Structural basis for recognition and catalysis by the bifunctional dCTP deaminase and dUTPase from Methanococcus jannaschii.
Potentially mutagenic uracil-containing nucleotide intermediates are generated by deamination of dCTP, either spontaneously or enzymatically as the first step in the conversion of dCTP to dTTP. dUTPases convert dUTP to dUMP, thus avoiding the misincorporation of dUTP into DNA and creating the substrate for the next enzyme in the dTTP synthetic pathway, thymidylate synthase. Although dCTP deaminase and dUTPase activities are usually found in separate but homologous enzymes, the hyperthermophile Methanococcus jannaschii has an enzyme, DCD-DUT, that harbors both dCTP deaminase and dUTP pyrophosphatase activities. DCD-DUT has highest activity on dCTP, followed by dUTP, and dTTP inhibits both the deaminase and pyrophosphatase activities. To help clarify structure-function relationships for DCD-DUT, we have determined the crystal structure of the wild-type DCD-DUT protein in its apo form to 1.42A and structures of DCD-DUT in complex with dCTP and dUTP to resolutions of 1.77A and 2.10A, respectively. To gain insights into substrate interactions, we complemented analyses of the experimentally defined weak density for nucleotides with automated docking experiments using dCTP, dUTP, and dTTP. DCD-DUT is a hexamer, unlike the homologous dUTPases, and its subunits contain several insertions and substitutions different from the dUTPase beta barrel core that likely contribute to dCTP specificity and deamination. These first structures of a dCTP deaminase reveal a probable role for an unstructured C-terminal region different from that of the dUTPases and possible mechanisms for both bifunctional enzyme activity and feedback inhibition by dTTP.


High incidence of relapses in thrombotic thrombocytopenic purpura. Clinical study of 38 patients.
Described in this study are 38 patients who received treatment for thrombotic thrombocytopenic purpura in 15 hospitals in Israel and the New York City area since 1977, when plasma therapy was introduced. Thirty-seven patients received plasma therapy and 30 survived. In 12 patients (37 percent of survivors), relapsing thrombotic thrombocytopenic purpura developed, manifested by thrombocytopenia and microangiopathic hemolytic anemia, and less frequently by neurological or renal abnormalities. Six patients had a second relapse, and two had five relapses. To assess the severity of the disease, a scoring system was designed based on the four major manifestations of thrombotic thrombocytopenic purpura listed above. The patients who died had a significantly higher score than those who survived. The initial episodes and the relapses of patients with relapsing thrombotic thrombocytopenic purpura were milder than those in patients who only had a single episode and survived. Two relapses, however, were fatal, demonstrating that relapsing thrombotic thrombocytopenic purpura is not a benign disorder. Infections, pregnancy and surgery were frequently associated with the initial episodes and the relapses. Hence, patients who recover from thrombotic thrombocytopenic purpura should be alerted to the possibility of relapse in association with these conditions.


Lithium chloride inhibits cell survival, overcomes drug resistance, and triggers apoptosis in multiple myeloma via activation of the Wnt/β-catenin pathway.
Multiple myeloma (MM) is an extremely malignant plasma cell disease, which is still incurable due to its drug resistance. Lithium chloride (LiCl) functions in many pathological processes, including bipolar disorder, acute brain injuries, and chronic neurodegenerative diseases, but its antagonistic role in MM progression has not been reported thus far. In this study, we found that LiCl inhibited MM cell proliferation and induced MM cell cycle G2/M phase arrest in a dose-dependent manner. Moreover, LiCl overcomes bortezomib (BTZ)-mediated resistance in MM cells and induces apoptosis in BTZ-resistant cells. Our data preliminarily indicate that LiCl induces MM cell apoptosis via activating the Wnt/β-catenin signaling pathway. Overall, our results define LiCl as an inducer of MM cell apoptosis and unveil a crosstalk between BTZ and LiCl in facilitating cell apoptosis.


A Nonsense N -Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency.
The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G > A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.


Recognization of the HLA-A*24:516 allele in a Chinese patient and his daughter.
HLA-A*24:516 has one nucleotide change from HLA-A*24:02:01:01 at nucleotide 194 where Alanine (41) is changed to Glycine.


Penicillin-induced formation of ribonuclease in rice (Oryza sativa L.) endosperm and its inhibition by abscisic acid.
Penicillin stimulates the formation of ribonuclease in embryoless rice (Oryza sativa L.) endosperm and enhances gibberelin-induced response. Penicillin-induced RNase production is completely inhibited by abscisic acid.


The Decoy Substrate of a Pathogen Effector and a Pseudokinase Specify Pathogen-Induced Modified-Self Recognition and Immunity in Plants.
In plants, host response to pathogenic microbes is driven both by microbial perception and detection of modified-self. The Xanthomonas campestris effector protein AvrAC/XopAC uridylylates the Arabidopsis BIK1 kinase to dampen basal resistance and thereby promotes bacterial virulence. Here we show that PBL2, a paralog of BIK1, is similarly uridylylated by AvrAC. However, in contrast to BIK1, PBL2 uridylylation is specifically required for host recognition of AvrAC to trigger immunity, but not AvrAC virulence. PBL2 thus acts as a decoy and enables AvrAC detection. AvrAC recognition also requires the RKS1 pseudokinase of the ZRK family and the NOD-like receptor ZAR1, which is known to recognize the Pseudomonas syringae effector HopZ1a. ZAR1 forms a stable complex with RKS1, which specifically recruits PBL2 when the latter is uridylylated by AvrAC, triggering ZAR1-mediated immunity. The results illustrate how decoy substrates and pseudokinases can specify and expand the capacity of the plant immune system.


Aging but not estrogen alters regional [3H]5-HT binding in the CNS of female Fischer 344 rats.
Age-related changes in serotonergic regulation of neuroendocrine function were investigated in female Fischer 344 rats; serotonin ([3H]5-HT) binding sites were characterized in several brain regions. Neither the number (Bmax) nor the affinity (Kd) of [3H]5-HT sites were altered in the frontal cortex of reproductively young and senescent groups. However, a significant decline in receptor affinity was observed in the hypothalamus and midbrain dorsal raphe nucleus. An increase in the density of binding sites was also observed in the hypothalamus with advancing age. Acute 48 h exposure to estrogen failed to influence [3H]5-HT binding site characteristics in these brain regions. In summary, these results suggest that age-related changes in [3H]5-HT binding are regionally specific. Moreover, the observed changes in hypothalamic 5-HT function may underlie neuroendocrine aging events.


Lectin-mediated reactions in histamine release caused by bacteria.
The bacteria-induced release of histamine was studied in human basophil leukocytes and in isolated rat mast cells. Whole bacteria of Staph. aureus caused release in a 98% pure population of peritoneal mast cells from germ-free rats, indicating a non-immunological mechanism and a direct interaction between the bacteria and the target cells. Probably the bacterial cell wall interacts with the cell membrane, since a preparation of the bacterial cell wall caused a dose-dependent release of histamine from basophil leukocytes similar to that induced by whole bacteria, and repeated washing of whole bacteria did not change the release. Inhibition studies by lectin-binding sugars indicate that aminosugars on the bacterial surface of Staph. aureus interact with lectins on the basophil cell membrane leading to histamine release.


Determination of PNU 157706, a new dual inhibitor of 5alpha-reductase, in rat plasma by high-performance liquid chromatography with ultraviolet detection.
A HPLC procedure was developed and validated for determining nanogram per milliliter concentrations of the dual 5alpha-reductase inhibitor PNU 157706 in rat plasma. The compound was extracted from plasma with diethyl ether followed by purification using a CN cartridge. The chromatographic separation was performed with a C18 column using a water-acetonitrile-methanol mixture as eluent. UV detection at 210 nm was used for the quantification of the compound over the concentration range 5-500 ng/ml plasma. The method has a lower limit of quantification of 5 ng/ml and good precision and accuracy. This method has performed well during analysis of several toxicokinetic and pharmacokinetic studies in the rat.


Measurement of macrophage adherence and spreading with weak electric fields.
A new method to monitor macrophage attachment on protein-coated surfaces and spreading in response to activating agents is described. Murine macrophages were cultured on small gold electrodes coated with protein, and attachment and spreading were detected as electrical impedance changes. The rate of attachment of cells to fibronectin-coated electrodes was measured to be significantly greater than to other proteins tested. Activation agents used included interferon-gamma, lipopolysaccharide and heat killed Listeria monocytogenes. Addition of each agent to macrophages on electrodes resulted in characteristic patterns in the impedance time course with impedance changes as large as 40%.


Folate receptor targeted 17-allylamino-17-demethoxygeldanamycin (17-AAG) loaded polymeric nanoparticles for breast cancer.
Low water solubility and hepatotoxicity limited the clinical use of 17-allylamino-17-demethoxy geldanamycin (17-AAG), an inhibitor of heat shock protein 90 (HSP90). Folate targeted polylactide-co-glycolide-polyethylene glycol-folic acid (PLGA-PEG-FA) nanoparticles containing 17-AAG were prepared and characterized. Cellular uptake and in vitro cytotoxicity of the prepared nanoparticles were determined in MCF-7 human breast cancer cells. The particle size of 17-AAG loaded folate targeted nanoparticles was 238.67±3.52 nm, drug loading was 8.25±2.49% and about 80% of drug was released from the nanoparticles over 10 days. Cellular uptake studies showed much higher intracellular uptake of folate targeted nanoparticle as compared to nontargeted nanoparticles. Cytotoxicity study showed 2 fold increase (P<0.05, n=3) in the cytotoxicity of folate targeted nanoparticle in comparison to free drug or nontargeted nanoparticles. Due to their targeting ability, nanometer size, high drug loading and controlled release behavior, 17-AAG loaded PLGA-PEG-FA nanoparticles might be developed as a targeted delivery system for breast and other cancer treatment.


