Treatment paradigms for cataplexy in narcolepsy: past, present, and future.
Cataplexy is defined as episodes of sudden loss of voluntary muscle tone triggered by emotions generally lasting <2 minutes. Cataplexy is most commonly associated with and considered pathognomonic for narcolepsy, a sleep disorder affecting ~0.05% of the general population. Knowledge of the pathophysiology of cataplexy has advanced through study of canine, murine, and human models. It is now generally considered that loss of signaling by hypothalamic hypocretin/orexin-producing neurons plays a key role in the development of cataplexy. Although the cause of hypocretin/orexin neuron loss in narcolepsy with cataplexy is unknown, an autoimmune etiology is widely hypothesized. Despite these advances, a literature review shows that treatment of cataplexy remains limited. Multiple classes of antidepressants have been commonly used off-label for cataplexy in narcolepsy and are suggested for this use in expert consensus guidelines based on traditional practice, case reports, and small trials. However, systematic research evidence supporting antidepressants for cataplexy is lacking. The single pharmacotherapy indicated for cataplexy and the guideline-recommended first-line treatment in Europe and the US is sodium oxybate, the sodium salt of gamma-hydroxybutyrate. Clinical trial evidence of its efficacy and safety in cataplexy is robust, and it is hypothesized that its therapeutic effects may occur through gamma-aminobutyric acid receptor type B-mediated effects at noradrenergic, dopaminergic, and thalamocortical neurons. Additional possible mechanisms for cataplexy therapy suggested by preliminary research include antagonism of the histamine H3 autoreceptor with pitolisant and intravenous immunoglobulin therapy for amelioration of the presumed autoimmune-mediated hypocretin/orexin cell loss. Further research and development of therapeutic approaches to cataplexy are needed.


Ag13-Centered Cuboctahedral Architecture in Inorganic Cluster Chemistry: A DFT Investigation.
The bonding in the [Ag13{μ3-Fe(CO)4}8]3-/5- clusters, which exhibit an Ag13-centered cuboctahedral core, has been analyzed and rationalized by DFT calculations. Not considering the interaction with its encapsulated atom, the empty [Ag12{μ3-Fe(CO)4}8]4- cage can be considered as the assembly of 12 linearly coordinated 14-electron AgI metal centers. Adding a supplementary Ag+ at the center allows some covalent delocalized bonding which to some extent tends to reduce the electron deficiency of the 14-electron centers. Adding now two electrons strengthens the delocalized bonding between the encapsulated atom and its host, making [Ag13{μ3-Fe(CO)4}8]5- a superatom with two jellium (5s-type) electrons. TDDFT calculations predict near-IR absorption for this penta-anion, because of the presence of an a1g HOMO in the middle of an energy gap. Luminescence in the same optical range is also suggested. Other related cubococtahedral species, such as [Ag23(SH)16]-, a model for the known 8-electron [Au23(SR)16]- species which exhibits a bicapped centered dodecahedral kernel structure, have also been investigated.


The multidrug resistance and apoptosis evaluation in acute myeloid leukemia cells after the in vitro doxorubicin treatment.
The apoptosis failure in cytostatic treatment of haemoblastosis is one of the means of chemoresistance. We were interested in the relationship of the after-doxorubicin-treatment-AML cells apoptosis and the immunophenotype, selected clinical and laboratory parameters, and also the P-gp, MRP, LRP, Bcl-2, Bax proteins expression. All analysis were evaluated with the flow cytometry method. To detect apoptotic cells in the sample, we used three methods: annexin test, TUNEL (TdT-mediated dUTP nick end labeling) test, and caspase 8 detection. After the cell cultivation the statisticaly important increase of apoptotic cells in the culture was apparent. The relation between the AML blast in vitro reaction and some clinical parameters such as the age of patient, white blood cell count, and blast percentage was also observed.


[A Case of Nephrotic Syndrome Induced by FOLFIRI plus Ramucirumab for Metastatic Descending Colon Cancer].
We report a case of multiple lung metastases of RAS mutant type descending colon cancer with development of nephrotic syndrome after the introduction of FOLFIRI plus ramucirumab(RAM). A female patient in her 50s underwent adjuvant chemotherapy with capecitabine and oxaliplatin after primary tumor and partial lung resection. For recurrent multiple lung metastases, 4 years of capecitabine and bevacizumab therapy was administered. FOLFIRI plus RAM therapy was introduced because of tumor progression. After treatment, the patient showed increased urine protein content, decreased serum albumin levels, marked hypertension, and increased edema, and was diagnosed with nephrotic syndrome. The patient's condition improved with prednisolone, additional doses of antihypertensive, and diuretics. Even in cases where it is possible to control proteinuria during bevacizumab administration, it is necessary to keep in mind that RAM administration as second-line therapy may cause nephrotic syndrome.


Gastric and colorectal cancers in Scotland: a study of the geographical distributions and selected associations.
The geographical distributions of gastric and colorectal cancers in Scotland were investigated by analysing the data available for those diseases in the Annual Reports of the Registrar General for Scotland. For gastric cancer, the standardised mortality ratios (SMRs) for the 234 traditional communities in 1969-73 and for the 56 districts in 1979-83 were calculated. For colorectal cancer, only the data for the latter period were available, and SMRs for that period were calculated similarly. Possible determinants on the resulting pattern of high and low SMRs were investigated. Gastric cancer was generally associated with industrial and urban environments, particularly in west central Scotland, although mortality in Dundee was high in both periods; this cancer also showed significant negative correlations with social class II. By contrast, colorectal cancer showed no strong geographical pattern, no urban-rural gradient, and no social class associations. The cancers showed a weak association with each other.


Regulatory T Cells in Pregnancy Adverse Outcomes: A Systematic Review and Meta-Analysis.
Several studies report the role of Regulatory T-cells (Tregs) in the pathophysiology of pregnancy adverse outcomes. The aim of this systematic review and meta-analysis was to determine whether there is an association between regulatory T cell levels and pregnancy adverse outcomes (PAOs), including pre-eclampsia and preterm birth (PTB). Literature searches were conducted in PubMed/MEDLINE, Embase, and Cochrane CENTRAL databases. Inclusion criteria were original articles (clinical trials, case-control studies and cohort studies) comparing Tregs, sampled from the decidua or maternal blood, in healthy pregnant women versus women with pre-eclampsia or PTB. The outcome was standardised mean difference (SMD) in Treg numbers. The tau-squared (Tau²), inconsistency index (I²), and chi-squared (χ²) test quantified heterogeneity among different studies. Analyses were performed in RevMan software V.5.4.0 for Mac using a random-effects model with outcome data reported with 95% confidence intervals (CI). This study was prospectively registered with PROSPERO (CRD42020205469). PRISMA guidelines were followed. From 4,085 unique studies identified, 36 were included in qualitative synthesis, and 34 were included in quantitative synthesis (meta-analysis). In total, there were 1,783 participants in these studies: healthy controls=964, pre-eclampsia=759, PTB=60. Thirty-two studies compared Tregs in healthy pregnant women and women with pre-eclampsia, and 30 of these sampled Tregs from peripheral blood showing significantly higher Treg numbers in healthy pregnancies (SMD; 1.46; 95% CI, 1.03-1.88; I²=92%). Four studies sampled Tregs from the maternal decidua showing higher Tregs in healthy pregnancies (SMD, 0.76; 95% CI, -0.13-1.65; I²=84%). No difference was found in the number of Tregs between early versus late pre-eclampsia (SMD,-1.17; 95% CI, -2.79-0.44; I²=94%). For PTB, two studies compared Tregs sampled from the peripheral blood with a tendency for higher Tregs in healthy pregnancies but this did not reach significance (SMD, 2.18; 95% CI, -1.34-5.70; I²=96%). Subcohort analysis using Treg analysis (flow cytometry vs. qPCR vs. immunofluorescence tissue staining) showed similar associations. Lower Tregs in pregnancy, sampled from the maternal peripheral blood, are associated with pre-eclampsia. There is a need for further studies to confirm a relationship between low Tregs and PTB. As the precise mechanisms by which Tregs may mediate pre-eclampsia and PTB remain unclear, further fundamental research is necessary to elucidate the underlying processes and highlight the causative link. PROSPERO, identifier CRD42020205469.


Borrelia persica Infection in Immunocompetent Mice--A New Tool to Study the Infection Kinetics In Vivo.
Borrelia persica, a bacterium transmitted by the soft tick Ornithodoros tholozani, causes tick-borne relapsing fever in humans in the Middle East, Central Asia and the Indian peninsula. Immunocompetent C3H/HeOuJ mice were infected intradermally with B. persica at varying doses: 1 x 10(6), 1 x 10(4), 1 x 10(2) and 4 x 10(0) spirochetes/mouse. Subsequently, blood samples were collected and screened for the presence of B. persica DNA. Spirochetes were detected in all mice infected with 1 x 10(6), 1 x 10(4) and 1 x 10(2) borrelia by real-time PCR targeting the flaB gene of the bacterium. Spirochetemia developed with a one- to two-day delay when 1 x 10(4) and 1 x 10(2) borrelia were inoculated. Mice injected with only four organisms were negative in all tests. No clinical signs were observed when infected mice were compared to negative control animals. Organs (heart, spleen, urinary bladder, tarsal joint, skin and brain) were tested for B. persica-specific DNA and cultured for the detection of viable spirochetes. Compiled data show that the target organs of B. persica infections are the brain and the skin. A newly developed serological two-tiered test system (ELISA and western blot) for the detection of murine IgM, IgG and IgA antibody titers against B. persica showed a vigorous antibody response of the mice during infection. In conclusion, the infection model described here for B. persica is a platform for in vivo studies to decipher the so far unexplored survival strategies of this Borrelia species.


