Roles of the conserved aspartate and arginine in the catalytic mechanism of an archaeal beta-class carbonic anhydrase.
The roles of an aspartate and an arginine, which are completely conserved in the active sites of beta-class carbonic anhydrases, were investigated by steady-state kinetic analyses of replacement variants of the beta-class enzyme (Cab) from the archaeon Methanobacterium thermoautotrophicum. Previous kinetic analyses of wild-type Cab indicated a two-step zinc-hydroxide mechanism of catalysis in which the k(cat)/K(m) value depends only on the rate constants for the CO(2) hydration step, whereas k(cat) also depends on rate constants from the proton transfer step (K. S. Smith, N. J. Cosper, C. Stalhandske, R. A. Scott, and J. G. Ferry, J. Bacteriol. 182:6605-6613, 2000). The recently solved crystal structure of Cab shows the presence of a buffer molecule within hydrogen bonding distance of Asp-34, implying a role for this residue in the proton transport step (P. Strop, K. S. Smith, T. M. Iverson, J. G. Ferry, and D. C. Rees, J. Biol. Chem. 276:10299-10305, 2001). The k(cat)/K(m) values of Asp-34 variants were decreased relative to those of the wild type, although not to an extent which supports an essential role for this residue in the CO(2) hydration step. Parallel decreases in k(cat) and k(cat)/K(m) values for the variants precluded any conclusions regarding a role for Asp-34 in the proton transfer step; however, the k(cat) of the D34A variant was chemically rescued by replacement of 2-(N-morpholino)propanesulfonic acid buffer with imidazole at pH 7.2, supporting a role for the conserved aspartate in the proton transfer step. The crystal structure of Cab also shows Arg-36 with two hydrogen bonds to Asp-34. Arg-36 variants had both k(cat) and k(cat)/K(m) values that were decreased at least 250-fold relative to those of the wild type, establishing an essential function for this residue. Imidazole was unable to rescue the k(cat) of the R36A variant; however, partial rescue of the kinetic parameter was obtained with guanidine-HCl indicating that the guanido group of this residue is important.


Distinct associations between fronto-striatal glutamate concentrations and callous-unemotional traits and proactive aggression in disruptive behavior.
Disruptive behavior is associated with societally and personally problematic levels of aggression and has been linked to abnormal structure and function of fronto-amygdala-striatal regions. Abnormal glutamatergic signalling within this network may play a role in aggression. However, disruptive behavior does not represent a homogeneous construct, but can be fractionated across several dimensions. Of particular interest, callous-unemotional (CU) traits have been shown to modulate the severity, neural and behavioural characterisation, and therapeutic outcomes of disruptive behaviour disorders (DBDs) and aggression. Further, individuals showing disruptive behavior differ to the extent that they engage in subtypes of aggression (i.e., proactive [PA] and reactive aggression [RA]) which may also represent distinct therapeutic targets. Here we investigated how glutamate signalling within the fronto-amygdala-striatal circuitry was altered along these dimensions in youths showing disruptive behavior (n = 140) and typically developing controls (TD, n = 93) within the age-range of 8-18 years. We used proton magnetic resonance spectroscopy (1H-MRS) in the anterior cingulate cortex (ACC), striatum, amygdala and insula and associated glutamate concentrations with continuous measures of aggression and CU-traits using linear mixed-effects models. We found evidence of a dissociation for the different measures and glutamate concentrations. CU traits were associated with increased ACC glutamate ('callousness': b = .19, t (108) = 2.63, p = .01, r = .25; 'uncaring': b = .18, t (108) = 2.59, p = .011, r = .24) while PA was associated with decreased striatal glutamate concentration (b = -.23, t (28) = -3.02, p = .005, r = .50). These findings suggest dissociable correlates of CU traits and PA in DBDs, and indicate that the ACC and striatal glutamate may represent novel pharmacological targets in treating these different aspects.


Comparison of Doppler and oscillometric ankle blood pressure measurement in patients with angiographically documented lower extremity arterial occlusive disease.
To assess the reliability of the oscillometric method in patients with peripheral vascular disease, ankle blood pressure measurement by Doppler and oscillometry was compared. This study represents a prospective, non-blinded examination of pressure measurements in 168 patients. Twenty-two patients were included who had abdominal aortic aneurysms (AAA) and 146 had peripheral arterial occlusive disease (PAOD). Patients with PAOD were divided into 2 groups according to angiography results: a crural artery occlusion group (CAO, n = 32), and a no crural artery occlusion group (NCAO, n = 114). All subjects underwent pressure measurement by both Doppler and oscillometry. The correlation coefficient was 0.928 in AAA patients and 0.922 in PAOD patients. In CAO patients, there were significantly fewer patients whose oscillometric pressure was equivalent to the Doppler pressure (DP), as compared to NCAO patients, because the oscillometric pressure (OP) was 10% higher than DP in 44% of CAO patients. A high correlation exists between Doppler and oscillometric ankle pressure measurements irrespective of the type of vascular disease. However, the oscillometric method could not be substituted for the Doppler method completely, because there were several patients whose OP was greater than DP especially in those with crural artery occlusive disease.


Relationship between upper gastrointestinal symptoms and lifestyle, psychosocial factors and comorbidity in the general population: results from the Domestic/International Gastroenterology Surveillance Study (DIGEST).
The Domestic/International Gastroenterology Surveillance Study (DIGEST) investigated the prevalence and economic/quality-of-life impact of upper gastrointestinal (GI) symptoms over 3 months among the general population of seven international sites (n = 5581). Respondents were classified as having relevant or non-relevant symptoms, and were further classified as having gastro-oesophageal reflux disease (GORD)-, ulcer-, or dysmotility-like symptoms, based on their most bothersome symptom. Associations were investigated between the prevalence of relevant upper GI symptoms and these subtypes, and the following potential risk factors: psychosocial variables (income, educational level, marital status, having children, occupation, any significant life event during previous year); lifestyle variables (tobacco use, levels of alcohol and caffeine consumption); comorbidity variables (illnesses or symptoms experienced in the previous 3 months, concurrent conditions diagnosed by a doctor, prescriptions and over-the-counter (OTC) medications taken in the previous 3 months for health problems other than upper GI symptoms). The most notable risk factors for the occurrence of upper GI symptoms, including symptoms indicative of GORD, were found to be various indicators of psychological stress (particularly recent life events) and psychiatric disease. A wide range of other non-psychiatric illnesses and their treatments was also clearly associated with the occurrence of upper GI symptoms, consistent with these symptoms occurring in many organic illnesses or as adverse effects of their treatments. Smoking was also found to be associated with GORD-like symptoms.


Intravascular contrast agent T2* relaxivity in brain tissue.
Dynamic susceptibility-weighted contrast-enhanced (DSC) MRI perfusion measurements depend on estimating intravascular contrast agent (CA) concentrations (C) from signal intensity changes in T2*-weighted images after bolus injection. Generally, linearity is assumed between relaxation and C, but previous studies have shown that compartmentalization of CA and secondary magnetic field perturbations generate deviations from linearity. Physical phantoms using bulk blood have been used to empirically determine the relationship between relaxation rate and C in large vessels. However, the relaxivity of CA in the microvasculature is not easily measured since constructing appropriate phantoms is difficult. Instead, theoretical relaxivity models have been developed. In this study, we empirically tested a non-linear expression based on static dephasing regime (SDR) and linear approximation. Signal-time curves in white (WM) and grey matter (GM) were converted to concentration time curves (CTCs) using both expressions. Parameters for both linear and non-linear formulations were adjusted to give a best agreement between cerebral blood volumes (CBV) calculated from WM and arterial CTCs in a group of normal subjects scanned at 3T. Optimized parameters were used to calculate blood volume in WM and GM in healthy subjects scanned at 3T and in meningioma patients scanned at 1.5T. Results from this study showed that a non-linear SDR formulation gave an acceptable functional form for tissue relaxivity, giving reliable CBV estimates at different field strengths and echo times.


Protease degradable tethers for controlled and cell-mediated release of nanoparticles in 2- and 3-dimensions.
Strategies to control the release rate of bioactive signals from tissue engineering scaffolds are essential for tissue regeneration and tissue engineering applications. Here we report on a strategy to achieve temporal control over nanoparticle release from biomaterials using cell-secreted proteases. This cell-triggered release approach utilizes peptides that are degraded by matrix metalloproteinases (MMPs) at different rates to immobilize nanoparticles directly to the biomaterial surface. Thus, the peptide-immobilized nanoparticles are released with temporal control through the action of cell-released MMPs. We found that release rates of peptide-immobilized nanoparticles were a function of peptide sensitivity to proteases, the number of tethers between the nanoparticle and the surface and the concentration of proteases used to induce release. Cellular internalization of the peptide-immobilized nanoparticles was also a function of the peptide sensitivity to proteases, the number of tethers between the nanoparticle and the surface and MMP expression profile of the cells. Similar trends were observed for peptide-immobilized nanoparticles inside micro-porous hydrogels, indicating protease sensitive tethers are effective in controlling release rate and internalization of nanoparticles. Such a temporal delivery strategy of nanoparticles loaded with therapeutic payloads (e.g. protein, DNA, siRNA) can be an ideal means to guide tissue formation.


Effect of a Mediterranean diet during pregnancy on fetal growth and preterm delivery: results from a French Caribbean Mother-Child Cohort Study (TIMOUN).
Recent studies suggest that a Mediterranean dietary pattern during pregnancy may influence pregnancy outcomes. The aim of this study was to evaluate the effect of adherence to a Mediterranean diet (MD) during pregnancy on fetal growth restriction (FGR) and preterm delivery (PTD) in a French Caribbean island where the population is largely of African descent and presents dietary patterns similar to MD. Using data from the TIMOUN Mother-Child Cohort Study conducted in Guadeloupe (French West Indies) between 2004 and 2007, we analysed data for 728 pregnant women who delivered liveborn singletons without any major congenital malformations. Degree of adherence to MD during pregnancy was evaluated with a semi-quantitative food frequency questionnaire based on nine dietary criteria. Multiple logistic regression models were used to analyse birth outcomes while taking potential confounders into account. Overall there was no association between MD adherence during pregnancy and the risk of PTD or FGR. However, pre-pregnancy body mass index was a strong effect modifier, and MD adherence was associated with a decreased risk of PTD specifically in overweight and obese women (adjusted odds ratio 0.7, 95% confidence interval 0.6, 0.9) (P heterogeneity <0.01). These results suggest that Caribbean diet during pregnancy may carry some benefits of MD and may contribute to reduce the risk of PTD in overweight and obese pregnant women.


