Further evidence for geographic differentiation in R. appendiculatus (Acari: Ixodidae) from Eastern and Southern provinces of Zambia.
Studies in the biology, ecology and behaviour of R. appendiculatus in Zambia have shown considerable variation within and between populations often associated with their geographical origin. We studied variation in the mitochondrial COI (mtCOI) gene of adult R. appendiculatus ticks originating from the Eastern and Southern provinces of Zambia. Rhipicephalus appendiculatus ticks from the two provinces were placed into two groups on the mtCOI sequence data tree. One group comprised all haplotypes of specimens from the Eastern province plateau districts of Chipata and Petauke. The second group consisted of a single haplotype of specimens from the Southern province districts and Nyimba, an Eastern province district on the fringes of the valley. This variation provides additional evidence to the earlier observations in the 12S rDNA and ITS2 data for the geographic subdivision of R. appendiculatus from Southern province and Eastern province plateau. The geographic subdivision further corresponds with differences in body size and diapause between R. appendiculatus from these geographic areas. The possible implications of these findings on the epidemiology of East Coast fever (ECF) the disease for which R. appendiculatus is one of the vectors are discussed.


Azelaic Acid Topical Formulations: Differentiation of 15% Gel and 15% Foam.
In this article, the author reviews topical formulations of azelaic acid used to treat papulopustular rosacea. Emphasis is placed on differences in vehicle technology and potential clinical impact of the possibility for neurosensory cutaneous tolerability reactions.


The effect of different surface treatments on cement-retained implant-supported restorations.
The purpose of this study was to evaluate the effects of the various surface treatment methods on the retention of single crowns on implant abutments. The study included 50 single crowns that were cemented with adhesive resin cement onto the ITI solid abutments. The specimens were randomly divided into 5 groups, each including 10 specimens according to the following surface treatments: group C, control, abutments remained unaltered as control; group L, etching with CO(2) laser; group SB, sandblasting with 50-μm Al(2)O(3); group MS: coating with titanium nitride (TiAlN) with a radiofrequency magnetron sputtering system; and group SP, silicoating by Silano-Pen. After the surface treatment procedures were finished, the casted crowns were cemented onto the abutments, and thermocycling was applied to simulate oral environment. The uniaxial tensile force was applied to all test crowns using a universal test machine (Instron) with a crosshead speed of 0.5 mm/min. The load required to dislodge each crown was recorded in Newton. The lowest tensile bond strength values were obtained with group MS (223.26 ± 14.30 N) and significantly differ from all other groups except group C. Group SB showed highest test results (506.02 ± 18.04 N) and differs from other groups (P < .05). The test values that were obtained in group MS-group C did not show significant differences (P > .05). Sandblasting is an effective method to increase bond strength. Also, Silano-Pen and laser application is advisable for increasing the crown retention to abutments. Titanium aluminum nitride coating with magnetron sputtering technique seems to be ineffective.


Oridonin induces G2/M cell cycle arrest and apoptosis in human oral squamous cell carcinoma.
Oridonin, an active diterpeniod isolated from Rabdosia rubescens, has been reported for its anti-tumor activity on several cancers, however, its effect on oral squamous cell carcinoma (OSCC) remains unclear. In this study, we demonstrated for the first time that oridonin inhibited the growth of OSCC cells both in vitro and in vivo. Oridonin decreased the proliferation and clonal formation of cultured OSCC cells in a dose-dependent manner. Further study indicated that oridonin induced G2/M phase arrest in OSCC cells, which was associated with the downregulation of proteins related to G2/M transition including cdc25C, cdc2 and cyclin B1, as well as the upregulation of p53 and phosphorylated-cdc2. In addition, we discovered that oridonin induced OSCC cell apoptosis by activating the intrinsic apoptotic pathway, which was indicated by the increased expression of cleaved-caspase 3, cleaved-caspase 9 and proapoptotic protein Bax and reduced expression of caspase 9 and antiapoptotic protein Bcl-xl. Finally, oridonin suppressed the growth of OSCC in an xenograft mouse model. Immunohistochemical analysis showed a reduction of cyclin B1-positive cancer cells and an increase of TUNEL-positive cancer cells in oridonin-treated mice. Therefore, oridonin may be a potentially effective agent for the treatment of OSCC in future.


Extraction of social information from gait in schizophrenia.
The human face and body are rich sources of socio-emotional cues. Accurate recognition of these cues is central to adaptive social functioning. Past studies indicate that individuals with schizophrenia (SZ) show deficits in the perception of emotion from facial cues but the contribution of bodily cues to social perception in schizophrenia is undetermined. The present study examined the detection of social cues from human gait patterns presented by computer-generated volumetric walking figures. A total of 22 SZ and 20 age-matched healthy control participants (CO) viewed 1 s movies of a 'digital' walker's gait and subsequently made a forced-choice decision on the emotional state (angry or happy) or the gender of the walker presented at three intensity levels. Overall sensitivity to the social cues and bias were computed. For SZ, symptom severity was assessed. SZ were less sensitive than CO on both emotion and gender discrimination, regardless of intensity. While impaired overall, greater signal intensity did improve performance of SZ. Neither group differed in their response bias in either condition. The discrimination sensitivity of SZ was unrelated to their social functioning or symptoms but a bias toward perceiving gait as happy was associated with better social functioning. These results suggest that SZ are impaired in extracting social information from gait but SZ benefited from increased signal intensity of social cues. Inaccurate perception of social cues in others may hinder adequate preparation for social interactions.


International study on the prevalence of malnutrition in centralized care for colorectal cancer patients.
Patients with different diseases may show signs of malnutrition both before and during the hospital stay. The presence of malnutrition may impact the recovery and length of stay and consequently the costs. Early identification of malnutrition is thus a critical factor. The objective of this multicenter study is to determine the prevalence of malnutrition in colorectal cancer centers. Another objective is to investigate possible consequences, such as complications or length of stay. In addition, the study aims to demonstrate the relevance of nutrition management in colorectal cancer centers. At the same time, relevant requirements clearly demanded by the Certification Commission for Certified Colorectal Cancer Centers are met through implementation of the study. Between 2019 and 2021, patients in colorectal cancer centers were examined in the preoperative phase. In addition to questions about patients' state of health and nutrition, the validated screening forms-Subjective Global Assessment (SGA) and Nutritional Risk Screening Tool 2002 (NRS 2002)-were used to assess malnutrition. The data were processed by univariate analysis. In total, data records of 3,102 patients were evaluated. The mean age of the participants was 68.5 ± 11.9 years, and their average body mass index (BMI) was 26.8 ± 5.3 kg/m2. The SGA questionnaire indicated that 23 % of the participants suffered from malnutrition and 38 % were at risk of malnutrition (NRS≥3). Malnutrition was found more frequently in patients with colorectal carcinomas than in patients with rectal carcinomas (53.1 vs. 32.1 %). The length of stay in hospital and the rate of complications were significantly higher when malnutrition was identified. Approximately one in three to four patients with a colorectal carcinoma has an increased risk of malnutrition. The two screening methods calculated a different prevalence (23 and 38 %). Any malnutrition that is present demonstrably has a significant impact both on the rate of complications and the length of stay and may therefore have a decisive influence on the costs. The results of this multicenter study underscore the need for systematic screening for malnutrition and at the same time should increase clinics awareness of the importance of establishing a nutrition management policy.


Improving Graduate Medical Education Through Faculty Empowerment Instead of Detailed Guidelines.
Calls for improvement and reform in graduate medical education (GME) have led to more detail in educational and curricular guidelines. The current level of detail in curriculum guidelines for GME training programs is high, encompassing, for example, competency frameworks, entrustable professional activities, and milestones. In addition, faculty must employ an increasing number of assessment tools and elaborate portfolio systems for their residents. It is questionable whether any further increase in curriculum detail and assessment formats leads to better GME programs. Focusing on this type of system development may even lead to less engaged faculty if faculty are not encouraged to use their own professional judgment and creativity for teaching residents. Therefore, faculty members must be empowered to engage in curricular innovation, since system development alone will not result in better training programs. Raising faculty members' awareness of their virtues and value as teachers and involving them in the debate about how GME can be enhanced might increase their engagement in resident training.


De novo design - hop(p)ing against hope.
Current trends in computational de novo design provide a fresh approach to 'scaffold-hopping' in drug discovery. The methodological repertoire is no longer limited to receptor-based methods, but specifically ligand-based techniques that consider multiple properties in parallel, including the synthetic feasibility of the computer-generated molecules and their polypharmacology, provide innovative ideas for the discovery of new chemical entities. The concept of fragment-based and virtual reaction-driven design enables rapid compound optimization from scratch with a manageable complexity of the search. Starting from known drugs as a reference, such algorithms suggest drug-like molecules with motivated scaffold variations, and advanced mathematical models of structure-activity landscapes and multi-objective design techniques have created new opportunities for hit and lead finding.


Predicting important residues and interaction pathways in proteins using Gaussian Network Model: binding and stability of HLA proteins.
A statistical thermodynamics approach is proposed to determine structurally and functionally important residues in native proteins that are involved in energy exchange with a ligand and other residues along an interaction pathway. The structure-function relationships, ligand binding and allosteric activities of ten structures of HLA Class I proteins of the immune system are studied by the Gaussian Network Model. Five of these models are associated with inflammatory rheumatic disease and the remaining five are properly functioning. In the Gaussian Network Model, the protein structures are modeled as an elastic network where the inter-residue interactions are harmonic. Important residues and the interaction pathways in the proteins are identified by focusing on the largest eigenvalue of the residue interaction matrix. Predicted important residues match those known from previous experimental and clinical work. Graph perturbation is used to determine the response of the important residues along the interaction pathway. Differences in response patterns of the two sets of proteins are identified and their relations to disease are discussed.


Differential antigen presentation kinetics of CD8+ T-cell epitopes derived from the same viral protein.
The kinetics of peptide presentation by major histocompatibility complex class I (MHC-I) molecules may contribute to the efficacy of CD8+ T cells. Whether all CD8+ T-cell epitopes from a protein are presented by the same MHC-I molecule with similar kinetics is unknown. Here we show that CD8+ T-cell epitopes derived from SIVmac239 Gag are presented with markedly different kinetics. We demonstrate that this discrepancy in presentation is not related to immunodominance but instead is due to differential requirements for epitope generation. These results illustrate that significant differences in presentation kinetics can exist among CD8+ T-cell epitopes derived from the same viral protein.