Development of new atherosclerotic plaque in hypertensive patients: an observational registry study from the Campania-Salute network.
Carotid atherosclerotic plaques (CAPs) can develop despite appropriate antihypertensive therapy. In this observational study, we assessed characteristics associated with risk of incident CAP in a large hypertensive registry. We evaluated 2143 hypertensive patients without evidence of CAP. Incident CAP was censored at the time of the first ultrasound control in which CAP was detected. CAP was defined according to European Society of Hypertension/European Society of Cardiology guidelines. At a median follow-up period of 56.6 months, about one-third of patients (32%; N = 688) exhibited new CAP. Those patients were older, more frequently smokers, diabetic, more often with metabolic syndrome, chronic kidney disease (CKD), longer hypertension history, higher baseline SBP, pulse pressure (PP), fasting glucose, total cholesterol and triglycerides, greater left ventricular mass index, higher PP/stroke index ratio and carotid intima-media thickness (IMT; all P < 0.05). In-treatment BP control was similar in both groups. In multivariable Cox regression, CAP was predicted by older age, diabetes, smoking habit, CKD and higher value of initial IMT (all P < 0.02), independently of BP control during follow-up, antihypertensive therapy and other confounders. In this registry of treated hypertensive patients, after adjusting for age and other confounders, risk of incident CAP did not depend on BP control and type of antihypertensive therapy, whereas it was independently related to the magnitude of initial IMT, independently of significant effect of prevalent diabetes and smoking habit. These findings suggest that antihypertensive treatment strategy to stop progression of cardiovascular disease might be difficult to achieve, once target organ damage is established.


Beta-blockers for congestive heart failure.
The prognosis of patients with congestive heart failure (CHF) can be significantly improved with drug therapy targeted at the renin-angiotensin and adrenergic nervous system. beta-adrenergic blocking drugs, once contraindicated in CHF, have now been shown to improve survival in CHF.


Reverse self-splicing of the tetrahymena group I intron: implication for the directionality of splicing and for intron transposition.
Using short oligoribonucleotides as ligated exon substrates, we show that splicing of the Tetrahymena rRNA group I intron is fully reversible in vitro. Incubation of ligated exon RNA with linear intron produces a molecule in which the splice site sequences of the precursor are reformed. Reversal of self-splicing is favored by high RNA concentration, high magnesium and temperature, and the absence of guanosine. 5' exon sequences that can pair with the internal guide sequence of the intron are required, whereas 3' exon sequences are not essential. Integration of the intron into ligated exon substrates that have the ability to form stem-loop structures is reduced at least one order of magnitude over short, unstructured substrates. We propose that the formation of these structures helps drive splicing in the forward direction. We also show that the Tetrahymena intron can integrate into a beta-globin transcript. This has implications for transposition of group I introns.


Randomized, double-blind trial of exifone versus cognitive problems in Parkinson's disease.
Exifone is a novel substance of the benzophenone group that possesses potent scavenging properties. Initial findings demonstrate beneficial effects on age-related cognitive disorders. In this double-blind clinical trial versus placebo, the efficacy of 2 dosages (600 and 1200 mg/d) was evaluated with regard to Parkinson's disease (PD)-related cognitive disorders, for which there is increasing suspicion of a free-radicals origin. Despite disparities between the treatment groups as assessed by validated scales and subtests, and a considerable placebo effect on main parameters, both dose levels of exifone produced statistically significant improvement of the cognitive items most commonly impaired by PD: immediate recall, naming of objects presented, spatiotemporal orientation, and calculation. These properties suggest a new slot for exifone in the range of therapeutics available.


Role of the prefrontal--thalamic axis in classical conditioning.
The major conclusion to be drawn from the above-described research on the role of the PFCag in classical conditioning is obviously that it plays a primary and perhaps necessary role in the establishment of visceral cues associated with exposure to classical conditioning contingencies. Specifically, these visceral changes appear to be of an inhibitory character. This is significant, since we have postulated that inhibitory cardiac changes invariably accompany initial processing of sensory stimuli for informational value. Such visceral changes are thus not epiphenomena associated with other simultaneously occurring physiological events. A variety of lesion experiments implicate the PFCm as a central structure in this process, since damage to this area greatly attenuates, and in the case of hypothalamic knife cuts, completely eliminates learned bradycardia. Neuroanatomical tract-tracing experiments revealed that the PFCm and lag have direct projections to the NTS and DVM in the dorsomedial medulla and the nucleus ambiguous in the ventral medulla, all of which provide medullary output control of visceral activities. The nucleus ambiguous and DVM have been specifically implicated in vagal control in the rabbit (Ellenberger et al., 1983). Electrical stimulation of the PFCm provides additional evidence that this area of the brain participates in parasympathetic activities, including cardiac inhibition, since stimulation of the entire MD projection cortex, including the PFCm, produces HR decelerations accompanied by depressor responses. However, since lesions of the Iag produced relatively little effect on conditioned bradycardia, this part of the PFCag does not appear to play a major role in the development of conditioned bradycardia. Electrophysiological recording studies, including both multiple unit as well as extracellular single unit studies reinforce these conclusions. A short latency (40-180 msec) CS-evoked increase in MUA was recorded from cells in both the dorsomedial as well as central PFCm. The magnitude of these CS-evoked neuronal changes (a) was correlated with the magnitude of concomitantly occurring conditioned bradycardia; (b) was trial-related; (c) was not obtained in a similar pseudoconditioning group; and (d) declined to pretraining levels during subsequent experimental extinction. Similar, but not identical, CS-evoked changes in neuronal activity were recorded from MD. Although tone-evoked increases in MUA were also obtained from the Iag, this activity did not show the characteristics of associative learning. Single unit analysis also suggests the importance of the PFCm in elicitation of conditioned bradycardia.(ABSTRACT TRUNCATED AT 400 WORDS)


Procalcitonin and infection in elderly patients.
To compare the usefulness of procalcitonin (PCT) in detecting infection in elderly patients with that of other clinical and biological markers. Prospective observational study to compare PCT levels in infected and uninfected patients. Geriatric teaching hospital in Switzerland. Two hundred eighteen elderly patients aged 75 and older admitted to an acute geriatric care unit. Demographic characteristics, comorbidities, Charlson index, general signs (respiratory rate, temperature, pulse rate, confusion, falls, shivering), presence of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, functional score (Functional Independence Measurement (FIM)) biological parameters (PCT, C-reactive protein (CRP), leukocytes, albumin), and definite diagnosis at admission were collected prospectively for each patient. Long-term corticotherapy, chronic immune diseases, fever of 38 degrees C or higher, white blood cell count, pulse rate, FIM, SIRS, sepsis, CRP of 3 mg/mL or higher, and PCT of 0.5 ng/mL or higher were associated with an infection at admission. In multivariate analysis, only sepsis and CRP of 3 mg/mL or higher were still associated with an infection; PCT levels do not show any significant association in the multivariate analysis. In addition, when PCT had good specificity (94%), it had low sensitivity (24%). False-negative PCT was related to lower severity of infection (lower inflammatory reaction and lower acute renal failure) than true-positive PCT. This finding may also be related to aging per se. PCT may be useful to identify severely ill elderly patients admitted to an acute geriatric ward but not to discriminate patients with infection from those without.


The application of virus-like particles as vaccines and biological vehicles.
Virus-like particles (VLPs) can be spontaneously self-assembled by viral structural proteins under appropriate conditions in vitro while excluding the genetic material and potential replication probability. In addition, VLPs possess several features including can be rapidly produced in large quantities through existing expression systems, highly resembling native viruses in terms of conformation and appearance, and displaying repeated cluster of epitopes. Their capsids can be modified via genetic insertion or chemical conjugation which facilitating the multivalent display of a homologous or heterogeneous epitope antigen. Therefore, VLPs are considered as a safe and effective candidate of prophylactic and therapeutic vaccines. VLPs, with a diameter of approximately 20 to 150 nm, also have the characteristics of nanometer materials, such as large surface area, surface-accessible amino acids with reactive moieties (e.g., lysine and glutamic acid residues), inerratic spatial structure, and good biocompatibility. Therefore, assembled VLPs have great potential as a delivery system for specifically carrying a variety of materials. This review summarized recent researches on VLP development as vaccines and biological vehicles, which demonstrated the advantages and potential of VLPs in disease control and prevention and diagnosis. Then, the prospect of VLP biology application in the future is discussed as well.


D3R Grand Challenge 4: prospective pose prediction of BACE1 ligands with AutoDock-GPU.
In this paper we describe our approaches to predict the binding mode of twenty BACE1 ligands as part of Grand Challenge 4 (GC4), organized by the Drug Design Data Resource. Calculations for all submissions (except for one, which used AutoDock4.2) were performed using AutoDock-GPU, the new GPU-accelerated version of AutoDock4 implemented in OpenCL, which features a gradient-based local search. The pose prediction challenge was organized in two stages. In Stage 1a, the protein conformations associated with each of the ligands were undisclosed, so we docked each ligand to a set of eleven receptor conformations, chosen to maximize the diversity of binding pocket topography. Protein conformations were made available in Stage 1b, making it a re-docking task. For all calculations, macrocyclic conformations were sampled on the fly during docking, taking the target structure into account. To leverage information from existing structures containing BACE1 bound to ligands available in the PDB, we tested biased docking and pose filter protocols to facilitate poses resembling those experimentally determined. Both pose filters and biased docking resulted in more accurate docked poses, enabling us to predict for both Stages 1a and 1b ligand poses within 2 Å RMSD from the crystallographic pose. Nevertheless, many of the ligands could be correctly docked without using existing structural information, demonstrating the usefulness of physics-based scoring functions, such as the one used in AutoDock4, for structure based drug design.


Organoids to model liver disease.
The organoid model represents a major breakthrough in cell biology that has revolutionised biomedical research. Organoids are 3D physiological in vitro structures that recapitulate morphological and functional features of in vivo tissues and offer significant advantages over traditional cell culture methods. Liver organoids are of particular interest because of the pleiotropy of functions exerted by the human liver, their utility to model different liver diseases, and their potential application as cell-based therapies in regenerative medicine. Moreover, because they can be derived from patient tissues, organoid models offer new perspectives in personalised medicine and drug discovery. In this review, we discuss the current liver organoid models for the study of liver disease.