A gene family in Mycoplasma imitans closely related to the pMGA family of Mycoplasma gallisepticum.
The avian pathogen Mycoplasma gallisepticum possesses a large gene family encoding lipoproteins which function as haemagglutinins. Representative species of the pneumoniae phylogenetic group of mycoplasmas were examined for the presence of genes homologous to members of this multigene family. Antisera against the pMGA1.1 lipoprotein recognized a 35 kDa protein in Mycoplasma imitans, but did not recognize proteins of Mycoplasma genitalium, Mycoplasma pneumoniae, Mycoplasma pirum, Mycoplasma penetrans of Mycoplasma iowae in Western blots. A fragment of the pMGA 1.2 gene and oligonucleotide probes complementary to highly conserved coding and non-coding regions of pMGA genes bound to fragments of genomic DNA of M. imitans, but not to the genomes of M. genitalium, M. pneumoniae, M. pirum or M. penetrans, and only one probe bound to a fragment of the M. iowae genome. One homologue of the pMGA genes was amplified from the M. imitans genome by PCR and used as a probe to clone a 3.1 kbp DNA fragment from a library of HindIII-digested M. imitans genomic DNA. The contiguous DNA sequence of the PCR and HindIII clones was predicted to encode one complete and one partial ORF which shared some peptide sequence identity with the pMGA genes, including the signal peptidase II cleavage site and the proline-rich amino-terminal region. Like the pMGA genes, the M. imitans genes were found to be members of a large gene family, with an association with GAA trinucleotide repeats, a feature which distinguishes these two families from the homologous vlhA gene family in Mycoplasma synoviae. The identification of these gene families in three phylogenetically distinct avian mycoplasma species, but not in human mycoplasmas, suggests their horizontal transfer between species infecting the same host.


Free-standing electrochemical electrode based on Ni(OH)2/3D graphene foam for nonenzymatic glucose detection.
Three-dimensional graphene foam (3DGF) is a superior sensing material because of its high conductivity, large specific surface area and wide electrochemical potential windows. In this work, hexagonal Ni(OH)2 nanosheets are deposited on the surface of chemical vapor deposition-grown 3DGF through a facial hydrothermal process without any auxiliary reagents. The morphology and structure of the composite are characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), Raman spectroscopy, and X-ray diffraction (XRD). Based on the Ni(OH)2/3DGF composite, a free-standing electrochemical electrode is fabricated. Being employed as a nonenzymatic glucose detection electrochemical electrode, it exhibits a high sensitivity (∼2.65 mA mM(-1) cm(-2)), low detection limit (0.34 μM) and excellent selectivity with a linear response from 1 μM to 1.17 mM. The excellent sensing properties of the Ni(OH)2/3DGF electrode may be attributed to the synergistic effect of the high electrocatalytic activity of Ni(OH)2 nanosheets and the high conductivity and large surface area of 3DGF.


Association of Preexisting Disability With Severe Maternal Morbidity or Mortality in Ontario, Canada.
Severe maternal morbidity and mortality are important indicators of maternal health. Pregnancy rates are increasing in women with disabilities, but their risk of severe maternal morbidity and mortality is unknown, despite their significant social and health disparities. To determine the risk of severe maternal morbidity or mortality among women with a physical, sensory, or intellectual/developmental disability compared with women without disabilities. This population-based cohort study used linked health administrative data in Ontario, Canada, from 2003 to 2018. The cohort included all singleton births to women with preexisting physical, sensory, and intellectual/developmental disabilities as well as with 2 disabilities or more compared with women without a disability. Data analysis was conducted from September 2019 to September 2020. Disabilities were identified with published algorithms applied to diagnoses in 2 physician visits or more or at least 1 emergency department visit or hospitalization. Severe maternal morbidity (a validated composite of 40 diagnostic and procedural indicators) or all-cause maternal mortality, arising between conception and 42 days post partum. Relative risks were adjusted for maternal age, parity, income quintile, rurality, chronic medical conditions, mental illness, and substance use disorders. The cohort comprised women with physical disabilities (144 972 women; mean [SD] age, 29.8 [5.6] years), sensory disabilities (45 259 women; mean [SD] age, 29.1 [6.0] years), intellectual/developmental disabilities (2227 women; mean [SD] age, 26.1 [6.4] years), and 2 or more disabilities (8883 women; mean [SD] age, 29.1 [6.1] years), and those without disabilities (1 601 363 women; mean [SD] age, 29.6 [5.4] years). The rate of severe maternal morbidity or death was 1.7% (27 242 women) in women without a disability. Compared with these women, the risk of severe maternal morbidity or death was higher in women with a physical disability (adjusted relative risk [aRR], 1.29; 95% CI, 1.25-1.34), a sensory disability (aRR, 1.14; 95% CI, 1.06-1.21), an intellectual/developmental disability (aRR, 1.57; 95% CI, 1.23-2.01), and 2 or more disabilities (aRR, 1.74; 95% CI, 1.55-1.95). Similar aRRs were observed for severe maternal morbidity or death arising in pregnancy, from birth to 42 days post partum, and from 43 to 365 days post partum. Women with disabilities were more likely than those without disabilities to experience multiple severe maternal morbidity indicators. The most prevalent indicators in all groups were intensive care unit admission, severe postpartum hemorrhage, puerperal sepsis, and severe preeclampsia. In this study, women with a preexisting disability were more likely to experience severe maternal morbidity or mortality. Preconception and perinatal care provisions should be considered among women with a disability to mitigate the risk of these rare but serious outcomes.


Sulfated glycosaminoglycan content of glomerular and tubular basement membranes of individuals of different ages.
The glycosaminoglycan content of glomerular and tubular basement membranes in individuals ranging from preterm neonates to 90-years-old people was determined with a spectrophotometric assay after papain digestion. A decrease of glycosaminoglycans until the age of 2.5 years was observed only in glomerular basement membrane. Tubular basement membranes did not show significant changes with age. Glomerular basement membranes of neonates had a higher glycosaminoglycan content than tubular basement membranes.


The effect of sediment grain properties and porewater flow on microbial abundance and respiration in permeable sediments.
Sandy sediments cover 50-60% of the continental shelves and are highly efficient bioreactors in which organic carbon is remineralized and inorganic nitrogen is reduced to N2. As such they seem to play an important role, buffering the open ocean from anthropogenic nitrogen inputs and likely remineralizing the vast amounts of organic matter formed in the highly productive surface waters. To date however, little is known about the interrelation between porewater transport, grain properties and microbial colonization and the consequences for remineralization rates in sandy sediments. To constrain the effect of theses factors on remineralization in silicate sands, we incubated North Sea sediments in flow-through reactors after separating into five different grain size fractions. Bulk sediment and sediment grain properties were measured along with microbial colonization and cell abundances, oxygen consumption and denitrification rates. Volumetric oxygen consumption ranged from 14 to 77 µmol O2 l-1 h-1 while nitrogen-loss via denitrification was between 3.7 and 8.4 µmol N l-1 h-1. Oxygen consumption and denitrification rates were linearly correlated to the microbial cell abundances, which ranged from 2.9 to 5.4·108 cells cm-3. We found, that cell abundance and consumption rates in sandy sediments are influenced (i) by the surface area available for microbial colonization and (ii) by the exposure of these surfaces to the solute-supplying porewater flow. While protective structures such as cracks and depressions promote microbial colonization, the oxygen demand is only met by good ventilation of these structures, which is supported by a high sphericity of the grains. Based on our results, spherical sand grains with small depressions, i.e. golf ball like structures, provide the optimal supporting mineral structure for microorganisms on continental shelves.


Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1β/CXCL1 Signaling.
Objective: Severe acute pancreatitis (SAP) can lead to acute lung injury (ALI). This study investigated the therapeutic effect of emodin and its molecular mechanisms in a rat model of SAP-ALI. Methods: Forty male Sprague-Dawley rats were randomly divided into the groups: Control (CON), SAP (SAP), emodin (EMO), and C23 (C23). The latter three groups of rats were induced for SAP-ALI by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and were treated with vehicle, emodin or C23, respectively. One day post induction, their pancreatic and lung injury was assessed by histology and arterial blood gas analysis. In vitro, rat alveolar macrophages (NR8383 cells) were treated with recombinant rat CIRP in the presence or absence of TAK242 (a TLR4 inhibitor), C23 or emodin. The CIRP-mediated activation of the NLRP3/IL-1β/CXCL1 signaling in rat lungs and NR8383 cells was determined. Similarly, the role of IL-1β in the CIRP-induced CXCL1 expression was investigated. Results: Emodin treatment significantly reduced inflammation and tissue damages in the pancreatic and lung tissues in rats with SAP-ALI, accompanied by decreasing serum amylase, CIRP and IL-1β levels and improving lung function. Furthermore, emodin significantly mitigated the SAP-up-regulated CIRP expression in the pancreatic islets and lung tissues, and attenuated the SAP-activated NF-κB signaling, NLRP3 inflammasome formation and CXCL1 expression in lung resident macrophages as well as neutrophil infiltration in the lungs of rats. In addition, treatment with CIRP significantly activated the NF-κB signaling and NLRP3 inflammasome formation and induced IL-1β and CXCL1 expression and pyroptosis in NR8383 cells, which were abrogated by TAK242 and significantly mitigated by C23 or emodin. Moreover, CIRP only induced very lower levels of CXCL1 expression in IL-1β-silencing NR8383 cells and treatment with IL-1β induced CXCL1 expression in NR8383 cells in a dose and time-dependent manner. Conclusion: Emodin may inhibit the CIRP-activated NLRP3/IL-1β/CXCL1signaling to decrease neutrophil infiltration and ameliorate the SAP-ALI in rats.