C-type natriuretic peptide regulates cellular condensation and glycosaminoglycan synthesis during chondrogenesis.
C-type natriuretic peptide (CNP) has recently been identified as a key anabolic regulator of endochondral bone growth, but the cellular and molecular mechanisms involved are incompletely understood. Although CNP has been shown to stimulate proliferation and hypertrophic differentiation of growth plate chondrocytes, it is unknown whether CNP affects the earliest stages of endochondral bone development, condensation of mesenchymal precursor cells, and chondrogenesis. Here we demonstrate that CNP increases the number of chondrogenic condensations of mouse embryonic limb bud cells in micromass culture. This is accompanied by increased expression of the cell adhesion molecule N-cadherin. In addition, CNP stimulates glycosaminoglycan synthesis as indicated by increased Alcian blue staining. However, expression of the chondrogenic transcription factors Sox9, -5, and -6 or of the main extracellular matrix genes encoding collagen II and aggrecan is not affected by CNP. Instead, we show that CNP increases expression of enzymes involved in chondroitin sulfate synthesis, a required step in the production of cartilage glycosaminoglycans. In summary, we demonstrate a novel role of CNP in promoting chondrogenesis by stimulating expression of molecules involved in cell adhesion molecules and glycosaminoglycan synthesis.


Common Ophthalmic Preservatives in Soft Contact Lens Care Products: Benefits, Complications, and a Comparison to Non-Preserved Solutions.
Preservatives are essential for preventing contact lens (CL)-related microbial keratitis (MK). The purpose of this review is to summarize the current knowledge related to the use of common ophthalmic preservatives in CL care products with respect to both safety and efficacy. Manuscripts written in English were obtained by searching PubMed.gov with the term contact lens plus antimicrobial, benzalkonium chloride, biguanide, Aldox, polyquaternium, preservative, thimerosal, EDTA (ethylenediaminetetraacetic acid), chlorhexidine, or blister pack. This review found that first-generation preservatives are no longer used in CL multipurpose solutions (MPS) due to their high levels of ocular toxicity. Modern, high-molecular-weight preservatives, including polyquaternium-1 (PQ-1) and biguanides (PHMB), are generally effective against bacteria, minimally effective against fungi, and not effective against Acanthamoeba. PQ-1 and PHMB are likely safe when used with CLs, but they may cause ocular adverse events, with roughly equal risk between the two preservatives. Some CL MPS contain both PQ-1 and PHMB, but no increased risk of adverse events has been reported when combining the two. Hydrogen-peroxide (H2O2) solutions are effective against all common ocular microbes, including Acanthamoeba, and they have been proven safe with proper compliance. Povidone-iodine (P-I) solutions are not currently commercially available in North America, but they have been shown in other countries to be safe and effective. Patients should be monitored when using PQ-1 or PHMB-containing solutions since they have been associated with ocular adverse events. If events are detected, patients should be switched to an alternative solution. H2O2 or P-I solutions are preferred for any patient who may expose their CLs to water because they are the only solution categories effective against Acanthamoeba.


The association of endothelial nitric oxide synthase gene G894T polymorphism and serum nitric oxide concentration with microalbuminuria in patients with gestational diabetes.
Gestational diabetes mellitus (GDM) is a glucose intolerant condition that affects 14% of all pregnancies. Diabetes mellitus (DM) occurs in 30 - 70% of patients with GDM after delivery. DM and GDM are associated with structural and functional deterioration of the renovascular system. Our aim is to investigate the association Glu- 298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene with serum nitric oxide levels and microalbuminuria in patients with GDM and healthy pregnancies. Serum nitric oxide (NO) levels, urinary excretion of albumin and Glu298Asp polymorphism of the eNOS gene were analyzed in 68 patients with GDM and 73 healthy controls. High performance liquid chromatography (HPLC-Griess) method was used to analyze serum NO levels. Microalbuminuria was evaluated by rate nephelometry method. The Glu298Asp polymorphism of the eNOS gene was determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Nitric oxide, glucose, creatinine, and microalbuminuria were significantly different between the patients and the control subjects (p = 0.001, p = 0.001, p = 0.002, and p = 0.005, respectively). There was a significant difference between groups in terms of the ratio of GG/GT+TT of eNOS gene Glu- 298Asp (p = 0.02). The patients with GT+TT genotype had significantly higher microalbuminuria levels and lower NO concentrations (22.16 vs. 9.51, p = 0.005, and 10.56 vs. 12.73, p = 0.021, respectively). The presence of T allele of eNOS gene is an independent predictor of microalbuminuria (OR: 2.346, 95% confidence interval: 1.247 - 5.238, p = 0.02) as well as serum glucose and NO concentration. The G894T polymorphism of eNOS gene and decreased NO concentration seem to be independent predictors of increased urinary excretion of albumin in patients with GDM. Determining the frequency of eNOS gene G894T polymorphism may help to identify pregnancies at increased risk of microalbuminuria.


Identification of a murine CD28 dileucine motif that suppresses single-chain chimeric T-cell receptor expression and function.
Recent preclinical and clinical trials have demonstrated the therapeutic potential of T lymphocytes redirected with genetically engineered T-cell receptor (TCR) surrogates against infected, cancerous, or autoreactive cells. These surrogate TCRs link a ligand-recognition domain to signaling regions from the TCR. We previously compared the function of surrogate TCRs that include TCR or TCR and CD28 signaling regions. We found that primary murine T cells modified to specifically target Kb-restricted CD8+ T cells using either Kb-zeta or Kb-CD28-zeta receptors had similar functional activities, although the CD28-zeta receptor showed a 2-fold to 4-fold decreased expression. We have now identified a previously unrecognized dileucine motif in the murine CD28 signaling domain that accounts for this reduced expression. Inactivation of this motif increased chimeric receptor surface expression 2- to 5-fold. T cells expressing the dileucine-mutated CD28-zeta chimeric receptor demonstrated enhanced proliferation, cytokine production, and cytolytic activities. Further, cells expressing this dileucine-mutated receptor were highly effective in eliminating antigen-specific CD8+ T lymphocytes in vivo. These results therefore identify a critical motif limiting the function of receptor-modified T lymphocytes, demonstrate that inactivation of this motif enhances chimeric receptor function, and illustrate a potential novel application of receptor-modified T lymphocytes in the induction of immune tolerance.


Routine parathyroid autotransplantation during thyroidectomy.
Parathyroid autotransplantation (PTHAT) during thyroidectomy has been shown to reduce the incidence of permanent hypoparathyroidism. Although selective PTHAT is most commonly adopted, the value of routine PTHAT has not been well documented. From January, 1998 to March, 1999, an operative strategy incorporating routine autotransplantation of at least 1 parathyroid gland was used during thyroidectomy. The postoperative outcome of patients (n = 118) was evaluated and compared with patients (n = 271) operated during a policy of selective PTHAT (January, 1995 to October, 1997). Two or more parathyroid glands were autotransplanted in 26 patients (22%) while 92 patients (78%) received autotransplantation of 1 parathyroid gland. Postoperative hypocalcemia occurred in 29 patients (25%) and 2 patients (1.7%) had permanent hypocalcemia develop. When a policy of selective PTHAT was adopted, 98 patients (36%) underwent PTHAT, and 5 patients developed permanent hypocalcemia (1.8%). The incidence of postoperative hypocalcemia was higher in patients who underwent routine PTHAT (25%) compared with that in patients who underwent selective PTHAT (15%) (P =.014). In addition, the operating time was significantly longer when routine PTHAT was adopted (153 minutes vs 130 minutes; P <.001). A low incidence of permanent hypoparathyroidism can be achieved by either routine or selective PTHAT during thyroidectomy but routine PTHAT is associated with a high incidence of postoperative hypocalcemia.


Imaging and manipulating calcium transients in developing Xenopus spinal neurons.
Many forms of electrical excitability expressed in the embryonic nervous system depend on Ca(2+) influx. This discovery has stimulated investigation of the functions of spontaneous elevations of intracellular Ca(2+) and their roles in neuronal development. We present a protocol for imaging different classes of intracellular Ca(2+) transients in embryonic Xenopus (amphibian) spinal neurons grown in dissociated cell culture and in the intact neural tube (the developing spinal cord), focusing on early stages of neuronal differentiation around the time of neural tube closure. The protocol describes methods for gain-of-function and loss-of-function experiments to reveal the functions of these Ca(2+) transients. The methods can also be applied to explant and organotypic cultures. The procedures are sufficiently simple that they can be further adapted for dissociated neuronal cell cultures from other developing embryos, embryonic spinal cords of vertebrates such as zebrafish, and ganglia in the developing nervous systems of invertebrates.


[Diabetic coma and hypoglycemia in children. What to do when in an emergency].
With a few very rare exceptions, hypoglycemia and diabetic coma almost always occur in patients with diabetes mellitus, and are among the most common emergencies in children. For the emergency physician, it is important, on the basis of a specific history-taking and information from, for example, family members, supplemented by a clinical examination done in the light of knowledge of the typical symptoms of each of the entities, to determine whether hypoglycemia or diabetic coma is presenting. The most important technical examination is the measurement of blood glucose. In the event of hypoglycemia, the first therapeutic measure is the administration of sugar--in the case of a comatose patient via a venous line. The s.c. or i.m. administration of glucagon to achieve short-term improvement might be considered. In the event of a diabetic coma, abundant electrolyte solution is initially needed, followed by i.v. insulin. Referral to hospital is mandatory.


