallow water table surface is often used as a source/sink boundary condition, as model grid scale precludes simulation of the water table aquifer. This approach is appropriate when the water table surface is relatively stationary. Since water table surface maps are not readily available, the elevation of the water table used in model cells is estimated via a two-step process. First, a regression equation is developed using existing land and water table elevations from wells in the area. This equation is then used to predict the water table surface for each model cell using land surface elevation available from digital elevation models (DEM). Two methods of processing DEM for estimating the land surface for each cell are commonly used (value nearest the cell centroid or mean value in the cell). This article demonstrates how these two methods of DEM processing can affect the simulated water budget. For the example presented, approximately 20% more total flow through the aquifer system is simulated if the centroid value rather than the mean value is used. This is due to the one-third greater average ground water gradients associated with the centroid value than the mean value. The results will vary depending on the particular model area topography and cell size. The use of the mean DEM value in each model cell will result in a more conservative water budget and is more appropriate because the model cell water table value should be representative of the entire cell area, not the centroid of the model cell.


Chest wall reconstruction using iliac bone allografts and muscle flaps.
Technically we can divide full-thickness thoracic reconstruction into 2 parts: providing a rigid support and ensuring well-vascularized coverage. Since 1986, the authors' center has had ample experience with bone banks and the use of cryopreserved bone grafts, which led them to consider the possibility of using these grafts for full-thickness chest wall reconstruction. They describe 3 patients in whom resection of the tumor and reconstruction of the thorax were carried out using iliac bone allografts covered with muscle flaps (1 pectoralis major and 2 rectus abdominis). None of the patients experienced breathing difficulties, pain, or instability after 14 months, 18 months, and 11 years of follow-up. The result of the reconstruction was excellent in all 3 patients in terms of function and aesthetics. The advantage of allografts compared with synthetic materials is their potential integration; they can become part of the host patient's living tissue.


Nuclear factor-kappa B localization and function within intrauterine tissues from term and preterm labor and cultured fetal membranes.
The objective of this study was to quantify the nuclear localization and DNA binding activity of p65, the major transactivating nuclear factor-kappa B (NF-kappaB) subunit, in full-thickness fetal membranes (FM) and myometrium in the absence or presence of term or preterm labor. Paired full-thickness FM and myometrial samples were collected from women in the following cohorts: preterm no labor (PNL, N = 22), spontaneous preterm labor (PTL, N = 21), term no labor (TNL, N = 23), and spontaneous term labor (STL, N = 21). NF-kappaB p65 localization was assessed by immunohistochemistry, and DNA binding activity was evaluated using an enzyme-linked immunosorbent assay (ELISA)-based method. Nuclear p65 labeling was rare in amnion and chorion, irrespective of clinical context. In decidua, nuclear p65 labeling was greater in the STL group relative to the TNL cohort, but there were no differences among the TNL, PTL, and PNL cohorts. In myometrium, diffuse p65 nuclear labeling was significantly associated with both term and preterm labor. There were no significant differences in ELISA-based p65 binding activity in amnion, choriodecidual, and myometrial specimens in the absence or presence of term labor. However, parallel experiments using cultured term fetal membranes demonstrated high levels of p65-like binding even the absence of cytokine stimulation, suggesting that this assay may be of limited value when applied to tissue specimens. These results suggest that the decidua is an important site of NF-kappaB regulation in fetal membranes, and that mechanisms other than cytoplasmic sequestration may limit NF-kappaB activation prior to term.


Prospective randomised non-inferiority trial of pelvic drain placement vs no pelvic drain placement after robot-assisted radical prostatectomy.
To determine if eliminating the prophylactic placement of a pelvic drain (PD) after robot-assisted radical prostatectomy (RARP) affects the incidence of early (90-day) postoperative adverse events. In this parallel-group, blinded, non-inferiority trial, we randomised patients planning to undergo RARP to one of two arms: no drain placement (ND) or PD placement. Patients with demonstrable intraoperative leakage upon bladder irrigation were excluded. Randomisation sequence was determined a priori using a computer algorithm, and included a stratified design with respect to low vs intermediate/high D'Amico risk classifications. Surgeons remained blinded to the randomisation arm until final eligibility was verified at the end of the RARP. The primary endpoint was overall incidence of 90-day complications which, based on our standard treatment using PD retrospectively, was estimated at 13%. The non-inferiority margin was set at 10%, and the planned sample size was 312. An interim analysis was planned and conducted when one-third of the planned accrual and follow-up was completed, to rule out futility if the delta margin was in excess of 0.1389. From 2012 to 2016, 189 patients were accrued to the study, with 92 patients allocated to the ND group and 97 to the PD group. Due to lower than expected accrual rates, accrual to the study was halted by regulatory entities, and we did not reach the intended accrual goal. The ND and PD groups were comparable for median PSA level (6.2 vs 5.8 ng/mL, P = 0.5), clinical stage (P = 0.8), D'Amico risk classification (P = 0.4), median lymph nodes dissected (17 vs 18, P = 0.2), and proportion of patients receiving an extended pelvic lymph node dissection (70.7% vs 79.4%, P = 0.3). Incidence of 90-day overall and major (Clavien-Dindo grade >III) complications in the ND group (17.4% and 5.4%, respectively) was not inferior to the PD group (26.8% and 5.2%, respectively; P < 0.001 and P = 0.007 for difference of proportions <10%, respectively). Symptomatic lymphocoele rates (2.2% in the ND group, 4.1% in the PD group) were comparable between the two arms (P = 0.7). Incidence of adverse events in the ND group was not inferior to the group who received a PD. In properly selected patients, PD placement after RARP can be safely withheld without significant additional morbidity.


A controlled trial of acute effects of human exposure to traffic particles on pulmonary oxidative stress and heart rate variability.
For many individuals, daily commuting activities on roadways account for a substantial proportion of total exposure, as well as peak-level exposures, to traffic-related air pollutants (TRAPS) including ultrafine particles, but the health impacts of these exposures are not well-understood. We sought to determine if exposure to TRAPs particles during commuting causes acute oxidative stress in the respiratory tract or changes in heart rate variability (HRV), a measure of autonomic activity. We conducted a randomized, cross-over trial in which twenty-one young adults took two 1.5-hr rides in a passenger vehicle in morning rush-hour traffic. The subjects wore a powered-air-purifying respirator, and were blinded to high-efficiency particulate air (HEPA) filtration during one of the rides. At time points before and after the rides, we measured HRV and markers of oxidative stress in exhaled breath condensate (EBC) including nitrite, the sum of nitrite and nitrate, malondialdehyde, and 8-isoprostane. We used mixed linear models to evaluate the effect of exposure on EBC and HRV outcomes, adjusting for pre-exposure response levels. We used linear models to examine the effects of particle concentrations on EBC outcomes at post-exposure time points. Mean EBC nitrite and the sum of nitrite and nitrate were increased from baseline at immediately post-exposure comparing unfiltered to filtered rides (2.11 μM vs 1.70 μM, p = 0.02 and 19.1 μM vs 10.0 μM, p = 0.02, respectively). Mean EBC malondialdehyde (MDA) concentrations were about 10% greater following the unfiltered vs. filtered exposures, although this result was not statistically significant. We found no significant associations between exposure to traffic particles and HRV outcomes at any of the time points. At immediately post-exposure, an interquartile range increase in particle number concentration was associated with statistically significant increases in nitrite (99.4%, 95% CI 32.1% to 166.7%) and nitrite + nitrate (75.7%, 95% CI 21.5% to 130.0%). Increases in markers of oxidative stress in EBC may represent early biological responses to widespread exposures to TRAPs particles that affect passengers in vehicles on heavily trafficked roadways.