Deployment technique that takes advantage of the characteristics of Enterprise VRD2: an in vitro study.
Enterprise VRD, a stent frequently used to assist coil embolization of cerebral aneurysms, has been upgraded to reduce the risk of incomplete stent apposition (ISA), a known risk factor for thromboembolic complications. To compare the performances of Enterprise VRD and Enterprise VRD2 in curved vessels, and to investigate a deployment method that takes advantage of the features of Enterprise VRD2 to achieve better vessel wall apposition. A silicone vascular model connected to a temperature-adjustable perfusion circuit was used. First, Enterprise VRD and Enterprise VRD2 were deployed under fluoroscopy and then ISA was evaluated as the stent cross-sectional area ratio at the curved segment of the vessel. For the measurements, each stent was deployed in vessels with different angles of curvature. Second, the incidence of ISA after insertion of Enterprise VRD2 by the 'pushing over outer curve technique', in which stents are deployed along the outer curve of vessels with continuous wire advancement, was compared with 'Heller's push and pull technique'. For all stents, the cross-sectional area ratio decreased with acute curvature of the vessel. Comparisons of the two stents showed that Enterprise VRD2 was better than Enterprise VRD in maintaining a greater cross-sectional area ratio in curved vessels. In addition, kinking with an acute curvature was also minimized with Enterprise VRD2. Furthermore, ISA was reduced using our technique with Enterprise VRD2. Enterprise VRD2 is superior to Enterprise VRD in reducing ISA in curved vessels and can alter ISA according to the deployment technique used.


Using the capture-recapture method to estimate the human immunodeficiency virus-positive population.
The capture-recapture method was applied to estimate the number of human immunodeficiency virus (HIV)-positive individuals not registered with any data sources. This cross-sectional study was conducted in Lorestan Province, in the west of Iran, in 2016. Three incomplete sources of HIV-positive individuals, with partially overlapping data, were used, including: (a) transfusion center, (b) volunteer counseling and testing centers (VCTCs), and (c) prison. The 3-source capture-recapture method, using a log-linear model, was applied for data analysis. The Akaike information criterion and the Bayesian information criterion were used for model selection. Of the 2,456 HIV-positive patients registered in these 3 data sources, 1,175 (47.8%) were identified in transfusion center, 867 (35.3%) in VCTCs, and 414 (16.8%) in prison. After the exclusion of duplicate entries, 2,281 HIV-positive patients remained. Based on the capture-recapture method, 14,868 (95% confidence interval, 9,923 to 23,427) HIV-positive individuals were not identified in any of the registries. Therefore, the real number of HIV-positive individuals was estimated to be 17,149, and the overall completeness of the 3 registries was estimated to be around 13.3%. Based on capture-recapture estimates, a huge number of HIV-positive individuals are not registered with any of the provincial data sources. This is an urgent message for policymakers who plan and provide health care services for HIV-positive patients. Although the capture-recapture method is a useful statistical approach for estimating unknown populations, due to the assumptions and limitations of the method, the population size may be overestimated as it seems possible in our results.


Retinal development of West Australian dhufish, Glaucosoma hebraicum.
An investigation of retinal specializations was carried out in larval and juvenile dhufish, Glaucosoma hebraicum (Glaucosomidae, Teleostei). The development of photoreceptors and formation of the retinal mosaic was followed by light and electron microscopy. At hatching the eye was undifferentiated. Cone photoreceptors were present by day 3 posthatch (dph), when exogenous feeding began. Single and multiple cones were present in a row arrangement from 3 dph to 20 dph, when the first rod nuclei were observed. Between 20 dph and approximately 3 months posthatch (mph), the row arrangement was replaced by a square mosaic of four double cones surrounding a single cone, and the cones increased in size, with the outer segments reaching up to 30 microm in length. During the period of spatial rearrangement, triple cones were often observed. From their first appearance, rod photoreceptors were added rapidly. Investigation of ganglion cell topography in 3-mph fish that had attained the adult-like square photoreceptor mosaic was carried out using retinal wholemounts. The highest densities of neurones in the ganglion cell layer were in temporal retina but no well-defined area centralis was observed. Microspectrophotometric measurements of the visual pigments within the outer segments of the photoreceptors of 3-mph fish revealed double cones with identical absorption spectra in each member of the outer segment, and the wavelength of maximum absorption (lambda(max)) located at 522 nm. Single cones were found to possess a visual pigment with lambda(max) at 460 nm and rods with a lambda(max) of 498 nm. The results imply that the larvae and juveniles are adapted for survival in coastal waters and may be active in relatively low light levels from early stages of development.


Assessing weight perception accuracy to promote weight loss among U.S. female adolescents: a secondary analysis.
Overweight and obesity have become a global epidemic. The prevalence of overweight and obesity among U.S. adolescents has almost tripled in the last 30 years. Results from recent systematic reviews demonstrate that no single, particular intervention or strategy successfully assists overweight or obese adolescents in losing weight. An understanding of factors that influence healthy weight-loss behaviors among overweight and obese female adolescents promotes effective, multi-component weight-loss interventions. There is limited evidence demonstrating associations between demographic variables, body-mass index, and weight perception among female adolescents trying to lose weight. There is also a lack of previous studies examining the association of the accuracy of female adolescents' weight perception with their efforts to lose weight. This study, therefore, examined the associations of body-mass index, weight perception, and weight-perception accuracy with trying to lose weight and engaging in exercise as a weight-loss method among a representative sample of U.S. female adolescents. A nonexperimental, descriptive, comparative secondary analysis design was conducted using data from Wave II (1996) of the National Longitudinal Study of Adolescent Health (Add Health). Data representative of U.S. female adolescents (N = 2216) were analyzed using STATA statistical software. Descriptive statistics and survey weight logistic regression were performed to determine if demographic and independent (body-mass index, weight perception, and weight perception accuracy) variables were associated with trying to lose weight and engaging in exercise as a weight-loss method. Age, Black or African American race, body-mass index, weight perception, and weight perceptions accuracy were consistently associated with the likeliness of trying to lose weight among U.S. female adolescents. Age, body-mass index, weight perception, and weight-perception accuracy were positively associated (p < 0.05) with trying to lose weight. Black/African American subjects were significantly less likely than their White counterparts to be trying to lose weight. There was no association between demographic or independent variables and engaging in exercise as a weight-loss method. Findings suggest that factors influencing weight-loss efforts, including age, race, body-mass index, weight perception, and weight-perception accuracy, should be incorporated into existing or new multi-component weight-loss interventions for U.S. adolescent females in order to help reduce the national epidemic of overweight and obesity among U.S. female adolescents.


Oxidized ATM governs stemness of breast cancer stem cell through regulating ubiquitylation and acetylation switch.
Cancer stem cells (CSCs), as parts of tumor initiation cells, play a crucial role to tumorigenesis, development and recurrence. However, the complicated mechanisms of CSCs to adapt to tumor microenvironment and its stemness maintenance remains unclear. Here, we show that oxidized ATM, a hypoxia-activated cytoplasm ATM, acts a novel function to maintain CSC stemness in triple-negative breast cancer cells (BCSCs) via regulating histone H4 acetylation. Mechanistically, oxidized ATM phosphorylates TRIM21 (a E3 ubiquitin ligase) serine 80 and serine 469. Serine 80 phosphorylation of TRIM21 is essential for the ubiquitination activity of TRIM21. TRIM21 binds with SIRT1 (one of deacetylase), resulting in ubiquitylation-mediated degradation of SIRT1. The reduced SIRT1 leads to increase of histone H4 acetylation, thus facilitating CSC-related gene expression. Clinical data verify that high level of ATM in breast tumors is positively correlated with malignant grade, and is closely related with low SIRT1, high p-TRIM21, and high CD44 expression. In conclusion, our study provides a novel mechanism by which oxidized ATM governing BCSCs stemness and reveals an important link among oxidized ATM, histone acetylation, and BCSCs maintenance.


Shikonin extracted from medicinal Chinese herbs exerts anti-inflammatory effect via proteasome inhibition.
Shikonin, extracted from medicinal Chinese herb (Lithospermum erythrorhizo), was reported to exert anti-inflammatory and anti-cancer effects both in vitro and in vivo. We have found that proteasome was a molecular target of shikonin in tumor cells, but whether shikonin targets macrophage proteasome needs to be investigated. In the current study, we report that shikonin inhibited inflammation in mouse models as efficiently as dexamethasone. Shikonin at 4 μM reduced the Lipopolysaccharides (LPS)-mediated TNFα release in rat primary macrophage cultures, and blocked the translocation of p65-NF-κB from the cytoplasm to the nucleus, associated with decreased proteasomal activity. Consistently, shikonin accumulated IκB-α, an inhibitor of NF-κB, and ubiquitinated proteins in rat primary macrophage cultures, demonstrating that the proteasome is a target of shikonin under inflammatory conditions. Shikonin also induced macrophage cell apoptosis and cell death. These results demonstrate for the first time that proteasome inhibition by shikonin contributes to its anti-inflammatory effect. The novel finding about macrophage proteasome as a target of shikonin suggests that this medicinal compound has great potential to be developed into an anti-inflammatory agent.


Predicting Antiseizure Medication Treatment in Children with Rare Tuberous Sclerosis Complex-Related Epilepsy Using Deep Learning.
Tuberous sclerosis complex disease is a rare, multisystem genetic disease, but appropriate drug treatment allows many pediatric patients to have positive outcomes. The purpose of this study was to predict the effectiveness of antiseizure medication treatment in children with tuberous sclerosis complex-related epilepsy. We conducted a retrospective study involving 300 children with tuberous sclerosis complex-related epilepsy. The study included the analysis of clinical data and T2WI and FLAIR images. The clinical data consisted of sex, age of onset, age at imaging, infantile spasms, and antiseizure medication numbers. To forecast antiseizure medication treatment, we developed a multitechnique deep learning method called WAE-Net. This method used multicontrast MR imaging and clinical data. The T2WI and FLAIR images were combined as FLAIR3 to enhance the contrast between tuberous sclerosis complex lesions and normal brain tissues. We trained a clinical data-based model using a fully connected network with the above-mentioned variables. After that, a weighted-average ensemble network built from the ResNet3D architecture was created as the final model. The experiments had shown that age of onset, age at imaging, infantile spasms, and antiseizure medication numbers were significantly different between the 2 drug-treatment outcomes (P < .05). The hybrid technique of FLAIR3 could accurately localize tuberous sclerosis complex lesions, and the proposed method achieved the best performance (area under the curve = 0.908 and accuracy of 0.847) in the testing cohort among the compared methods. The proposed method could predict antiseizure medication treatment of children with rare tuberous sclerosis complex-related epilepsy and could be a strong baseline for future studies.