The glycine receptor: pharmacological studies and mathematical modeling of the allosteric interaction between the glycine- and strychnine-binding sites.
The displacement by glycine of 3H-strychnine binding to rat spinal cord membranes cannot be explained by a simple competitive interaction. Indeed, protein-modifying reagents can completely abolish the inhibition of 3H-strychnine binding by glycine and other agonists, whereas the interaction of strychnine itself and other related compounds with the binding site is unimpaired. Moreover, glycine cannot inhibit completely saturable 3H-strychnine binding, the extent of its maximum inhibitory effect depending on the ionic composition of the medium. Hill coefficients less than 1 (whose magnitude also depends on the assay medium) were obtained from glycine displacement curves. These properties are consistent with a mathematical model of two different, but mutually interacting, binding sites for strychnine and glycine on the glycine receptor. The effect of ions and protein-modifying reagents might be explained in this model as modifications of the mechanisms that mediate the allosteric interaction, and/or the affinity of glycine for the receptor. The agonists beta-alanine and taurine and the new antagonists, THAZ, iso-THAZ, and 4,5-TAZA, also seem to interact with a site different from the strychnine-binding site, probably the glycine-binding site.


Argonaute 2 drives miR-145-5p-dependent gene expression program in breast cancer cells.
To perform their regulatory functions, microRNAs (miRNAs) must assemble with any of the four mammalian Argonaute (Ago) family of proteins, Ago1-4, into an effector complex known as the RNA-induced silencing complex (RISC). While the mature miRNA guides the RISC complex to its target mRNA, the Ago protein represses mRNA translation. The specific roles of the various Ago members in mediating miRNAs activity, however, haven't been clearly established. In this study, we investigated the contribution of Ago2, the only human Ago protein endowed with nuclease activity, to the function of tumor-suppressor miR-145-5p in breast cancer (BC). We show that miR-145-5p and Ago2 protein are concomitantly downregulated in BC tissues and that restoration of miR-145-5p expression in BC cells leads to Ago2 protein induction through the loosening of Ago2 mRNA translational repression. Functionally, miR-145-5p exerts its inhibitory activity on cell migration only in presence of Ago2, while, upon Ago2 depletion, we observed increased miR-145/Ago1 complex and enhanced cell motility. Profiling by microarray of miR-145-5p target mRNAs, in BC cells depleted or not of Ago2, revealed that miR-145-5p drives Ago2-dependent and -independent activities. Our results highlight that the Ago2 protein in cancer cells strictly dictates miR-145-5p tumor suppressor activity.


Subcellular trafficking of HPMA copolymer-Tat conjugates in human ovarian carcinoma cells.
One of the main obstacles to efficient intracellular delivery of therapeutic macromolecules is the barrier posed by the plasma membrane. In this study, the cell penetrating peptide Tat was conjugated to a synthetic macromolecule based on N-(2-hydroxypropyl)methacrylamide (HPMA) and its subcellular distribution in human ovarian carcinoma cell lines was studied. The Tat peptide mediated uptake resulted in cytoplasmic and nuclear localization and was found to be energy independent. Time and concentration studies verified the rapidity and dependence of the transport process on these parameters. Enhanced uptake of a polymer bound anticancer drug doxorubicin was also demonstrated. These results were corroborated independently by subcellular fractionation.


Real-time Neural Connectivity Inference with Presynaptic Spike-driven Spike Timing-Dependent Plasticity.
Brain-like artificial intelligence in electronics can be built efficiently by understanding the connectivity of neuronal circuitry. The concept of neural connectivity inference with a two-dimensional cross-bar structure memristor array is indicated in recent studies; however, large-scale implementation is challenging owing to device variations and the requirement of online parameter adaptation. This study proposes a neural connectivity inference method with one-dimensional spiking neurons using spike timing-dependent plasticity and presynaptic spike-driven spike timing-dependent plasticity learning rules, designed for a large-scale neuromorphic system. The proposed learning process decreases the number of spiking neurons by half. We simulate 12 ground-truth neural networks comprising one-dimensional eight and 64 neurons. We analyze the correlation between the neural connectivity of the ground truth and spiking neural networks using the Matthews correlation coefficient. In addition, we analyze the sensitivity and specificity of inference. Validation using the presynaptic spike-driven spike timing-dependent plasticity learning rule implies a potential approach for large-scale neural network inference with real hardware realization of large-scale neuromorphic systems.


Null but not void: considerations for hypothesis testing.
Standard statistical theory teaches us that once the null and alternative hypotheses have been defined for a parameter, the choice of the statistical test is clear. Standard theory does not teach us how to choose the null or alternative hypothesis appropriate to the scientific question of interest. Neither does it tell us that in some cases, depending on which alternatives are realistic, we may want to define our null hypothesis differently. Problems in statistical practice are frequently not as pristinely summarized as the classic theory in our textbooks. In this article, we present examples in statistical hypothesis testing in which seemingly simple choices are in fact rich with nuance that, when given full consideration, make the choice of the right hypothesis test much less straightforward. Published 2012. This article is a US Government work and is in the public domain in the USA.


A Prospective, Randomized, Clinical Trial on the Effects of a Valveless Trocar on Respiratory Mechanics During Robotic Radical Cystectomy: A Pilot Study.
Prolonged pneumoperitoneum and Trendelenburg positioning for robot-assisted radical cystectomy (RARC) are essential for optimizing visualization of the operative field, although they worsen hemodynamic and respiratory function. Our hypothesis is that the use of a valveless trocar (VT) may improve respiratory mechanics. In this prospective, 2-arm parallel trial, patients ASA II to III undergoing RARC were randomly assigned into 2 groups: in the VT group, the capnoperitoneum was maintained with a VT; in the control group, the capnoperitoneum was maintained with a standard trocar (ST group). Inspiratory plateau pressure (Pplat), static compliance (Cstat), minute volume (MV), tidal volume (Vt), and carbon dioxide (CO2) elimination rate were recorded at these times: 15 minutes after anesthesia induction (T0), 10 minutes (T1) and 60 minutes (T2) after first robot docking, 10 minutes before first undocking (T3), 10 minutes (T4) and 60 minutes (T5) after second docking, 10 minutes before second undocking (T6), and 10 minutes before extubation (T7). The primary end point of the study was the assessment of Pplat mean value from T1 to T6. A total of 56 patients were evaluated: 28 patients in the VT group and 28 in the ST group. VT group had lower Pplat (means and standard error, VT group 30 [0.66] versus ST group 34 [0.66] cm H2O, with estimated mean difference and 95% confidence interval, -4.1 [-5.9 to -2.2], P < .01), lower MV (means and standard error, VT group 8.2 [0.22] versus ST group 9.8 [0.21] L min, P < .01), lower CO2 elimination rate (means and standard error, VT group 4.2 [0.25] versus ST group 5.4 [0.24] mL kg min, P < .01), lower end-tidal CO2 (ETCO2) (means and standard error, VT group 28.8 [0.48] versus ST group 31.3 [0.46] mm Hg, P < .01), and higher Cstat (means and standard error, VT group 26 [0.9] versus ST group 22.1 [0.9] mL cm H2O, P < .01). Both groups had similar Vt (P = .24). During RARC, use of a VT was associated with a significantly lower Pplat and improvement in other respiratory parameters.


Evaluation of the ICR 6201 G3 ambulatory electrocardiography system in quantitation of arrhythmias.
The performance of a commercial ambulatory electrocardiography analyzer was evaluated when used for the quantitative analysis of arrhythmias in an antiarrhythmic research investigation. The detection and classification of the QRS complexes were examined. The variation between the edited trend report obtained in the investigation and the true arrhythmia quantities established by visual counting was determined for ventricular and atrial premature beats. The analyzer system adequately fulfilled the demands of the research program in establishing changes in the frequency of the arrhythmias.


Detection of Babesia species in questing Ixodes ricinus ticks in England and Wales.
Babesiosis, a disease in humans and animals is caused by piroplasms from the genus Babesia and is transmitted by ixodid ticks. Bovine babesiosis, commonly called redwater fever, is reported in cattle from many regions of the British Isles. The presence of Babesia in questing ticks in the United Kingdom (UK) and its potential impact on public and animal health has not been widely studied. Therefore, this study aimed to assess the presence of Babesia spp. in England and Wales using ticks collected over a six-year period. Questing Ixodes ricinus nymphs were collected at 20 recreational areas between 2014 and 2019 and screened for Babesia. Of 3912 nymphs tested, Babesia spp. were detected in 15, giving an overall prevalence of 0.38% [95%CI: 0.21-0.63%]. A number of Babesia species were identified including B. venatorum (n = 9), B. divergens/capreoli (n = 5) and B. odocoilei-like species (n = 1). Based on the low prevalence of Babesia detected in questing I. ricinus nymphs in the recreational areas studied, the likelihood of exposure to Babesia-infected ticks is lower compared to other pathogens more widely studied in the UK (e.g. Borrelia burgdorferi s.l.). However, localized areas of elevated risk may occur in pockets in England and Wales.


Twelve Cases of Hb Manitoba [α102(G9)Ser→Arg]: the Fluctuation in the Variant Expression.
Hb Manitoba [α102(G9)Ser→Arg] is a rare α chain variant with diverse ethnic origins. It is mildly unstable with an expression of around 10.0-14.2% in the heterozygous state in most literature. In this study, 12 cases of Hb Manitoba [11 cases carried Hb Manitoba II (HBA1: c.309C>A) and one case carried Hb Manitoba IV (HBA1: c.307A>C)] were detected during a wide-spectrum study of α chain variants in the UK. Fluctuation in variant expression from 6.9 to 15.2% of total Hb on high performance liquid chromatography (HPLC) would pose a diagnostic dilemma in routine laboratories. Focusing on the variant expression, the median of Hb Manitoba was around 11.5% of total Hb in three cases, apparently with normal hemoglobin (Hb), and normal red blood cell (RBC) indices. Two cases showed a higher expression (13.9 and 15.2%) and five cases showed a lower expression (6.9-9.9%). The common α-thalassemia (α-thal) -α3.7 (rightward) deletion coexisted with one case of increased Hb Manitoba expression. Iron (or other nutrient) deficiency was likely the cause of decreased Hb Manitoba percentage in this study. The α73(EF2)Val→Val (α2) (HBA2: c.222G>T) polymorphism is published for the first time and coexisted with two cases. The Cap +14 (C>G) (HBA2: c.-24C>G) polymorphism coexisted with another case in a heterozygous state. In conclusion, the fluctuation in variant expression can cause a diagnostic dilemma, especially in routine laboratories. Screening for the common -α3.7 deletion and iron deficiency is recommended when an α chain variant is suspected.