Variability in Brain Structure and Function Reflects Lack of Peer Support.
Humans are a highly social species. Complex interactions for mutual support range from helping neighbors to building social welfare institutions. During times of distress or crisis, sharing life experiences within one's social circle is critical for well-being. By translating pattern-learning algorithms to the UK Biobank imaging-genetics cohort (n = ~40 000 participants), we have delineated manifestations of regular social support in multimodal whole-brain measurements. In structural brain variation, we identified characteristic volumetric signatures in the salience and limbic networks for high- versus low-social support individuals. In patterns derived from functional coupling, we also located interindividual differences in social support in action-perception circuits related to binding sensory cues and initiating behavioral responses. In line with our demographic profiling analysis, the uncovered neural substrates have potential implications for loneliness, substance misuse, and resilience to stress.


An evaluation of the benefits of pulsatile versus nonpulsatile perfusion during cardiopulmonary bypass procedures in pediatric and adult cardiac patients.
The controversy over the benefits of pulsatile and nonpulsatile flow during cardiopulmonary bypass procedures continues. The objective of this investigation was to review the literature in order to clarify the truths and dispel the myths regarding the mode of perfusion used during open-heart surgery in pediatric and adult patients. The Google and Medline databases were used to search all of the literature on pulsatile vs. nonpulsatile perfusion published between 1952 and 2006. We found 194 articles related to this topic in the literature. Based on our literature search, we determined that pulsatile flow significantly improved blood flow of the vital organs including brain, heart, liver, and pancreas; reduced the systemic inflammatory response syndrome; and decreased the incidence of postoperative deaths in pediatric and adult patients. We also found evidence that pulsatile flow significantly improved vital organ recovery in several types of animal models when compared with nonpulsatile perfusion. Several investigators have also shown that pulsatile flow generates more hemodynamic energy, which maintains better microcirculation compared with nonpulsatile flow. These results clearly suggest that pulsatile flow is superior to nonpulsatile flow during and after open-heart surgery in pediatric and adult patients.


Males do not reduce the fitness of their female co-twins in contemporary samples.
Lummaa et al. (2007) presented historical data collected from twins born in Finland between 1734 and 1888 which suggested that females (N = 31) born as part of an opposite sex (OS) twin pair were 25% less likely to reproduce than female twins (N = 35) born as part of a same sex (SS) pair. They hypothesized that this reduction in fitness was due to masculinization of the female fetus via prenatal effects of the hormones of a male fetus. Because such masculinization would presumably take place in modern populations as well, it would seem important to establish to what degree it does so, and if so, whether reproduction is affected. We therefore address the question of reproduction differences in individual female twins from same-sex (N = 1979) and opposite-sex (N = 913) dizygotic pairs in studies carried out in Australia, the Netherlands, and the United States. In all three samples, there were no differences in the number of children or age of first pregnancies in women from same sex pairs compared to those from opposite sex pairs. Similarly, there were no differences in psychological femininity between women from pairs of the same or opposite sex.


Basophil production III: relation of histamine to guinea pig basophil growth in vitro.
Histamine has been measured by an isotopic enzyme conversion assay in guinea pig bone marrow cultures under conditions which stimulate basophilopoiesis. A high degree of correlation was observed between histamine values and basophil counts in suspension cultures. Cultures of normal marrow with splenic conditioned medium (CM) prepared from spleen cells of ovalbumin (OA)-treated animals or coculture of marrow cells from these animals with autologous spleen cells demonstrated rises in histamine values which paralleled basophil counts, with a mean calculated histamine of 0.3 pg/basophil. Addition to marrow cells from OA-treated animals of autologous splenic T-lymphocytes or culture of normal marrow in the presence of CM derived from PHA-stimulated splenic T-lymphocytes caused in vitro increases in histamine significantly greater than when T-lymphocyte depleted spleen cells or CM derived from the latter were used, respectively (P less than 0.02). The presence of OA in marrow-spleen cultures significantly enhanced basophilopoiesis when whole or T-enriched, but not T-depleted, spleen fractions were used (P less than 0.02). The magnitude of in vitro increases in histamine over one week was 10-30 nanograms, accompanied by appropriate increases in basophils in CM-stimulated normal marrow cultures. From these data it can be concluded that histamine is an independent criterion of basophilopoiesis in vitro. An entirely new population of histamine-synthesizing cells appears to arise over 1 week in vitro under conditions of antigen or T-cell product stimulation.


Cotton GhMKK5 affects disease resistance, induces HR-like cell death, and reduces the tolerance to salt and drought stress in transgenic Nicotiana benthamiana.
Mitogen-activated protein kinase (MAPK) cascades are involved in various processes from plant growth and development to biotic and abiotic stress responses. MAPK kinases (MAPKKs), which link MAPKs and MAPKK kinases (MAPKKKs), play crucial roles in MAPK cascades to mediate a variety of stress responses in plants. However, few MAPKKs have been functionally characterized in cotton (Gossypium hirsutum). In this study, a novel gene, GhMKK5, from cotton belonging to the group C MAPKKs was isolated and characterized. The expression of GhMKK5 can be induced by pathogen infection, abiotic stresses, and multiple defence-related signal molecules. The overexpression of GhMKK5 in Nicotiana benthamiana enhanced the plants' resistance to the bacterial pathogen Ralstonia solanacearum by elevating the expression of pathogen resistance (PR) genes, including PR1a, PR2, PR4, PR5, and NPR1, but increased the plants' sensitivity to the oomycete pathogen Phytophthora parasitica var. nicotianae Tucker. Importantly, GhMKK5-overexpressing plants displayed markedly elevated expression of reactive oxygen species-related and cell death marker genes, such as NtRbohA and NtCDM, and resulted in hypersensitive response (HR)-like cell death characterized by the accumulation of H(2)O(2). Furthermore, it was demonstrated that GhMKK5 overexpression in plants reduced their tolerance to salt and drought stresses, as determined by statistical analysis of seed germination, root length, leaf water loss, and survival rate. Drought obviously accelerated the cell death phenomenon in GhMKK5-overexpressing plants. These results suggest that GhMKK5 may play an important role in pathogen infection and the regulation of the salt and drought stress responses in plants.


Tir Triggers Expression of CXCL1 in Enterocytes and Neutrophil Recruitment during Citrobacter rodentium Infection.
The hallmarks of enteropathogenic Escherichia coli (EPEC) infection are formation of attaching and effacing (A/E) lesions on mucosal surfaces and actin-rich pedestals on cultured cells, both of which are dependent on the type III secretion system effector Tir. Following translocation into cultured cells and clustering by intimin, Tir Y474 is phosphorylated, leading to recruitment of Nck, activation of N-WASP, and actin polymerization via the Arp2/3 complex. A secondary, weak, actin polymerization pathway is triggered via an NPY motif (Y454). Importantly, Y454 and Y474 play no role in A/E lesion formation on mucosal surfaces following infection with the EPEC-like mouse pathogen Citrobacter rodentium. In this study, we investigated the roles of Tir segments located upstream of Y451 and downstream of Y471 in C. rodentium colonization and A/E lesion formation. We also tested the role that Tir residues Y451 and Y471 play in host immune responses to C. rodentium infection. We found that deletion of amino acids 382 to 462 or 478 to 547 had no impact on the ability of Tir to mediate A/E lesion formation, although deletion of amino acids 478 to 547 affected Tir translocation. Examination of enterocytes isolated from infected mice revealed that a C. rodentium strain expressing Tir_Y451A/Y471A recruited significantly fewer neutrophils to the colon and triggered less colonic hyperplasia on day 14 postinfection than the wild-type strain. Consistently, enterocytes isolated from mice infected with C. rodentium expressing Tir_Y451A/Y471A expressed significantly less CXCL1. These result show that Tir-induced actin remodeling plays a direct role in modulation of immune responses to C. rodentium infection.