High-sensitive troponin T and I are related to invasive hemodynamic data and mortality in patients with left-ventricular dysfunction and precapillary pulmonary hypertension.
High-sensitive (hs) cardiac troponin assays are clinically useful in various cardiac conditions. We aimed to extend current evidence by assessing the relations of hs-cardiac troponin T (hs-cTnT) and I (hs-cTnI) to invasive hemodynamic data and outcome in stable patients with left-ventricular (LV) dysfunction or precapillary pulmonary hypertension (PAH). Hs-cTnT (Roche Diagnostics) and hs-cTnI (Beckman-Coulter) were measured in 103 stable patients with LV-dysfunction and 56 patients with precapillary PAH referred for right-heart catheterization. Up to 47.6% of patients with LV-dysfunction, and up to 37.5% of patients with precapillary PAH had hs-troponin levels above the respective 99th percentiles. In patients with LV-dysfunction, both hs-troponins exhibited significant associations to hemodynamics, NT-proBNP and mortality (hs-cTnT: age/sex-adjusted HR 2.0 [95% CI 1.3-3.1]; hs-cTnI: age/sex-adjusted HR 1.9 [1.2-2.8]). Both hs-troponins demonstrated weaker associations to hemodynamics in patients with precapillary PAH but correlated significantly to NT-proBNP. Mortality was only predicted by hs-cTnI (age/sex-adjusted HR 3.0 [1.5-6.1]). Hs-troponins are related to indices of impaired myocardial performance in patients with LV-dysfunction and precapillary PAH. Both hs-troponins were also predictive for mortality in patients with LV-dysfunction. In precapillary PAH, only hs-cTnI was independently prognostic which might depend on the superior analytical performance of this assay.


Application of random forests methods to diabetic retinopathy classification analyses.
Diabetic retinopathy (DR) is one of the leading causes of blindness in the United States and world-wide. DR is a silent disease that may go unnoticed until it is too late for effective treatment. Therefore, early detection could improve the chances of therapeutic interventions that would alleviate its effects. Graded fundus photography and systemic data from 3443 ACCORD-Eye Study participants were used to estimate Random Forest (RF) and logistic regression classifiers. We studied the impact of sample size on classifier performance and the possibility of using RF generated class conditional probabilities as metrics describing DR risk. RF measures of variable importance are used to detect factors that affect classification performance. Both types of data were informative when discriminating participants with or without DR. RF based models produced much higher classification accuracy than those based on logistic regression. Combining both types of data did not increase accuracy but did increase statistical discrimination of healthy participants who subsequently did or did not have DR events during four years of follow-up. RF variable importance criteria revealed that microaneurysms counts in both eyes seemed to play the most important role in discrimination among the graded fundus variables, while the number of medicines and diabetes duration were the most relevant among the systemic variables. We have introduced RF methods to DR classification analyses based on fundus photography data. In addition, we propose an approach to DR risk assessment based on metrics derived from graded fundus photography and systemic data. Our results suggest that RF methods could be a valuable tool to diagnose DR diagnosis and evaluate its progression.


Sequences of Regressions Distinguish Nonmechanical from Mechanical Associations between Metabolic Factors, Body Composition, and Bone in Healthy Postmenopausal Women.
There is increasing recognition of complex interrelations between the endocrine functions of bone and fat tissues or organs. The objective was to describe nonmechanical and mechanical links between metabolic factors, body composition, and bone with the use of graphical Markov models. Seventy postmenopausal women with a mean ± SD age of 62.3 ± 3.7 y and body mass index (in kg/m2) of 24.9 ± 3.8 were recruited. Bone outcomes were peripheral quantitative computed tomography measures of the distal and diaphyseal tibia, cross-sectional area (CSA), volumetric bone mineral density (vBMD), and cortical CSA. Biomarkers of osteoblast and adipocyte function were plasma concentrations of leptin, adiponectin, osteocalcin, undercarboxylated osteocalcin (UCOC), and phylloquinone. Body composition measurements were lean and percent fat mass, which were derived with the use of a 4-compartment model. Sequences of Regressions, a subclass of graphical Markov models, were used to describe the direct (nonmechanical) and indirect (mechanical) interrelations between metabolic factors and bone by simultaneously modeling multiple bone outcomes and their relation with biomarker outcomes with lean mass, percent fat mass, and height as intermediate explanatory variables. The graphical Markov models showed both direct and indirect associations linking plasma leptin and adiponectin concentrations with CSA and vBMD. At the distal tibia, lean mass, height, and adiponectin-UCOC interaction were directly explanatory of CSA (R2 = 0.45); at the diaphysis, lean mass, percent fat mass, leptin, osteocalcin, and age-adiponectin interaction were directly explanatory of CSA (R2 = 0.49). The regression models exploring direct associations for vBMD were much weaker, with R2 = 0.15 and 0.18 at the distal and diaphyseal sites, respectively. Lean mass and UCOC were associated, and the global Markov property of the graph indicated that this association was explained by osteocalcin. This study, to our knowledge, offers a novel approach to the description of the complex physiological interrelations between adiponectin, leptin, and osteocalcin and the musculoskeletal system. There may be benefits to jointly targeting both systems to improve bone health.


Nonlinear femtosecond pulse propagation in an all-solid photonic bandgap fiber.
Nonlinear femtosecond pulse propagation in an all-solid photonic bandgap fiber is experimentally and numerically investigated. Guiding light in such fiber occurs via two mechanisms: photonic bandgap in the central silica core or total internal reflection in the germanium doped inclusions. By properly combining spectral filtering, dispersion tailoring and pump coupling into the fiber modes, we experimentally demonstrate efficient supercontinuum generation with controllable spectral bandwidth.


Fluorescence digital imaging microscopy in cell biology.
Developments in microscope, sensor, and image-processing technologies have led to integrated systems for the quantification of low-light-level emission signals from biological samples. Specificity is provided in the form of monoclonal antibodies and other ligands or enzyme substrates conjugated with efficient fluorophores. Fluorescent probes are also available for cellular macromolecular constituents and for free ions of biological interest such as H+ and Ca2+. The entire spectrum of photophysical phenomena can be exploited. Representative data are presented from studies of DNA conformation and architecture in polytene chromosomes and from studies of receptor-mediated endocytosis, calcium distribution, and the organization of the contractile apparatus in muscle cells.


[Characteristics of blood distribution in the tissues of the lower extremities after lumbar sympathectomy].
By means of a polarographic method, the peculiarities of blood distribution in the tissues of the lower extremities in 34 patients with obliterative atherosclerosis and in 29--with obliterative endarteritis after sympathectomy were studied. In successful intervention, the prognostically significant increase in oxygen tension in the muscles at the level of crura and feet was noted. It is suggested to use this test under conditions of medicinal ganglionectomy with the aim of prognostication of the effectiveness of the forthcoming lumbar sympathectomy.


Feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the Activity and Cognitive Therapy in ICU (ACT-ICU) trial.
Cognitive impairment after critical illness is common and debilitating. We developed a cognitive therapy program for critically ill patients and assessed the feasibility and safety of administering combined cognitive and physical therapy early during a critical illness. We randomized 87 medical and surgical ICU patients with respiratory failure and/or shock in a 1:1:2 manner to three groups: usual care, early once-daily physical therapy, or early once-daily physical therapy plus a novel, progressive, twice-daily cognitive therapy protocol. Cognitive therapy included orientation, memory, attention, and problem-solving exercises, and other activities. We assessed feasibility outcomes of the early cognitive plus physical therapy intervention. At 3 months, we also assessed cognitive, functional, and health-related quality of life outcomes. Data are presented as median (interquartile range) or frequency (%). Early cognitive therapy was a delivered to 41/43 (95%) of cognitive plus physical therapy patients on 100% (92-100%) of study days beginning 1.0 (1.0-1.0) day following enrollment. Physical therapy was received by 17/22 (77%) of usual care patients, by 21/22 (95%) of physical therapy only patients, and 42/43 (98%) of cognitive plus physical therapy patients on 17% (10-26%), 67% (46-87%), and 75% (59-88%) of study days, respectively. Cognitive, functional, and health-related quality of life outcomes did not differ between groups at 3-month follow-up. This pilot study demonstrates that early rehabilitation can be extended beyond physical therapy to include cognitive therapy. Future work to determine optimal patient selection, intensity of treatment, and benefits of cognitive therapy in the critically ill is needed.


Influenza and the winter increase in mortality in the United States, 1959-1999.
In economically developed countries, mortality increases distinctly during winter. Many causes have been suggested, including light-dark cycles, temperature/weather, and infectious agents. The authors analyzed monthly mortality in the United States during the period 1959-1999 for four major disease classes. The authors isolated the seasonal component of mortality by removing trends and standardizing the time series. They evaluated four properties: coincidence in mortality peaks, autocorrelation structure and autoregressive integrated moving average (ARIMA) models, magnitude, and age distribution. Peak months of mortality for ischemic heart disease, cerebrovascular disease, and diabetes mellitus coincided appropriately with peaks in pneumonia and influenza, and coefficients of autocorrelation and ARIMA models were essentially indistinguishable. The magnitude of the seasonal component was highly correlated with traditional measures of excess mortality and was significantly larger in seasons dominated by influenza A(H2N2) and A(H3N2) viruses than in seasons dominated by A(H1N1) or B viruses. There was an age shift in mortality during and after the 1968/69 pandemic in each disease class, with features specific to influenza A(H3N2). These findings suggest that the cause of the winter increase in US mortality is singular and probably influenza. Weather and other factors may determine the timing and modulate the magnitude of the winter-season increase in mortality, but the primary determinant appears to be the influenza virus.