Contrasting effects of calcium channel blockade versus converting enzyme inhibition on proteinuria in African Americans with non-insulin-dependent diabetes mellitus and nephropathy.
Hypertension is a common finding in non-insulin-dependent diabetes mellitus (NIDDM) nephropathy. African Americans have a high prevalence of NIDDM and hypertension, and are relatively resistant to the antihypertensive effects of converting enzyme inhibitors (CEI) but respond well to calcium channel blockers (CCB). In the long-term study presented here, the effects of isradipine, a dihydropyridine calcium antagonist, on the course of the nephropathy were investigated and compared with the effects of captopril in 31 African Americans with NIDDM and proteinuria (> or = 500 mg/day). The patients were stratified by levels of GFR and proteinuria, and they were randomized to receive isradipine (N = 16) or captopril (N = 15); doses were adjusted to maintain similar BP levels (< 140/90). At 6 months, mean arterial pressure was similar (102 +/- 3 and 104 +/- 3 mm Hg in the isradipine and captopril groups, respectively) and GFR was unchanged (delta = -4 +/- 3 and +1 +/- 3 ml/min/1.73 in the isradipine and captopril groups, respectively; P = NS). However, proteinuria in the isradipine group increased by approximately 50% (2.01 +/- 0.40 versus 3.04 +/- 0.70 mg/mg creatinine at baseline versus 6 months, respectively, P < 0.05), whereas captopril reduced proteinuria by 30% after 6 months (2.85 +/- 0.70 at baseline versus 2.30 +/- 0.70 mg/mg creatinine, P < 0.05). Dietary protein, sodium intake, and HbA1C levels were similar in both groups and did not differ from baseline. It was concluded that over 6 months, captopril reduces and isradipine increases proteinuria in African Americans with NIDDM and nephropathy. Whether this contrasting effect on proteinuria will result in different rates of progression is not known, but dihydropyridine CCB should be used cautiously in African Americans with diabetic nephropathy.


Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling.
Cardiomyocytes contract against a mechanical load during each heartbeat, and excessive mechanical stress leads to heart diseases. Using a cell-in-gel system that imposes an afterload during cardiomyocyte contraction, we found that nitric oxide synthase (NOS) was involved in transducing mechanical load to alter Ca(2+) dynamics. In mouse ventricular myocytes, afterload increased the systolic Ca(2+) transient, which enhanced contractility to counter mechanical load but also caused spontaneous Ca(2+) sparks during diastole that could be arrhythmogenic. The increases in the Ca(2+) transient and sparks were attributable to increased ryanodine receptor (RyR) sensitivity because the amount of Ca2(+) in the sarcoplasmic reticulum load was unchanged. Either pharmacological inhibition or genetic deletion of nNOS (or NOS1), but not of eNOS (or NOS3), prevented afterload-induced Ca2(+) sparks. This differential effect may arise from localized NO signaling, arising from the proximity of nNOS to RyR, as determined by super-resolution imaging. Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) and nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) also contributed to afterload-induced Ca(2+) sparks. Cardiomyocytes from a mouse model of familial hypertrophic cardiomyopathy exhibited enhanced mechanotransduction and frequent arrhythmogenic Ca(2+) sparks. Inhibiting nNOS and CaMKII, but not NOX2, in cardiomyocytes from this model eliminated the Ca2(+) sparks, suggesting mechanotransduction activated nNOS and CaMKII independently from NOX2. Thus, our data identify nNOS, CaMKII, and NOX2 as key mediators in mechanochemotransduction during cardiac contraction, which provides new therapeutic targets for treating mechanical stress-induced Ca(2+) dysregulation, arrhythmias, and cardiomyopathy.


Evaluation of postural stability in children: current theories and assessment tools.
Children with many types of motor dysfunction have problems maintaining postural stability. Because maintenance of postural stability is an integral part of all movements, therapists evaluate and treat to improve postural stability in these children. This article reviews current pediatric assessment tools for postural stability and issues affecting testing this construct in children. The tests and measurements are classified according to their testing purpose and the National Center for Medical Rehabilitation Research disablement framework, focusing on the impairment and functional limitation dimensions. Postural stability is defined from a systems perspective with tests related to the sensory, motor, and biomechanical systems described. Reliability and validity information on the measurements is discussed. Relatively few measurements of postural stability in children are available that have acceptable reliability and validity documentation. Suggestions for research on test development in this area are discussed.


Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials.
Postmastectomy radiotherapy was shown in previous meta-analyses to reduce the risks of both recurrence and breast cancer mortality in all women with node-positive disease considered together. However, the benefit in women with only one to three positive lymph nodes is uncertain. We aimed to assess the effect of radiotherapy in these women after mastectomy and axillary dissection. We did a meta-analysis of individual data for 8135 women randomly assigned to treatment groups during 1964-86 in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery versus the same surgery but no radiotherapy. Follow-up lasted 10 years for recurrence and to Jan 1, 2009, for mortality. Analyses were stratified by trial, individual follow-up year, age at entry, and pathological nodal status. 3786 women had axillary dissection to at least level II and had zero, one to three, or four or more positive nodes. All were in trials in which radiotherapy included the chest wall, supraclavicular or axillary fossa (or both), and internal mammary chain. For 700 women with axillary dissection and no positive nodes, radiotherapy had no significant effect on locoregional recurrence (two-sided significance level [2p]>0·1), overall recurrence (rate ratio [RR], irradiated vs not, 1·06, 95% CI 0·76-1·48, 2p>0·1), or breast cancer mortality (RR 1·18, 95% CI 0·89-1·55, 2p>0·1). For 1314 women with axillary dissection and one to three positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·68, 95% CI 0·57-0·82, 2p=0·00006), and breast cancer mortality (RR 0·80, 95% CI 0·67-0·95, 2p=0·01). 1133 of these 1314 women were in trials in which systemic therapy (cyclophosphamide, methotrexate, and fluorouracil, or tamoxifen) was given in both trial groups and, for them, radiotherapy again reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·67, 95% CI 0·55-0·82, 2p=0·00009), and breast cancer mortality (RR 0·78, 95% CI 0·64-0·94, 2p=0·01). For 1772 women with axillary dissection and four or more positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·79, 95% CI 0·69-0·90, 2p=0·0003), and breast cancer mortality (RR 0·87, 95% CI 0·77-0·99, 2p=0·04). After mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes in these trials even when systemic therapy was given. For today's women, who in many countries are at lower risk of recurrence, absolute gains might be smaller but proportional gains might be larger because of more effective radiotherapy. Cancer Research UK, British Heart Foundation, UK Medical Research Council.