Suicide gene therapy of human breast cancer in SCID mice model by the regulation of Tet-On.
RevTet-On gene expression system was used to deliver the suicide gene tk to human breast cancer cell line MCF-7 and control the tk gene expression level. The animal model of human breast cancer on severe combined immune deficiency (SCID) mice was set up to explore the suicide gene therapy by the regulation of Tet-On. Herpes simplex virus-thymidine kinase (HSVtk) gene was inserted into the plasmid pRevTRE and the recombinant retroviral vector pRevTRE/HSVtk was constructed. Using modified calcium phosphate co-precipitation method, two transfections, pRevTRE/HSVtk and pRevTet-On were performed for MCF-7 cell line and selected by hygromycin B and G418. MCF-7 cell line that stably expressed Tet-regulated tk gene was established. HSVtk gene expression in the MCF/TRE/tk/Tet-On cell line was under the control of Doxycycline (Dox). Cell viability was also determined by MTT assay, whereas HSVtk gene expression was analyzed by reverse transcription-PCR (RT-PCR). MCF/TRE/tk/Tet-On cell survival rate was decreased from 100% to less than 20% when ganciclovir (GCV) concentration was increased from 0 to 1000 microg/ml at 1 microg/ml of Dox after 72 hours of GCV administration. At 1 microg/ml of GCV concentration, the cell numbers decreased from 7 x 10(4) cells/ml to 2 x 10(4) cells/ml when Dox concentration was increased from 0 to 1500 ng/ml after 72 hours culture. In addition, bystander effects were generated in vitro when 10% - 25% of transduced MCF-7 cells were mixed in untransduced MCF-7 cells. On the other hand, the human breast cancer models in SCID mice were set up. The tk gene was expressed with the regulated character after MCF/TRE/tk/Tet-On cells were implanted into the female SCID mice 7 days after Dox induction followed by intraperitoneally administration of GCV for 23 days. Subcutaneous tumors in SCID mice that were implanted with MCF/TRE/tk/Tet-On cells shrank remarkably after Dox and GCV administration as compared with the control. The human breast tumor cells (MCF-7) expressing HSVtk gene can be eradicated by administration of GCV and induced with tetracycline or its derivative Dox in vitro and in vivo.


A Potassium-Based Quality-of-Service Metric Reduces Phlebotomy Errors, Resulting in Improved Patient Safety and Decreased Cost.
Poor phlebotomy technique can introduce pseudohyperkalemia without hemolysis, requiring additional workup and placing a significant burden on patients, clinical teams, and laboratories. Such preanalytical biases can be detected through systematic evaluation of potassium concentrations on a per-phlebotomist basis. We report our long-term experience with a potassium-based quality-of-service phlebotomy metric and its effects on resource utilization. Potassium monitoring and retraining of 26 full-time phlebotomists were piloted as a quality-of-service intervention. Changes in potassium concentrations and impact on resource utilization were assessed. An algorithm for data monitoring and phlebotomist feedback was developed, followed by institution-wide implementation. Systematic intervention and retraining normalized K+ concentrations and lowered the percentage of venipunctures with K+ above 5.2 mmol/L, leading to a marked increase in phlebotomist compliance. This change resulted in resources savings of 13% to 100% for individual phlebotomists, reducing the total extra laboratory time required for repeat phlebotomies to determine hyperkalemia, mostly in the high-volume phlebotomist group. A quality-of-service algorithm that involved monitoring potassium concentrations on a per-phlebotomist basis with feedback and retraining contributed to a concrete, data-based quality improvement plan. The institution-wide implementation of this metric allowed for significant cost savings and a reduction in critical value alerts, directly affecting the quality of patient care.


Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice.
Tetrahydrobiopterin (BH4), which fosters the formation of and stabilizes endothelial NO synthase (eNOS) as an active dimer, tightly regulates eNOS coupling / uncoupling. Moreover, studies conducted in genetically-modified models demonstrate that BH4 pulmonary deficiency is a key determinant in the pathogenesis of pulmonary hypertension. The present study thus investigates biopterin metabolism and eNOS expression, as well as the effect of sepiapterin (a precursor of BH4) and eNOS gene deletion, in a mice model of hypoxic pulmonary hypertension. In lungs, chronic hypoxia increased BH4 levels and eNOS expression, without modifying dihydrobiopterin (BH2, the oxidation product of BH4) levels, GTP cyclohydrolase-1 or dihydrofolate reductase expression (two key enzymes regulating BH4 availability). In intrapulmonary arteries, chronic hypoxia also increased expression of eNOS, but did not induce destabilisation of eNOS dimers into monomers. In hypoxic mice, sepiapterin prevented increase in right ventricular systolic pressure and right ventricular hypertrophy, whereas it modified neither remodelling nor alteration in vasomotor responses (hyper-responsiveness to phenylephrine, decrease in endothelium-dependent relaxation to acetylcholine) in intrapulmonary arteries. Finally, deletion of eNOS gene partially prevented hypoxia-induced increase in right ventricular systolic pressure, right ventricular hypertrophy and remodelling of intrapulmonary arteries. Collectively, these data demonstrate the absence of BH4/BH2 changes and eNOS dimer destabilisation, which may induce eNOS uncoupling during hypoxia-induced pulmonary hypertension. Thus, even though eNOS gene deletion and sepiapterin treatment exert protective effects on hypoxia-induced pulmonary vascular remodelling, increase on right ventricular pressure and / or right ventricular hypertrophy, these effects appear unrelated to biopterin-dependent eNOS uncoupling within pulmonary vasculature of hypoxic wild-type mice.


Mapping and functional dissection of the rumpless trait in Piao chicken identifies a causal loss of function mutation in the novel gene Rum.
Rumpless chickens exhibit an abnormality in their tail development. The genetics and biology of this trait has been studied for decades to illustrate a broad variation in both the types of inheritance and the severity in the developmental defects of the tail. In this study, we created a backcross pedigree by intercrossing Piao (rumpless) with Xianju (normal) to investigate the genetic mechanisms and molecular basis of the rumpless trait in Piao chicken. Through genome-wide association (GWAS) and linkage analyses, the candidate region was fine-mapped to 798.5 kb (chromosome 2:86.9-87.7 Mb). Whole-genome sequencing analyses identified a single variant, a 4.2 kb deletion, which was completely associated with the rumpless phenotype. Explorations of the expression data identified a novel causative gene, Rum, that produced a long, intronless transcript across the deletion. The expression of Rum is embryo-specific and that it regulates expression of MSGN1, a key factor in regulating T-box transcription factors required for mesoderm formation and differentiation. These results provide genetic and molecular experimental evidence for a novel mechanism regulating tail development in chicken and report the likely causal mutation for the tail abnormity in the Piao chicken. The novel regulatory gene, Rum, will due to its role in fundamental embryo development be of interest for further explorations of a potential role in tail and skeletal development also in other vertebrates.


Outcomes of dental hygiene baccalaureate degree education in Canada.
There is little published literature about the outcomes of dental hygiene baccalaureate degree education, particularly in Canada. Since there are various dental hygiene entry-to-practice educational models in Canada, exploring baccalaureate dental hygiene education is becoming an increasingly important subject. The purpose of this study was to explore the personal outcomes and dental hygiene practice outcomes of dental hygiene degree-completion education in Canada from the perspectives of diploma dental hygienists who have continued their education to the bachelor's degree level. This study employed a qualitative phenomenological design, using a maximum variation purposeful sampling strategy. Data generation occurred with sixteen dental hygienists across Canada through individual semistructured interviews. Interviews were audiorecorded, transcribed verbatim, and coded for data analysis, involving pattern recognition and thematic development. Themes that emerged included changes in self-perception, values, and knowledge base. Changes in self-perception were reflected in a reported increase in self-confidence and perceived credibility. Changes in values included a greater appreciation for lifelong learning. Advancements in knowledge strengthened the development of specific abilities that ultimately influenced participants' dental hygiene practice. These abilities included an increased ability to think critically, to make evidence-based decisions, and to provide more comprehensive care. Participants also commented on having more career opportunities available to them outside of the private clinical practice setting. These results reveal important insights into the impact of earning a dental hygiene baccalaureate degree on oneself and one's dental hygiene practice.


Anti-JNK2 peptide-siRNA nanostructures improve plaque endothelium and reduce thrombotic risk in atherosclerotic mice.
A direct and independent role of inflammation in atherothrombosis was recently highlighted by the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, showing the benefit of inhibiting signaling molecules, eg, interleukins. Accordingly, we sought to devise a flexible platform for preventing the inflammatory drivers at their source to preserve plaque endothelium and mitigate procoagulant risk. p5RHH-siRNA nanoparticles were formulated through self-assembly processes. The therapeutic efficacy of p5RHH-JNK2 siRNA nanoparticles was evaluated both in vitro and in vivo. Because JNK2 is critical to macrophage uptake of oxidized lipids through scavenger receptors that engender expression of myriad inflammatory molecules, we designed an RNA-silencing approach based on peptide-siRNA nanoparticles (p5RHH-siRNA) that localize to atherosclerotic plaques exhibiting disrupted endothelial barriers to achieve control of JNK2 expression by macrophages. After seven doses of p5RHH-JNK2 siRNA nanoparticles over 3.5 weeks in ApoE-/- mice on a Western diet, both JNK2 mRNA and protein levels were significantly decreased by 26% (P=0.044) and 42% (P=0.042), respectively. Plaque-macrophage populations were markedly depleted and NFκB and STAT3-signaling pathways inhibited by 47% (P<0.001) and 46% (P=0.004), respectively. Endothelial barrier integrity was restored (2.6-fold reduced permeability to circulating 200 nm nanoparticles in vivo, P=0.003) and thrombotic risk attenuated (200% increased clotting times to carotid artery injury, P=0.02), despite blood-cholesterol levels persistently exceeding 1,000 mg/dL. No adaptive or innate immunoresponses toward the nanoparticles were observed, and blood tests after the completion of treatment confirmed the largely nontoxic nature of this approach. The ability to formulate these nanostructures rapidly and easily interchange or multiplex their oligonucleotide content represents a promising approach for controlling deleterious signaling events locally in advanced atherosclerosis.