Comparative Proteomic Analysis of the Effect of the Four-Herb Chinese Medicine ANBP on Promoting Mouse Skin Wound Healing.
Traditional Chinese medicine has great potential to improve wound healing. ANBP, the mixture of 4 Chinese herbs- Agrimoniapilosa, Nelumbonucifera, Boswelliacarteri, and Pollen typhae-is effective in trauma treatment while its mechanism is still elusive. In this study, quantitative proteomics and bioinformatics analyses were performed to decipher the possible roles of ANBP in accelerated wound healing of mouse skin. Among all 3171 identified proteins, 90, 71, 80, and 140 proteins were found to be differently expressed in 6 hours, 3 days, 7 days, and 14 days ANBP-treated tissues compared with corresponding control tissues, respectively. The result showed that different biological processes and pathways were activated at different healing stages. At the early healing stage, ANBP treatment mainly affected several biological processes, including immune and defense response, vascular system restoration, hemostasis and coagulation regulation, lipid metabolism and signal transduction, while muscle tissue, hair, epidermis, extracellular matrix and tissue remodeling related activities were the major events in ANBP promoted later wound healing. This is the first quantitative proteome study of ANBP-treated wound tissues, which provide a new perspective for the mechanism of ANBP accelerated wound healing and is of guiding significance for clinical application of ANBP in trauma disorders cure.


Affinity labelling of smooth-muscle myosin light-chain kinase with 5'-[p-(fluorosulphonyl)benzoyl]adenosine.
5'-(p-(Fluorosulphonyl)[14C]benzoyl)adenosine (FSBA) was synthesized and used as a probe to study the ATP-binding site of smooth-muscle myosin light-chain kinase (MLCK). FSBA modified both free MLCK and calmodulin/MLCK complex, resulting in inactivation of the kinase activity. Nearly complete protection of the calmodulin/MLCK complex against FSBA modification was obtained by addition of excess ATP whereas MLCK activity alone was lost in a dose-dependent manner even in the presence of excess ATP. These results suggest that FSBA modified ATP-binding sites and ATP-independent sites, and the latter sites are protected by calmodulin binding. The results also suggest that the ATP-binding site is accessible to the nucleotide substrate regardless of calmodulin binding. The FSBA-labelled MLCK was completely proteolysed by alpha-chymotrypsin, and the 14C-labelled peptides were isolated and sequenced. The sequence of the labelled peptide was Ala-Gly-X-Phe, where X is the labelled residue. The sequence was compared with the known MLCK sequence, and the labelled residue was identified as lysine-548, which is located downstream of the GXGXXG motif conserved among ATP-utilizing enzymes.


Inflammation risk before cardiac surgery and the treatment effect of intraoperative dexamethasone.
Patients who exhibit high systemic inflammation after cardiac surgery may benefit most from pre-emptive anti-inflammatory treatments. In this secondary analysis (n = 813) of the randomised, double-blind Intraoperative High-Dose Dexamethasone for Cardiac Surgery trial, we set out to develop an inflammation risk prediction model and assess whether patients at higher risk benefit from a single intraoperative dose of dexamethasone (1 mg/kg). Inflammation risk before surgery was quantified from a linear regression model developed in the placebo arm, relating preoperatively available covariates to peak postoperative C-reactive protein. The primary endpoint was the interaction between inflammation risk and the peak postoperative C-reactive protein reduction associated with dexamethasone treatment. The impact of dexamethasone on the main clinical outcome (a composite of death, myocardial infarction, stroke, renal failure, or respiratory failure within 30 days) was also explored in relation to inflammation risk. Preoperatively available covariates explained a minority of peak postoperative C-reactive protein variation and were not suitable for clinical application (R2 = 0.058, P = 0.012); C-reactive protein before surgery (excluded above 10 mg/L) was the most predictive covariate (P < 0.001). The anti-inflammatory effect of dexamethasone increased as the inflammation risk increased (-0.689 mg/L per unit predicted peak C-reactive protein, P = 0.002 for interaction). No treatment-effect heterogeneity was detected for the main clinical outcome (P = 0.167 for interaction). Overall, risk predictions from a model of inflammation after cardiac surgery were associated with the degree of peak postoperative C-reactive protein reduction derived from dexamethasone treatment. Future work should explore the impact of this phenomenon on clinical outcomes in larger surgical populations.


Evaluation of Chemotherapy Induced Peripheral Neuropathy, Sarcopenia and Fatigue in Children with Acute Lymphoblastic Leukaemia and Lymphoma in Tertiary Care Hospital, Dakshina Kannada.
The study aims to assess the proportion and magnitude of chemotherapy-induced peripheral neuropathy (CIPN) and other common complications reported in children with acute lymphoblastic leukaemia (ALL)/ acute lymphoblastic lymphoma (LBL) undergoing chemotherapy. The study included children between 5 and 18 years old with ALL/LBL undergoing chemotherapy in Tertiary Care Hospitals, Mangalore. The study was conducted using various instruments, including paediatric-modified total neuropathy scale for CIPN, handheld dynamometer for muscle strength, bioimpedance analyser for muscle mass, timed up-and-go test for physical performance, and national comprehensive cancer network (NCCN) guidelines for scoring cancer-related fatigue at 3-time points. The collected data were analysed by IBM Statistical Package for the Social Sciences version 29 using Z-scores with standard deviation for distinct ALL/LBL types. In addition, the Paired t-test compared the baseline outcome to the 3rd and 6th time points. The study evaluated 25 children with ALL undergoing chemotherapy based on the UKALL 2003 protocol during their maintenance phase. The study found that 25 children experienced CIPN, with changes in sensory and pin sensibility scores at 3 and 6 months. The study found a significant change in handgrip strength, body mass index, and muscle mass at 3 months, with no significant change in physical performance over time. Fatigue scores increased from baseline to 3 months, with significant changes observed for the 7-12 years age group at 3 months but not for the 5-6 years age group at 6 months. Children with ALL/LBL undergoing chemotherapy experience CIPN and other side effects such as sarcopenia and fatigue. The study highlights the potential benefits of physiotherapy interventions and supportive care strategies aimed at managing the adverse effects of chemotherapy in children with ALL/LBL.


Colorimetric and ratiometric near-infrared fluorescent cyanide chemodosimeter based on phenazine derivatives.
Two new near-infrared chemodosimeters for cyanide anion based on 5,10-dihexyl-5,10-dihydrophenazine were designed and synthesized. With dicyano-vinyl groups as the recognition site and electron-withdrawing groups on both sides, probe 1 exhibited an intramolecular charge transfer (ICT) absorption band at 545 nm and emission band at 730 nm, respectively, and thus showed an ICT block process and realized an "on-off" response after bilateral reaction with cyanide anions in CH₃CN. Probe 2 utilized an unreactive formyl group instead of one of the two reactive dicyano-vinyl groups as the electron-withdrawing component. Due to the unilateral recognition process the ICT of probe 2 was redirected and lead to a remarkably colorimetric and ratiometric near-infrared (NIR) fluorescent response for cyanine. Both probes provided high sensitivity and selectivity with apparent response signals which can be observed by naked eyes, even in the copresence of various other interference anions. Optical spectroscopic techniques, NMR titration measurements, and density functional theory calculations were conducted to rationalize the sensing mechanisms of these two probes.


Transient outward K+ current can strongly modulate action potential duration and initiate alternans in the human atrium.
Efforts to identify the mechanisms for the initiation and maintenance of human atrial fibrillation (AF) often focus on changes in specific elements of the atrial "substrate," i.e., its electrophysiological properties and/or structural components. We used experimentally validated mathematical models of the human atrial myocyte action potential (AP), both at baseline in sinus rhythm (SR) and in the setting of chronic AF, to identify significant contributions of the Ca2+-independent transient outward K+ current ( Ito) to electrophysiological instability and arrhythmia initiation. First, we explored whether changes in the recovery or restitution of the AP duration (APD) and/or its dynamic stability (alternans) can be modulated by Ito. Recent reports have identified disease-dependent spatial differences in expression levels of the specific K+ channel α-subunits that underlie Ito in the left atrium. Therefore, we studied the functional consequences of this by deletion of 50% of native Ito (Kv4.3) and its replacement with Kv1.4. Interestingly, significant changes in the short-term stability of the human atrial AP waveform were revealed. Specifically, this K+ channel isoform switch produced discontinuities in the initial slope of the APD restitution curve and appearance of APD alternans. This pattern of in silico results resembles some of the changes observed in high-resolution clinical electrophysiological recordings. Important insights into mechanisms for these changes emerged from known biophysical properties (reactivation kinetics) of Kv1.4 versus those of Kv4.3. These results suggest new approaches for pharmacological management of AF, based on molecular properties of specific K+ isoforms and their changed expression during progressive disease. NEW & NOTEWORTHY Clinical studies identify oscillations (alternans) in action potential (AP) duration as a predictor for atrial fibrillation (AF). The abbreviated AP in AF also involves changes in K+ currents and early repolarization of the AP. Our simulations illustrate how substitution of Kv1.4 for the native current, Kv4.3, alters the AP waveform and enhances alternans. Knowledge of this "isoform switch" and related dynamics in the AF substrate may guide new approaches for detection and management of AF.


Comparison of rapid cranial MRI to CT for ventricular shunt malfunction.
To compare the accuracy of rapid cranial magnetic resonance imaging (MRI) with that of computed tomography (CT) for diagnosing ventricular shunt malfunction. We performed a single-center, retrospective cohort study of children ≤21 years of age who underwent either rapid cranial MRI or cranial CT in the emergency department (ED) for evaluation of possible ventricular shunt malfunction. Each neuroimaging study was classified as "normal" (unchanged or decreased ventricle size) or "abnormal" (increased ventricle size). We classified a patient as having a ventricular shunt malfunction if operative revision for relief of mechanical causes of altered shunt flow was needed within 72 hours of initial ED evaluation. Our primary analysis tested noninferiority of the accuracy of rapid cranial MRI to CT for diagnosing shunt malfunction (noninferiority margin 10%). We included 698 ED visits for 286 unique patients, with a median age at visit of 10.0 years (interquartile range 5.9-15.5 years). Patients underwent CT in 336 (48%) or rapid cranial MRI in 362 (52%) of ED visits for evaluation of possible shunt malfunction. Patients had operative revision for ventricular shunt malfunction in 140 ED visits (20%). The accuracy of rapid cranial MRI was not inferior to that of CT scan for diagnosing ventricular shunt malfunction (81.8% MRI vs 82.4% CT; risk difference 2.0%; 95% confidence interval, -4.2% to 8.2%). Rapid cranial MRI was not inferior to CT for diagnosing ventricular shunt malfunction and offers the advantage of sparing a child ionizing radiation exposure.