Raman efficiencies of natural rocks and minerals: performance of a remote Raman system for planetary exploration at a distance of 10 meters.
Raman spectroscopy is a powerful technique for materials analysis, and we are developing and analyzing a remote Raman system for use on a planetary lander or rover. We have acquired data at a distance of 10m from a variety of geologic materials using different instrument designs. We have employed a pulsed laser with both an ungated detector and a gated detector. A gated detector can reduce long-lived fluorescence while still collecting all Raman signal. In order to design a flight instrument, we need to quantify how natural surfaces will respond to laser stimulus. We define remote Raman efficiency of natural surfaces as the ratio of radiant exitance leaving a natural surface to the irradiance of the incident laser. The radiant exitance of a natural surface is the product of the sample radiance, the projected solid angle, and the full-width-half-maximum of the Raman signal. We have determined the remote Raman efficiency for a variety of rocks and minerals. The best efficiencies are achieved for large, clear, single crystals that produce the most radiant exitance, while darker fine-grained mineral mixtures produce lower efficiencies. By implementing a pulsed laser, gated detector system we have improved the signal detection and have generally decreased the integration time necessary to detect Raman signal from natural surfaces.


Proposal for revision of the TNM classification system for renal cell carcinoma.
The current study defined an optimal tumor size breakpoint to stratify localized renal cell carcinoma (RCC) into groups with significantly different cancer-related outcomes and proposed a revision of the TNM classification system. The authors analyzed the data from 1138 patients who had undergone partial or radical nephrectomy for localized RCC at 7 European urologic centers. The optimal pathologic size breakpoint was calculated using the martingale residuals from a Cox proportional hazards regression model. The mean follow-up time was 87 months. The scatterplot of tumor size versus expected risk of death per patient suggested that an interval of 5-6 cm was appropriate. A total of 720 (63.3%) and 418 (36.7%) patients had tumors measuring < or = 5.5-cm and tumors measuring > 5.5-cm, respectively. Significant cancer-specific survival differences between the two groups of patients were reported in the series by all the centers participating in the study. On univariate analysis, the other variables found to be associated with cancer-specific survival were the patient's age, symptomatic tumor presentation, and the Fuhrman nuclear grade. On multivariate analysis, the pathologic stage of the primary tumor defined according to the 5.5-cm breakpoint was found to be an independent predictor of cancer-specific survival, as well as age, mode of presentation, and nuclear grade. According to the multivariate analysis, the authors clustered patients into 3 groups with statistically significant outcome differences: 1) patients with < or = 5.5-cm incidentally detected RCC; 2) patients with < or = 5.5-cm symptomatic RCC; and 3) patients with > 5.5-cm RCC. This cancer-related outcome stratification was valid regardless of the patient's age. The 5.5-cm breakpoint was found to be the optimal tumor size breakpoint with which to stratify patients with organ-confined RCC. The study supported the upgrade of the TNM classification system according to this breakpoint.


Serotonin depletion by 5,7-dihydroxytryptamine or para-chloroamphetamine does not affect cancer anorexia.
Anorectic tumor-bearing rats exhibited increased brain levels of the 5-HT precursor, tryptophan, and metabolite, 5-hydroxyindoleacetic acid (5-HIAA). In an effort to determine whether indoleamine systems had any role in the etiology of cancer anorexia the anorectic effects of cancer (Walker 256 carcinosarcoma) were investigated in immature female rats that had been depleted of brain serotonin (5-HT) by the intracisternal injection of 5,7-dihydroxytryptamine (5,7-DHT) or the systemic injection of para-chloramphetamine (PCA). Although both 5,7-DHT and PCA significantly reduced brain concentrations of 5-HT and 5-HIAA by approximately 50%, no effects on the onset or severity of the anorectic response to cancer were observed. Similarly, neither drug affected eating in non-tumor-bearing control animals. Therefore, these data do not support increased brain 5-HT activity as a primary mediator of cancer anorexia.


The effect of lifetime sodium saccharin dosing on mice initiated with the carcinogen 2-acetylaminofluorene.
Sodium saccharin has been reported to promote the development of urinary bladder tumors in rats following low doses of several carcinogens. To evaluate the generality of this effect between species, an initiation-promotion study was conducted in mice. Weanling female BALB/c mice were initiated with 200 ppm dietary 2-acetylaminofluorene for 90 days. Following a 2-week period of control diet, saccharin was administered at 0, 0.1, 0.5, 1.0, and 5.0% in the diet for the remainder of the 132-week study. An elevated incidence of persistent bladder transitional cell hyperplasia and a low incidence of urothelial and hepatocellular tumors indicated that these organs achieved an adequate dose of the initiator. However, sodium saccharin dosing did not result in an increased incidence of tumors in either the bladder or liver and is therefore not considered to be a promoter of carcinogenesis at these sites in the mouse. Furthermore, sodium saccharin exhibited a modest inhibitory effect on the rate of development of lymphomas in both initiated and noninitiated animals. Interspecies differences in the bladder tumorigenic effect of sodium saccharin and their association with differences in urinary tract physiology are discussed.


Are Discrepancies in Waiting Time for Chest Pain at Emergency Departments between African Americans and Whites Improving Over Time?
One of the Healthy People 2010 goals was to eliminate racial disparities in the U.S health system. To date, we have limited knowledge about the impact of Healthy People on racial disparities at emergency departments (EDs). We sought to investigate whether there has been an improvement in ED waiting time to see a physician for African Americans (AAs) compared to whites with chest pain symptoms that suggest acute coronary syndrome (ACS). A retrospective analysis of the National Hospital and Ambulatory Care Survey data from 2004 to 2011 was conducted in adults with visits related to ACS. We compared covariate-adjusted odds ratios for race for each study year and 2011. In addition, adjusted average differences in waiting times (i.e., time to see a physician) for AAs and whites for each study year were compared. A total of 15,438 visits related to ACS symptoms were made during the study period. The waiting time for AAs (median, 33 min) was statistically longer compared to whites (median, 21 min). In addition, the adjusted waiting time for AAs was 30% longer compared to whites (95% confidence interval, 24-36%). Pairwise comparison of adjusted odds ratios between the year 2011 and other years was not significantly different (all p values = 0.32), suggesting no change in the difference in waiting times during the study period. Among patients presenting to the ED with symptoms suggesting ACS, AA compared to whites waited longer to receive care. In addition, this difference in waiting time persisted during the study period, even after the implementation of the Healthy People 2010 initiative. Additional research is warranted to investigate the underlying reasons for unequal care offered to AAs at EDs and the implications on disease outcome.


Inbreeding and haploid chromosomes: a response to Hedrick (2011).
We have shown that inbreeding allows maternally transmitted organelles to respond to selection on male-specific fitness effects (Wade and Brandvain 2009, see also Unckless and Herren 2009). Hedrick (2011) confirms our results, but takes issue with our characterization of "inbreeding" at mitochondrial loci. The reason for this disagreement is straightforward-we define inbreeding as the process of mating between relatives, whereas Hedrick (2011) defines inbreeding as increased homozygosity at autosomal loci genome-wide, which occurs because of mating between relatives. Here, we insist that our definition is not incorrect, and highlight some benefits of our view.


Electrical double layer interactions between dissimilar oxide surfaces with charge regulation and Stern-Grahame layers.
Models of surfaces with intrinsic ionisable amphoteric surface sites governed by the dissociation of acid-base potential determining ion species together with the capacity for the adsorption of anion and cations of the supporting electrolyte are required to describe both the results of electrokinetic and titration measurements of inorganic oxides. The Gouy-Chapman-Stern-Grahame (CGSG) model is one such model that has been widely used in the literature. The electrical double layer interaction between two dissimilar CGSG surfaces has been studied by Usui recently [S. Usui, J. Colloid Interface Sci. 280 (2004) 113] where erroneous discontinuities in the slope of the pressure-separation relation were observed. We revisit this calculation and provide a simple general methodology to analyse the electrical double layer interaction between dissimilar ionisable surfaces with ion adsorption.


Prostaglandins inhibit inflammatory mediator release from rat mast cells.
Mast cells have been implicated in the pathogenesis of gastric ulceration. It is possible that prostaglandins exert cytoprotective effects by inhibiting the release of proulcerogenic mediators from mast cells. The effects of three prostaglandins on the release of platelet-activating factor, tumor necrosis factor, and histamine from rat mast cells (peritoneal and intestinal mucosal) activated with calcium ionophore or antigen were assessed. Upon stimulation with either agonist, intestinal mucosal and peritoneal mast cells released significant quantities of platelet-activating factor. Preincubation for 5 minutes with misoprostol, prostaglandin (PG)E2, 16,16-dimethyl PGE2, ketotifen, or PF-5901 concentration-dependently reduced ionophore-stimulated platelet-activating factor release; significant effects were observed with picomolar to nanomolar concentrations of the prostaglandins and micromolar concentrations of the other compounds. Tumor necrosis factor release from peritoneal and mucosal mast cells was also significantly inhibited by the prostaglandins in picomolar to nanomolar concentrations. Misoprostol and PGE2 at concentrations of 5-50 nmol/L significantly inhibited histamine release from peritoneal mast cells stimulated with ionophore but did not affect histamine release stimulated by antigen. These results show potent inhibitory effects of prostaglandins on the release of pro-ulcerogenic inflammatory mediators from mast cells. Such effects may contribute to the protective and anti-inflammatory effects of prostaglandins in the gastrointestinal tract and elsewhere.