Hypothyroidism presenting as growth retardation. A case report.
An unusual case of hypothyroidism presenting as growth retardation is reported. The clinical features of childhood hypothyroidism and the essential laboratory and special investigations needed to make the diagnosis are discussed. The importance of considering hypothyroidism in the differential diagnosis of short stature is emphasized since early treatment can result in normal mental development and growth. Screening programmes to detect hypothyroidism in the newborn are needed.


Dispersion self-free energies and interaction free energies of finite-sized ions in salt solutions.
The role for many-body dipolar (dispersion) potentials in ion-solvent and ion-solvent-interface interactions is explored. Such many-body potentials, accessible in principle from measured dielectric data, are necessary in accounting for Hofmeister specific ion effects. Dispersion self-energy is the quantum electrodynamic analogue of the Born electrostatic self-energy of an ion. We here describe calculations of dispersion self-free energies of four different anions (OH-, Cl-, Br-, and I-) that take finite ion size into account. Three different examples of self-free energy calculations are presented. These are the self-free energy of transfer of an ion to bulk solution, which influences solubility; the dispersion potential acting between one ion and an air-water interface (important for surface tension calculations); and the dispersion potential acting between two ions (relevant to activity coefficient calculations). To illustrate the importance of dispersion self-free energies, we compare the Born and dispersion contributions to the free energy of ion transfer from water to air (oil). We have also calculated the change in interfacial tension with added salt for air (oil)-water interfaces. A new model is used that includes dispersion potentials acting on the ions near the interface, image potentials, and ions of finite size that are allowed to spill over the solution-air interface. It is shown that interfacial free energies require a knowledge of solvent profiles at the interface.


Short- and Long-Term Dentin Bond Strength of Bioactive Glass-Modified Dental Adhesives.
This study investigated the short- and long-term effects of dental adhesives doped with nano-sized bioactive glass 45S5 (BAG) on the resin-dentin interfacial bond strength. Two etch-and-rinse adhesives (Adper Scotchbond Multi-Purpose (ASB) and Solobond Plus (SB)) and one self-etch adhesive (Clearfil SE Bond (CF)) were doped with different concentrations of BAG (5, 10, and 20 wt%). The unmodified (0 wt% BAG) commercial adhesives served as control groups. Dentin of 120 molars (n = 10 per group) was treated with the different adhesives, followed by buildups with a conventional composite restorative material. From each tooth, 14 sticks were prepared for micro-tensile bond strength (µTBS) testing. The sticks were stored in simulated body fluid at 37 °C and tested after 24 h or six months for µTBS and failure mode. Data were analyzed using Kruskal-Wallis tests in combination with post-hoc Conover-tests and Wilcoxon signed-rank tests at a level of significance of α = 0.05. After 24 h and six months, both etch-and-rinse adhesives with a low BAG content (up to 10 wt% for ASB and 5 wt% for SB) showed similar µTBSs as their respective control groups (0 wt% BAG). CF showed a significant decrease in µTBS even after addition of 5 wt% BAG. At a high concentration of added BAG (20 wt%), all three adhesives showed a significant decrease in µTBS compared to the unmodified controls. The CF control group showed significantly lower µTBS after 6 months of storage than after 24 h. In contrast, the µTBS of all CF groups modified with BAG was unaffected by aging. In conclusion, the tested etch-and-rinse adhesives can be modified with up to 5 wt% (SB), or 10 wt% (ASB) of BAG without reducing their short- and long-term dentin bond strength. Moreover, the addition of nano-sized BAG may prevent long-term bond strength deterioration of a self-etch adhesive.


Exportin 6: a novel nuclear export receptor that is specific for profilin.actin complexes.
Active macromolecular transport between the nucleus and cytoplasm proceeds through nuclear pore complexes and is mostly mediated by transport receptors of the importin beta-superfamily. Here we identify exportin 6 (Exp6) as a novel family member from higher eukaryotes and show that it mediates nuclear export of profilin.actin complexes. Exp6 appears to contact primarily actin, but the interaction is greatly enhanced by the presence of profilin. Profilin thus functions not only as the nucleotide exchange factor for actin, but can also be regarded as a cofactor of actin export and hence as a suppressor of actin polymerization in the nucleus. Even though human and Drosophila Exp6 share only approximately 20% identical amino acid residues, their function in profilin.actin export is conserved. A knock-down of Drosophila Exp6 by RNA interference abolishes nuclear exclusion of actin and results in the appearance of nuclear actin paracrystals. In contrast to a previous report, we found no indications of a major and direct role for CRM1 in actin export from mammalian or insect nuclei.


Role of soy protein with normal or reduced isoflavone content in reversing bone loss induced by ovarian hormone deficiency in rats.
Soy protein, a rich source of isoflavones, fed immediately after an ovariectomy prevents bone loss in rats. Reports of the effectiveness of natural and synthetic isoflavones in preventing or treating osteoporosis led us to examine the effect of soy protein in reversing established bone loss. Seventy-two 95-d-old female Sprague-Dawley rats were assigned to 6 groups. The rats were either sham operated (SHAM; 2 groups) or ovariectomized (OVX; 4 groups) and then fed a casein-based, semipurified diet. Thirty-five days after surgery, 1 SHAM and 1 OVX group were killed to examine the occurrence of bone loss. Thereafter, the other SHAM and 1 OVX groups continued to receive the casein-based diet. Whereas the remaining 2 OVX groups received diets in which casein was replaced by soy protein with normal (OVX+SOY) or reduced (OVX+SOY-) isoflavone content for 65 days. The OVX control group had significantly lower femoral and fourth lumbar vertebral bone densities than the SHAM group. Femoral density of rats fed SOY or SOY- diets were not significantly different from SHAM or OVX controls. This suggests a slight reversal of cortical bone loss that may be partially due to higher femoral insulin-like growth factor I mRNA transcripts resulting from both the SOY and SOY- diets. The ovariectomy-induced increases in indexes of bone turnover were not ameliorated by either of the soy diets, suggesting that any positive effect of soy was achieved through enhanced bone formation rather than slowed bone resorption. Long-term consumption of soy or its isoflavones may be needed to produce small but continued increments in bone mass.


Coordinating cellular events during spermatogenesis: a biochemical model.
Throughout spermatogenesis, a select pool of germ cells, the leptotene spermatocytes, must traverse the blood-testis barrier (BTB) to enter the adluminal compartment of the seminiferous epithelium. This event requires extensive restructuring of cell junctions, and it must also coincide with germ cell cycle progression in preparation for primary spermatocyte meiosis. Recent findings show that cell-cycle-associated kinases and phosphatases, including mitogen-activated protein kinases (MAPKs), participate in the pathways that also direct germ cell adhesion and movement. Our new biochemical model explains, in part, how two distinct cellular events, BTB restructuring and spermiation, are coordinated to maintain spermatogenesis and fertility. In this way, MAPKs would synchronize cell cycle progression in primary spermatocytes with junction remodeling and cell migration across the BTB.


Ultrasonography of the urinary tract in children.
The various urologic abnormalities for which ultrasonography can be a valuable diagnostic tool are discussed, including renal masses, nonfunction of the kidney, and abnormalities of the lower urinary tract. Ultrasonography is a useful adjunct to radionuclide imaging, intravenous urography, and renl angiography, and is particularly well suited for the pediatric population.


Adaptations to isolated shoulder fatigue during simulated repetitive work. Part II: Recovery.
The shoulder allows kinematic and muscular changes to facilitate continued task performance during prolonged repetitive work. The purpose of this work was to examine changes during simulated repetitive work in response to a fatigue protocol. Participants performed 20 one-minute work cycles comprised of 4 shoulder centric tasks, a fatigue protocol, followed by 60 additional cycles. The fatigue protocol targeted the anterior deltoid and cycled between static and dynamic actions. EMG was collected from 14 upper extremity and back muscles and three-dimensional motion was captured during each work cycle. Participants completed post-fatigue work despite EMG manifestations of muscle fatigue, reduced flexion strength (by 28%), and increased perceived exertion (∼3 times). Throughout the post-fatigue work cycles, participants maintained performance via kinematic and muscular adaptations, such as reduced glenohumeral flexion and scapular rotation which were task specific and varied throughout the hour of simulated work. By the end of 60 post-fatigue work cycles, signs of fatigue persisted in the anterior deltoid and developed in the middle deltoid, yet perceived exertion and strength returned to pre-fatigue levels. Recovery from fatigue elicits changes in muscle activity and movement patterns that may not be perceived by the worker which has important implications for injury risk.