[The detoxification of Naja naja atra venom and preparation of potent antivenin].
The 99.2% toxicity of Naja naja atra venom can be detoxified by treatment with 0.25% GA (glutaraldehyde) solution at pH 6.8 and still remains its antigenicity. Using the GA treated venom incorporated with Freund's complete adjuvant as immunogen, the titer of immune horse sera can be enhanced rapidly. The modified immunization method not only shortened the period of immunization (from 180 to 60 days), but also increased the potency of immune sera (from 75 to 170 units). The method also diminished the mortality rate of the horse during the immunization period (from 37 to 0%) and increased the antibody production rate (from 20 to 100%), as compared to Tanaka's method. With the present method, significant economic effects can be achieved. The neutralization antibody titer of Naja naja atra antivenin could be elevated 3.55 times through purification of the antivenin with the pepsin digestion method. The antivenin recovery rate using the pepsin digestion method was about 55.44%. The solubility of lyophilized antivenin was significantly improved by the addition of 2% glycine. In addition to an increase of antivenin potency and purity, the problem of an inadequate production rate has also been resolved. Now lyophilized antivenin can be supplied even to remote areas, thus providing excellent opportunities for clinical application. This Institute has already adopted this new immunization schedule in lieu of the old Tanaka method.


A Life Course Perspective on Child Health, Academic Experiences and Occupational Skill Qualifications in Adulthood: Evidence from a British Cohort.
Existing research rarely examines the social consequences of poor childhood health from a longitudinal perspective. Using data from the British National Child Development Study, I follow a cohort from before birth through middle age to examine whether children's health limitations before and during the educational process predict occupational skill qualifications in mid-adulthood, and whether any negative consequences are strongest for children in persistently poor health. I also examine whether differences in achievement explain the observed associations, and at what point during the schooling process performance begins to play a large explanatory role. Poor health is strongly negatively related to qualifications in adulthood, particularly for children in persistently poor health. These associations are largely explained by differences in performance early in children's academic careers, before the first important transition point. The relationship between prenatal maternal smoking and mid-adulthood qualifications is more persistent. This paper demonstrates that a static conceptualization of childhood health is inadequate to fully understand the dynamic process through which social status and health over the course of childhood have long-run consequences for the adult life course.


Iridoplasty for plateau iris syndrome: a systematic review.
Plateau iris syndrome (PIS) is a frequent cause of angle closure. Argon laser peripheral iridoplasty (ALPI) has been proposed in PIS to widen the iridocorneal angle. The objective of the present study was to perform a systematic review of the available studies evaluating the efficacy of ALPI on intraocular pressure (IOP), iridocorneal angle opening and the number of medications in patients with chronic angle-closure associated with PIS. One prospective and seven retrospective studies with a minimum 1 month of follow-up were included. Although ALPI seemed to lower IOP, to decrease the number of topical antiglaucoma medications and widen the iridocorneal angle shortly after the procedure, there is no current evidence of long-term efficacy. To date, there is no robust scientific evidence to advocate ALPI as a treatment for chronic angle-closure caused by PIS.


Biochemical evidence on the potential role of organophosphates in hepatic glucose metabolism toward insulin resistance through inflammatory signaling and free radical pathways.
Several studies show that organophosphate pesticides exert several effects on glucose homeostasis. The current study investigates the influence of subchronic exposure to malathion (MT) on hepatic gluconeogenesis in relation to acetyl cholinesterase (AChE) inhibition, oxidative stress and inflammatory response in the rat. MT was administered by gavage at doses of 25, 50 and 100 mg/kg for 32 days. Fasting hyperglycemia was seen in line with an increased activity of hepatic phosphoenolpyruvate carboxykinase, glucose 6-phosphatase and tumor necrosis factor α. In addition to the impaired glucose tolerance and inhibition of AChE in a dose-dependent manner, there were significant increases in hepatic lipid peroxidation, carbonyl groups and 8-deoxyguanosine as the biomarkers of reactive oxygen species-mediated damage to lipid, protein and DNA, respectively. Altered quality of the liver in glucose production especially gluconeogenesis could be a compensatory mechanism against MT toxicity or even result in tissue damage. MT-induced insulin resistance in the liver occurs through oxidative and inflammatory signaling pathways.


Tension free vaginal tape: is the intra-operative cough test necessary?
The tension-free vaginal tape (TVT) procedure is recognised as an effective treatment for genuine stress incontinence. It was first described using local anaesthesia, with an intra-operative cough test helping to correctly position the tape. Many patients prefer general anaesthesia and often, patients with genuine stress incontinence do not leak when supine. This aim of this study was to compare the outcome in TVTs performed under general anaesthesia with those performed under spinal anaesthesia. Retrospective analysis of 105 patients, all of whom had urodynamically proven genuine stress incontinence and underwent TVT procedure, was performed: 52 under spinal anaesthesia and 53 under general anaesthesia. The primary and secondary outcome measures were the success or failure of the procedure and the complication rate, respectively. There was no significant difference in outcome or complication rate between the two groups. The type of anaesthetic used does not influence the outcome and we question the necessity of an intra-operative cough test.


Pranlukast Antagonizes CD49f and Reduces Stemness in Triple-Negative Breast Cancer Cells.
Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clinically tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces conformational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transactivation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients.


Chrisman-Snook ankle ligament reconstruction outcomes--a local experience.
Chrisman-Snook reconstruction is a surgical method of treating chronic lateral ankle instability. This study aims to examine the outcome and possible factors including joint hypermobility that may influence the outcome in our local population. Twenty-four ankles with chronic lateral ankle instabilities were treated with the Chrisman-Snook reconstruction procedure between May 1995 and November 1997. Fifteen were available for review at an average follow-up period of 35.3 months, ranging from 26 to 51 months. The patients were young and the average age was 24 years. The lateral ligaments were reconstructed by rerouting half the peroneus brevis tendon, based distally, through the lateral malleolus and anchoring it to the calcaneum. Functional results were assessed using the Kaikkonen ankle stability score. Joint hypermobility was assessed by the Beighton et al score. Excellent results were achieved in ten cases, good in four, and fair in one. None had poor results. Best outcomes tended to occur in patients with joint hypermobility. Complications included decreased sensation in a small area of the lateral foot. Chrisman-Snook reconstruction is a surgical option for young patients who have failed conservative treatment for chronic ankle instability. In our local population with a higher incidence of joint hypermobility, it gave good results with few serious complications.


Isolation and quantification of apolipoproteins C-I, C-II, and C-III0-2 in very-low-density lipoproteins by "high-performance" anion-exchange chromatography.
Using "high-performance" anion-exchange chromatography, we isolated and quantified human C apolipoproteins (apo C) from very-low-density lipoproteins (VLDL) in serum. As revealed by isoelectric focusing and double immunodiffusion against monospecific antisera, apo C-I, apo C-II, apo C-III0, apo C-III1, and apo C-III2 were purified to homogeneity. Assay reproducibility (coefficients of variation) ranged between 0.9% and 4.7%. The relative percentages of apo C subspecies in VLDL from normal and hypertriglyceridemic serum samples agreed with data obtained by alternative methods. This precise technique is suitable for detecting and analyzing abnormalities of C apolipoproteins in VLDL.


Systematic relationships and cospeciation of bacterial endosymbionts and their carpenter ant host species: proposal of the new taxon Candidatus Blochmannia gen. nov.
The systematic relationships of intracellular bacteria of 13 Camponotus species (carpenter ants) from America and Europe were compared to those of their hosts. Phylogenetic trees of the bacteria and the ants were based on 16S rDNA (rrs) gene sequences and mitochondrial cytochrome oxidase subunit I (COI) gene sequences, respectively. The bacterial endosymbionts of Camponotus spp. form a distinct lineage in the y-subclass of the Proteobacteria. The taxa most closely related to these bacteria are endosymbionts of aphids and the tsetse fly. The bacterial and host phylogenies deduced from the sequence data show a high degree of congruence, providing significant evidence for cospeciation of the bacteria and the ants and a maternal transmission route of the symbionts. The cloned rrs genes of the endosymbionts contain putative intervening sequences (IVSs) with a much lower G+C content than the mean of the respective rrs genes. By in situ hybridization specific 16S rDNA oligonucleotide probes verified the presence of the bacteria within tissues of three of the eukaryotic hosts. It is proposed that the endosymbionts of these three carpenter ants be assigned to a new taxon 'Candidatus Blochmannia gen. nov.' with the symbionts of the individual ants being species named according to their host, 'Candidatus Blochmannia floridanus sp. nov.', 'Candidatus Blochmannia herculeanus sp. nov.' and 'Candidatus Blochmannia rufipes sp. nov.'.


[Phlebothrombosis of the amputation femur stump: certain aspects of pathogenesis and prophylactics].
An experience with treatment of 455 patients who underwent transfemoral amputation was analyzed. In 54 patients (11.9%) phlebothrombosis of the femur stump developed in the early postoperative period. Certain little studied problems of pathogenesis of the complication in question are considered, possible variants of the clinical picture are described. Negative role of thrombosis of the femur stump veins is shown in the development of thromboembolism of the lung artery that was a direct cause of death of 20 patients. Prophylactics of stump phlebothrombosis allows getting less frequency of the development of this complication, decreased lethality, improvement of quality of life and duration of life of patients after transfemoral amputation.