Efficient double-strand scission of plasmid DNA by quaternized-chitosan zinc complex.
N-[(2-Hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTACC) was prepared to construct a chitosan-based zinc complex (HTACC-Zn(II)) as a catalyst with good water solubility for rapid DNA cleavage. Results indicated that the observed rate constant (k(obs)) of plasmid DNA cleaved by HTACC-Zn(II) could be enhanced by 10(7)-fold compared with that of uncatalyzed DNA cleavage. The kinetic behavior of HTACC-Zn(II) for DNA cleavage is well fitted by Michaelis-Menten model. The results of gel electrophoresis suggested that HTACC-Zn(II) preferentially perform double-strand break of plasmid DNA.


Following weight loss in massively obese patients correction of the insulin resistance of fat metabolism is delayed relative to the improvement in carbohydrate metabolism.
Intermediary metabolite and serum insulin concentrations have been measured during incremental intravenous low-dose insulin infusion in massively obese patients before, and 3 months and 12 months after gastroplasty. Fasting blood glucose was similar on the three occasions, but fasting serum insulin was significantly higher preoperatively and showed a progressive fall with weight loss. Significant negative linear correlations were found between serum insulin and blood glucose, plasma nonesterified fatty acids, blood glycerol and blood total ketone bodies concentrations. The insulin-glucose dose-response curve showed a significant left shift at 3 months with a further significant improvement at 12 months. No significant change in the responses for nonesterified fatty acids, glycerol, and ketone bodies was observed at 3 months, but all three showed a significant left shift at 12 months. Massively obese patients are resistant to the action of insulin on carbohydrate and fat metabolism. Weight loss following gastroplasty results in an improvement in sensitivity to insulin, which is evident earlier in carbohydrate metabolism than in fat metabolism.


Taking the psycho out of psychosomatic: using systemic approaches in a paediatric setting for the treatment of adolescents with unexplained physical symptoms.
Difficulty expressing emotional distress verbally is widely thought to underlie the presentation of physical symptoms which cannot be explained in medical terms. Children presenting with so called psychosomatic symptoms therefore bridge both the medical and psychological domains and create a conundrum for professionals from either field if working with them alone. A multidisciplinary rehabilitative approach has long been considered the treatment of choice for children exhibiting chronic physical problems. However, there has been little focus on the use of this approach with children diagnosed as suffering from nonorganic physical symptoms, or on the nuts and bolts of the psychological interventions which have been found beneficial. This article outlines a psychological model which has been integrated into a multidisciplinary team approach with good outcomes. The unique features of each case means that evidence for treatment is limited and relies upon such examples of good practice.


Antibody-drug conjugates targeting Trop-2: Clinical developments in early breast cancer therapy.
Although breast cancer has a good prognosis compared with various cancers, metastatic breast cancer has an aggressive disease course and remains incurable. Therefore, treatment of early breast cancer to prevent recurrence and metastasis is crucial. Recently, the development of anti-cancer drugs, such as targeted agents and immuno-oncology, has been accelerating. Antibody-drug conjugates (ADCs) are also building a new paradigm. Particularly, ADCs targeting Trop-2 were approved for their efficacy in metastatic triple-negative breast cancer patients who received ≥2 prior systemic therapies and showed significant results in heavily pretreated hormone receptor-positive/HER2-negative breast cancer. In this brief review, we provide an overview of ongoing clinical trials of ADCs targeting Trop-2 in early breast cancer, specifically sacituzumab govitecan.


Effect of milk constituents on hepatic cholesterol-genesis.
Two preparations active in reducing hepatic cholesterol biosynthesis were isolated from bovine skim milk. One of the inhibitors was in the dialysate and was identified as orotic acid (OA). The other inhibitor, present in the retentate, was not identified. Orotic acid appears to act by inhibiting cholesterol biosynthesis before the formation of mevalonate, whereas the retentate inhibitor exerts its effect beyond the formation of mevalonate in the biosynthetic pathway. Human milk also inhibited the incorporation of both labeled acetate and mevalonate into cholesterol by rat liver. Orotic acid was not detectable in human milk samples employed in this study. Administration of [6-14C]orotate to rats revealed its conversion to uracil in the liver. Subsequent work demonstrated that uracil had inhibitory activity on hepatic cholesterol biosynthesis similar to that of orotate when incubated with rat liver slices.


COVID-19 is rapidly changing: Examining public perceptions and behaviors in response to this evolving pandemic.
Since the emergence of SARS-CoV-2, the virus that causes coronavirus disease (COVID-19) in late 2019, communities have been required to rapidly adopt community mitigation strategies rarely used before, or only in limited settings. This study aimed to examine the attitudes and beliefs of Australian adults towards the COVID-19 pandemic, and willingness and capacity to engage with these mitigation measures. In addition, we aimed to explore the psychosocial and demographic factors that are associated with adoption of recommended hygiene-related and avoidance-related behaviors. A national cross-sectional online survey of 1420 Australian adults (18 years and older) was undertaken between the 18 and 24 March 2020. The statistical analysis of the data included univariate and multivariate logistic regression analysis. The survey of 1420 respondents found 50% (710) of respondents felt COVID-19 would 'somewhat' affect their health if infected and 19% perceived their level of risk as high or very high. 84·9% had performed ≥1 of the three recommended hygiene-related behaviors and 93·4% performed ≥1 of six avoidance-related behaviors over the last one month. Adopting avoidance behaviors was associated with trust in government/authorities (aOR: 6.0, 95% CI 2.6-11·0), higher perceived rating of effectiveness of behaviors (aOR: 4·0, 95% CI: 1·8-8·7), higher levels of perceived ability to adopt social distancing strategies (aOR: 5.0, 95% CI: 1·5-9.3), higher trust in government (aOR: 6.0, 95% CI: 2.6-11.0) and higher level of concern if self-isolated (aOR: 1.8, 95% CI: 1.1-3.0). In the last two months, members of the public have been inundated with messages about hygiene and social (physical) distancing. However, our results indicate that a continued focus on supporting community understanding of the rationale for these strategies, as well as instilling community confidence in their ability to adopt or sustain the recommendations is needed.


Atherosclerosis precursors in Finnish children and adolescents. II. Height, weight, body mass index, and skinfolds, and their correlation to metabolic variables.
In a Finnish Multicentre Study, height, weight and skinfold thicknesses were measured in 3-, 6-, 9-, 12-, 15-, and 18-year-old children (N = 3,596). Height and weight percentiles superimposed on the current Finnish growth charts were above the standards in 6-15-year-old boys and 3-12-year-old girls. Triceps skinfold thickness percentiles (10% and 90%) appeared to be closest to British values and below American values. Weight, body mass index (BMI) and skinfold thicknesses showed good intercorrelations (up to .90) except in young boys. Height had a low positive correlation with BMI (.28 to .36) and with skinfold thickness (.23 to .36) in the age groups 6-12 years. BMI and subscapular skinfold seem to be useful obesity indicators. No consistent correlations were seen between physical variables and serum LDL- or total cholesterol and apoprotein B concentrations. There was a slight negative correlation between the physical variables and serum HDL-cholesterol. Apoprotein A1 correlated negatively to all obesity indicators in 12-year-old girls. Serum triglycerides showed slight positive correlation to physical variables. BMI and skinfolds had a low to moderate correlation with insulin (.21-.51) mainly in the three oldest age groups. On the ground of BMI and skinfold measurements we have reason to believe that the prevalence of obesity at 3-18 years of age is similar in Finland as in other countries in Europe.


A prospective study of a focused, surgeon-performed ultrasound examination for the detection of occult common femoral vein thrombosis in critically ill patients.
A focused, surgeon-performed ultrasound examination of the common femoral veins is an accurate screening tool for the detection of common femoral vein thrombosis in high-risk, critically ill patients. A prospective study using a focused ultrasound examination for findings consistent with deep vein thrombosis of the common femoral veins. The results of these examinations were compared with those of duplex imaging or computed tomographic venography studies. Surgical intensive care unit. All critically ill patients who were admitted to the surgical intensive care unit and considered to be at high risk for the development of deep vein thrombosis. Presence of deep vein thrombosis in the common femoral veins. During a 16-month period, surgeons performed 306 ultrasound examinations on 220 critically ill surgical patients. The results included 295 true negative, 9 true positive, 1 false negative, and 1 false positive, yielding a 90.0% sensitivity, 99.6% specificity, and 99.3% accuracy. A focused, surgeon-performed ultrasound examination is a rapid and accurate screening method to detect common femoral vein thrombosis in critically ill patients as well as to examine those patients in whom pulmonary embolism is strongly suspected.


Gradient optimization of multi-layered density-graded foam laminates for footwear material design.
Several sports-related injuries and orthopedic treatments need the necessity of corrective shoes that can assuage the excessive pressure on sensitive locations of the foot. In the present work, we study the mechanical and energy absorption characteristics of density-graded foams designed for shoe midsoles. The stress-strain responses of polyurea foams with relative densities (nominal density of foam divided by the density of water) of 0.095, 0.23, and 0.35 are obtained experimentally and used as input to a semi-analytical model. Using this model, three-layered foam laminates with various gradients are designed and characterized in terms of their weight, strength, and energy absorption properties. We show that, in comparison with monolithic foams, significant improvement in strength and energy absorption performance can be achieved through density gradation. Our findings also suggest that there is not a single gradient that offers a superior combination of strength, energy absorption, and weight. Rather, an optimal gradient depends on the plantar location and pressure. Depending on the magnitude of the local plantar pressure, density gradients that lead to the highest specific energy absorption are identified for normal walking and running conditions.


Idiopathic spinal cord herniation: report of eight cases and review of the literature.
A case series of eight patients with idiopathic spinal cord herniation and a review of the literature. To report on this rare entity, provide insight on its natural history, and propose an optimal management strategy. Idiopathic spinal cord herniation is a rare disease with 50 cases reported before the current study. Eight cases (follow-up 1 month to 8 years) are reported using available information from patient charts, interviews, and assessments. All imaging studies are reviewed. The review of the literature was performed using PUBMED. Four patients, followed without surgical intervention, have not progressed. Of the three patients who underwent surgical repair by one of the authors, two improved and one was unchanged. A fourth patient, who was initially treated by another surgeon who failed to identify the dural defect and herniation, had a poor outcome. The pathophysiology of the dural defect is still uncertain. The typical presentation is Brown-Séquard syndrome. Microsurgical repair in cases with progression of neurologic deficits is usually successful in achieving recovery of function or arrest of progression.