Supplementary eye field as defined by intracortical microstimulation: connections in macaques.
In macaques, the frontal eye field and the recently defined supplementary eye field play a role in the production of eye movements. Whereas the structure and function of the frontal eye field are well understood, little is known about the supplementary eye field. The goal of this study was to determine the connections of the physiologically defined supplementary eye field. In each case, the location of the supplementary eye field was determined by using intracortical microstimulation, the borders were marked with small electrolytic lesions, and horseradish peroxidase conjugated to wheat germ agglutinin was injected into the supplementary eye field. After the tissue was incubated with tetramethyl benzidine, it was determined that in three cases the injection site was confined to the physiologically defined supplementary eye field. The present results indicate that the supplementary eye field is reciprocally connected with the claustrum, ventral anterior nucleus, including pars magnocellularis, nucleus X, posterior subdivision of the ventral lateral nucleus, multiform, parvocellular, magnocellular, and densocellular subdivisions of the medial dorsal nucleus, central lateral nucleus, parafascicular nucleus, and suprageniculate-limitans complex. The supplementary eye field projects to the putamen, caudate, reticular nucleus of the thalamus, central densocellular nucleus, zona incerta, subthalamic nucleus, rostral interstitial nucleus of the medial longitudinal fasciculus, parvocellular part of the red nucleus, intermediate and deep layers of the superior colliculus, central gray, cuneiform nucleus, mesencephalic reticular formation, pontine gray, nucleus reticularis tegmenti pontis, and nucleus reticularis pontis oralis. The supplementary eye field is reciprocally and bilaterally connected with periprincipal and inferior prefrontal cortex, with periarcuate cortex, including the frontal eye field, the frontal ventral region, and with postarcuate premotor cortex, and cortex surrounding the supplementary eye field, including the supplementary motor area. The supplementary eye field is also reciprocally connected ipsilaterally with cortex in and around the cingulate sulcus and the intraparietal sulcus, whereas cortex within the superior temporal sulcus projects to the supplementary eye field. The connections of the physiologically defined supplementary eye field are compared to previously demonstrated connections of the supplementary motor region and of the physiologically defined frontal eye field. Comparisons between the connections of the frontal and supplementary eye fields reveal that both regions are connected with structures related to visuomotor functions, but the frontal eye field has more extensive connections with vision-related structures, and the supplementary eye field has more extensive connections with structures related to prefrontal and skeletomotor functions. Such connectional differences suggest functional differences between these two sensorimotor regions of the frontal lobe.


[Extended surgery in locally invasive pancreatic cancer. An original revascularization technique].
The end results of surgery for pancreatic tumors remains very poor. In patients with locally invasive tumors a by-pass type of surgery is usually performed with low survival and poor life quality. Seven patients with locally invasive pancreatic tumors were operated by the authors and extensive radical surgery was done with good results. An original revascularization technique of the hepatic artery is described.


The management of ocular allergy.
There is a broad spectrum of ocular allergy. In the mild forms it is no more than an inconvenience, but severe forms such as eczematous kerato-conjunctivitis can be sight-threatening. However, with proper understanding of the diseases and constructive management, most patients can be satisfactorily controlled.


Characteristics of clinician input in Canadian funding decisions for cancer drugs: a cross-sectional study based on CADTH reimbursement recommendations.
To examine characteristics of clinician input to the pan-Canadian Oncology Drug Review (pCODR) for cancer drug funding recommendations from 2016 to 2020. Descriptive, cross-sectional study including 62 reimbursement decisions from pCODR from 2016 to 2020. pCODR recommendations were analysed for the number of clinicians consulted on each submission, affiliation, number of submissions per clinician, declared financial conflicts of interest (FCOIs), randomisation, type of blinding, primary endpoint, study phase, and whether the study demonstrated improvement in overall survival (OS) and progression-free survival (PFS). The main outcome was clinician support for the initial funding recommendation. Secondary outcome measures were the association between clinician FCOIs and clinical benefit in positive recommendations. The study consisted of 62 submissions, in which 48 included clinician input. A total of 129 unique clinicians provided 342 consultations. The majority (59%) provided input on less than 5 submissions; however, a small proportion (4%) consulted on over 10. Nearly all clinicians were physicians (125; 96%). From the 342 consultations, 228 declared financial conflicts (67%). The most common conflicts were payments for advisory roles (51%) and honorariums (23%). Of the 48 cancer drugs under review, clinicians recommended funding 46 (96%). Only 12 (25%) demonstrated substantial benefit, according to the European Society for Medical Oncology Magnitude of Clinical Benefit Scale score. Drugs recommended for funding were more likely to have improved PFS and OS data. However, most cancer drugs supported by clinicians demonstrated no change in health-related quality of life (HRQoL), including one that demonstrated worsened HRQoL. There was no statistically significant difference between FCOI status and recommending drugs with health gains. Clinicians offer crucial information on funding decisions. However, we found clinicians strongly supported funding nearly all cancer drugs under review, despite most not offering substantial benefit to patients nor gains in quality of life. While these drugs might be helpful options in clinical practice, funding numerous cancer drugs may be unsustainable for public health systems.


Clinical review of grayanotoxin/mad honey poisoning past and present.
Grayanotoxin is a naturally occurring sodium channel toxin which enters the human food supply by honey made from the pollen and nectar of the plant family Ericaceae in which rhododendron is a genus. Grayanotoxin/mad honey poisoning is a little known, but well studied, cholinergic toxidrome resulting in incapacitating and, sometimes, life-threatening bradycardia, hypotension, and altered mental status. Complete heart blocks occur in a significant fraction of patients. Asystole has been reported. Treatment with saline infusion and atropine alone is almost always successful. A pooled analysis of the dysrhythmias occurring in 69 patients from 11 different studies and reports is presented. The pathophysiology, signs, symptoms, clinical course, and treatment of grayanotoxin/mad honey poisoning are discussed. In the nineteenth century grayanotoxin/mad honey poisoning was reported in Europe and North America. Currently, documented poisoning from locally produced honey in Europe or North America would be reportable. Possible reasons for this epidemiologic change are discussed.


Self-nanoemulsifying drug delivery system of nifedipine: impact of hydrophilic-lipophilic balance and molecular structure of mixed surfactants.
A simple but novel mixed surfactant system was designed to fabricate a self-nanoemulsifying drug delivery system (SNEDDS) based on hydrophilic-lipophilic balance (HLB) value. The impacts of HLB and molecular structure of surfactants on the formation of SNEDDS were investigated. After screening various oils and surfactants, nifedipine (NDP)-loaded liquid SNEDDS was formulated with Imwitor(®) 742 as oil and Tween(®)/Span(®) or Cremophor(®)/Span(®) as mixed surfactant. Droplet size of the emulsions obtained after dispersing SNEDDS containing Tween(®)/Span(®) in aqueous medium was independent of the HLB of a mixed surfactant. The use of the Cremophor(®)/Span(®) blend gave nanosized emulsion at higher HLB. The structure of the surfactant was found to influence the emulsion droplet size. Solid SNEDDS was then prepared by adsorbing NDP-loaded liquid SNEDDS comprising Cremophor(®) RH40/Span(®) 80 onto Aerosil(®) 200 or Aerosil(®) R972 as inert solid carrier. Solid SNEDDS formulations using higher amounts (30-50% w/w) of Aerosil(®) 200 exhibited good flow properties with smooth surface and preserved the self-emulsifying properties of liquid SNEDDS. Differential scanning calorimetry and X-ray diffraction studies of solid SNEDDS revealed the transformation of the crystalline structure of NDP due to its molecular dispersion state. In vitro dissolution study demonstrated higher dissolution of NDP from solid SNEDDS compared with NDP powder.


[Testicular tumors in childhood. Review of cases in the course of 13 years].
Testicular and paratesticular tumors are rare in childhood, representing 1-2 percent of the solid tumors in the pediatric age. In patients under 14 years, the incidence is 0.5-2/100,000. The evolution differs from that of the adult. Since 1981 to 1994 we have treated 14 cases of testicular and paratesticular tumors. Mean age was 2.54 years, the younger patients presenting germinal tumors. The most frequent tumor was the yolk sac tumor (36%), followed by teratoma mature (29%), and Leydig cell tumor, epidermoid cyst, paratesticular fibrous hamartoma, paratesticular neuroblastoma and paratesticular rabdomyosarcoma (7% each). A testicular mass was present in all cases (100%). Testicular ultrasound was used in 100%. In all the patients with malignant tumors a thoraco-abdominal CT scans was done to rule out extension or the tumor, being negative in all cases. Alphafetoprotein were high in all the cases of yolk sac tumor, being within normal range one month after surgery except in one case. In 11 patients an orquiectomy was done through an inguinal approach, and in three cases a simple tumorectomy without orquiectomy. No lymphadenectomy was done. All the malignants neoplasms were stage I tumors, except one yolk sac tumor stage III. Postop chemotherapy was applied in this one and in the embrionary rabdomyosarcoma. There were no recurrences after a follow-up mean time of 3.98.