Maternal smoking during and after pregnancy and lung function in early adulthood: a prospective study.
There is a paucity of evidence about whether exposure to antenatal smoking impacts on offspring's lung function in early adulthood. This study aimed to examine whether (1) in utero exposure to maternal smoking is related to poorer respiratory functioning in early adulthood; (2) the impact of prenatal smoking is independent of postnatal maternal smoking; and (3) the link between prenatal smoking and a young adult's lung function is explained by the child's birth weight, smoking or history of asthma. Data were from a 21-year follow-up of mothers and their children recruited into the Mater-University of Queensland Study of Pregnancy, a longitudinal prebirth cohort. The study is based on 2409 young adults (1185 males and 1224 females) who had prospective data available on respiratory function at 21 years and maternal smoking during and after pregnancy. A Spirobank G spirometer system was used to measure forced vital capacity (FVC), forced expiratory volume in 1 s (FEV(1)) and forced expiratory flow between 25% and 75% of FVC (FEF(25-75)). In utero exposure to maternal smoking was associated with a reduction in FEV(1) and FEF(25-75) in males (regression coefficient, -0.16; 95% CI, -0.30 to -0.02), after accounting for maternal smoking after pregnancy. At least part of the effect of in utero smoking on young adults' lung function was explained by the child's birth weight and subsequent asthma. Adverse effects of antenatal smoking on development of airway growth may persist into early adulthood. Gender differences noted in this longitudinal cohort need to be explored further.


Fatal pneumococcal sepsis eleven years after distal pancreatectomy with splenectomy for pancreatic cancer.
Overwhelming post-splenectomy sepsis is defined as septicaemia and/or meningitis, usually fulminant, occurring days to several years after removal of the spleen. We report a case of a fulminant pneumococcal sepsis with a fatal outcome, occurring 11 years after distal pancreatectomy and splenectomy for pancreatic adenocarcinoma. A 58-year-old woman presented to the emergency room in December 2011 with a 2-day history of mild fever and diarrhea, followed by hypotension, dyspnea, and peripheral cyanosis. Past medical history revealed a left breast quadrantectomy for lobular carcinoma, and distal pancreatectomy with splenectomy for ductal pancreatic adenocarcinoma in October 2000. The patient was not aware of the need for prophylactic antibiotics and vaccination after splenectomy. At admission, blood tests revealed abnormal coagulation screen, abnormal liver and kidney function, and metabolic acidosis. Despite the administration of intravenous fluid, vasopressor agents, antibiotics and mechanical ventilatory support, the patient died for multiorgan failure 7 hours after admission in intensive care unit. Blood culture showed the growth of Streptococcus pneumonia. Necropsy showed multiorgan failure with adrenal necrotic hemorrhage due to pneumococcal septicemia. No recurrence of pancreatic cancer was noted. Overwhelming post-splenectomy sepsis is a well-known fatal complication which can occur in asplenic patients. The role of vaccination and antibiotics in preventing such complication is well-defined, but cases of fatal post-splenectomy sepsis are still reporting, also in vaccinated patients. High index of suspicion must be maintained for any febrile illness in asplenic patients.


Application of adjoint Monte Carlo to accelerate simulations of mono-directional beams in treatment planning for boron neutron capture therapy.
This paper deals with the application of the adjoint transport theory in order to optimize Monte Carlo based radiotherapy treatment planning. The technique is applied to Boron Neutron Capture Therapy where most often mixed beams of neutrons and gammas are involved. In normal forward Monte Carlo simulations the particles start at a source and lose energy as they travel towards the region of interest, i.e., the designated point of detection. Conversely, with adjoint Monte Carlo simulations, the so-called adjoint particles start at the region of interest and gain energy as they travel towards the source where they are detected. In this respect, the particles travel backwards and the real source and real detector become the adjoint detector and adjoint source, respectively. At the adjoint detector, an adjoint function is obtained with which numerically the same result, e.g., dose or flux in the tumor, can be derived as with forward Monte Carlo. In many cases, the adjoint method is more efficient and by that is much quicker when, for example, the response in the tumor or organ at risk for many locations and orientations of the treatment beam around the patient is required. However, a problem occurs when the treatment beam is mono-directional as the probability of detecting adjoint Monte Carlo particles traversing the beam exit (detector plane in adjoint mode) in the negative direction of the incident beam is zero. This problem is addressed here and solved first with the use of next event estimators and second with the application of a Legendre expansion technique of the angular adjoint function. In the first approach, adjoint particles are tracked deterministically through a tube to a (adjoint) point detector far away from the geometric model. The adjoint particles will traverse the disk shaped entrance of this tube (the beam exit in the actual geometry) perpendicularly. This method is slow whenever many events are involved that are not contributing to the point detector, e.g., neutrons in a scattering medium. In the second approach, adjoint particles that traverse an adjoint shaped detector plane are used to estimate the Legendre coefficients for expansion of the angular adjoint function. This provides an estimate of the adjoint function for the direction normal to the detector plane. In a realistic head model, as described in this paper, which is surrounded by 1020 mono-directional neutron/gamma beams and from which the best ones are to be selected, the example calculates the neutron and gamma fluxes in ten tumors and ten organs at risk. For small diameter beams (5 cm), and with comparable relative errors, forward Monte Carlo is seen to be 1.5 times faster than the adjoint Monte Carlo techniques. For larger diameter neutron beams (10 and 15 cm), the Legendre technique is found to be 6 and 20 times faster, respectively. In the case of gammas alone, for the 10 and 15 cm diam beams, both adjoint Monte Carlo Legendre and point detector techniques are respectively 2 and 3 times faster than forward Monte Carlo.


An ounce of prevention or a pound of cure: bioeconomic risk analysis of invasive species.
Numbers of non-indigenous species--species introduced from elsewhere - are increasing rapidly worldwide, causing both environmental and economic damage. Rigorous quantitative risk-analysis frameworks, however, for invasive species are lacking. We need to evaluate the risks posed by invasive species and quantify the relative merits of different management strategies (e.g. allocation of resources between prevention and control). We present a quantitative bioeconomic modelling framework to analyse risks from non-indigenous species to economic activity and the environment. The model identifies the optimal allocation of resources to prevention versus control, acceptable invasion risks and consequences of invasion to optimal investments (e.g. labour and capital). We apply the model to zebra mussels (Dreissena polymorpha), and show that society could benefit by spending up to US$324 000 year(-1) to prevent invasions into a single lake with a power plant. By contrast, the US Fish and Wildlife Service spent US$825 000 in 2001 to manage all aquatic invaders in all US lakes. Thus, greater investment in prevention is warranted.