Sequential formation of covalently bonded hydrogel multilayers through surface initiated photopolymerization.
A novel method for the sequential formation of hydrogel multilayers is described. Formation of the first layer is based on surface initiated photopolymerization of hydrogel precursors on eosin derivatized surfaces. In order to attach subsequent layers it is necessary to be able to functionalize intermediate hydrogel layers with eosin. In the present work, this is accomplished by introducing poly(ethylene glycol) amino acrylate (NH2-PEG-Acr) along with other hydrogel precursors such as poly(ethylene glycol) diacrylate (PEG-DA) on the intermediate layers. The pendant amine groups allow functionalization of the intermediate layers with eosin for subsequent photopolymerization of new hydrogel layers. The process can be repeated sequentially to construct multilayered hydrogel membranes. The NH2-PEG-Acr monomer can be formed by coupling cysteamine to PEG-DA by a conjugate addition reaction. The approach to multilayer formation could allow the incorporation of specific functionalities or compositions within each hydrogel layer so that multifunctional membranes can be formed. It could also be implemented, through proper photopatterning procedures, for the formation of 3-D hydrogel structures. The mild photopolymerization conditions employed using visible (514 nm), rather than ultraviolet light would make this technique especially attractive for tissue engineering, drug delivery, biomaterials, biosensor development and other situations where the elements incorporated are sensitive to UV light exposure.


[Antigen detection in stools as a first choice for laboratory diagnosis of Helicobacter pylori disease].
Several techniques have been suggested for Helicobacter pylori infection diagnosis, invasive (histology) and not invasive (Urea Breath Test C13, or serological assays). An enzyme immunoassay able to detect Helicobacter pylori antigen directly in stool specimens was recently developed. A study was carried out in order to evaluate the sensibility and the specificity of this test comparing it with the Urea Breath Test C13 and histology. The patients studied are all in pediatric age, and great are the advantages of a non-invasive method to detect infection. In this study 60 patients were enrolled. In 34 of them Helicobacter pylori infection was diagnosed by Urea Breath Test C13, all confirmed by histology. In all the 60 patients studied the fecal antigen was researched by an immunoenzymatic method (Premier Platinum HpSA, Meridian Diag.). The detection of Helicobacter pylori in stool shows a sensibility of 100% and a specificity of 97%. Sensibility and specificity, considering also the low cost of the examination, the short time to perform it and the very easy technique, allows us to propose the test as the first choice in the diagnosis of Helicobacter pylori disease.


The neurocomputational bases of explore-exploit decision-making.
Flexible decision-making requires animals to forego immediate rewards (exploitation) and try novel choice options (exploration) to discover if they are preferable to familiar alternatives. Using the same task and a partially observable Markov decision process (POMDP) model to quantify the value of choices, we first determined that the computational basis for managing explore-exploit tradeoffs is conserved across monkeys and humans. We then used fMRI to identify where in the human brain the immediate value of exploitative choices and relative uncertainty about the value of exploratory choices were encoded. Consistent with prior neurophysiological evidence in monkeys, we observed divergent encoding of reward value and uncertainty in prefrontal and parietal regions, including frontopolar cortex, and parallel encoding of these computations in motivational regions including the amygdala, ventral striatum, and orbitofrontal cortex. These results clarify the interplay between prefrontal and motivational circuits that supports adaptive explore-exploit decisions in humans and nonhuman primates.


Fetal and postnatal exposure to tobacco smoke and respiratory health in children.
The aim of this paper was to find out whether fetal exposure to environmental tobacco smoke (ETS), as compared to postnatal ETS exposure, is an independent risk factor for respiratory symptoms and diseases in younger schoolchildren. The cross-sectional epidemiological study comprised population of 1,561 Polish schoolchildren, aged 9-11 years. Information on the exposure to tobacco smoke and other sources of indoor air pollution at home, respiratory and allergic health status, and socio-economic status of the family was obtained by questionnaire survey. The respiratory health status was described by presence of wheezing, attacks of dyspnoea (noted during the last year or ever), bronchitis, wheezy bronchitis and asthma, ever diagnosed by a physician. Multivariate logistic regression analysis with adjustment for age, sex, area of residence, household density, damp and mould stains found at home, use of coal-fired stove, co-habitant pets, mother's education and paternal current and past smoking habit was used to assess the effect of fetal and postnatal exposures on respiratory health outcomes. The results of the multivariate analyses revealed statistically significant associations between fetal exposure to ETS and wheezing ever: log OR = 1.4 (95% CI: 1.0-2.0), attacks of dyspnoea ever: log OR = 1.8 (95% CI: 1.1-2.9), bronchitis: log OR = 2.1 (95% CI: 1.5-2.9), and wheezy bronchitis: log OR = 1.8 (95% CI: 1.1-2.9). The effect of postnatal ETS was statistically significant only for bronchitis: log OR = 1.4 (95% CI: 1.1-1.9). The results of our study showed that fetal exposure to tobacco smoke is an independent risk factor for symptoms of wheeze and wheezy bronchitis in schoolchildren when compared to postnatal ETS exposure.


Cortically induced masticatory rhythm in masseter motoneurons after blocking inhibition by strychnine and tetanus toxin.
In the first series of experiments, we studied whether or not strychnine (STR)-resistant inhibition of masseter motoneurons (MASS . MNS) was involved in their rhythmical inhibition that occurs during masticatory activity, induced by repetitive stimulation of the cortical masticatory area (CMA) in the cat. After systemic STR injection, repetitive CMA stimulation induced rhythmically alternating activity in the masseteric and anterior digastric nerves with a shorter cycle time than before STR-administration. The short-latency IPSPS in the MASS . MNS evoked by single shocks applied to the CMA were abolished. In contrast, repetitive CMA stimulation still induced a rhythmical alternation of EPSPS and IPSPS in the MASS . MNS, although the IPSPS were significantly reduced in amplitude. In the second series, we attempted to abolish the STR-resistant component of the rhythmical IPSP with tetanus toxin (TT). This was injected into one superficial masseter muscle of the guinea pig. In the majority of animals, repetitive CMA stimulation induced a tonic EMG superimposed by rhythmical bursts in the TT-intoxicated masseter muscle. Repetitive CMA stimulation induced a rhythmical sequence of EPSPS and superimposed spikes in the MASS . MNS innervating the TT-intoxicated masseter muscle in paralyzed guinea pigs. It was concluded that: (1) the cortically-evoked short-latency inhibition of MASS . MNS is STR-sensitive, as is part of the rhythmical inhibition during CMA-induced mastication; and (2) rhythmical inhibition is not essential for the central generation of the rhythmical activity in the MASS . MNS.


Youth's Perspective of Responsibility: Exploration of a Construct for Measurement with Youth with Developmental Disabilities.
There is a need to develop self-reports that measure youth's responsibility for major life tasks. We examined if the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test's (PEDI-CAT) operationalization of responsibility is salient to youth with developmental disabilities (DD). The PEDI-CAT defines responsibility as, "the extent to which the young person…take[s] control over organizing and managing major life tasks." During six focus groups (n = 43), youth generated examples of behaviors and actions that demonstrated responsibility. Data were coded as "responsibility" or "discrete skills" per PEDI-CAT definitions. We reviewed examples in both categories and compared and contrasted how youth described responsibility. Youth's descriptions of responsibility aligned with the PEDI-CAT's responsibility construct 42.75% of the time. In these instances, youth perceived themselves as causal agents who had to make decisions and self-regulate to manage and organize major life tasks. Otherwise, youth described themselves as causal agents who adhered to rules, social norms, and expectations of others during the execution of discrete skills. Youth perceive themselves as responsible, causal agents during both the coordination and management of major life tasks and during the execution of discrete skills. As this is not aligned with the PEDI-CAT's operationalization of responsibility, there is a need to further explore youth's perceptions of responsibility prior to developing a self-report.


Effects of external interactions on protein sequence-structure relations of beta-trefoil fold.
Proteins with symmetric structures are ideal models to investigate the sequence-structure relations. We investigate proteins with beta-trefoil fold and find they have different degrees of sequence symmetries although they show similar symmetric structures. To understand this, we calculate the strength of interactions of the beta-trefoil folds with surrounding environments and find the low degrees of sequence symmetries are often correlated with large external interactions. Our results give an additional confirmation of Anfinsen's thermodynamic hypothesis that protein structures are not only determined by their sequences but also by their surrounding environments. We suggest the external interactions should be considered additionally in protein structure prediction through ab initio folding.


The natural antisense transcript HAS2-AS1 regulates breast cancer cells aggressiveness independently from hyaluronan metabolism.
Hyaluronan (HA) is a ubiquitous extracellular matrix component playing a crucial role in the regulation of cell behaviors, including cancer. Aggressive breast cancer cells tend to proliferate, migrate and metastatize. Notably, triple-negative breast cancer cells lacking the expression of estrogen receptor (ER) as well as progesterone receptor and HER2 are more aggressive than ER-positive ones. As currently no targeted therapy is available for triple-negative breast cancer, the identification of novel therapeutic targets has a high clinical priority. In ER-negative cells, tumoral behavior can be reduced by inhibiting HA synthesis or silencing the enzymes involved in its metabolism, such as HA synthase 2 (HAS2). HAS2-AS1 is a long non-coding RNA belonging to the natural antisense transcript family which is known to favor HAS2 gene expression and HA synthesis, thus bolstering malignant progression in brain, ovary, and lung tumors. As the role of HAS2-AS1 has not yet been investigated in breast cancer, in this work we report that ER-positive breast cancers had lower HAS2-AS1 expression compared to ER-negative tumors. Moreover, the survival of patients with ER-negative tumors was higher when the expression of HAS2-AS1 was elevated. Experiments with ER-negative cell lines as MDA-MB-231 and Hs 578T revealed that the overexpression of either the full-length HAS2-AS1 or its exon 2 long or short isoforms alone, strongly reduced cell viability, migration, and invasion, whereas HAS2-AS1 silencing increased cell aggressiveness. Unexpectedly, in these ER-negative cell lines, HAS2-AS1 is involved neither in the regulation of HAS2 nor in HA deposition. Finally, transcriptome analysis revealed that HAS2-AS1 modulation affected several pathways, including apoptosis, proliferation, motility, adhesion, epithelial to mesenchymal transition, and signaling, describing this long non-coding RNA as an important regulator of breast cancer cells aggressiveness.