Positron Emission Tomography-Determined Hyperemic Flow, Myocardial Flow Reserve, and Flow Gradient-Quo Vadis?
Positron emission tomography/computed tomography (PET/CT) applied with positron-emitting flow tracers such as 13N-ammonia and 82Rubidium enables the quantification of both myocardial perfusion and myocardial blood flow (MBF) in milliliters per gram per minute for coronary artery disease (CAD) detection and characterization. The detection of a regional myocardial perfusion defect during vasomotor stress commonly identifies the culprit lesion or most severe epicardial narrowing, whereas adding regional hyperemic MBFs, myocardial flow reserve (MFR), and/or longitudinal flow decrease may also signify less severe but flow-limiting stenosis in multivessel CAD. The addition of regional hyperemic flow parameters, therefore, may afford a comprehensive identification and characterization of flow-limiting effects of multivessel CAD. The non-specific origin of decreases in hyperemic MBFs and MFR, however, prompts an evaluation and interpretation of regional flow in the appropriate context with the presence of obstructive CAD. Conversely, initial results of the assessment of a longitudinal hyperemic flow gradient suggest this novel flow parameter to be specifically related to increases in CAD caused epicardial resistance. The concurrent assessment of myocardial perfusion and several hyperemic flow parameters with PET/CT may indeed open novel avenues of precision medicine to guide coronary revascularization procedures that may potentially lead to a further improvement in cardiovascular outcomes in CAD patients.


Using Latent Semantic Analysis to Score Short Answer Constructed Responses: Automated Scoring of the Consequences Test.
Automated scoring based on Latent Semantic Analysis (LSA) has been successfully used to score essays and constrained short answer responses. Scoring tests that capture open-ended, short answer responses poses some challenges for machine learning approaches. We used LSA techniques to score short answer responses to the Consequences Test, a measure of creativity and divergent thinking that encourages a wide range of potential responses. Analyses demonstrated that the LSA scores were highly correlated with conventional Consequence Test scores, reaching a correlation of .94 with human raters and were moderately correlated with performance criteria. This approach to scoring short answer constructed responses solves many practical problems including the time for humans to rate open-ended responses and the difficulty in achieving reliable scoring.


Utility of Prehospital Quantitative End Tidal CO2?
End tidal CO2 (ETCO2) has been established as a standard for confirmation of an airway, but its role is expanding. In certain settings ETCO2 closely approximates the partial pressure of arterial CO2 (PaCO2) and has been described as a tool to optimize a patient's ventilatory status. ETCO2 monitors are increasingly being used by EMS personnel to guide ventilation in the prehospital setting. Severely traumatized and burn patients represent a unique population to which this practice has not been validated. The sole use of ETCO2 to monitor ventilation may lead to avoidable respiratory acidosis. A consecutive series of patients with burns or trauma intubated in the prehospital setting over a 24-month period were evaluated. Prehospital arrests were excluded. Absence of ETCO2 transport data and patients without an arterial blood gas (ABG) within 15 minutes of arrival were also excluded. Data collected included demographics, place and time of intubation, service performing intubation, ETCO2 maintained en-route to hospital, and ABG upon arrival. Further data included length of stay, mortality, and injury severity scores. One hundred sixty patients met the inclusion criteria. Prehospital ETCO2 did not correlate with measured PaCO2 (R2 = 0.08). Mean ETCO2 was significantly lower than mean PaCO2 (34 mmHg vs 44 mmHg, P < .005). Patients arriving acidotic were more likely to die. Mean pH on arrival for survivors and decedents was 7.32 and 7.19 respectively (P < .001). Mortality, acidosis, higher base deficits, and more severe injury patterns were all predictors for a worse correlation between ETCO2 and PaCO2 and increased mean difference between the two values. Decedents and patients presenting with a pH <7.2 demonstrated the greatest discrepancy between ETCO2 and PaCO2. The data suggest that patients may be hypoventilated by prehospital providers in order to obtain a prescribed ETCO2. ETCO2 is an inadequate tool for predicting PaCO2 or optimizing ventilation in severely injured patients. Adherence to current ETCO2 guidelines in the prehospital setting may contribute to acidosis and increased mortality. Consideration should be given to developing alternate protocols to guide ventilation of the severely injured in the prehospital setting.


Yin yang 1 modulates taxane response in epithelial ovarian cancer.
Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary serous epithelial ovarian cancer and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function.


Orbital inflammatory syndromes with systemic involvement may mimic metastatic disease.
Physical examination of a 9-year-old girl with a 2-month history of swelling of the left orbit demonstrated an orbital mass, blepharoptosis, and proptosis. Computed tomography revealed a 2 x 3-cm mass in the superior left orbit that expanded orbital dimensions. Radiography showed abnormalities in the parietal and frontal bones and distal right tibia. Magnetic resonance imaging demonstrated an 8.5-cm abnormality of the marrow space of the right mid-tibia. Bone marrow biopsy was unremarkable. Orbital and tibial biopsies showed a nonspecific chronic inflammation. Idiopathic inflammation that involves the orbit (orbital pseudotumor) and that has systemic manifestations may mimic more serious conditions, such as metastases from rhabdomyosarcoma or Ewing sarcoma, chronic recurrent multifocal osteomyelitis (CRMO), and SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis). Accurate diagnosis requires careful clinical and pathologic examinations.


Characterization of rhesus macaque B-lymphoblastoid cell lines infected with simian type D retrovirus.
A simian type D retrovirus designated SRV induces a fatal immunosuppressive disease in rhesus macaques. This syndrome shows many clinical similarities to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus-infected individuals. To investigate the mechanisms of immune dysfunction in SRV infection, we have focused on the interactions of SRV serotype 1 (SRV-1) with macaque B-lymphoblastoid cell lines (B-LCL). Procedures were optimized for establishing B-LCL by immortalization of macaque B lymphocytes with rhesus Epstein-Barr virus (EBV). These cell lines express B-cell surface markers, secrete immunoglobulins of the IgG or IgM isotypes, and release EBV which transforms monkey B cells. In vitro cultures of B-LCL supported replication of SRV-1. Several B-LCL infected with SRV-1 showed downregulation of major histocompatibility complex (MHC) class II antigen expression whereas levels of MHC class I antigen remained unchanged. Infection of B-LCL with SRV-1 did not alter the level of secreted immunoglobulin. Rhesus EBV was also used to obtain B-LCL from macaques infected with SRV-1; these cell lines were found to release infectious SRV-1. Investigations on the interactions of SRV-1 with B cells will be useful for elucidating mechanisms involved in the immunopathogenesis of primate retroviruses.


Case report. Candida lusitaniae peritonitis in a patient on continuous ambulatory peritoneal dialysis.
We report a case of Candida lusitania peritonitis in continuous ambulatory peritoneal dialysis. Since fluconazole therapy was not successful in this patient, the peritoneal catheter was removed and antifungal therapy continued, and the patient was then converted to haemodialysis. This treatment protocol was successful. We suggest that early peritoneal catheter removal should be considered in such cases.


Clumping factor A mediates binding of Staphylococcus aureus to human platelets.
The direct binding of bacteria to platelets may be an important virulence mechanism in the pathogenesis of infective endocarditis. We have previously described Staphylococcus aureus strain PS12, a Tn551-derived mutant of strain ISP479, with reduced ability to bind human platelets in vitro. When tested in an animal model of endocarditis, the PS12 strain was less virulent than its parental strain, as measured by bacterial densities in endocardial vegetations and incidence of systemic embolization. We have now characterized the gene disrupted in PS12 and its function in platelet binding. DNA sequencing, Southern blotting, and PCR analysis indicate that PS12 contained two Tn551 insertions within the clumping factor A (ClfA) locus (clfA). The first copy was upstream from the clfA start codon and appeared to have no effect on ClfA production. The second insertion was within the region encoding the serine aspartate repeat of ClfA and resulted in the production of a truncated ClfA protein that was secreted from the cell. A purified, recombinant form of the ClfA A region, encompassing amino acids 40 through 559, significantly reduced the binding of ISP479C to human platelets by 44% (P = 0.0001). Immunoprecipitation of recombinant ClfA that had been incubated with solubilized platelet membranes coprecipitated a 118-kDa platelet membrane protein. This protein does not appear to be glycoprotein IIb. These results indicate that platelet binding by S. aureus is mediated in part by the direct binding of ClfA to a novel 118-kDa platelet membrane receptor.


Fate and transport of mercury in environmental media and human exposure.
Mercury is emitted to the atmosphere from various natural and anthropogenic sources, and degrades with difficulty in the environment. Mercury exists as various species, mainly elemental (Hg(0)) and divalent (Hg(2+)) mercury depending on its oxidation states in air and water. Mercury emitted to the atmosphere can be deposited into aqueous environments by wet and dry depositions, and some can be re-emitted into the atmosphere. The deposited mercury species, mainly Hg(2+), can react with various organic compounds in water and sediment by biotic reactions mediated by sulfur-reducing bacteria, and abiotic reactions mediated by sunlight photolysis, resulting in conversion into organic mercury such as methylmercury (MeHg). MeHg can be bioaccumulated through the food web in the ecosystem, finally exposing humans who consume fish. For a better understanding of how humans are exposed to mercury in the environment, this review paper summarizes the mechanisms of emission, fate and transport, speciation chemistry, bioaccumulation, levels of contamination in environmental media, and finally exposure assessment of humans.


Protease-activated receptor-2 activates NQO-1 via Nrf2 stabilization in keratinocytes.
Protease-activated receptor-2 (PAR-2) mediates inflammation and immune responses by serine proteinases. NF-E2-related factor 2 (Nrf2) confers protection against tissue injury through antioxidant responses to oxidative stress induced by a variety of factors, including electrophilic chemicals, hydrogen peroxide, and ultraviolet irradiation. In this study, we investigated if PAR-2 activation can stimulate Nrf2 signaling to preserve homeostasis in keratinocytes. We performed western blotting, real-time reverse transcription polymerase chain reaction, and immunocytochemistry of keratinocyte cultures, as well as immunohistochemical labeling of human skin samples. Short interfering RNA (siRNA) was employed to confirm the effects of PAR-2 activation. PAR-2 activation with a selective PAR-2 agonist peptide increased the nuclear level of Nrf2 protein and subsequently induced phase II enzyme expression. Nrf2 signaling via PAR-2 activation was confirmed with experiments using PAR-2-siRNA-treated keratinocytes. The activation of an Nrf2-targeted gene by PAR-2 activation was not induced by new production of Nrf2 but by prolonged stabilization of Nrf2. Lesional skin samples from vitiligo patients showed significantly lower expression of PAR-2 and Nrf2 than control skin samples. Collectively, PAR-2 activation enhanced nuclear Nrf2 translocation, and PAR-2-mediated Nrf2 activation was attributable to existing Nrf2 stabilization rather than de novo production. Our findings suggest that in addition to induction of inflammation, PAR-2 can play a chemopreventative role via Nrf2 stabilization in keratinocytes.