Role of Water in the Puzzling Mechanism of the Final Aromatization Step Promoted by the Human Aromatase Enzyme. Insights from QM/MM MD Simulations.
The enzyme human aromatase (HA) catalyzes the conversion of androgens to estrogens via two hydroxylation reactions and a final unique aromatization step. Despite the great interest of HA as a drug target against breast cancer detailed structural and spectroscopic information on this enzyme became available only in the past few years. As such, the enigmatic mechanism of the final aromatization step is still a matter of debate. Here, we investigated the final step of the HA enzymatic cycle via hybrid quantum-classical (QM/MM) metadynamics and blue-moon ensemble simulations. Our results show that the rate-determining step of the aromatization process is the nucleophilic attack of the distal oxygen of a peroxo-ferric species on the formyl carbon of the enol-19-oxo-androstenedione, which occurs with a free energy barrier (ΔF(#)) of ∼ 16.7 ± 1.9 kcal/mol, in good agreement with experimental data. This reaction is followed by a water mediated 1β-hydrogen abstraction (ΔF(#) = 7.9 ± 0.8 kcal/mol) and by the formation of a hydroxo-ferric moiety. This latter may be finally protonated by a hydrogen delivery channel involving Asp309 and Thr310, both residues pointed out as crucial for HA activity. In the absence of the catalytic water in the active site the substrate does not assume a position suitable to undergo the nucleophilic attack. Our data not only reveal a novel possible mechanism for the aromatization process consistent with some of the spectroscopic and kinetic data available in the literature, complementing current knowledge on the mechanism of this enzyme, but also point out a remarkable influence of the level of theory used on the calculated free energy barriers. The structural information obtained in this study may be used for the rational structure-based drug design of HA inhibitors to be employed in breast cancer therapy.


Diverticulum With Papillae: Does Position of Papilla Affect Technical Success?
The presence of peripapillary diverticulum (PPD) can cause some biliary diseases, especially common bile duct stones, and also, literally, can change the technique of endoscopic retrograde cholangiopancreatography (ERCP) and affect the complication ratio of this procedure. In this study, we investigate the effect of localization and position of the papilla according to the diverticulum on the success of therapeutic ERCP procedures. The study was conducted prospectively in the patients with naive papillae, who underwent ERCP for a period of 16 months. In all patients, the position of papillae according to the diverticulum (the periphery of the diverticulum is thought as the clock circumference, and the position of papillae is defined as the dials of clock), the success rate of biliary cannulation, total procedure time, overall treatment success rate of ERCP, and the complications are investigated. During this period, 222 (18.5%) of the 1205 enrolled patients who underwent ERCP had PPD. Of the patients with PPD, 123 (55.4%) were female and 99 (44.6%) were male, and the median age was 68.9±10.1 years. According to the position of the papilla by the diverticulum, 90 (40.5%) patients have it on 7 o'clock position, 64 (28.8%) patients have on 6 o'clock position, 63 (28.3%) patients have on 5 o'clock position, and 5 (2.3%) patients have on 1 o'clock position. In the cases of the papilla on 1 o'clock position according to the diverticulum, cannulation procedures were found to be more difficult than other patients (P<0.05). The presence of the diverticulum did not affect the success of therapeutic procedures and did not increase the ratio of complications. In the presence of PPD, additional cannulation techniques may be required for the procedure. Particularly, the aid of percutaneous techniques may be needed for the papilla on 1 o'clock position.


Effect of occupational noise on the course and outcome of pregnancy.
The goal of this investigation was to examine the effects of occupational noise during pregnancy prospectively. The exposed group [continuous A-weighted sound level (LAeq(8 h)) > or = 78 dB] consisted of 111 pregnant women, and the reference group comprised 181 pregnant women with approximately similar work conditions but without noise exposure. The noise-exposed women had more frequently other inconveniences in their work, however, like shift work, impulse noise exposure, vibration, and a high or low temperature. With the limit of 78 dB (LAeq (8 h)), the course and outcome of pregnancy did not differ between the groups. When the noise exposure was 90 dB (LAeq (8 h)) or more, a decline in birthweight, either absolute [mean 3304 (SD 585) g for the exposed versus mean (SD 548) g for the unexposed, 95% CI of mean difference -471--+15 g] or related to the gestational age (below the 10th percentile [5 of 25 (20%) versus 13 of 180 (7%)]), was seen. These findings were more pronounced if the woman was simultaneously exposed to a standing work position or shift work. Working in high noise exposure can be considered a form of risk during pregnancy.


Combining 3-D plasmonic gold nanorod arrays with colloidal nanoparticles as a versatile concept for reliable, sensitive, and selective molecular detection by SERS.
The detection of molecules at an ultralow level by Surface-Enhanced Raman Spectroscopy (SERS) has recently attracted enormous interest for various applications especially in biological, medical, and environmental fields. Despite the significant progress, SERS systems are still facing challenges for practical applications related to their sensitivity, reliability, and selectivity. To overcome these limitations, in this study, we have proposed a simple yet facile concept by combining 3-D anisotropic gold nanorod arrays with colloidal gold nanoparticles having different shapes for highly reliable, selective, and sensitive detection of some hazardous chemical and biological warfare agents in trace amounts through SERS. The gold nanorod arrays were created on the BK7 glass slides or silicon wafer surfaces via the oblique angle deposition (OAD) technique without using any template material or lithography technique and their surface densities were adjusted by manipulating the deposition angle (α). It is found that gold nanorod arrays fabricated at α = 10° exhibited the highest SERS enhancement in the absence of colloidal gold nanoparticles. Synergetic enhancement was obviously observed in SERS signals when combining gold nanorod arrays with colloidal gold nanoparticles having different shapes (i.e., spherical, rod, and cage). Due to their ability to produce localized surface plasmons (LSPs) in transverse and longitudinal directions, utilization of colloidal gold nanorods as a synergetic agent led to an increase in the enhancement factor by about tenfold compared to plain gold nanorod arrays. Moreover, we have tested our approach to detect some chemical and biological toxins namely dipicolinic acid (DIP), methyl parathion (MP), and diethyl phosphoramidate (DP). For all toxins, Raman spectra with high signal-to-noise ratios and reproducibility were successfully obtained over a broad concentration range (5 ppm-10 ppb). Our results suggest that the slightly tangled and closely-packed anisotropic gold nanorod arrays reinforced by the gold nanoparticles may serve as an ideal SERS substrate to detect any analyte in trace amounts.