Advances in understanding of the oxysterol-binding protein homologous in yeast and filamentous fungi.
Oxysterol-binding protein is an important non-vesicular trafficking protein involved in the transportation of lipids in eukaryotic cells. Oxysterol-binding protein is identified as oxysterol-binding protein-related proteins (ORPs) in mammals and oxysterol-binding protein homologue (Osh) in yeast. Research has described the function and structure of oxysterol-binding protein in mammals and yeast, but little information about the protein's structure and function in filamentous fungi has been reported. This article focuses on recent advances in the research of Osh proteins in yeast and filamentous fungi, such as Aspergillus oryzae, Aspergillus nidulans, and Candida albicans. Furthermore, we point out some problems in the field, summarizing the membrane contact sites (MCS) of Osh proteins in yeast, and consider the future of Osh protein development.


'Mind the gap' between the development of therapeutic innovations and the clinical practice in oncology: A proposal of the European Organisation for Research and Treatment of Cancer (EORTC) to optimise cancer clinical research.
In Europe, most of the cancer clinical research dedicated to therapeutic innovations aims primarily at regulatory approval. Once an anticancer drug enters the common market, each member state determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an innovation-centred clinical research landscape might neglect patient-relevant issues in real-world setting, such as comparative effectiveness of distinct treatment options or long-term safety monitoring. The European Organisation for Research and Treatment of Cancer (EORTC) advocates reforming the current 'innovation-centred' system to a truly 'patient-centred' paradigm with systematically coordinated applied clinical research in conjunction with drug development, featuring the following strategy.


An efficient low-temperature route to nitrogen-doping and activation of mesoporous carbons for CO2 capture.
An innovative strategy for post-synthesis nitrogen-doping of mesoporous carbons (MCs) with high yields (>90%) at low temperatures (230-380 °C) by using a strong base, sodium amide (NaNH2), was developed. The as-prepared N-doped MCs exhibit a significantly enhanced CO2 adsorption performance in terms of capacity and selectivity when compared to their parent MCs.


Artificial sweeteners in food and beverage products at school.
Experts recommend that products containing artificial sweeteners are not marketed to children or sold at schools. The present study aimed to provide a baseline assessment of the extent to which state laws and local school district wellness policies (LWP) address restrictions on the use of artificial sweeteners in competitive foods and beverages (CF&B) sold at schools. A descriptive, cross-sectional study of policies in place for the 2014-15 school year. Data were collected on laws in all fifty states and Washington, DC. LWP were compiled for 496/518 school food authorities (SFA) for which data were collected as part of the US Department of Agriculture's School Nutrition and Meal Cost Study. State laws and LWP respectively were coded on a 0-3 ordinal scale for the strength of their restrictions on artificial sweeteners in CF&B sold in each of five CF&B venues, separately by grade level. Prevalence of state laws and LWP for SFA nationwide was computed. Thirteen states addressed the use of artificial sweeteners. Six states addressed the use of artificial sweeteners in both CF&B. District-level artificial sweetener policies were most frequently addressed for beverages in elementary schools' vending machines. District policies also were more likely to address artificial sweeteners in states with laws addressing artificial sweeteners. Most state laws and LWP do not address artificial sweeteners in CF&B. This is not surprising given the Food and Drug Administration has approved eight artificial sweeteners for consumption and the Smart Snacks regulation does not limit artificial sweeteners for CF&B.


In praise of erroneous hypotheses.
In the sixties Cove and Pateman discovered that mutants of Aspergillus nidulans lacking nitrate reductase activity were constitutive for the expression of genes induced by nitrate and dependent on the transcription factor NirA. They proposed that the nitrate protein acted as a repressor, preventing the transcription factor activity of NirA. Nitrate-mediated regulation behaved similarly in other organisms. This "autogenous regulation hypothesis" has recently shown to be erroneous, in the very organism for which it was first proposed. Nevertheless this erroneous hypothesis have led to a thorough dissection of the process of regulation of nitrate assimilation and more importantly to a hypothesis bearing on the origin of metabolite-responsive transcription factors. In this article I discuss the heuristic value and evolutionary importance of autogenous regulation.


Correction: Neural correlates of creative insight: Amplitude of low-frequency fluctuation of resting-state brain activity predicts creative insight.
[This corrects the article DOI: 10.1371/journal.pone.0203071.].


Impact of Tobacco Smoking on Health Care Utilization and Medical Costs in Chronic Obstructive Pulmonary Disease, Coronary Heart Disease and Diabetes.
To determine the impact of smoking on disease-specific health care utilization and medical costs in patients with chronic non-communicable diseases (NCDs). Participants were middle-aged and elderly adults with chronic NCDs from a prospective cohort in China. Logistic regressions and linear models were used to assess the relationship between tobacco smoking, health care utilization and medical costs. Totally, 1020 patients with chronic obstructive pulmonary disease (COPD), 3144 patients with coronary heart disease (CHD), and 1405 patients with diabetes were included in the analysis. Among patients with COPD, current smokers (β: 0.030, 95% CI: -0.032-0.092) and former smokers (β: 0.072, 95% CI: 0.014-0.131) had 3.0% and 7.2% higher total medical costs than never smokers. Medical costs of patients who had smoked for 21-40 years (β: 0.028, 95% CI:-0.038-0.094) and ≥41 years (β: 0.053, 95% CI: -0.004β0.110) were higher than those of never smokers. Patients who smoked ≥21 cigarettes (β: 0.145, 95% CI: 0.051-0.239) per day had more inpatient visits than never smokers. The association between smoking and health care utilization and medical costs in people with CHD group was similar to that in people with COPD; however, there were no significant associations in people with diabetes. This study reveals that the impact of smoking on health care utilization and medical costs varies among patients with COPD, CHD, and diabetes. Tobacco control might be more effective at reducing the burden of disease for patients with COPD and CHD than for patients with diabetes.


Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma.
Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC. Sequential cohorts of 3 to 6 patients with advanced RCC received dose-escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5-5 mg daily or 20-30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained. Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed. The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC.


High prevalence of eating disorders not otherwise specified in northwestern Spain: population-based study.
To determine the incidence and prevalence of eating disorder and its clinical forms. All new ED cases of both genders, ≥15 years old, diagnosed from January 2005 to December 2009 were included. All patients who suffered from ED in December 2009 were included in the prevalence study. This is a prospective, population-based study. Cumulative incidence rates and 20-year prevalence were calculated. The ED incidence was 14.1 (95% CI 11.4-16.1) cases per 100,000 inhabitants per year, for AN, BN and EDNOS 3.1 (95% CI 2.00-4.1), 4.4 (95% CI 3.0-8.00) and 6.5 (95% CI 4.8-7.9), respectively. The incidence of ED at the four age-intervals, 15-24, 25-34, 35-45 and >45 years, revealed that the 25-34-year interval had the highest incidence; moreover, new cases were observed even in the >45-year interval. The prevalence of ED was 82.8 (95% CI 69.4-94.5) per 100,000 inhabitants, being for AN, BN and EDNOS 18.6 (95% CI 12.5-24.4), 25.7 (95% CI 18.5-32.5) and 38.3 (95% CI 29.4-46.5), respectively. The incidence and prevalence of EDNOS are the highest in the ED cases; furthermore, new cases of ED are observed above the age of 45, which are remarkable data.


The accuracy of cancer diagnoses as reported in families with head and neck cancer: a case-control study.
The assessment of the risk of developing cancer is largely based on family history. This study aimed to confirm as many cancer diagnoses as possible in families of patients with second primary tumours after index squamous cell carcinoma of the head, single squamous cell carcinoma and spouse controls. Eighty patients with second primary tumours, 67 with single squamous cell carcinoma and 47 spouse controls were recruited into the study. A detailed interview was undertaken on all study participants, including information on all first-degree relatives for causes of death and possible diagnoses of cancer. Details were available from 1340 first-degree relatives: second primary tumour group 570 relatives, single squamous cell carcinoma 429 relatives and the spouse controls 341 relatives. There were 174 cases of cancer (76, 56 and 42, respectively). For those relatives that had died, submissions were made to the Office of National Statistics to confirm the cause and date of death. One hundred and thirty-three cases were submitted for Office of National Statistics flagging (58, 42 and 33, respectively). Seventy-four of the first-degree relatives with cancer were successfully traced. Tracing confirmed a cancer diagnosis but no further details of the primary site in 31 of the relatives. Thirty-eight of the first-degree relatives were confirmed to have the cancer site of diagnosis reported by the study participants. Thirteen of the reported diagnoses in the first-degree relatives were inaccurate with regard to the cancer site of origin. Five of the first-degree relatives did not have a cancer diagnosis confirmed on the death certificate. This study highlights the difficulties encountered in confirming cancer diagnoses among first-degree relatives within this cancer site. To improve such studies and our routine collection of data within the clinic setting, more robust systems are needed to interlink cancer registries, population data and hospital records.