Serotonin innervation of human basal ganglia.
This study aimed to provide a first detailed description of the serotonin (5-hydroxytryptamine, 5-HT) innervation of the human basal ganglia under nonpathological conditions. We applied an immunohistochemical approach to postmortem human brain material with antibodies directed against the 5-HT transporter and the 5-HT-synthesizing enzyme (tryptophane hydroxylase) to visualize 5-HT axons and cell bodies, respectively. Adjacent sections were immunostained for tyrosine hydroxylase to compare the distribution of 5-HT axons with that of dopamine axons. Human basal ganglia are innervated by 5-HT axons that emerge chiefly from the dorsal and, less abundantly, from the median raphe nuclei. These axons form thick ascending fascicles that fragment themselves as they penetrate the decussation of the superior cerebellar peduncle. They regroup within the ventral tegmental area and ascend along the medial forebrain bundle, immediately beneath the dopamine ascending fibers. At regular intervals along their course, 5-HT axons detach themselves from the medial forebrain bundle and sweep laterally to arborize within all basal ganglia components, where they display highly variable densities and patterns of innervation. The substantia nigra is the most densely innervated component of the basal ganglia, whereas the caudate nucleus is more heterogeneously innervated than the putamen and pallidum. The subthalamic nucleus harbors 5-HT-immunoreactive fibers that display a mediolateral-decreasing gradient. The fact that all components of human basal ganglia receive a dense 5-HT input indicates that, in concert with dopamine, 5-HT plays a crucial role in the functional organization of these motor-related structures, which are often targeted in neurodegenerative diseases.


The value of plants used in traditional medicine for drug discovery.
In this review we describe and discuss several approaches to selecting higher plants as candidates for drug development with the greatest possibility of success. We emphasize the role of information derived from various systems of traditional medicine (ethnomedicine) and its utility for drug discovery purposes. We have identified 122 compounds of defined structure, obtained from only 94 species of plants, that are used globally as drugs and demonstrate that 80% of these have had an ethnomedical use identical or related to the current use of the active elements of the plant. We identify and discuss advantages and disadvantages of using plants as starting points for drug development, specifically those used in traditional medicine.


[Social-economic and obstetric factors associated to premature rupture of membranes].
The premature rupture of membranes is the delivery of amniotic liquid after 20 weeks of gestation and before the beginning of labour. To evaluate the association between premature rupture of membranes and sociodemographics and obstetrics antecedents. Unmatched case-control study carried out in patients from Hospital Civil de Culiacan, Sinaloa (Mexico), from January 2003 to December 2006. Risk factors frequency was compared in women with and without premature rupture of membranes (cases: 1,399; controls: 1,379). Most important variables were: socio-economic level, smoking, and gyneco-obstetric history (sexual partners, pregnancies, newborns, abortions, prenatal control and intergenesic interval). Odds ratio, crude and adjusted, and interval of confidence (IC 95%) were obtained by means of non-conditional logistic regression models. Prevalence of premature rupture of membranes was 8.9%. Socio-economic level was similar in both groups. Premature rupture of membranes was associated with smoking, beginning of sexual activity, and intergenesic interval. History of two or more cesarean sections was considered a protective factor of premature rupture of membranes. Number of sexual partners was marginally meaningful (p = 0.053). Preterm birth frequency was higher in cases group. Resolution of pregnancy was the same for both groups (p = 0.233). Premature rupture of membranes was significantly associated with smoking, beginning of sexual activiti, intergenesic interval and a preterm birth history. Two or more previous caesarean sections were considered as protective factor.


Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages.
To determine the efficacy, dose-response relationship, and safety of 30, 60, and 90 mg of a single intravenous dose of an aminobisphosphonate, pamidronate (APD), for the treatment of moderate to severe hypercalcemia of malignancy. Patients with histologically proven cancer and a corrected serum calcium level of at least 12.0 mg/dL after 48 hours of normal saline hydration were enrolled in a double-blind, multicenter, randomized clinical trial. Pamidronate in 30-, 60-, or 90-mg doses was administered as a single 24-hour infusion. Serum calcium corrected for albumin, urine hydroxyproline, and calcium excretion, and serum parathyroid hormone (PTH) (1-84) were determined before and after pamidronate therapy. Thirty-two men and 18 women entered the study. A dose-response relationship for normalization of corrected serum calcium was seen after pamidronate administration. Corrected serum calcium normalized in 40% of patients who received 30 mg, in 61% of patients who received 60 mg, and in 100% of patients who received 90 mg of pamidronate. The decline in the serum calcium level was associated with decreased osteoclastic skeletal resorption evidenced by a decrease in urine calcium and hydroxyproline excretion. Among those with a normalized corrected serum calcium level, the mean (median) duration of normalization of the corrected serum calcium value was 9.2 (4), 13.3 (5), and 10.8 (6) days in the 30-, 60-, and 90-mg treatment groups, respectively. The response of hypercalcemia to pamidronate was not significantly influenced by the presence of skeletal metastases. PTH 1-84, suppressed in patients on entry into this study, increased to a greater extent in those patients with osteolytic skeletal metastases compared with those with humoral hypercalcemia of malignancy. Clinical improvement, including improved mental status and decreased anorexia, accompanied the decline in the corrected serum calcium level in all three treatment groups. Side effects included low-grade fever, asymptomatic hypocalcemia, hypomagnesemia, and hypophosphatemia. A single-dose infusion of 60 to 90 mg of pamidronate was highly effective and well tolerated and normalized corrected serum calcium in nearly all patients (61% to 100%) with hypercalcemia of malignancy.


The children's eating behavior inventory: reliability and validity results.
Eating and mealtime problems are common in childhood. They occur across a broad age span, in normally developing children and in a wide variety of developmental and medical disorders. There is no currently available standard instrument by which to assess these problems. The Children's Eating Behavior Inventory (CEBI) was developed according to a conceptual framework based upon a transactional/systemic understanding of parent-child relationships. It was completed by 206 mothers of nonclinic children and 110 mothers of clinic children. Results of test-retest and internal reliability testing indicate that the CEBI meets criteria for instrument reliability. Construct validity is demonstrated by the significant difference between the clinic and nonclinic groups in the mean total eating problem score and in the mean number of items perceived to be a problem.


Long-term exposure to music enhances the sensitivity of the auditory system in children.
This event-related brain potential study aims to contribute to the present debate regarding the effect of musical training on the maturation of the human auditory nervous system. To address this issue, we recorded the mismatch negativity (MMN) evoked by violin and pure sine-wave tones in a group of 7.5- to 12-year-old children who had either several years of musical experience with Suzuki violin lessons, or no musical training. The strength of the MMN responses to violin tones evident in the Suzuki students clearly surpassed responses in controls; the reverse pattern was observed for sine-wave tones. Suzuki students showed significantly shorter MMN latencies to violin tones than to pure tones; the MMN latency did not differ significantly between pure tones and violin sounds in the control group. Thus, our data provide general evidence of how and to what extent extensive musical experience affects the maturation of human auditory function at multiple levels, namely, accuracy and speed of auditory discrimination processing. Our findings add to the present understanding of neuroplastic organization and function of the mammalian nervous system. Furthermore, behavioural recordings obtained from the participating children provide corroborating evidence for a relationship between the duration and intensity of training, the specific sensitivity to instrumental timbre, and pitch recognition abilities.


[Kinetics of electron transport, proton transfer and photophosphorylation in chloroplasts and their relation to temperature-induced structural changes in the thylakoid membrane].
Effects of various temperatures on the rates of electron transport between two photosystems, the light-induced uptake of protons, kinetics of proton efflux from the chloroplasts in the dark and photophosphorylation were studied in isolated chloroplasts. There are correlations between the physical state of thylakoid membrane and the rates of electron- and proton transport processes. The temperature dependence of "structural" parameter (fluidity of lipids in membrane) as well as the rates of electron- and proton transport processes reveal the breaks under the same temperatures. Stimulation of photophosphorylation by temperature increasing correlates with the heat activation of chloroplasts latent ATPase due to thermoinduced structural changes in the heat activation of chloroplasts latent ATPase due to thermoinduced structural changes in the protein part of CF0-CF1 complex. The rate of photophosphorylation also correlates with the physical state of membrane lipids. Thermoinduced "melting" of the thylakoid membrane inhibits the ATP formation because of a decrease in photosystem 2 photochemical activity and stimulation of membrane conductivity for protons.