Taking Guatemala From Cobalt to IMRT: A Tale of US Agency Collaboration With Academic Institutions and Industry.
The not-for-profit organization La LIGA Nacional Contra el Cáncer, with its hospital Instituto de Cancerología (INCAN), is responsible for cancer treatment of much of the indigent population in Guatemala, a country with a population of 16 million. Annually, approximately 70% of patients at INCAN are seen in late stages of cancer, which places a great strain on the hospital's limited resources. Private clinics account for 75% of radiation therapy centers in Guatemala and have considerable resources. However, private facilities are fee-based, which creates a barrier for low-income patients; this is an especially significant problem in Guatemala, which has the highest income inequalities and poverty rates in Latin America. This article describes a project on the transition from cobalt to a Halcyon radiation therapy system at INCAN through a partnership with the US Agency for International Development's Office of American Schools and Hospitals Abroad (USAID/ASHA), Washington University in St. Louis (WUSTL), industry partner Varian Medical Systems, and the US National Nuclear Security Administration to provide access to state-of-the-art radiation therapy technology while increasing the overall treatment capacity for the underserved population of Guatemala.


Institutional deliveries and stillbirth and neonatal mortality in the Global Network's Maternal and Newborn Health Registry.
Few studies have shown how the move toward institutional delivery in low and middle-income countries (LMIC) impacts stillbirth and newborn mortality. The study evaluated trends in institutional delivery in research sites in Belagavi and Nagpur India, Guatemala, Kenya, Pakistan, and Zambia from 2010 to 2018 and compared them to changes in the rates of neonatal mortality and stillbirth. We analyzed data from a nine-year interval captured in the Global Network (GN) Maternal Newborn Health Registry (MNHR). Mortality rates were estimated from generalized estimating equations controlling for within-cluster correlation. Cluster-level analyses were performed to assess the association between institutional delivery and mortality rates. From 2010 to 2018, a total of 413,377 deliveries in 80 clusters across 6 sites in 5 countries were included in these analyses. An increase in the proportion of institutional deliveries occurred in all sites, with a range in 2018 from 57.7 to 99.8%. In 2010, the stillbirth rates ranged from 19.3 per 1000 births in the Kenyan site to 46.2 per 1000 births in the Pakistani site and by 2018, ranged from 9.7 per 1000 births in the Belagavi, India site to 40.8 per 1000 births in the Pakistani site. The 2010 neonatal mortality rates ranged from 19.0 per 1000 live births in the Kenyan site to 51.3 per 1000 live births in the Pakistani site with the 2018 neonatal mortality rates ranging from 9.2 per 1000 live births in the Zambian site to 50.2 per 1000 live births in the Pakistani site. In multivariate modeling, in some but not all sites, the reductions in stillbirth and neonatal death were significantly associated with an increase in the institutional deliveries. There was an increase in institutional delivery rates in all sites and a reduction in stillbirth and neonatal mortality rates in some of the GN sites over the past decade. The relationship between institutional delivery and a decrease in mortality was significant in some but not all sites. However, the stillbirth and neonatal mortality rates remain at high levels. Understanding the relationship between institutional delivery and stillbirth and neonatal deaths in resource-limited environments will enable development of targeted interventions for reducing the mortality burden. The study is registered at clinicaltrials.gov . ClinicalTrial.gov Trial Registration: NCT01073475 .


GRADE equity guidelines 3: considering health equity in GRADE guideline development: rating the certainty of synthesized evidence.
The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process. Consensus-based guidance developed by the GRADE working group members and other methodologists. We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings. The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society.


Aspects of nursing with evidence-base when nursing frail older adults: a phenomenographic analysis of interviews with nurses in municipal care.
In earlier research as well as in political discussion and documents, the topic of evidence has been highlighted as one of the most important concerns in nursing care. This study focuses on understanding what lies behind nurses' ways of acting regarding evidence-based nursing through an illumination of the way they perceive the phenomena. The aim was to identify and describe the different ways municipal care nurses perceive aspects of working with evidence when nursing frail older adults. An explorative design with a phenomenographic approach based on interviews with nurses working with home-based care within the municipality was used in order to gain understanding of nurse's perceptions of the phenomena. Findings revealed that the nurses perceived a variety of aspects when working with evidence when nursing frail older people. Aspects with a spectra of different perceptions shown in the analysis were as follows: Evidence-based nursing as a desired intention/mission, lack of practical supporting structures to apply evidence, lack of confidence in own capacity to apply evidence and a belief that it will work anyway. Findings reveal that it is a challenge to implement research both on an individual as well as on an organisational level. Understanding the contextual perceptions of evidence by nurses can cast light on the barriers as well as the prerequisites of working with evidence while caring for frail older adults in municipal care.


Pathogen-host associations and predicted range shifts of human monkeypox in response to climate change in central Africa.
Climate change is predicted to result in changes in the geographic ranges and local prevalence of infectious diseases, either through direct effects on the pathogen, or indirectly through range shifts in vector and reservoir species. To better understand the occurrence of monkeypox virus (MPXV), an emerging Orthopoxvirus in humans, under contemporary and future climate conditions, we used ecological niche modeling techniques in conjunction with climate and remote-sensing variables. We first created spatially explicit probability distributions of its candidate reservoir species in Africa's Congo Basin. Reservoir species distributions were subsequently used to model current and projected future distributions of human monkeypox (MPX). Results indicate that forest clearing and climate are significant driving factors of the transmission of MPX from wildlife to humans under current climate conditions. Models under contemporary climate conditions performed well, as indicated by high values for the area under the receiver operator curve (AUC), and tests on spatially randomly and non-randomly omitted test data. Future projections were made on IPCC 4(th) Assessment climate change scenarios for 2050 and 2080, ranging from more conservative to more aggressive, and representing the potential variation within which range shifts can be expected to occur. Future projections showed range shifts into regions where MPX has not been recorded previously. Increased suitability for MPX was predicted in eastern Democratic Republic of Congo. Models developed here are useful for identifying areas where environmental conditions may become more suitable for human MPX; targeting candidate reservoir species for future screening efforts; and prioritizing regions for future MPX surveillance efforts.