Antibody and pre- plus post-transplant prednisone treatments support T cell-depleted stem cell engraftment without drug-induced morbidity.
Rigorous T cell depletion methods can now be used to reduce the risk of graft-versus-host disease (GVHD) associated with allogeneic, hematopoietic stem cell transplantation (HSCT). However, full T cell depletion is also associated with a significant risk of graft failure. Here we hypothesize that engraftment failures after T cell-depleted HSCT may be due, in part, to the absence of GVHD prophylaxis. To test this hypothesis, we used a haploidentical mouse model to systematically measure the effects of immunosuppressive drug treatments and anti-T cell antibodies on engraftment. Results showed that engraftment was supported in all animals when hosts were pre-treated with anti-T cell antibodies, but donor chimerism was significantly improved when hosts were also treated with prednisone. Interestingly, when hosts received only pre-HSCT prednisone treatments, engraftment was not improved; when hosts received only post-HSCT prednisone (initiated near the time of irradiation), the animals became extremely ill. Results therefore demonstrated the need for both pre- and post-HSCT prednisone treatments as a means to ensure engraftment without morbidity in all host animals.


Evaluation of the Axillary Surgery Performed in Clinically Node-Positive Breast Cancer Patients Following Neoadjuvant Chemotherapy.
The American College of Surgeons Oncology Group Z1071 trial in 2013 demonstrated the fesability of sentinel lymph node biopsy in clinically node-positive patients following neoadjuvant chemotherapy. The goal of this study was to determine the continued impact of this study on our practice pattern. This is a retrospective review of institutional changes in the management of axillary nodal disease following the publication of Z1071. Patients with clinically node-positive disease that completed neoadjuvant chemotherapy between 2014 and 2020 were included. The Cocoran-Armitage trend test was used to analyze change in categorical variables over time, and the Spearman's rank coefficient was used to analyze two-ranked variables. A cohort of 102 patients were included in the study and demonstrated that the number of sentinel lymph node biopsies to evaluate axillary disease increased over time. Additionally, the number of biopsies of suspicious nodes, and the use of marker clips on the biopsied nodes increased over time. Our institution has continued to incorporate the result from Z1071 in our practice patterns.


ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis.
Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood-brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets. Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis. Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis. ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.


Review of AAPM Task Group No. 43 recommendations on interstitial brachytherapy sources dosimetry. American Association of Physicists in Medicine.
In 1995, the American Association of Physicists in Medicine (AAPM) Task Group No. 43 (TG-43) published its recommendations on the dosimetry of interstitial brachytherapy sources. The report recommended the use of a new dose calculation formalism based on measured quantities. The formalism in modular form permits the computation of doses in two dimensions for 103Pd, 125I, and 192Ir sources. The TG-43 dose calculation formalism introduced new and updated quantities such as air kerma strength, dose rate constant, radial dose function, anisotropy function and anisotropy factor. The dose rate obtained using the TG-43 dose calculation formalism and updated source dosimetry data can be expected to be different from some of the currently used systems by as much as 17%. For the same treatment and implementing the TG-43 dosimetry with point source approximation, the widely prescribed dose of 160 Gy for 125I permanent implants using model 6711 sources changes to 144 Gy. In addition to the dose calculation formalism, TG-43 report also stated that the air kerma strength provided by NIST is estimated to be approximately 7-10% higher than it should be, due to low energy photon contamination for 125I. This difference has not been accounted for in the TG-43 report.


Effects of nicorandil and nifedipine on protection of ischemic myocardium.
The effects of nicorandil and nifedipine on ischemia--reperfusion-induced myocardial infarct size following a 2-h occlusion and 30-min reperfusion period of the left anterior descending coronary artery (LAD) were compared in anesthetized dogs. Myocardial blood flow was measured using the radioactive microsphere technique, and infarct size was determined using triphenyl tetrazolium chloride histochemical stain. Vehicle, nicorandil (100-micrograms/kg bolus followed by 25 micrograms/kg/min), or nifedipine (10-micrograms/kg bolus followed by 1 microgram/kg/min) was administered intravenously 10 min after LAD occlusion and infused throughout the occlusion and reperfusion periods. Nicorandil and nifedipine reduced mean arterial blood pressure similarly (15 mm Hg) during infusion. However, neither drug altered collateral blood flow to the ischemic region during occlusion. In all three groups, left ventricular mass, area at risk mass, percentage of the left ventricle at risk, and retrograde flow during occlusion were similar. As compared with the control group, nicorandil reduced myocardial infarct size as determined by absolute mass, percentage of the area at risk infarcted, and percentage of the left ventricle infarcted. Nifedipine had no significant effect on infarct size. This beneficial effect of nicorandil was not related to an improvement in myocardial blood flow or a change in global hemodynamics.


Kidney stones: various forms and treatment.
Calcium urolithasis is not a homogeneous entity, but is a result of many etiologies, with different physicochemical and physiological backgrounds. This diversity of presentation requires an appreciation of specific diagnostic criteria, and a selection of an appropriate treatment regimen for each cause.


Malignant teratoma in the brain. An immunohistochemical study.
A case of intracranial malignant teratoma found in a 27-year-old man was reported. This unique tumor was found in the right frontal lobe separated from the pineal region and revealed various tissue components such as stratified squamous epithelium, glandular tissues, neuron, glia, ependyma, fibromuscular tissue, cartilage, bone, hemangiomatous lesion, melanin-laden cells, and some germ cell components. An immunohistochemical study demonstrated the presence of S-100 protein, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), and Factor VIII in some tumourous components. In particular, the distribution of S-100 protein in some germ cells suggested the possibility of the neuroectodermal origin of the germ cells or, alternatively, differentiation to the neuroectoderm.


Comparison of traditional, trimmed traditional and robust Youden charts.
Traditional Youden chart can be distorted by non-normally distributed data. Here, an optimized Youden chart was developed and compared with the traditional and trimmed traditional Youden charts. The urea concentrations were determined by 28 laboratories to provide data for the construction of Youden charts. Normality of these data was tested. Outliers were excluded prior to construction of the trimmed traditional Youden chart. Non-robust and robust estimators were computed to construct the traditional and robust Youden charts, respectively. Robust between-laboratory z-score (ZBi) and within-laboratory z-score (ZWi) were obtained to assess whether or not these charts can reasonably present the urea results. Expected outcomes were the points related to acceptable (|ZBi| and |ZWi| ≤ 2), questionable (2 < |ZBi| < 3 and/or 2 < |ZWi| < 3), and unacceptable (|ZBi| and/or |ZWi| ≥ 3) results fall inside, on/near, and outside the ellipse, respectively. Only the data from lot 201111 are non-normally distributed. Five- and 2-pair outliers are excluded from the data of lots 201111 and 201112, respectively. The concordance rates of the traditional, trimmed traditional and robust Youden charts are 87.1%, 92.9%, and 94.3%, respectively. Among the three charts, the robust Youden chart presents the urea results best.


Correction: Li, X.; et al. Identification and Characterization of the WOX Family Genes in Five Solanaceae Species Reveal Their Conserved Roles in Peptide Signaling. Genes 2018, 9, 260.
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Evaluation of surgical treatment of pyothorax with special reference to the usefulness of the omental pedicle flap method.
The operative results in a series of 17 patients with pyothorax were reviewed. Of these, 10 had chronic empyema (group 1), and 7 had postoperative empyema (group 2). A single-stage operation was performed in eight patients in group 1 (decortication in six, thoracoplasty in one, omental plombage in one) and in all patients in group 2 (omentopexy in five, thoracoplasty in two). Two-stage procedures were performed in two patients in group 1. We obtained favorable postoperative results in eight patients in group 1, and in four patients in group 2. In our series, good results were not obtained by thoracoplasty alone; however, satisfactory results were achieved by short-term management in patients treated with the omental method. We think this series demonstrates the value of the omental pedicle flap method, which prevents loss of function due to a defective organ and offers excellent therapeutic results following an easy operative procedure. Further active application of this method can be expected in the management of thoracic disorders.


In vivo temporal EPR imaging for estimating the kinetics of a nitroxide radical in the renal parenchyma and pelvis in rats.
The kinetics of a nitroxide radical in the renal parenchyma and pelvis in rats were investigated by employing an in vivo EPR imaging system equipped with a surface-coil-type resonator (SCR). The exposed kidney of a living rat was inserted into the single-turn coil of the SCR, with the renal major axis aligned with the direction of alternative magnetic field (B(1)). After the injection of nitroxide radical via the tail vein, EPR measurements were repeated. From the temporal EPR images of the kidney on the 2-D projection to the plane which is perpendicular to the direction of B(1,) the decay rate of nitroxide radical in the renal parenchyma and pelvis was estimated. The parenchymal decay rate was found to be significantly shorter than that for the pelvis.


Ceruminous adenocarcinoma: An analysis of the Surveillance Epidemiology and End Results (SEER) database.
Ceruminous adenocarcinoma is a rare malignancy. However, due to the paucity of cases, this has been difficult to study. Using a population-based national database, patient demographics and survival trends were analyzed to further elucidate the management of this malignancy. The SEER database was queried for patients diagnosed with ceruminous adenocarcinoma between 1973 and 2010. Twenty-two patients were identified in the database. The average age of diagnosis was between 60 and 64 years. All of the patients underwent surgical resection of the primary malignancy. Eight patients (36%) also had postoperative radiation. Ceruminous adenocarcinoma is uncommon but may not have as poor a prognosis as previously thought. Surgical resection alone appears to be a reasonable treatment option. Larger prospective studies are needed, but database analysis like this may provide clarity on the management of uncommon diseases.