Papillomatous digital dermatitis in 458 dairies.
To estimate prevalence of papillomatous digital dermatitis (PDD) in California dairies during 1993, to describe temporal and spatial patterns of PDD and response of cows to treatment, and to evaluate herd-related risk factors for PDD. Epidemiologic survey. All southern California dairies and a 50% random sample of the rest of California dairies. A questionnaire was mailed to managers of 1,429 selected dairies. Prevalence of PDD during 1993 was significantly higher for dairies in the south (75.3%) and central (68.8%) regions, compared with north coast (33.3%) and north (23.1%) regions of the state. Herd mean and median proportions of affected cows in PDD-affected herds were 11.6 (SEM = 0.9) and 5%, respectively. Most (74%) dairy managers surveyed observed PDD for the first time during 1992 or 1993. Highest PDD activity was reported as taking place in summer in the south and in fall and winter in the north coast and north regions; an obvious pattern was not determined for the central region. PDD was widespread in California dairies during 1993 and affected a high proportion of cows, especially in the south and central regions of the state.


Conservation of the 2,4-diacetylphloroglucinol biosynthesis locus among fluorescent Pseudomonas strains from diverse geographic locations.
The broad-spectrum antibiotic 2,4-diacetylphloroglucinol (PHL) is a major determinant in the biological control of a range of plant pathogens by many fluorescent Pseudomonas spp. A 4.8-kb chromosomal DNA region from Pseudomonas fluorescens Q2-87, carrying PHL biosynthetic genes, was used as a probe to determine if the PHL biosynthetic locus is conserved within PHL-producing Pseudomonas strains of worldwide origin. The phl gene probe hybridized with the genomic DNA of all 45 PHL-producing Pseudomonas strains tested, including well-characterized biocontrol strains from the United States and Europe and strains isolated from disease-suppressive soils from Switzerland, Washington, Italy, and Ghana. The PHL producers displayed considerable phenotypic and genotypic diversity. Two phenotypically distinct groups were detected. The first produced PHL, pyoluteorin, and hydrogen cyanide and consisted of 13 strains from almost all locations sampled in the United States, Europe, and Africa. The second produced only PHL and HCN and consisted of 32 strains from the U.S. and European soils. Analysis of restriction patterns of genomic DNA obtained after hybridization with the phl gene probe and cluster analysis of restriction patterns of amplified DNA coding for 16S rRNA (ARDRA) and randomly amplified polymorphic DNA (RAPD) markers indicated that the strains that produced both PHL and pyoluteorin were genetically highly similar. In contrast, there was more diversity at the genotypic level in the strains that produced PHL but not pyoluteorin. ARDRA analysis of these strains indicated two clusters which, on the basis of RAPD analysis, split into several subgroups with additional polymorphisms. In general, the occurrence of phenotypically and genotypically similar groups of PHL producers did not correlate with the geographic origin of the isolates, and highly similar strains could be isolated from diverse locations worldwide.


Development of an innovative physical examination course involving handheld ultrasound devices.
This article was migrated. The article was marked as recommended. Several studies in recent years have shown that the physical examination skills of medical students are inadequate. In response to this deficit, a new teaching intervention has been developed consisting of five physical examination courses and a set of corresponding bedside teaching modules. The bedside modules are primarily intended to provide the opportunity for practical application of the examination techniques learned. One particularity of the bedside teaching was the use of handheld ultrasound (HHU) units in order to be able to visualize and verify/falsify diagnostic findings immediately. Since this demonstration of findings was standardized according to the specifications of the Rapid Ultrasound in Shock and Hypotension (RUSH) protocol, it constituted the basis for the communication of basic emergency ultrasound skills. A pilot study, which included an initial evaluation, has demonstrated this concept is feasible and is met with great interest on the part of the students.


The repressor DREAM acts as a transcriptional activator on Vitamin D and retinoic acid response elements.
DREAM (downstream regulatory element antagonist modulator) is a transcriptional repressor, which binds DREs (downstream response elements) in a Ca2+-regulated manner. The DREs consist of core GTCA motifs, very similar to binding motifs for non-steroid nuclear receptors. In this work, we find that DREAM stimulates basal and ligand-dependent activation of promoters containing vitamin D and retinoic acid response elements (VDREs and RAREs), consisting of direct repeats of the sequence AGT/GTCA spaced by 3 or 5 nt, respectively. Stimulation occurs when the element is located upstream, but not downstream, the transcription initiation site. Activation requires both Ca2+ binding to the EF-hands and the leucine-charged domains (LCDs), analogous to those responsible for the interaction of the nuclear receptors with coregulators. Further more, DREAM can bind both 'in vitro' and in chromatin immunoprecipitation assays to these elements. Importantly, 'in vivo' binding is only observed in vitamin D- or RA-treated cells. These results show that DREAM can function as an activator of transcription on certain promoters and demonstrate a novel role for DREAM acting as a potential modulator of genes containing binding sites for nuclear receptors.


Use of an anti-low density lipoprotein receptor antibody to quantify the role of the LDL receptor in the removal of chylomicron remnants in the mouse in vivo.
Lipoproteins are removed from the plasma by LDL receptor-dependent and -independent pathways. The relative contribution of these has been established for LDL by using modified lipoproteins, but this has not been possible for apoE-rich lipoproteins, such as chylomicron remnants. To do this, we used a monospecific antibody to the rat LDL receptor. The antibody was injected intravenously into mice followed by 125I-lipoproteins. Blood samples were obtained sequentially and radioactivity measured to determine the plasma clearance of the lipoproteins. The animals were then sacrificed and the tissues removed, dried, and the radioactivity measured to determine tissue uptake. An albumin space was also measured to correct for blood trapping. With 125I-human LDL, approximately 50% of the injected dose was cleared in 180 min. This was reduced to 30% by the antibody and this was identical to the disappearance of reductively methylated LDL. This is a lower estimate of LDL-mediated uptake (40%) than in other species. LDL uptake per gram tissue was similar for the liver and the adrenal gland and was approximately 50% LDL receptor-dependent in both tissues. With 125I-chylomicron remnants, clearance was much more rapid with approximately 50% cleared in 5 min. By agarose gel electrophoresis, radioactivity was not transferred from chylomicron remnants to other lipoprotein classes. Chylomicron remnants with label on only apoB or in 3H-cholesterol esters showed a similar pattern. Combining the estimates of the three labeling procedures, approximately 35% of the 30 s and 25% of the 5 min chylomicron remnant disappearance was LDL receptor dependent. The liver, per gram tissue, took up five times as much radioactivity as the adrenal gland. At 5 min, at least 50% of this was LDL receptor-dependent in liver and 65% in adrenal gland. We conclude that the LDL receptor plays a major, and somewhat similar quantitative role in the clearance of both LDL and chylomicron remnants in the mouse. However, at least in the mouse, non-LDL receptor-mediated lipoprotein clearance is quantitatively important and is also very rapid for chylomicron remnants. Thus, for chylomicron remnants, it can easily compensate for LDL receptors if they are blocked or absent. Further, the tissue distribution of lipoprotein uptake may be directed by factors other than LDL receptor density.


Rotor-Stator Emulsification in the Turbulent Inertial Regime: Experiments toward a Robust Correlation for the Droplet Size.
The Sauter mean diameter, d32, is a representative parameter in emulsions that indicates the average size of the oil droplets once the emulsion becomes stable. Several mathematical and physical approaches have been employed in the literature to seek expressions for d32 under different conditions. The present work sheds light on this rich literature and emphasizes that the characterization of emulsions is still a fertile field for investigation. In this paper, a new Π-theorem-based model to predict the normalized Sauter mean diameter for the specific case of rotor-stator emulsification is sought by applying a multiple regression analysis on experimental data of oil-in-water (O-W) emulsions produced using three different oils: paraffin, soybean oil, and isopropyl myristate, at different oil-to-water (O/W) ratios and rotor speeds. The proposed model quantifies the roles of the viscous, inertial, and interfacial tension forces, besides the O/W ratio, in the emulsification process within the turbulent inertial subrange. The developed empirical correlation is then contrasted with relevant literature models for reliability assessment; predictions of the present explicit model are proven to be more accurate for the fluid properties and the experimental conditions under study.


Nobiletin is main fungistat in tangerines resistant to mal secco.
A number of crystalline compounds isolated from peel of tangerines resistant to "mal secco" were characterized and tested for fungistatic activity toward Deuterophoma tracheiphila. Nobiletin exhibited strong fungistatic activity, tangeritin was weakly active, and hesperidin slightly stimulated fungal growth. Rough lemon seedlings, inoculated with the pathogenic fungus, rapidly developed the symptoms of mal secco, whereas continuous infusion of the inoculated seedlings with nobiletin solution largely prevented appearance of the disease.


Abuse liability assessment of anxiolytics/hypnotics: rationale and laboratory lore.
This paper describes the rationale, practical details, and laboratory lore relevant to conducting an acute dose-effect crossover evaluation for abuse liability of a novel anxiolytic/hypnotic compound relative to a standard compound. Basic principles underlying meaningful abuse liability assessments are presented and illustrated with examples from a comparative evaluation of the hypnotics zolpidem and triazolam. These principles include using a double-blind placebo-controlled design, selecting an appropriate comparison compound, evaluating a wide range of doses including supratherapeutic doses, using subjects with histories of sedative drug abuse, and using a range of dependent measures. The dose-effect crossover evaluation is proposed as a crucial first step in any rigorous drug abuse liability evaluation of a novel anxiolytic or hypnotic drug. Such a study can be expected to generate a broad data base which not only provides a prediction about the likelihood of abuse of the novel compound, but provides an assessment of some of the adverse consequences of recreational abuse. The crossover study also establishes parameters for subsequent studies such as direct assessment of reinforcing effects with drug self-administration testing.