Infliximab Trough Levels at Induction to Predict Treatment Failure During Maintenance.
Infliximab (IFX) is indicated for the treatment of inflammatory bowel diseases (IBD). Nevertheless, loss of response (LOR) to IFX is reported in up to 10% to 30% of patients within the first year of treatment. Our objective was to evaluate the impact of the pharmacokinetics of IFX at induction on treatment failure. This is a longitudinal cohort study on 269 patients with IBD treated with IFX in a single center. A total of 2331 blood samples were prospectively collected from 2007 until March 2015 with a retrospective analysis of clinical data. IFX trough levels (TLs) were measured by enzyme-linked immunosorbent assay. Antibodies to IFX were measured by drug-sensitive bridging assay. During follow-up, patients were defined according to treatment outcome. At week 6, median IFX TL in patients requiring a switch to another treatment due to LOR (LOR switched group) (2.32 μg/mL [0.12-19.93 μg/mL]) was lower than in patients with long-term response (long-term responders) (8.66 μg/mL [0.12-12.09 μg/mL], P = 0.007) and in patients responding to optimization (LOR optimized group) (7.28 μg/mL [0.17-14.91 μg/mL], P = 0.021). At week 2, median IFX TL was lower in the LOR switched group (5.7 μg/mL [0.15-12.09 μg/mL]) compared with the long-term responders (11.92 μg/mL [0.14-19.93 μg/mL], P = 0.041) but no significant difference was reached with the LOR optimized group (11.91 μg/mL [0.23-12.09 μg/mL], P = 0.065). In the LOR switched group, median IFX TL at induction (weeks 2 and 6) was significantly lower when patients had been previously exposed to anti-tumor necrosis factor compared with naive patients (0.91 μg/mL [0.12-4.4 μg/mL] versus 6.6 μg/mL [0.15-19.93 μg/mL], P = 0.044). This study suggests that patients who do not respond to any optimization strategy have lower IFX TLs during induction at week 6. IFX TLs measured early on at induction might predict treatment failure to IFX during maintenance.


Effect of melatonin on attenuating the isoflurane-induced oxidative damage is related to PKCα/Nrf2 signaling pathway in developing rats.
Isoflurane, an inhalational anesthesia, has frequently been used in pediatric anesthesia. However, research indicates that isoflurane can induce oxidative stress and affect neural and cognitive development. Melatonin, an endogenous hormone that exhibits antioxidant functions, can play a neuroprotective role by activating the PKCα/Nrf2 signaling pathway in response to oxidative stress. This study aims to determine whether the effect of melatonin on isoflurane-induced oxidative stress is related to activation of the PKCα/Nrf2 signaling pathway. Rat pups at postnatal day 7 were treated with control or 1.5% isoflurane for 4 h after pretreatment for 15 min with either melatonin (10 mg/kg i.p.) or 1% ethanol. The hematoxylin and eosin staining and transmission electron microscopic examination were used for observation of histopathology. The oxidative stress-related indicators were detected by using assay kits. The western blotting, immunohistochemistry and immunofluorescence were used to detect the activation of PKCα/Nrf2 signaling pathway. Results showed that isoflurane induced nerve damage in the hippocampus, and melatonin could reduce this injury. Oxidative stress-related indicators suggested that isoflurane can significantly increase reactive oxygen species and malondialdehyde levels, and decrease superoxide dismutase and glutathione activity compared with the control group, whereas melatonin ameliorated these indices. Expression of proteins associated with the PKCα/Nrf2 signaling pathway indicated that the neuroprotective effect of melatonin is related to activation of the PKCα/Nrf2 signaling pathway. These results suggest that the attenuating effect of melatonin on isoflurane-induced oxidative stress is related to activation of the PKCα/Nrf2 signaling pathway. These findings promote further research into underlying mechanisms and effective treatments to attenuate anesthesia neurotoxicity.


In situ detection of programmed cell death in Nicotiana tabacum leaves during senescence.
Leaf senescence is a highly regulated developmental process, during which cell constituents are dismantled in an ordered progression. The final death phase of senescence is a type of programmed cell death (PCD). We showed DNA fragmentation characteristic for PCD by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay not only in senescing leaves but also in young, still developing tobacco leaves.


Age Differences in Voice Evaluation: From Auditory-Perceptual Evaluation to Social Interactions.
The factors that influence the evaluation of voice in adulthood, as well as the consequences of such evaluation on social interactions, are not well understood. Here, we examined the effect of listeners' age and the effect of talker age, sex, and smoking status on the auditory-perceptual evaluation of voice, voice-related psychosocial attributions, and perceived speech tempo. We also examined the voice dimensions affecting the propensity to engage in social interactions. Twenty-five younger (age 19-37 years) and 25 older (age 51-74 years) healthy adults participated in this cross-sectional study. Their task was to evaluate the voice of 80 talkers. Statistical analyses revealed limited effects of the age of the listener on voice evaluation. Specifically, older listeners provided relatively more favorable voice ratings than younger listeners, mainly in terms of roughness. In contrast, the age of the talker had a broader impact on voice evaluation, affecting auditory-perceptual evaluations, psychosocial attributions, and perceived speech tempo. Some of these talker differences were dependent upon the sex of the talker and his or her smoking status. Finally, the results also show that voice-related psychosocial attribution was more strongly associated with the propensity of the listener to engage in social interactions with a person than auditory-perceptual dimensions and perceived speech tempo, especially for the younger adults. These results suggest that age has a broad influence on voice evaluation, with a stronger impact for talker age compared with listener age. While voice-related psychosocial attributions may be an important determinant of social interactions, perceived voice quality and speech tempo appear to be less influential. https://doi.org/10.23641/asha.5844102.


A comparative study of mammalian tracheal mucous glands.
We have compared the distribution, numbers and volume of mucous glands in the tracheas of 11 mammalian species. No glands were present in the rabbit. The mouse only contained glands at the border between the trachea and larynx. In the rat, glands were commonest in the cephalad third of the trachea, but on average were much scarcer than in the larger species. Between species, there was a significant correlation between airway diameter and gland volume per unit surface area, suggesting that the rate of deposition of inhaled particles may increase in large airways. In the ventral portion of the trachea of about half the species, the glands were concentrated between the cartilaginous rings; in others they were evenly distributed over and between the rings. In most species in which the trachealis muscle attached to the internal surface of the cartilaginous rings, the glands were external to the muscle. In all species in which the muscle attached to the external surface of the cartilaginous rings, the glands were internal to the muscle. In the ox, goat, dog and sheep, the volume of glands per unit tracheal surface area was markedly greater in the ventral than the dorsal aspect of the trachea. The reverse was true of the pig. In humans, gland density in the 2 regions was similar. The frequency of gland openings was determined in the ox, goat, pig, dog and sheep tracheas, and ranged from 0.3 per mm2 in the dorsal portion of the sheep trachea to 1.5 per mm2 in the ventral portion of the ox trachea. For these 5 species, the volume of gland acini per unit luminal surface area varied linearly with the numbers of gland openings, with the volume of individual glands being constant at approximately 120 nl.


Reversible crystal-to-crystal chiral resolution: making/breaking non-bonding SO interactions.
An achiral organic molecule adopts a chiral conformation, crystallizing in two morphologies: a racemic form, stable <70 °C, and a homochiral form, stable ≥70 °C. Upon seeding, crystal-to-crystal phase transitions occur reversibly between the racemic and chiral forms. Liquid-to-solid chiral crystallization is observed >90% of the time from the melt.