Precise prediction of the radiation pneumonitis in lung cancer: an explorative preliminary mathematical model using genotype information.
Purpose: Radiation pneumonitis (RP) is the most significant dose-limiting toxicity and is one major obstacle for lung cancer radiotherapy. Grade ≥2 RP usually needs clinical interventions and serve RP could be life threatening. Clinically, tissue response could be strikingly different even two similar patients after identical radiotherapy. Previous methods for the RP prediction can hardly distinguish substantial variations among individuals. Reliable predictive factors or methods emphasizing the individual differences are strongly desired by clinical radiation oncologists. The purpose of this study is to develop an approach for the personalized RP risk prediction. Experimental Design: One hundred eighteen lung cancer patients who received radiotherapy were enrolled. Seven hundred thousand single-nucleotide polymorphism (SNP) sites were assessed via Generalized Linear Models via Lasso and Elastic-Net Regularization (GLMNET) to determine their synergistic effects on the RP risk prediction. Non-genetic factors including patient's phenotypes and clinical interventional parameters were separately assessed by statistic test. Based on the results of the aforementioned analysis, a multiple linear regression model named Radiation Pneumonitis Index (RPI) was built, for the assessment of Grade ≥2RP risk. Results: Only previous surgery and fractional dose were discovered statistical significantly associated with grade ≥2RP. Thirty-nine effective SNPs for predicting the Grade ≥2RP risk were discovered and their coefficients of the synergistic effect were determined. The RPI score can successfully distinguish the RP≥2 population with 92.0% sensitivity and 100% specificity. Conclusions: Individual radiation sensitivity can be determined with genotype information and personalized radiotherapy could be achieved based on mathematical model result.


Antibiotic and sulfonamide agents in bob veal calf muscle, liver, and kidney.
During the fiscal year 1988, USDA-FSIS detected 3,095 antimicrobial violations in bob veal calves, using the calf antibiotic and sulfonamide test. Of the 3,095 carcass submissions involved, 945 were tested further to identify the causative agents. The results of tests on the available kidney, liver, and muscle specimens are reported. Kidney specimens yielded a specific agent most often (71.2%), with neomycin (42.6%) being cited most among agents found in kidneys. Neomycin was found less frequently in liver (4.5%) and muscle (0.2%). Among all tissues, unidentified microbial inhibitors were either the largest or second largest category found (kidney, 10.5%; liver, 27.1%; muscle, 7.8%), and no other agent exceeded 7.0% (streptomycin in kidney). The proportion of liver and muscle specimens that had unidentified microbial inhibitors is particularly important because the next most common classes were streptomycin in liver at 5.5% and sulfamethazine in muscle at 2%. The frequency of unidentified microbial inhibitors may justify the addition of tests to the FSIS battery for identification of agents. Not all tissues were tested for sulfonamides, hence these agents are likely to have been underreported. Less than 10% of the muscle specimens evaluated yielded an agent, suggesting most calf antibiotic and sulfonamide test-positive carcasses may have been safe with regard to residues in meat, although organs might have been adulterated. Specimens for verification were not selected completely randomly from the population of all calf antibiotic and sulfonamide test-positive animals and calves selected for testing were not chosen strictly by random sampling; therefore, extrapolation of the contents of this report to the bob veal calf industry must be done with caution.


[Bronchopulmonary diseases in workers engaged in deep-mined extraction of copper-nickel ore].
Examinations were made in 220 male workers exposed to dust-gas (low-silicon dioxide, nitric oxides, and carbon oxide) mixture, physical exercises, and cooling microclimate on deep-mined output of copper-nickel ore. Twenty-eight per cent of the workers were found to have evolving chronic bronchitis that did not substantially affect the patients' working capacity; 3.2% had chronic obstructive pulmonary disease and 1.4% had asthma that had developed before the onset of professional activity. 32.3% of the examinees were ascertained to have individual clinicofunctional disorders that permit their identification as a bronchopulmonary disease risk group to carry out early preventive and rehabilitative measures.


The B-cell receptor pathway: a critical component of healthy and malignant immune biology.
The pathogenesis and progression of normal B-cell development to malignant transformation of chronic lymphocytic leukemia (CLL) is still poorly understood and has hampered attempts to develop targeted therapeutics for this disease. The dependence of CLL cells on B-cell receptor signaling has fostered a new area of basic and therapeutic research interest. In particular, identification of the dependence of CLL cells on both phosphatidylinositol 3-kinase delta and Bruton's tyrosine kinase signaling for survival and proliferation has come forth through well-performed preclinical studies and subsequent trials demonstrating dramatic efficacy. This review outlines essential components of B-cell receptor signaling and briefly addresses therapeutics that are emerging to target these in patients with CLL and related lymphoid malignancies.


Mitogenic effects of hydroxyapatite and calcium pyrophosphate dihydrate crystals on cultured mammalian cells.
Synthetic hydroxyapatite (HA) crystals in 1% serum stimulated 3H thymidine uptake into quiescent canine synovial fibroblasts and human foreskin fibroblast cultures, as did 10% serum. The onset of stimulation and peak uptake of thymidine after crystal addition were delayed by 2-3 hours as compared with the effects produced by 10% serum. Stimulation of 3H thymidine uptake was proportional to the serum concentration used. HA crystals (50 micrograms/ml) stimulated nuclide uptake at each serum concentration used. 3H thymidine uptake was also proportional to the dose of HA or calcium pyrophosphate dihydrate crystals, although larger doses of the latter crystal were required to produce equivalent effects. Not all particulates were effective mitogenic agents. Latex beads and diamond crystals had no effect. Monosodium urate crystals modestly stimulated and calcium urate crystals markedly stimulated nuclide uptake. The more complex crystals found in a naturally occurring condition (calcinosis) were as mitogenic as the pure synthetic HA. The synovial cell hyperplasia sometimes associated with crystals might be explained in part by their mitogenic activity.


Activity and Safety of Cetuximab Plus Modified FOLFOXIRI Followed by Maintenance With Cetuximab or Bevacizumab for RAS and BRAF Wild-type Metastatic Colorectal Cancer: A Randomized Phase 2 Clinical Trial.
The combination of a triple-drug chemotherapy regimen with an anti-epidermal growth factor receptor (EGFR) agent as a first-line treatment of metastatic colorectal cancer (mCRC) showed promising activity along with safety concerns in single-arm phase 2 trials. The role of maintenance following chemotherapy and anti-EGFR and the optimal regimen to be adopted are not established. To evaluate the activity and safety of cetuximab plus modified FOLFOXIRI (mFOLFOXIRI) and explore the role of maintenance with cetuximab or bevacizumab in RAS and BRAF wild-type mCRC. In a prospective, noncomparative, open-label, multicenter, randomized phase 2 trial, patients aged 18 to 75 years with unresectable, previously untreated RAS and BRAF wild-type (before amendment, KRAS wild-type) mCRC were recruited from 21 oncology units in Italy from October 19, 2011, to March 1, 2015 (followed up through May 31, 2017). In total, 323 patients were screened and 143 were randomized to 2 treatment arms to receive as a first-line induction a regimen of mFOLFOXIRI plus cetuximab followed by cetuximab (arm A) or bevacizumab (arm B) until disease progression. Primary analyses were conducted in a modified intention-to-treat population. mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles, followed by maintenance with cetuximab or bevacizumab until disease progression. The primary end point was the 10-month progression-free rate (PFR); secondary end points included progression-free and overall survival, response rate, rate of metastases resection, and adverse events. Of 143 patients randomized, 116 (81.1%) (median [interquartile range (IQR)] age, 59.5 [53-67] years; 34 [29.3%] women) had RAS and BRAF wild-type mCRC. At a median (IQR) follow-up of 44.0 (30.5-52.1) months, 10-month PFRs were 50.8% (90% CI, 39.5%-62.2%) in arm A and 40.4% (90% CI, 29.4%-52.1%) in arm B. The overall response rate was 71.6% (95% CI, 62.4%-79.5%). Main grade 3/4 adverse events were neutropenia (occurring in 36 patients [31%]), diarrhea (in 21 patients [18%]), skin toxic effects (in 18 patients [16%]), asthenia (in 11 patients [9%]), stomatitis (in 7 patients [6%]), and febrile neutropenia (in 3 patients [3%]). Although neither of the 2 arms met the primary end point, the findings indicate that a 4-month induction regimen of mFOLFOXIRI plus cetuximab is feasible and provides relevant activity results, leading to a high surgical resection rate. clinicaltrials.gov Identifier: NCT02295930.


Cost-Effectiveness of Smoking Cessation Interventions in the Lung Cancer Screening Setting: A Simulation Study.
Guidelines recommend offering cessation interventions to smokers eligible for lung cancer screening, but there is little data comparing specific cessation approaches in this setting. We compared the benefits and costs of different smoking cessation interventions to help screening programs select specific cessation approaches. We conducted a societal-perspective cost-effectiveness analysis using a Cancer Intervention and Surveillance Modeling Network model simulating individuals born in 1960 over their lifetimes. Model inputs were derived from Medicare, national cancer registries, published studies, and micro-costing of cessation interventions. We modeled annual lung cancer screening following 2014 US Preventive Services Task Force guidelines plus cessation interventions offered to current smokers at first screen, including pharmacotherapy only or pharmacotherapy with electronic and/or web-based, telephone, individual, or group counseling. Outcomes included lung cancer cases and deaths, life-years saved, quality-adjusted life-years (QALYs) saved, costs, and incremental cost-effectiveness ratios. Compared with screening alone, all cessation interventions decreased cases of and deaths from lung cancer. Compared incrementally, efficient cessation strategies included pharmacotherapy with either web-based cessation ($555 per QALY), telephone counseling ($7562 per QALY), or individual counseling ($35 531 per QALY). Cessation interventions continued to have costs per QALY well below accepted willingness to pay thresholds even with the lowest intervention effects and was more cost-effective in cohorts with higher smoking prevalence. All smoking cessation interventions delivered with lung cancer screening are likely to provide benefits at reasonable costs. Because the differences between approaches were small, the choice of intervention should be guided by practical concerns such as staff training and availability.