Causes and risk factors for fatal accidents in non-commercial twin engine piston general aviation aircraft.
Accidents in twin-engine aircraft carry a higher risk of fatality compared with single engine aircraft and constitute 9% of all general aviation accidents. The different flight profile (higher airspeed, service ceiling, increased fuel load, and aircraft yaw in engine failure) may make comparable studies on single-engine aircraft accident causes less relevant. The objective of this study was to identify the accident causes for non-commercial operations in twin engine aircraft. A NTSB accident database query for accidents in twin piston engine airplanes of 4-8 seat capacity with a maximum certified weight of 3000-8000lbs. operating under 14CFR Part 91 for the period spanning 2002 and 2012 returned 376 accidents. Accident causes and contributing factors were as per the NTSB final report categories. Total annual flight hour data for the twin engine piston aircraft fleet were obtained from the FAA. Statistical analyses employed Chi Square, Fisher's Exact and logistic regression analysis. Neither the combined fatal/non-fatal accident nor the fatal accident rate declined over the period spanning 2002-2012. Under visual weather conditions, the largest number, n=27, (27%) of fatal accidents was attributed to malfunction with a failure to follow single engine procedures representing the most common contributing factor. In degraded visibility, poor instrument approach procedures resulted in the greatest proportion of fatal crashes. Encountering thunderstorms was the most lethal of all accident causes with all occupants sustaining fatal injuries. At night, a failure to maintain obstacle/terrain clearance was the most common accident cause leading to 36% of fatal crashes. The results of logistic regression showed that operations at night (OR 3.7), off airport landings (OR 14.8) and post-impact fire (OR 7.2) all carried an excess risk of a fatal flight. This study indicates training areas that should receive increased emphasis for twin-engine training/recency. First, increased training should be provided on single engine procedures in the event of an engine failure. Second, more focus should be placed on instrument approaches and recovery from unusual aircraft attitude where visibility is degraded. Third, pilots should be made aware of appropriate speed selection for inadvertent flights in convective weather. Finally, emphasizing the importance of conducting night operations under instrument flight rules with its altitude restrictions should lead to a diminished proportion of accidents attributed to failure to maintain obstacle/terrain clearance.


MrgprA3 neurons selectively control myeloid-derived cytokines for IL-17 dependent cutaneous immunity.
Skin employs interdependent cellular networks to facilitate barrier integrity and host immunity through ill-defined mechanisms. This study demonstrates that manipulation of itch-sensing neurons bearing the Mas-related G protein-coupled receptor A3 (MrgprA3) drives IL-17+ γδ T cell expansion, epidermal thickening, and resistance to the human pathogen Schistosoma mansoni through mechanisms that require myeloid antigen presenting cells (APC). Activated MrgprA3 neurons instruct myeloid APCs to downregulate interleukin 33 (IL-33) and up-regulate TNFα partially through the neuropeptide calcitonin gene related peptide (CGRP). Strikingly, cell-intrinsic deletion of IL-33 in myeloid APC basally alters chromatin accessibility at inflammatory cytokine loci and promotes IL-17/23-dependent epidermal thickening, keratinocyte hyperplasia, and resistance to helminth infection. Our findings reveal a previously undescribed mechanism of intercellular cross-talk wherein "itch" neuron activation reshapes myeloid cytokine expression patterns to alter skin composition for cutaneous immunity against invasive pathogens.


White matter volume is decreased in bipolar disorder at early and late stages.
Bipolar disorder (BD) is a debilitating mood condition that affects approximately 1.3% of people worldwide, although some studies report up to 3.9% lifetime prevalence and 4-6% in adults when broad diagnostic criteria are applied. To compare differences in total white matter (WM), corpus callosum (CC) and total gray matter (GM) volumes in patients with type I BD at early and late stages compared with controls. Fifty-five subjects were enrolled in this study protocol. The double case-control design included 14 patients with BD at early stage; 15 patients at late stage; and their respective matched controls (14 and 12 subjects). CC and total WM volumes were significantly smaller in patients with BD at early and late stages vs. controls. There was no difference for total GM volume in the early stage group, but in patients at late stage total GM volume was significantly smaller than in controls. The total GM volume reduction in patients at late stage is in agreement with the neuroprogression theory of BD. The reduction of WM volumes in total WM and in the CC at early and late stages supports the possibility that an early demyelination process could occur underlying the clinical manifestation of BD. Our findings may direct to the investigation of WM abnormalities in populations at high risk to develop BD, perhaps as early biomarkers before the overt syndrome.


BioBLP: a modular framework for learning on multimodal biomedical knowledge graphs.
Knowledge graphs (KGs) are an important tool for representing complex relationships between entities in the biomedical domain. Several methods have been proposed for learning embeddings that can be used to predict new links in such graphs. Some methods ignore valuable attribute data associated with entities in biomedical KGs, such as protein sequences, or molecular graphs. Other works incorporate such data, but assume that entities can be represented with the same data modality. This is not always the case for biomedical KGs, where entities exhibit heterogeneous modalities that are central to their representation in the subject domain. We aim to understand how to incorporate multimodal data into biomedical KG embeddings, and analyze the resulting performance in comparison with traditional methods. We propose a modular framework for learning embeddings in KGs with entity attributes, that allows encoding attribute data of different modalities while also supporting entities with missing attributes. We additionally propose an efficient pretraining strategy for reducing the required training runtime. We train models using a biomedical KG containing approximately 2 million triples, and evaluate the performance of the resulting entity embeddings on the tasks of link prediction, and drug-protein interaction prediction, comparing against methods that do not take attribute data into account. In the standard link prediction evaluation, the proposed method results in competitive, yet lower performance than baselines that do not use attribute data. When evaluated in the task of drug-protein interaction prediction, the method compares favorably with the baselines. Further analyses show that incorporating attribute data does outperform baselines over entities below a certain node degree, comprising approximately 75% of the diseases in the graph. We also observe that optimizing attribute encoders is a challenging task that increases optimization costs. Our proposed pretraining strategy yields significantly higher performance while reducing the required training runtime. BioBLP allows to investigate different ways of incorporating multimodal biomedical data for learning representations in KGs. With a particular implementation, we find that incorporating attribute data does not consistently outperform baselines, but improvements are obtained on a comparatively large subset of entities below a specific node-degree. Our results indicate a potential for improved performance in scientific discovery tasks where understudied areas of the KG would benefit from link prediction methods.


Achieving and sustaining automated health data linkages for learning systems: barriers and solutions.
Delivering more appropriate, safer, and highly effective health care is the goal of a learning health care system. The Agency for Healthcare Research and Quality (AHRQ) funded enhanced registry projects: (1) to create and analyze valid data for comparative effectiveness research (CER); and (2) to enhance the ability to monitor and advance clinical quality improvement (QI). This case report describes barriers and solutions from one state-wide enhanced registry project. The Comparative Effectiveness Research and Translation Network (CERTAIN) deployed the commercially available Amalga Unified Intelligence System™ (Amalga) as a central data repository to enhance an existing QI registry (the Automation Project). An eight-step implementation process included hospital recruitment, technical electronic health record (EHR) review, hospital-specific interface planning, data ingestion, and validation. Data ownership and security protocols were established, along with formal methods to separate data management for QI purposes and research purposes. Sustainability would come from lowered chart review costs and the hospital's desire to invest in the infrastructure after trying it. CERTAIN approached 19 hospitals in Washington State operating within 12 unaffiliated health care systems for the Automation Project. Five of the 19 completed all implementation steps. Four hospitals did not participate due to lack of perceived institutional value. Ten hospitals did not participate because their information technology (IT) departments were oversubscribed (e.g., too busy with Meaningful Use upgrades). One organization representing 22 additional hospitals expressed interest, but was unable to overcome data governance barriers in time. Questions about data use for QI versus research were resolved in a widely adopted project framework. Hospitals restricted data delivery to a subset of patients, introducing substantial technical challenges. Overcoming challenges of idiosyncratic EHR implementations required each hospital to devote more IT resources than were predicted. Cost savings did not meet projections because of the increased IT resource requirements and a different source of lowered chart review costs. CERTAIN succeeded in recruiting unaffiliated hospitals into the Automation Project to create an enhanced registry to achieve AHRQ goals. This case report describes several distinct barriers to central data aggregation for QI and CER across unaffiliated hospitals: (1) competition for limited on-site IT expertise, (2) concerns about data use for QI versus research, (3) restrictions on data automation to a defined subset of patients, and (4) unpredictable resource needs because of idiosyncrasies among unaffiliated hospitals in how EHR data are coded, stored, and made available for transmission-even between hospitals using the same vendor's EHR. Therefore, even a fully optimized automation infrastructure would still not achieve complete automation. The Automation Project was unable to align sufficiently with internal hospital objectives, so it could not show a compelling case for sustainability.


Clinical characteristics and antimicrobial susceptibilities of viridans streptococcal bacteremia during febrile neutropenia in patients with hematologic malignancies: a comparison between adults and children.
This study was performed to compare the clinical characteristics and antibiotic susceptibilities of viridans streptococcal bacteremia (VSB) between febrile neutropenic adults and children with hematologic malignancies. The consecutive medical records of neutropenic patients with hematologic malignancies who were admitted to the Catholic Blood and Marrow Transplantation Center between April 2009 and July 2012, and who were subsequently diagnosed with VSB were reviewed retrospectively. A comparison was made between the clinical and laboratory characteristics of adults and pediatric patients and also between patients with cefepime susceptible or not susceptible VSB. A total of 202 episodes (141 in adults, 61 in children) of VSB were identified. Among them, 26 (12.9%) cases had severe complications including four (2.0%) cases of death attributable to VSB. For antibacterial prophylaxis, most adults received ciprofloxacin (97.1%), but children more frequently received trimethoprim/sulfamethoxazole (86.9%). Oral mucositis (p = 0.005) and abdominal pain (p = 0.001) were found more frequently in adults, and cough was found more frequently in children (p = 0.004). The occurrence rates of severe complications and death attributable to VSB were not significantly different between adults and children. Susceptibility rate to cefepime was significantly higher in adults than children (85.7% vs. 66.1%, p = 0.002). However, in multivariate analysis, cefepime susceptibility had no impact on clinical outcome. There was no significant difference in clinical outcome between adults and children with VSB despite a difference in cefepime susceptibility. Hence, different antibiotic treatment strategies may not be necessary.