Comparison of Löwenstein-Jensen and BACTEC MGIT 960 culture for Mycobacterium tuberculosis in people living with HIV.
The aim of the study was to clarify how HIV infection affects tuberculosis liquid and solid culture results in a resource-limited setting. We used baseline data from the Study on Outcomes Related to Tuberculosis and HIV Drug Concentrations in Uganda (SOUTH), which included 268 HIV/tuberculosis (TB)-coinfected individuals. Culture results from Löwenstein-Jensen (LJ) solid culture and mycobacteria growth indicator tube (MGIT) liquid culture systems and culture-based correlates for bacillary density from the sputum of HIV/TB-coinfected individuals at baseline were analysed. Of 268 participants, 243 had a CD4 cell count available and were included in this analysis; 72.2% of cultures showed growth on solid culture and 82.2% in liquid culture systems (P < 0.015). A higher CD4 cell count was predictive of LJ positivity [adjusted odds ratio (OR) 1.14; 95% confidence interval (CI) 1.03-1.25 per 50 cells/μL increase; P = 0.008]. The same, but insignificant trend was observed for MGIT positivity (adjusted OR 1.09; 95% CI 0.99-1.211 per 50 cells/μL increase; P = 0.094). A higher CD4 cell count was associated with a higher LJ colony-forming unit grade (adjusted OR 1.14; 95% CI 1.05-1.25 per 50 cells/μL increase; P = 0.011) and a shorter time to MGIT positivity [adjusted hazard ratio (HR) 1.08; 95% CI 1.04-1.12 per 50 cells/μL increase; P < 0.001]. In a resource-limited setting, the MGIT liquid culture system outperformed LJ solid culture in terms of culture yield and dependence on CD4 cell counts in HIV/TB-coinfected individuals. We therefore suggest considering an adaptation of diagnostic algorithms: when resources allow only one culture method to be performed, we recommend that MGIT liquid culture should be used exclusively in HIV-positive individuals as a first-line culture method, to reduce costs and make TB culture results accessible to more patients in resource-limited settings.


Reexamining the Call of Duty: Teaching Boundaries in Medical School.
Although healthy physician-patient boundaries are essential to medical practice, published research on how to teach this important topic to medical students is lacking. Physician-patient boundaries, the interpersonal limits placed on behavior within a clinical relationship, protect providers and patients alike, and they represent a key component of professionalism. However, these boundaries may be difficult to teach and frequently are not presented as part of the formal curriculum, except in communication-focused specialties such as psychiatry and palliative care. Medical students may be particularly susceptible to boundary concerns due to the inherent ambiguities of their role within the medical team. In this Perspective, the authors present the adapted, anonymized case of a medical student who encountered a boundary issue during a clinical rotation. Following a brief review of the limited published literature regarding the teaching of boundaries during medical school, the authors define key concepts, including the clinical frame, boundary crossings and violations, fiduciary duty, and dual relationships. Next, they provide examples of common boundary challenges that arise during the course of undergraduate medical education and later during clinical practice. The authors present factors that may contribute to boundary concerns, including characteristics of providers and patients, and they describe some of the potential consequences of boundary violations. They propose a curriculum for teaching medical students about boundaries, providing concrete suggestions for how to do so at both the preclinical and clinical levels. Before closing, they apply insights from the Perspective to the example case.


Evaluation of ray tracing and Monte Carlo algorithms in dose calculation and clinical outcomes for robotic stereotactic body radiotherapy of lung cancers.
Dose calculation in treatment planning must account for tissue heterogeneity, especially for tumors within low-density lung tissues. While Monte Carlo (MC) calculation methods are the most accurate, Ray Tracing (RT) methods are also commonly employed. We evaluated dose calculation differences between the RT and MC algorithms in central and peripheral lung tumors treated with CyberKnife SBRT to determine which planning parameters may predict dose differences. We also examined clinical outcomes of local-regional control (LRC) and long-term treatment-related toxicity as a function of calculation method. A retrospective series of 70 patient plans (19 central and 51 peripheral lung lesions) treated between 2009 and 2011 were analyzed. Among those, 33 were primary lung cancer and 37 were metastatic lesions. Thirty-three treatment plans were developed with the RT method, and 37 plans used MC. Groups were recalculated with the reciprocal method for dose comparison. Parameters examined to quantify dose differences between the two algorithms included: dose delivered to 95% (D95) of the planning target volume (PTV), dose heterogeneity, and dose to organs at risk (OAR). Dose differences were analyzed as a function of target volume, distance to soft tissue, and fraction of target overlap with soft tissue. For the subset of primary lung tumors, LRC was assessed radiographically at a median follow-up of 19 months (mo) (range, 2 to 41 mo). Compared to MC, the RT algorithm largely overestimated the dose delivered to the PTV. The dose difference between RT and MC plans correlated to the volume of PTV overlapping with soft tissue; the smaller the overlap volume, the larger the dose differences between RT and MC. Compared to MC, the RT algorithm overestimated the dose delivered to 10% of the ipsilateral lung (D10%). Evidence of local progression was noted in only one of the 31 patients treated for primary lung malignancy. DFS and OS were not significantly different between RT and MC plans. There is a significant range of discordance between MC and RT dose calculations for SBRT treated peripheral lung tumors. While variation is correlated to target size and proximity to soft tissue, no single parameter can reliably predict dose differences. Ultimately, local control and long-term toxicity appear independent of the dose calculation method.


Diversity among African pygmies.
Although dissimilarities in cranial and post-cranial morphology among African pygmies groups have been recognized, comparative studies on skull morphology usually pull all pygmies together assuming that morphological characters are similar among them and different with respect to other populations. The main aim of this study is to compare cranial morphology between African pygmies and non-pygmies populations from Equatorial Africa derived from both the Eastern and the Western regions in order to test if the greatest morphological difference is obtained in the comparison between pygmies and non-pygmies. Thirty three-dimensional (3D) landmarks registered with Microscribe in four cranial samples (Western and Eastern pygmies and non-pygmies) were obtained. Multivariate analysis (generalized Procrustes analysis, Mahalanobis distances, multivariate regression) and complementary dimensions of size were evaluated with ANOVA and post hoc LSD. Results suggest that important cranial shape differentiation does occur between pygmies and non-pygmies but also between Eastern and Western populations and that size changes and allometries do not affect similarly Eastern and Western pygmies. Therefore, our findings raise serious doubt about the fact to consider African pygmies as a homogenous group in studies on skull morphology. Differences in cranial morphology among pygmies would suggest differentiation after divergence. Although not directly related to skull differentiation, the diversity among pygmies would probably suggest that the process responsible for reduced stature occurred after the split of the ancestors of modern Eastern and Western pygmies.