Storage stability of 5-caffeoylquinic acid in powdered cocona pulp microencapsulated with hydrolyzed collagen and maltodextrin blend.
The encapsulation efficiency of spray-dried cocona pulp encapsulated with a blend of maltodextrin (MD) and hydrolyzed collagen (HC) (CP-ENC) and the stability, color parameters, antioxidant capacity (FRAP and ABTS), and 5-caffeoylquinic acid content were evaluated through 120 days of storage, at every 15 days, at 25 and 35 °C. The results of CP-ENC were compared to those of pure freeze-dried cocona pulp (CP-nENC). The sorption isotherms and glass transition temperatures (Tg) were determined in order to evaluate the stability of the cocona powder. The GAB model fitted well the experimental data for moisture sorption of samples. The high Tg for CP-ENC (132.02 °C) was attributed to the high molecular weight of encapsulating agents. The encapsulation efficiency and color parameters for CP-ENC kept constant values for 120 days. A loss of 30% in the antioxidant capacity occurred on day 75 for CP-ENC. The values of retention of 5-CQA for CP-ENC (83% and 68% when stored at 25 and 35 °C, respectively) were greater than those observed for CP-nENC. At 25 °C, stored CP-ENC had a higher retention and a longer half-life of 5-CQA (14.4 months) than CP-nENC. The results suggest that it is suitable to microencapsulate cocona pulp with MD and HC to improve protection of antioxidant compounds, throughout storage at 25 °C.


Subpopulations and functions of long C3-C5 propriospinal neurones.
Long C3-C5 propriospinal neurones (PNs) are classified in 3 types depending on their pyramidal and vestibular input. The first type of PNs received pyramidal excitation but lacked vestibular effects. The second type of PNs was excited from the medial vestibular nucleus but not from the pyramid. The third type of PNs was excited from the lateral vestibular nucleus either from second order neurones or from non-second order neurones. Monosynaptic excitatory postsynaptic potentials from neck afferents and/or oligosynaptic postsynaptic potentials from forelimb afferents were found in some of the PNs of the second and third type but not in those of the first type. Collision experiments revealed that cortico- and rubrospinal fibres to the long C3-C5 PNs terminate in the rostral spinal cord, presumably in the forelimb segments. Vestibular and reticular effects on the PNs are partly from fibres terminating in the rostral spinal cord and partly from fibres projecting to the lumbar cord. It is postulated that the different types of PNs contribute to the adjustment of hindlimb posture which is required during different movements of the forebody. It is suggested that the basic tonus is maintained mainly by the direct projection to the hindlimb segments from lateral vestibulospinal and reticulospinal neurones which excite antigravity muscles via lumbar interneurones and that the long C3-C5 PNs converge onto the same interneurones so that they act by modulation of the basic tonus.


Statistical comparison of mass spectra for identification of amphetamine-type stimulants.
A method for the statistical comparison of mass spectral data is demonstrated for applications in controlled substance analysis. The method uses an unequal variance t-test at each mass-to-charge ratio in the scan range to determine if two spectra are statistically associated or discriminated. If the two spectra are associated, a random-match probability is calculated to estimate the likelihood that the mass spectral fragmentation pattern in question occurs by random chance alone. If the two spectra are discriminated, the fragment ions responsible for the discrimination are determined. In this work, mass spectral data from case samples containing amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), phentermine, and psilocin were investigated. All spectra were collected in an accredited forensic laboratory using routine methods for controlled substance analysis. Using the statistical method, spectra of case samples were statistically associated to the corresponding reference standard at the 99.9% confidence level. In these instances, random-match probabilities ranged from 10-39 to 10-29, indicating the probability that the characteristic fragmentation pattern occurred by random chance is extremely small. Further, spectra of case samples were discriminated from other reference standards at the 99.9% or 99.0% confidence level, with 1-26 ions responsible for discrimination in each comparison.


Bilateral periventricular nodular heterotopia associated with coeliac disease and palatoschisis.
Periventricular nodular heterotopia (PNH) is considered a distinct entity in relation to the other forms of neuronal migration disorders (NMD), because PNH patients usually have normal neurological and mental examination results. We report the case of a 48-year-old woman with bilateral periventricular nodular heterotopia associated with epilepsy, coeliac disease, palatoschisis and other dysmorphic features. Her intelligence quotient (I.Q.) and the results of a neurological examination were normal, but she suffered from a drug-resistant epileptic syndrome characterised by predominantly generalised and sporadic partial seizures. It has recently been suggested that an X-linked dominant inheritance may play a role in bilateral periventricular nodular heterotopia, and it is thought that a genetic defect is probably responsible for coeliac disease. In our patient, a genetic disorder may have produced both diseases and the dysmorphic syndrome, although the coexistence of PNH, epileptic seizures, coeliac disease and palatoschisis could be coincidental. Further observations are needed to ascertain whether the simultaneous presence of these disorders is simply an unusual association of unrelated pathologies or a new and distinct pathological entity.


Machine-learning-based diagnosis of thyroid fine-needle aspiration biopsy synergistically by Papanicolaou staining and refractive index distribution.
We developed a machine learning algorithm (MLA) that can classify human thyroid cell clusters by exploiting both Papanicolaou staining and intrinsic refractive index (RI) as correlative imaging contrasts and evaluated the effects of this combination on diagnostic performance. Thyroid fine-needle aspiration biopsy (FNAB) specimens were analyzed using correlative optical diffraction tomography, which can simultaneously measure both, the color brightfield of Papanicolaou staining and three-dimensional RI distribution. The MLA was designed to classify benign and malignant cell clusters using color images, RI images, or both. We included 1535 thyroid cell clusters (benign: malignancy = 1128:407) from 124 patients. Accuracies of MLA classifiers using color images, RI images, and both were 98.0%, 98.0%, and 100%, respectively. As information for classification, the nucleus size was mainly used in the color image; however, detailed morphological information of the nucleus was also used in the RI image. We demonstrate that the present MLA and correlative FNAB imaging approach has the potential for diagnosing thyroid cancer, and complementary information from color and RI images can improve the performance of the MLA.


School-based delivery of routinely recommended vaccines and opportunities to check vaccination status at school, a global summary, 2008-2017.
School-based vaccination (SBV) and checking students' vaccination records at school have the potential to optimize vaccination coverage among school-aged children. The primary aim of this paper is to describe adoption of SBV by countries from 2008 to 2017, including target age groups and vaccines delivered in 2017, as reported annually through the World Health Organization (WHO)-United Nations Children's fund (UNICEF) Joint Reporting Form (JRF). Expanding upon previous analyses, country-specific rates of primary school enrollment and home-based record (HBR) ownership were linked to the WHO-UNICEF JRF data, to identify countries with high potential to implement vaccination record checks at school. The proportion of countries reporting delivery of at least one routinely recommended vaccine dose in school settings increased from 95 (of 163 reporting; 58%) in 2008 to 108 (of 181 reporting; 60%) in 2017. The 13 additional countries that reported using SBV in 2017 were among 31 countries for which SBV data from the JRF were unavailable in 2017. The most common antigens delivered through SBV in 2017 were tetanus (94 countries), diphtheria (89 countries), and human papillomavirus (52 countries). Among 93 countries with data available for net primary school enrollment and HBR ownership, 52 (56%) countries had both ≥80% net primary school enrollment and ≥80% of children aged 12-23 months ever owning an HBR; 33 (63%) of these used SBV. If not already doing so, these 33 countries represent an opportunity to introduce routine checking of vaccination status at entry to, or during primary school. With the growing number of new vaccines and booster doses of childhood vaccines targeting school-age children, implementation of SBV and checking of student vaccination records at school may help improve vaccination coverage; however, additional data are needed to assess global prevalence of checking vaccination status at school and to identify factors facilitating optimal implementation of this strategy.


Motivational stage of change in young patients undergoing day treatment for eating disorders.
The objective was to determine whether motivation to change is significantly altered over the course of partial hospitalization in children and adolescents with eating disorders (EDs). This study was a retrospective chart review of 30 sets of adolescents and their parents who completed the Motivational Stage of Change for Adolescents Recovering from an Eating Disorder (MSCARED) at both intake and discharge from partial hospitalization. The main outcome variables included change in stage of change (SOC) for patients and their parents. Secondary outcomes included correlations between SOC and other baseline variables, as well as changes in SOC and psychological test scores. The SOC was significantly higher at discharge than at intake in both the patients and parents, but the two groups were not in agreement at discharge. The change in the SOC was correlated with change in Children's Eating Attitudes Test scores. Assessment of decisional balance showed correlations with SOC. Age, change in weight, and psychiatric diagnoses did not correlate with initial SOC. The MSCARED may be a useful tool for monitoring young ED patients' psychological improvements with day treatment. Initial SOC is not predictive of treatment outcomes.


Chromatic opponency in 3-month-old human infants.
A test spectral sensitivity curve was measured on 3-month-old human infants using a steady 8 degrees test light on a 580 nm adapting field. The data show a "Sloan" notch near 580 nm and a peak near 610 nm. The results are compared to standard nonopponent and opponent models of color vision, and it is concluded that 3-month-old infants have a chromatically opponent detection channel.


Lumbar spinal stenosis. Treatment strategies and indications for surgery.
Initially, all patients with degenerative lumbar spinal stenosis should be treated conservatively. Rapid deterioration is unlikely. The majority of patients may either improve or remain stable over a long-term follow-up with nonoperative treatment. Surgery should be an elective decision by the patients who fail to improve after conservative treatment. Medical evaluation is mandatory in those elderly patients with frequent comorbidities. For central spinal stenosis, without significant grade I spondylolisthesis or deformity, decompression is the surgical treatment of choice. Iatrogenic instability must be avoided during decompression surgery by preserving the facet joint and the pars interarticularis. Limited decompression with laminotomy may be indicated for lateral canal stenosis. A limited decompression may avoid postoperative instability but is associated with more frequent neurologic sequelae. Postlaminectomy instability is uncommon, and too little decompression is a more frequent mistake than too much. Decompression is usually associated with good or excellent outcome in 80% of patients. Deterioration of initial post-operative improvement may occur over long-term follow-up. When spinal stenosis is associated with instability, degenerative spondylolisthesis, deformity, postoperative instability, or recurrent stenosis, fusion is often recommended. Instrumentation often improves the fusion rate but does not influence the clinical outcome. Generous decompression but selective fusion of the unstable segment only are preferable for degenerative spondylolisthesis and type I degenerative scoliosis with minimal rotation of the spine.