Humoral hypercalcemia complicating adenocarcinoma of the sigmoid colon: report of a case.
Humoral hypercalcemia can arise from a variety of malignancies, but its association with primary colorectal carcinoma is rare, with only 20 such cases documented in the English-language literature to date. We report an additional case to clarify the clinicopathologic features of colorectal carcinoma with humoral hypercalcemia. A 54-year-old woman was admitted with symptomatic hypercalcemia of 14.2 mg/dl and multiple hepatic metastases, 2 years after resection of sigmoid colon cancer. The hypercalcemia was caused by the circulating parathyroid hormone-related peptide (PTHrP) produced by poorly differentiated adenocarcinoma in the liver. The PTHrP level on admission was 13.5 pmol/l. Despite systemic chemotherapy, the patient died of disease progression 3 weeks after the humoral hypercalcemia was diagnosed. A review of the 21 reported cases, including ours, suggests that colorectal carcinoma associated with humoral hypercalcemia is characterized by a poorly differentiated tumor with or without squamous or neuroendocrine features, distant metastases, and a dismal prognosis.


Relationships between the outcome of Plasmodium falciparum infection and the intensity of transmission in Africa.
Establishing the relationship between transmission intensity and health outcomes is crucial for the planning of long-term malaria control programs. Unfortunately this is fraught with methodologic difficulties. In this report, we address some of these problems by considering some important parameters that have previously been ignored. One important consideration is that the incidence of infection for Plasmodium falciparum malaria is much lower than entomologic inoculation rates (EIRs), especially at higher transmission levels. Moreover, biting rates of malaria vectors per host depend on his or her biomass and thus age. We propose an algorithm for estimating human infection rates from the EIR with allowance for these two factors. We then re-analyzed 1) data on EIR and age-specific incidence of clinical malaria in two villages in Senegal and 2) a survey of infant and child mortality rates across Africa. In each case, we review analyses of incidence in relation to the EIR and carry out a new analysis of morbidity and mortality rates in relation to the estimated incidence of infection (h). Reduction in malaria transmission may result in a shift of acute malaria attacks to older ages, and thus have little impact on life-time risk of clinical attacks. However, our analysis of the Senegalese data indicates that the peak incidence rate of disease relative to infection rates is in the youngest age groups in both the villages of Dielmo (EIR = 200 infectious bites per year) and Ndiop (EIR = 20). This suggests that simple models of acquired clinical immunity can explain age-incidence profiles better when incidence is expressed in relation to h, than when expressed in relation to the EIR. Relationships of malaria transmission intensity (in endemic areas) with overall mortality are very different from those with acute morbidity. Infant mortality rates (IMRs) decrease substantially when the EIR is reduced, probably largely because of prevention of indirect mortality. However, we were are not yet able to draw strong conclusions about the shape of relationships between the IMR and h because many of the available data points have similar values of h. The effects of transmission reduction on mortality rates in older age groups are also uncertain. However, it is clear that reduction of exposure during infancy is not reflected in increased mortality at older ages.


Quantitative ultrastructural analysis of perifibrous lipid and its association with elastin in nonatherosclerotic human aorta.
Nonatherosclerotic areas in human arteries display an age-related accumulation of cholesteryl ester in the form of small, perifibrous lipid droplets in the deeper intimal layers. We treated human aortic specimens with an osmium-thiocarbohydrazide-osmium sequence en bloc after glutaraldehyde fixation in order to provide electron dense staining of neutral lipid for ultrastructural study. Neutral lipid was quantified in terms of area fractions on thin sections. Extracellular lipid, primarily in the form of small (less than 300 nm) droplets, accounted for 91% of the lipid found in the deep intimal region. Seventy-four percent of extracellular lipid appeared in droplets or aggregates that were demonstrated as adjacent to or within elastic fibers in the plane of section. The fraction of lipid adjacent to elastin in three dimensions is likely to be considerably higher than 74%. The results support the concept that an interaction between elastin or its associated components and lipids or lipoproteins may be important in extracellular lipid deposition in human arteries.


[Aberrant expressions of β-catenin and ZEB1 in bladder cancer and their significance].
To detect the expressions of β-catenin and zinc finger E-box binding homeobox 1 (ZEB1) in bladder cancer tissues, and analyze their correlation and significance in bladder cancer occurrence and progression. The study collected 79 specimens of bladder cancer. EnVision immunohistochemical staining was used to detect the expressions and distribution of β-catenin and ZEB1 protein. Their correlation was analyzed and their relationship with clinicopathological characteristics was investigated. There was a significant heterogeneity in the expression of β-catenin in bladder cancer tissues. It might be distributed in the cell membrane, cytoplasm or nucleus. In low-grade clinical and pathological urothelial carcinoma, β-catenin was mainly expressed in cell membrane and cytoplasm, but in high-grade clinical pathological bladder cancer tissues, it was mostly located in cell cytoplasm and nucleus. ZEB1 in bladder cancer tissues was mainly expressed in cell nucleus, and its expression was elevated with the increased tumor pathological grade and clinical stage. The expressions of the above two proteins were significantly correlated. Aberrant expressions of β-catenin and ZEB1 in bladder cancer tissues are relevant to bladder tumor differentiation and metastasis, and the two expressions are evidently correlated. The two proteins can be simultaneously used as candidate targets for early diagnosis and prognosis prediction.


Tumor progression despite efficient tumor antigen cross-presentation and effective "arming" of tumor antigen-specific CTL.
To determine whether APC function or "arming" of CTL for lytic function are the points at which Ags from a nonimmunogenic tumor fail to induce an effective immune response, we established a murine tumor model that expressed intracellular OVA and selected a clone (cOVA-9) that remained susceptible to lysis by specific CD8(+) T cells throughout tumor growth. Viable cOVA-9 tumor cells grew in normal mice at a rate similar to the parental tumor, and vaccination with irradiated cOVA-9 cells did not induce protection against itself or the parental line, confirming its nonimmunogenic status. In vivo evaluation during tumor growth demonstrated persisting tumor Ag cross-presentation accompanied by the generation of potent, specific CTL which were detectable when tumors were barely palpable. Despite the presence of highly active CTL in the tumor-draining lymph nodes, there was no apparent lysis of tumor-associated APC. These data show that tumor-draining APC are not dysfunctional with regard to two crucial processes, in vivo tumor Ag cross-presentation and specific CTL arming, and that failure to prevent tumor growth is not in the induction phase, but in the effector phase and occurs within the tumor itself before the tumor matrix is established.


The emerging function and clinical significance of circRNAs in Thyroid Cancer and Autoimmune Thyroid Diseases.
Thyroid cancer (TC) is one of the most common malignant tumors, with high morbidity and mortality rates worldwide. The incidence of TC, especially that of papillary thyroid carcinoma (PTC); has increased rapidly in recent decades. Autoimmune thyroid disease (AITD) is closely related to TC and has an estimated prevalence of 5%. Thus, it is becoming increasingly important to identify potential diagnostic biomarkers and therapeutic targets for TC and AITD. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently bonded circular structures that lack 5'-3' polarity and polyadenylated tails. Several circRNAs play crucial roles in the development of various diseases, including TC and AITD, and could be important new biomarkers and/or targets for the diagnosis and therapy of such disorders. Although there are four subtypes of TC, research on circRNA has largely focused on its connection to PTC. Therefore, this review mainly summarizes the relationships between circRNAs and PTC and AITD, including the molecular mechanisms underlying these relationships. In particular, the functions of "miRNA sponges" and their interactions with proteins and RNA are discussed. The possible targeting of circRNAs for the prevention, diagnosis, and treatment of TC and AITD is also described. CircRNAs could be potential biomarkers of TC and AITD, although validation will be required before they can be implemented in clinical practice.


Theoretical investigation of the SAW properties of ferroelectric film composite structures.
The characteristics of surface acoustic waves (SAW) propagating on a three-layered structure consisting of a perovskite-type ferroelectric film, a buffer layer and a semiconductor substrate have been studied theoretically. Large coupling coefficients (K(2)) can be obtained when the interdigital transducer (IDT) is on top of the perovskite-type ferroelectric film, with (type 4) and without (type 3) the floating-plane electrode at the perovskite-type ferroelectric film-buffer layer interface. In the above cases, the peak values of K (2) Of the Pb(Zr,Ti)O(3) (PZT) films (3.2%-3.8%) are higher than those of the BaTiO(3) (BT) and PbTiO(3) (PT) films. In the IDT configuration of type 4, there exists a minor peak of the coupling coefficients for the PZT and BT films, but not for the PT films when the normalized thickness (hK) of the perovskite-type ferroelectric film is about 0.3. The minor peak values of the coupling coefficients (0.62%-0.93%) for different layered structures (PZT/STO/Si, PZT/MgO/Si, and PZT/MgO/GaAs) all decrease when we increase hK value from 0 to 0.25. The results could be useful in the integration of ferroelectric devices, semiconductor devices, and SAW devices on the same substrate.