Why are hemoglobin F levels increased in HbE/beta thalassemia?
To try to further define the mechanisms that increase the levels of hemoglobin F (HbF) in the blood of patients with severe forms of beta thalassemia, we have studied two comparable populations of hemoglobin E (HbE)/beta thalassemics, one regularly transfused and one receiving only occasional blood transfusions. Regular transfusion was associated with a significant decrease in soluble transferrin receptor and erythropoietin levels. Globin chain synthesis studies also show a highly significant decrease in HbF synthesis relative to HbE in the transfused patients. This effect was confirmed by sequential data on one patient, studied before and after the commencement of regular blood transfusion; blood transfusion was followed by a marked increase in the alpha/gamma, beta(E)/gamma, and HbE/HbF ratios. These data suggest that the high HbF levels in HbE/beta thalassemia, and other beta thalassemia syndromes, result from increased erythropoietin levels leading to bone marrow expansion, and possibly increased F-cell production, combined with ineffective erythropoiesis giving a survival advantage to F cells. This study also suggests that alteration in blood transfusion regimes must be taken into account when interpreting changes in HbF levels seen in trials of HbF-promoting drugs.


Persistent Postprandial Angina in a Patient With Gastroesophageal Reflux Disease: A Diagnostic Dilemma.
Chest pain (CP) is a common reason for visits to the emergency department (ED). The underlying etiology of a good number of cases of CP can be diagnosed with adequate history taking and routine laboratory testing. However, atypical presentations of CP, in the settings of other causes of CP such as gastroesophageal reflux disease (GERD), can sometimes be tricky to diagnose with only routine lab tests and electrocardiogram (EKG). Herein, we present a 73-year-old male with a history of GERD and coronary artery disease who presented to our ED complaining of postprandial CP unaffected by exertion or rest. Initially, his symptoms were thought to be GERD-related but other heart-related causes of CP were considered due to the persistence of his CP postprandially. A cardiac stress test was subsequently done to rule out possible cardiac causes of his CP. His stress test was abnormal prompting heart catheterization that showed almost complete occlusion of his left anterior descending (LAD) and left circumflex (LCx) arteries. His symptoms resolved post-catheterization/stenting of his LAD and LCx arteries. He was later discharged unconditionally. His presentation highlights the required vigilance physicians must maintain when interrogating CP, even when other non-cardiac-related causes seem more plausible.


Cystine and Theanine Improve Survival after Gut Ischemia-Reperfusion.
Oral administration of cystine and theanine (CT) may modulate antioxidant glutathione (GSH) metabolism, thereby improving outcomes after gut ischemia reperfusion. Experiment 1: Institute of Cancer Research mice (n = 35) were assigned to a Vehicle (n = 11), a CT140 (n = 14), or a CT280 (n = 10) group. The CT140 and 280 groups were given CT at respective dosages of 140 and 280 mg/kg (cystine: theanine = 5: 2) once daily via gavage for 5 days. All mice underwent 75-min occlusion of the superior mesenteric artery (SMA). Survival after reperfusion was observed. Experiment 2: Mice (n = 67) were pretreated for 5 days (Vehicle: n = 24, CT280: n = 20, vehicle/sham: n = 23). The Vehicle and CT280 groups underwent 60-min SMA occlusion. Levels of GSH, the oxidized form of GSH, Glutathione-S-S-Glutathione (GSSG), and GSH-related amino acids (cysteine and glutamic acid) in the small intestine, and plasma cytokine (IL-6, IL-1β, TNFα) levels, were evaluated before (0 h), 3, 6, or 9 h after reperfusion. Experiment 1: The CT280 group showed significantly better survival than the Vehicle group. Experiment 2: Gut GSSG, cysteine, and glutamic acid levels were higher in the CT280 than in the Vehicle group after reperfusion. Plasma IL-6 and TNFα levels rose more rapidly in the CT280 than in the Vehicle group. Oral administration of CT improves survival after gut I/R, possibly through the modulation of the GSH-redox cycle and cytokine responses.


The Riddoch syndrome: insights into the neurobiology of conscious vision.
We have studied a patient, G.Y., who was rendered hemianopic following a lesion affecting the primary visual cortex (area VI), sustained 31 years ago, with the hope of characterizing his ability to discriminate visual stimuli presented in his blind field, both psychophysically and in terms of the brain activity revealed by imaging methods. Our results show that (i) there is a correlation between G.Y.'s capacity to discriminate stimuli presented in his blind field and his conscious awareness of the same stimuli and (ii) that G.Y.'s performance on some tasks is characterized by a marked variability, both in terms of his awareness for a given level of discrimination and in his discrimination for a given level of awareness. The observations on G.Y., and a comparison of his capacities with those of normal subjects, leads us to propose a simple model of the relationship between visual discrimination and awareness. This supposes that the two independent capacities are very tightly coupled in normal subjects (gnosopsia) and that the effect of a VI lesion is to uncouple them, but only slightly. This uncoupling leads to two symmetrical departures, on the one hand to gnosanopsia (awareness without discrimination) and on the other to agnosopsia (discrimination without awareness). Our functional MRI studies show that V5 is always active when moving stimuli, whether slow or fast, are presented to his blind field and that the activity in V5 co-varies with less intense activity in other cortical areas. The difference in cerebral activity between gnosopsia and agnosopsia is that, in the latter, the activity in V5 is less intense and lower statistical thresholds are required to demonstrate it. Direct comparison of the brain activity during individual 'aware' and 'unaware' trials, corrected for the confounding effects of motion, has also allowed us, for the first time, to titrate conscious awareness against brain activity and show that there is a straightforward relationship between awareness and activity, both in individual cortical areas, in this case area V5, and in the reticular activating system. The imaging evidence, together with the variability in his levels of awareness and discrimination, manifested in his capacity to discriminate consciously on some occasions and unconsciously on others, leads us to conclude that agnosopsia, gnosopsia and gnosanopsia are all manifestations of a single condition which we call the Riddoch syndrome, in deference to the British neurologist who, in 1917, first characterized the major aspect of this disability. We discuss the significance of these results in relation to historical views about the organization of the visual brain.


Concurrent RT with 5-FU/epirubicin and cisplatin or irinotecan for locally advanced upper GI adenocarcinoma.
From the results of recent studies, it is likely that multimodality therapy with chemotherapy and radiation treatment may improve the overall outcome of locally advanced upper gastrointestinal (GI) malignancies, including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective, more optimal, and less toxic chemotherapy regimen(s) with concomitant radiotherapy are needed beyond the concurrent continuous-infusion fluorouracil (5-FU) with radiation that is commonly applied in general practice. Epirubicin (Ellence), cisplatin, and irinotecan (Camptosar) are all active cytotoxic chemotherapy agents in upper GI cancers. Two phase I studies were designed to test the tolerability of the combination of radiotherapy with infusional 5-FU, epirubicin, and cisplatin (ECF) or 5-FU, irinotecan, and epirubicin (EIF) in the treatment of locally advanced upper GI malignancies.