Influence of murine leukemia proviral integrations on development of N-methyl-N-nitrosourea-induced thymic lymphomas in AKR mice.
The AKR mouse strain is characterized by a high incidence of spontaneous thymic lymphoma that appears in older animals (greater than 6 months of age) and is associated with novel provirus integrations of ecotropic and recombinant murine leukemia viruses (MuLVs). Treatment of 4- to 6-week-old AKR/J mice with the carcinogen N-methyl-N-nitrosourea (MNU) results in thymic lymphomas that arise as early as 3 to 4 months of age and contain novel somatically acquired MuLV provirus integrations. The AKR/J strain develops MNU-induced lymphoma with a higher incidence and shorter latency than has been observed for other inbred mouse strains. To determine whether provirus integrations of endogenous MuLV account for the enhanced susceptibility of the AKR strain, the incidence and latency of MNU-induced lymphoma development was compared in AKR/J and AKR.Fv-1b mice. The restrictive b allele of the Fv-1 locus restricts integration and replication of endogenous N-tropic MuLV; therefore, AKR-Fv-1b mice have a very low incidence of spontaneous lymphoma. In contrast, AKR.Fv-1b mice develop MNU-induced lymphomas with an incidence and latency similar to those of the AKR/J strain. Furthermore, thymic lymphomas from both strains express an immature CD4-8+ phenotype, indicating neoplastic transformation of the same thymocyte subset. Southern blot analysis confirmed that lymphoma DNA from AKR.Fv-1b mice did not contain somatically acquired provirus integrations. These results demonstrate that provirus integration does not contribute to the predisposition of AKR mice to develop a high incidence of early MNU-induced lymphomas. Nevertheless, MNU treatment stimulated high-level expression of infectious ecotropic MuLV in AKR.Fv-1b as well as in AKR/J mice, suggesting that viral gene products might enhance lymphoma progression.


Teaching NICO How to Grasp: An Empirical Study on Crossmodal Social Interaction as a Key Factor for Robots Learning From Humans.
To overcome novel challenges in complex domestic environments, humanoid robots can learn from human teachers. We propose that the capability for social interaction should be a key factor in this teaching process and benefits both the subjective experience of the human user and the learning process itself. To support our hypothesis, we present a Human-Robot Interaction study on human-assisted visuomotor learning with the robot NICO, the Neuro-Inspired COmpanion, a child-sized humanoid. NICO is a flexible, social platform with sensing and manipulation abilities. We give a detailed description of NICO's design and a comprehensive overview of studies that use or evaluate NICO. To engage in social interaction, NICO can express stylized facial expressions and utter speech via an Embodied Dialogue System. NICO is characterized in particular by combining these social interaction capabilities with the abilities for human-like object manipulation and crossmodal perception. In the presented study, NICO acquires visuomotor grasping skills by interacting with its environment. In contrast to methods like motor babbling, the learning process is, in part, supported by a human teacher. To begin the learning process, an object is placed into NICO's hand, and if this object is accidentally dropped, the human assistant has to recover it. The study is conducted with 24 participants with little or no prior experience with robots. In the robot-guided experimental condition, assistance is actively requested by NICO via the Embodied Dialogue System. In the human-guided condition, instructions are given by a human experimenter, while NICO remains silent. Evaluation using established questionnaires like Godspeed, Mind Perception, and Uncanny Valley Indices, along with a structured interview and video analysis of the interaction, show that the robot's active requests for assistance foster the participant's engagement and benefit the learning process. This result supports the hypothesis that the ability for social interaction is a key factor for companion robots that learn with the help of non-expert teachers, as these robots become capable of communicating active requests or questions that are vital to their learning process. We also show how the design of NICO both enables and is driven by this approach.


Clinical features and prognosis in young adults with infratentorial infarcts.
Many comprehensive descriptions of the clinical spectrum of infratentorial infarcts in elderly patients and with a retrospective design have been published. The aim of this study was to describe the clinical characteristics and prognosis in young patients with isolated infratentorial infarcts. In a prospective series of 105 patients aged 18-44 years with cerebral infarction 24 had a brainstem or cerebellar infarction. The patient selection was validated in a population-based epidemiological survey. The patients were assessed acutely and at 4 and 12 months after onset. Extensive evaluation included CT and MRI scans, angiography, ultrasonic duplex scanning, transesophageal echocardiography and a chemistry panel including hematologic testing. The modified Rankin scale and NIH stroke scale were used for assessment of disability and neurological dysfunction. Eighteen patients had a cerebellar infarct (posterior inferior cerebellar artery territory in 9 patients, superior cerebellar artery in 6, anterior inferior cerebellar artery in 2, nonterritorial in 1). Two patients had lateral medullary infarcts and 2 isolated pontine infarcts. In 2 patients MRI was normal despite repeated investigations. Hearing loss and tinnitus were the only explicit symptoms for superior cerebellar artery infarcts, but it was otherwise impossible to classify each case to a vascular territory according to clinical characteristics. The age-specific incidence of isolated cerebellar infarction was 1.8/100,000/year. The presumed causes were arterial dissection in 8 patients, idiopathic in 7, cardioembolic in 5, oral contraceptive use in 3 and protein S deficiency in 1 patient. One patient died during the acute phase and another developed a locked-in syndrome. At follow-up, 1 patient had a transitory ischemic attack and 1 a silent cerebral infarction. Twenty-two patients had a favorable outcome according to the modified Rankin scale (grade 0-2) and the NIH scale. Cerebellar infarctions are frequent among young stroke patients in northern Sweden. Arterial dissection is the prevailing stroke mechanism in infratentorial infarcts. The prognosis is favorable regarding motor impairment but cognitive deficits may prevent return to work.


Mechanism of ad5 vaccine immunity and toxicity: fiber shaft targeting of dendritic cells.
Recombinant adenoviral (rAd) vectors elicit potent cellular and humoral immune responses and show promise as vaccines for HIV-1, Ebola virus, tuberculosis, malaria, and other infections. These vectors are now widely used and have been generally well tolerated in vaccine and gene therapy clinical trials, with many thousands of people exposed. At the same time, dose-limiting adverse responses have been observed, including transient low-grade fevers and a prior human gene therapy fatality, after systemic high-dose recombinant adenovirus serotype 5 (rAd5) vector administration in a human gene therapy trial. The mechanism responsible for these effects is poorly understood. Here, we define the mechanism by which Ad5 targets immune cells that stimulate adaptive immunity. rAd5 tropism for dendritic cells (DCs) was independent of the coxsackievirus and adenovirus receptor (CAR), its primary receptor or the secondary integrin RGD receptor, and was mediated instead by a heparin-sensitive receptor recognized by a distinct segment of the Ad5 fiber, the shaft. rAd vectors with CAR and RGD mutations did not infect a variety of epithelial and fibroblast cell types but retained their ability to transfect several DC types and stimulated adaptive immune responses in mice. Notably, the pyrogenic response to the administration of rAd5 also localized to the shaft region, suggesting that this interaction elicits both protective immunity and vector-induced fevers. The ability of replication-defective rAd5 viruses to elicit potent immune responses is mediated by a heparin-sensitive receptor that interacts with the Ad5 fiber shaft. Mutant CAR and RGD rAd vectors target several DC and mononuclear subsets and induce both adaptive immunity and toxicity. Understanding of these interactions facilitates the development of vectors that target DCs through alternative receptors that can improve safety while retaining the immunogenicity of rAd vaccines.


Spinal sonography and magnetic resonance imaging in patients with repaired myelomeningocele: comparison of modalities.
The goals of this study were to evaluate the feasibility of using ultrasonography of the spine in the follow-up evaluation of patients with repaired myelomeningocele at birth and to compare sonography with the accepted modality of magnetic resonance imaging. Over a period of 4 years we performed 165 sonographic studies in 101 patients; 107 sonographic studies had MR imaging results for comparison. We collected our data prospectively. The quality of the sonograms was good in 110 of 129 studies, acceptable in 17 of 129, and poor in two of 129. The sonographic examinations failed in 33 of 165 studies (20%). Concordant information was obtained between ultrasonography and magnetic resonance imaging in the following percentage of studies: level of the distal end of the cord in 82%, position of the cord in the canal in 59%, presence of hydromyelia in 63%, cord duplication in 96%, adhesions in 16%, intradural mass in 37%, cord measurements in 85%, and dural sac measurements in 83%. At the lumbosacral level, we saw no cord pulsation in 57% of the studies in patients with cord adhesions and in 20% of those without adhesions. At the lower thoracic level, we saw no pulsation in 35% of the studies in patients with cord adhesions and in 7% of those without adhesions. Postoperative studies of cord release surgery in eight patients showed varied findings. We conclude that in those patients who have a spinal defect or interlaminar space allowing proper visualization of the lumbosacral spinal canal, ultrasound can provide fairly similar information to that obtained with magnetic resonance imaging of that area with no need for sedation and at a reduced cost. Ultrasonography seems more sensitive than magnetic resonance imaging in the detection of cord adhesions, which is particularly relevant in the diagnosis of tethering.


[Brazilian public health research output related to the environment].
Although there are few scientific studies on the environment in the Brazilian public health literature, there are indications of recent growth in this theme in research and graduate programs in Brazil, thus tending to consolidate the scientific output in this area. The objective of this study was to contribute to the understanding and characterization of this theme in public health, offering backing for establishing research focused on sustainability of the environment and health. We identified and analyzed the research output on the environment in the most important Brazilian scientific journals in public health (1992-2002), using as the reference Chapter 35 of Agenda 21 (science for sustainability). The results showed: research output highly concentrated in the more affluent Southeast region of the country; predominance of the biological concept of health and the biophysical concept of environment; prevalence of diagnoses versus the search for solutions; and few studies involving stakeholders' participation.


Trends in Labor Unionization Among US Health Care Workers, 2009-2021.
Labor unionization efforts have resurged in the US, and union membership has been shown to improve worker conditions in some industries. However, little is known about labor unionization membership and its economic effects across the health care workforce. To examine the prevalence of labor unionization among health care workers and its associations with pay, noncash benefits, and work hours. This cross-sectional study was conducted using data from the Current Population Survey and Annual Social and Economic Supplement from 2009 through 2021. The US nationally representative, population-based household survey allowed for a sample of 14 298 self-identified health care workers (physicians and dentists, advanced practitioners, nurses, therapists, and technicians and support staff). Self-reported membership status or coverage in a labor union. Prevalence and trend in labor unionization. Further comparisons included mean weekly pay, noncash benefits (pension or other retirement benefits; employer-sponsored, full premium-covered health insurance; and employer's contribution to the worker's health insurance plan), and work hours. The 14 298 respondents (81.5% women; 7.1% Asian, 12.0% Black, 8.5% Hispanic, 70.4% White individuals; mean [SD] age, 41.6 [13.4] years) included 1072 physicians and dentists, 981 advanced practitioners, 4931 nurses, 964 therapists, and 6350 technicians and support staff. After weighting, 13.2% (95% CI, 12.5% to 13.8%) of respondents reported union membership or coverage, with no significant trend from 2009 through 2021 (P = .75). Among health care workers, those who were members of a racial or ethnic minority group (Asian, Black, or Hispanic individuals compared with White individuals) and those living in metropolitan areas were more likely to report being labor unionized. Reported unionization was associated with significantly higher reported weekly earnings ($1165 vs $1042; mean difference, $123 [95% CI, $88 to $157]; P < .001) and higher likelihood of having a pension or other retirement benefits at work (57.9% vs 43.4%; risk ratio [RR], 1.33 [95% CI, 1.26 to 1.41]; P < .001) and having employer-sponsored, full premium-covered health insurance (22.2% vs 16.5%; RR, 1.35 [95% CI, 1.17 to 1.53]; P < .001). Union members reported more work hours (37.4 vs 36.3; mean differences, 1.11 [95% CI, 0.46 to 1.75]; P < .001) per week. White workers reported mean weekly earnings that were significantly more than members of racial and ethnic minority groups among nonunionized workers ($1066 vs $1001; mean difference, $65 [95% CI, $40 to $91]; P < .001), but there was no significant difference between the 2 groups among unionized workers ($1157 vs $1170; mean difference, -$13 [95% CI, -$78 to $52]; P = .70). From 2009 through 2021, labor unionization among US health care workers remained low. Reported union membership or coverage was significantly associated with higher weekly earnings and better noncash benefits but greater number of weekly work hours.


Experimental resistance to drug combinations in Leishmania donovani: metabolic and phenotypic adaptations.
Together with vector control, chemotherapy is an essential tool for the control of visceral leishmaniasis (VL), but its efficacy is jeopardized by growing resistance and treatment failure against first-line drugs. To delay the emergence of resistance, the use of drug combinations of existing antileishmanial agents has been tested systematically in clinical trials for the treatment of visceral leishmaniasis (VL). In vitro, Leishmania donovani promastigotes are able to develop experimental resistance to several combinations of different antileishmanial drugs after 10 weeks of drug pressure. Using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach, we identified metabolic changes in lines that were experimentally resistant to drug combinations and their respective single-resistant lines. This highlighted both collective metabolic changes (found in all combination therapy-resistant [CTR] lines) and specific ones (found in certain CTR lines). We demonstrated that single-resistant and CTR parasite cell lines show distinct metabolic adaptations, which all converge on the same defensive mechanisms that were experimentally validated: protection against drug-induced and external oxidative stress and changes in membrane fluidity. The membrane fluidity changes were accompanied by changes in drug uptake only in the lines that were resistant against drug combinations with antimonials, and surprisingly, drug accumulation was higher in these lines. Together, these results highlight the importance and the central role of protection against oxidative stress in the different resistant lines. Ultimately, these phenotypic changes might interfere with the mode of action of all drugs that are currently used for the treatment of VL and should be taken into account in drug development.


Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study.
Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing. To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RRMS. We identified all women with RRMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed. Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010); but no differences in spontaneous abortions, term or preterm births. We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month.


The Somatosensory World of the African Naked Mole-Rat.
The naked mole-rat (Heterocephalus glaber) is famous for its longevity and unusual physiology. This eusocial species that lives in highly ordered and hierarchical colonies with a single breeding queen, also discovered secrets enabling somewhat pain-free living around 20 million years ago. Unlike most mammals, naked mole-rats do not feel the burn of chili pepper's active ingredient, capsaicin, nor the sting of acid. Indeed, by accumulating mutations in genes encoding proteins that are only now being exploited as targets for new pain therapies (the nerve growth factor receptor TrkA and voltage-gated sodium channel, NaV1.7), this species mastered the art of analgesia before humans evolved. Recently, we have identified pain-insensitivity as a trait shared by several closely related African mole-rat species. In this chapter we will show how African mole-rats have evolved pain insensitivity as well as discussing what the proximate factors may have been that led to the evolution of pain-free traits.


Cancer risk at sites other than the breast following augmentation mammoplasty.
There has been limited investigation of cancer risk other than breast cancer among patients with breast implants, despite some clinical and laboratory evidence suggesting links with certain cancer sites, including hematopoietic and connective tissue malignancies. A retrospective cohort study of 13,488 patients who received cosmetic breast implants at 18 plastic surgery practices in six geographic areas was conducted to assess long-term health effects. After an average of 12 years of follow-up, questionnaires were administered to subjects located and alive (78% of eligible population). Attempts were made to obtain death certificates for deceased subjects and medical verification for all reported cancers. Expected numbers of cancers were derived using general population cancer incidence rates and an internal comparison series of 3936 patients who received other types of plastic surgery at the same practices as the implant patients. A total of 359 malignancies was observed versus 295.95 expected based on general population rates, resulting in a standardized incidence ratio (SIR) of 1.21 [95% confidence interval (CI) 1.1-1.4]. Individual malignancies for which incidence was significantly elevated included cancers of the stomach (SIR = 2.65), cervix (SIR = 3.18), vulva (SIR = 2.51), brain (SIR = 2.16), and leukemia (SIR = 2.19). No excess risks were observed for other hematopoietic malignancies, including multiple myeloma. The internal analyses, however, based on cancer rates derived among the comparison patients, showed no increased cancer risk among the implant patients [relative risk (RR) = 1.00, 95% CI 0.8-1.2], as well as no statistically significant elevations for most individual sites. Cervical cancer continued to be elevated (RR = 1.78), although to a lesser extent than in the external analyses, while the risk for respiratory cancers was higher (RR = 2.40). Non-significant elevations in risk persisted in this analysis for liver cancer (RR = 2.65), brain cancer (RR = 2.83), and leukemia (RR = 1.83). Many of the cancers showing excesses were defined on the basis of death certificates, requiring caution in interpretation. The histologies of the leukemias were quite varied, which makes a biologic relationship appear unlikely. However, respiratory cancers showed some evidence of increasing risk with follow-up time and both respiratory and brain cancers were elevated in the mortality analyses. Although excesses of cervical and vulvar cancer among implant patients might be attributable to lifestyle factors, reasons for excesses of respiratory and brain cancers were less apparent.


Dark Chocolate Intake Positively Modulates Redox Status and Markers of Muscular Damage in Elite Football Athletes: A Randomized Controlled Study.
Intensive physical exercise may cause increase oxidative stress and muscular injury in elite football athletes. The aim of this study was to exploit the effect of cocoa polyphenols on oxidative stress and muscular injuries induced by intensive physical exercise in elite football players. Oxidant/antioxidant status and markers of muscle damage were evaluated in 24 elite football players and 15 controls. Furthermore, the 24 elite football players were randomly assigned to either a dark chocolate (>85% cocoa) intake (n = 12) or a control group (n = 12) for 30 days in a randomized controlled trial. Oxidative stress, antioxidant status, and muscle damage were assessed at baseline and after 30 days of chocolate intake. Compared to controls, elite football players showed lower antioxidant power and higher oxidative stress paralleled by an increase in muscle damage markers. After 30 days of dark chocolate intake, an increased antioxidant power was found in elite athletes assuming dark chocolate. Moreover, a significant reduction in muscle damage markers (CK and LDH, p < 0.001) was observed. In the control group, no changes were observed with the exception of an increase of sNox2-dp, H2O2, and myoglobin. A simple linear regression analysis showed that sNox2-dp was associated with a significant increase in muscle damage biomarker release (p = 0.001). An in vitro study also confirmed that polyphenol extracts significantly decreased oxidative stress in murine myoblast cell line C2C12-derived. These results indicate that polyphenol-rich nutrient supplementation by means of dark chocolate positively modulates redox status and reduced exercise-induced muscular injury biomarkers in elite football athletes. This trial is registered with NCT03288623.


For Whom the Mind Wanders, and When, Varies Across Laboratory and Daily-Life Settings.
Undergraduates ( N = 274) participated in a weeklong daily-life experience-sampling study of mind wandering after being assessed in the lab for executive-control abilities (working memory capacity; attention-restraint ability; attention-constraint ability; and propensity for task-unrelated thoughts, or TUTs) and personality traits. Eight times a day, electronic devices prompted subjects to report on their current thoughts and context. Working memory capacity and attention abilities predicted subjects' TUT rates in the lab, but predicted the frequency of daily-life mind wandering only as a function of subjects' momentary attempts to concentrate. This pattern replicates prior daily-life findings but conflicts with laboratory findings. Results for personality factors also revealed different associations in the lab and daily life: Only neuroticism predicted TUT rate in the lab, but only openness predicted mind-wandering rate in daily life (both predicted the content of daily-life mind wandering). Cognitive and personality factors also predicted dimensions of everyday thought other than mind wandering, such as subjective judgments of controllability of thought. Mind wandering in people's daily environments and TUTs during controlled and artificial laboratory tasks have different correlates (and perhaps causes). Thus, mind-wandering theories based solely on lab phenomena may be incomplete.


Anemia during pregnancy and birth outcome: a meta-analysis.
To determine the relationship between maternal anemia [hemoglobin (Hgb) < 10-11 g/dL] and various birth outcomes, a meta-analysis was conducted based on published literature identified by MEDLINE and manual search from 1966 through 1999. Odds ratios (OR) from selected studies were pooled according to the gestational age at anemia diagnosis. The meta-analysis shows that maternal anemia during early pregnancy was associated with slightly increased preterm birth [pooled adjusted OR (aOR): 1.32, 95% confidence interval (CI): 1.01-1.74], and nonstatistically significant increased low birth weight [pooled aOR: 1.39 (0.70-2.74)], and was not associated with fetal growth restriction [pooled aOR: 1.01 (0.73-1.38)]. However, there was a nonstatistically significant inverse relationship between anemia during late pregnancy and preterm birth [pooled aOR: 0.92 (0.54-1.84)] and low birth weight [pooled aOR: 0.80 (0.64-1.00)]. Anemia was not statistically significantly associated with hypertensive disorders of pregnancy regardless of stage of pregnancy [pooled OR: 0.80 (0.53-1.20)]. The relationship between anemia and perinatal mortality was inconclusive. A few studies indicated that severe maternal anemia (Hgb < 8-8.5 g/dL) was associated with increased risk of poor outcomes. We conclude that early pregnancy anemia is associated with slightly increased risk of preterm birth. The trend toward an inverse association of anemia determined during late pregnancy with preterm birth and low birth weight may reflect the benefit of plasma volume expansion.


The multidimensionality of the niche reveals functional diversity changes in benthic marine biotas across geological time.
Despite growing attention on the influence of functional diversity changes on ecosystem functioning, a palaeoecological perspective on the long-term dynamic of functional diversity, including mass extinction crises, is still lacking. Here, using a novel multidimensional functional framework and comprehensive null-models, we compare the functional structure of Cambrian, Silurian and modern benthic marine biotas. We demonstrate that, after controlling for increases in taxonomic diversity, functional richness increased incrementally between each time interval with benthic taxa filling progressively more functional space, combined with a significant functional dissimilarity between periods. The modern benthic biota functionally overlaps with fossil biotas but some modern taxa, especially large predators, have new trait combinations that may allow more functions to be performed. From a methodological perspective, these results illustrate the benefits of using multidimensional instead of lower dimensional functional frameworks when studying changes in functional diversity over space and time.


[Sacrococcygeal teratoma: review of the literature].
Sacrococcygeal teratoma (SCT) is rare germ cell tumor composed of multiple types of cells derived from the three primitive germ cell layers. SCT is the most common tumor of germ cells. In recent years the routinely use of prenatal obstetric ultrasonography has led to increase in the prenatal diagnosis of type of malformation. Management should be multidisciplinary and integrated by pediatric neurosurgeons, pediatric surgeons, pediatricians and oncologists. The advent of fetal surgery to identify fetuses at risk has improve survival. We present a review of the literature aimed to enable better understanding of this pathology.


Role of cholinergic receptors in adrenal catecholamine secretion in spontaneously hypertensive rats.
We investigated the role of nicotinic and muscarinic receptors in secretion of catecholamines induced by transmural electrical stimulation (ES) from isolated perfused adrenal glands of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. ES (1-10 Hz) produced frequency-dependent increases in epinephrine (Epi) and norepinephrine (NE) output as measured in perfusate. The ES-induced increases in NE output, but not Epi output, were significantly greater in adrenal glands of SHRs than in those of WKY rats. Hexamethonium (10-100 microM) markedly inhibited the ES-induced increases in Epi and NE output from adrenal glands of SHRs and WKY rats. Atropine (0.3-3 microM) inhibited the ES-induced increases in Epi and NE output from adrenal glands of SHRs, but not from those of WKY rats. These results suggest that endogenous acetylcholine-induced secretion of adrenal catecholamines is predominantly mediated by nicotinic receptors in SHRs and WKY rats and that the contribution of muscarinic receptors may be different between these two strains.


Novel kinetic insights into treatment of unconjugated hyperbilirubinemia: phototherapy and orlistat treatment in Gunn rats.
Treatment with phototherapy or with the lipase inhibitor orlistat decreases plasma unconjugated bilirubin (UCB) concentrations in hyperbilirubinemic Gunn rats. We investigated the mechanism(s) underlying the effects of orlistat, phototherapy, and combined treatment, using steady-state 3H-UCB kinetics. After three weeks of treatment with orlistat (200 mg/kg chow), phototherapy (19 microW/cm2/nm) or combined treatment, tracer 3H-UCB was administered IV to treated and untreated (control) Gunn rats. Plasma samples and feces were collected every 12h for 60h, and bile for 30 min at 60h. The following results were obtained: 1) each treatment decreased plasma bilirubin levels compared with controls: orlistat- 19%, phototherapy-32%, combined treatment-53%; 2) plasma bilirubin concentrations were strongly, negatively correlated with fractional bilirubin turnover; 3) orlistat treatment induced net transmucosal excretion of UCB into the intestinal lumen, whereas phototherapy increased biliary UCB excretion rate; 4) all treatments profoundly increased the enterohepatic circulation of UCB derivatives, indicating enhanced metabolism by intestinal bacteria. In conclusion, orlistat and phototherapy lower plasma bilirubin concentrations in Gunn rats by increasing (net) intestinal influx of UCB, either by transmucosal excretion (orlistat), or increased biliary secretion (phototherapy). The mechanism of phototherapy and orlistat treatment involves increasing the availability of UCB in the intestinal lumen for fecal excretion and for metabolism by intestinal bacteria.


Predictors of outcome of single-dose brachytherapy for the palliation of dysphagia from esophageal cancer.
Single-dose brachytherapy is a commonly used palliative treatment modality for esophageal carcinoma, however, a considerable number of patients need additional treatment for persistent or recurrent dysphagia. Our aim was to establish predictors of an unfavorable outcome after single-dose brachytherapy. Between December 1999 and July 2002, 95 patients with dysphagia from inoperable esophageal carcinoma were treated with single-dose (12 Gy) brachytherapy. Patients were followed-up prospectively by monthly home visits by a specialized research nurse. We investigated the patient and tumor characteristics that influence the risk of persistent dysphagia (continuing dysphagia within 4 weeks after treatment necessitating a second treatment) or recurrent dysphagia (occurring more than 4 weeks after treatment) after single-dose brachytherapy, using logistic and Cox regressions. At 4 weeks after brachytherapy, the dysphagia score was improved in 62/84 (74%) patients. Major complications occurred in 11/95 (12%) patients. In total, 42/95 (44%) patients were treated for persistent (n = 18) and/or recurrent dysphagia (n = 28). Persistent dysphagia (n = 18) was caused by persisting obstructing tumor confirmed at endoscopy, and these patients were treated with stent placement. Patients needing dilation before treatment had a higher risk of persistent dysphagia (odds ratio = 4.1; 95% CI 1.3-12). There was a trend toward a higher risk of persistent dysphagia for patients previously treated with chemotherapy (odds ratio = 3.2; 95% CI 0.81-12). In total, 34 events of recurrent dysphagia occurred in 28 patients, caused by obstructing tumor regrowth (n = 26), food bolus obstruction (n = 5), or other reasons (n = 3). None of the investigated patient and tumor characteristics had a significant association with the risk of developing recurrent dysphagia. Of all patients needing additional treatment (42/95), those who needed dilation before treatment had a higher risk of persistent and/or recurrent dysphagia (hazard ratio = 2.1; 95% CI 1.1-4.1). Patients with stenotic esophageal tumors that cannot be bypassed or who previously underwent chemotherapy are poor candidates for single-dose brachytherapy. For these patients, a higher and/or fractionated dose of brachytherapy or alternative palliative treatment modalities should be considered.


Assessing the neural basis of uncertainty in perceptual category learning through varying levels of distortion.
The formation of new perceptual categories involves learning to extract that information from a wide range of often noisy sensory inputs, which is critical for selecting between a limited number of responses. To identify brain regions involved in visual classification learning under noisy conditions, we developed a task on the basis of the classical dot pattern prototype distortion task [M. I. Posner, Journal of Experimental Psychology, 68, 113-118, 1964]. Twenty-seven healthy young adults were required to assign distorted patterns of dots into one of two categories, each defined by its prototype. Categorization uncertainty was modulated parametrically by means of Shannon's entropy formula and set to the levels of 3, 7, and 8.5 bits/dot within subsets of the stimuli. Feedback was presented after each trial, and two parallel versions of the task were developed to contrast practiced and unpracticed performance within a single session. Using event-related fMRI, areas showing increasing activation with categorization uncertainty and decreasing activation with training were identified. Both networks largely overlapped and included areas involved in visuospatial processing (inferior temporal and posterior parietal areas), areas involved in cognitive processes requiring a high amount of cognitive control (posterior medial wall), and a cortico-striatal-thalamic loop through the body of the caudate nucleus. Activity in the medial prefrontal wall was increased when subjects received negative as compared with positive feedback, providing further evidence for its important role in mediating the error signal. This study characterizes the cortico-striatal network underlying the classification of distorted visual patterns that is directly related to decision uncertainty.


Development of new renal scars: a collaborative study.
In a study of the factors surrounding the development of renal scars clinical data and serial radiographs were analysed in 74 infants and children (66 girls and eight boys) without duplex kidney or obstruction. The development of new scars was seen radiologically in 87 kidneys (74 previously normal and 13 previously scarred). New scarring was extensive in 16 kidneys. Thirty four children were aged 5 or over when scarring occurred. Urinary infection occurred in all the children. Diagnosis and effective treatment were delayed in 45 of them; 58 suffered further urinary infections between the baseline intravenous urogram and the first showing new scarring. Vesicoureteric reflux was seen in 67 of the children. Investigation and treatment varied widely, and few children received long term prophylaxis. Social problems interfered with the management of 22 children. Early diagnosis, prompt effective treatment, investigation, and long term supervision of children with urinary infection are essential if renal scarring is to be reduced; those over the age of 5 are still vulnerable.


Does legislation to prevent alcohol sales to drunk individuals work? Measuring the propensity for night-time sales to drunks in a UK city.
By measuring alcohol retailers' propensity to illegally sell alcohol to young people who appear highly intoxicated, we examine whether UK legislation is effective at preventing health harms resulting from drunk individuals continuing to access alcohol. 73 randomly selected pubs, bars and nightclubs in a city in North West England were subjected to an alcohol purchase test by pseudo-drunk actors. Observers recorded venue characteristics to identify poorly managed and problematic (PMP) bars. 83.6% of purchase attempts resulted in a sale of alcohol to a pseudo-intoxicated actor. Alcohol sales increased with the number of PMP markers bars had, yet even in those with no markers, 66.7% of purchase attempts resulted in a sale. Bar servers often recognised signs of drunkenness in actors, but still served them. In 18% of alcohol sales, servers attempted to up-sell by suggesting actors purchase double rather than single vodkas. UK law preventing sales of alcohol to drunks is routinely broken in nightlife environments, yet prosecutions are rare. Nightlife drunkenness places enormous burdens on health and health services. Preventing alcohol sales to drunks should be a public health priority, while policy failures on issues, such as alcohol pricing, are revisited.