Structure of the glandular layer and koilin membrane in the gizzard of the adult domestic fowl (Gallus gallus domesticus).
The koilin membrane is formed by the secretions of gland, crypt and surface epithelial cells. Glands form a continuous layer and are arranged in groups of 10-20. They are straight tubes about 500 microns long and 15 microns in diameter and produce rodlets of hard koilin. Hard koilin rodlets (5 microns diameter) form clusters of five or six as they pass through the crypts and enter the koilin membrane. Each rodlet hardens within its gland and maintains its individuality throughout its entire length. Rodlet clusters have previously been called 'rods'. Most of the softer koilin, which fills the spaces between the rodlet clusters, is produced by the surface epithelial cells. These cells form gentle arches between the cavities of adjacent crypts. Horizontal branches between rodlet clusters ('rods') do not exist. There is approximately twice as much surface koilin as rodlet koilin within the membrane. Abrasion of the koilin membrane is not uniform but occurs in a patchy fashion.


Surface Conditioning Effects on Submerged Optical Sensors: A Comparative Study of Fused Silica, Titanium Dioxide, Aluminum Oxide, and Parylene C.
Optical sensors excel in performance but face efficacy challenges when submerged due to potential surface colonization, leading to signal deviation. This necessitates robust solutions for sustained accuracy. Protein and microorganism adsorption on solid surfaces is crucial in antibiofilm studies, contributing to conditioning film and biofilm formation. Most studies focus on surface characteristics (hydrophilicity, roughness, charge, and composition) individually for their adhesion impact. In this work, we tested four materials: silica, titanium dioxide, aluminum oxide, and parylene C. Bovine Serum Albumin (BSA) served as the biofouling conditioning model, assessed with X-ray photoelectron spectroscopy (XPS). Its effect on microorganism adhesion (modeled with functionalized microbeads) was quantified using a shear stress flow chamber. Surface features and adhesion properties were correlated via Principal Component Analysis (PCA). Protein adsorption is influenced by nanoscale roughness, hydrophilicity, and likely correlated with superficial electron distribution and bond nature. Conditioning films alter the surface interaction with microbeads, affecting hydrophilicity and local charge distribution. Silica shows a significant increase in microbead adhesion, while parylene C exhibits a moderate increase, and titanium dioxide shows reduced adhesion. Alumina demonstrates notable stability, with the conditioning film minimally impacting adhesion, which remains low.


Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis.
Rapamycin, a novel macrolide immunosuppressive drug, is increasingly used as an agent for posttransplant immunosuppression and treatment of autoimmune disease. The molecular mechanism related to rapamycin-mediated immunosuppression is that rapamycin binds to FK-506 binding protein 12, and the formed complex inhibits the function of the mammalian target of rapamycin (mTOR), which in turn reduces protein phosphorylation, cell cycle progression, and cytokine production. The aim of this study was to examine the effect of rapamycin against the development of fibrosis and autoimmunity in 2 different types of systemic sclerosis (SSc) model mice. Tight skin (TSK/+) mice and bleomycin- induced SSc model mice were used to evaluate the effect of rapamycin on fibrosis and immunologic abnormalities. Furthermore, the antifibrotic effect of rapamycin was assessed using TSK/+ mouse fibroblasts. Treatment with rapamycin reduced skin fibrosis of TSK/+ mice and skin and lung fibrosis of bleomycin-induced SSc model mice. The production of fibrogenic cytokines, such as interleukin-4 (IL-4), IL-6, IL-17, and transforming growth factor beta1, was attenuated by rapamycin. Hypergammaglobulinemia and anti-topoisomerase I antibody production were also reduced by rapamycin treatment in TSK/+ mice. In addition, mTOR expression levels were increased in TSK/+ mouse fibroblasts compared with those in wild-type mouse fibroblasts. Rapamycin treatment inhibited proliferation and collagen production of TSK/+ mouse fibroblasts in a dose-dependent manner. This study is the first to show that rapamycin has a significant inhibitory effect on fibrosis in both TSK/+ and bleomycin-induced SSc model mice. These results suggest that rapamycin might be an attractive candidate for clinical trials in SSc patients.


Effects of scapular stabilization exercise on pain related parameters in patients with scapulocostal syndrome: A randomized controlled trial.
The aim of this study was to evaluate the effects of scapular stabilization exercise (SSE) on pain intensity, pressure pain threshold (PPT), muscle tension and anxiety in patients with scapulocostal syndrome (SCS). Thirty-six patients were randomly assigned to receive a 30-minute session of either SSE or control (relaxed by lying supine quietly) for 12 sessions over a period of 4 weeks. Pain intensity, PPT, muscle tension and anxiety were assessed before and after a 4-week intervention period and 2 weeks after the intervention period. The adverse effects were evaluated after completion of the intervention period. Results indicated that the SSE group showed a significant improvement in all parameters after the intervention period and at 2 weeks after the intervention period (p < 0.05). For all outcomes, similar changes were not found in the control group. The adjusted post-test mean values of each assessment time point for pain intensity, muscle tension and anxiety were significantly lower in the SSE group than those of the control group (p < 0.05). Moreover, the values for PPT were significantly higher in the SSE group (p > 0.05). There were no reports of adverse effects in either group. We therefore conclude that SSE can improve pain related parameters and could be an effective intervention for SCS.


Echocardiographic diagnosis and intravenous digoxin management of fetal tachyarrhythmias and congestive heart failure.
Fetal echocardiography now affords an accurate clinical diagnosis of nonimmune fetal hydrops secondary to fetal tachyarrhythmias and/or certain types of congenital heart disease. Individual case reports of the treatment of tachyarrhythmias have been reported that use various drugs, including digoxin, propranolol hydrochloride, procainamide hydrochloride, and digoxin plus verapamil hydrochloride. We found no report of intrauterine treatment of congestive heart failure due to congenital heart disease with sinus rhythm. The seven cases presented herein include five cases of isolated supraventricular tachycardia, one with supraventricular tachycardia and myocardial tumors, and one of congenital heart disease with congestive heart failure. Maternal treatment with digoxin converted tachyarrhythmia to sinus rhythm in all six fetuses, and resolved the hydrops in the fetus with congenital heart disease. Premature delivery was avoided in five of the seven cases with favorable outcome in six of the cases. In five mothers who were given oral digitalization, the fetuses had delayed (three to 35 days) response to therapy. Two mothers were treated intravenously and the fetus responded to therapy in less than 24 hours. Because of problems possibly related to poor absorption and/or rapid clearance of digoxin, the intravenous route of administration should be used as the best way to achieve adequate therapeutic levels in the fetus.


Transformation of the intended direction of movement during continuous motor trajectories.
Chronometric and neurophysiological studies have demonstrated that mentally transforming the intended direction of a pointing movement is a time-consuming process, the duration of which increases with the angle of rotation. If the same time-consuming process occurred while tracing a curved trajectory, it would affect the time course of the movement. The data from subjects drawing simple figures match well the predictions made, and support the hypothesis that a time-consuming process of transformation of the intended movement direction operates during the production of continuous trajectories. This biologically inspired hypothesis provides a functional explanation for the relation between speed of the movement and curvature of the path. In addition, it contrasts with the view of continuous movements as essentially oscillatory motions.


Breast Cancer Awareness among Women in Western Amazon: a Population Based Cross-Sectional Study
Background: A general lack of women`s awareness of breast cancer has been one of the barriers to screening and early presentation. Thus, the aim of this study was to evaluate levels of knowledge about risk factors, and early warning signs of breast cancer, and to determine factors associated with better levels of comprehension. Methods: A population-based cross-sectional study was carried out among 478 women over 40 years old, living in Rio Branco city, western Amazon. All were interviewed using the "Breast cancer knowledge, attitudes and practice scale", developed by American Cancer Society. Results: Among the respondents, only 28.6% of women were aware that advanced age highly increases the risk. Around 30% of participants recognized nipple retraction as a sign of breast cancer. Breast cancer knowledge varied according to age in such a way that the mean scores were high from 40-69 years and decreased dramatically among those aged ≥70 (β=-0.06,p=0.031). Access to health services such as the Pap-test (β=2.45,p=0.027) and attending a gynecologist in the past two years (β=1.88,p=0.005) were statistically associated with the score of breast cancer knowledge. Conclusion: The findings indicate that women living in urban areas, having gynecological assessment, considering herself at high risk of developing breast cancer and thinking that breast cancer is a fatal disease are statistically associated with good knowledge of breast cancer risk factors, signs and symptoms, even adjusting for age and education.


Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease.
High levels of fetal hemoglobin (Hb F) protect from many of the complications of sickle cell disease and lead to improved survival. Butyrate and other short chain fatty acids were previously shown to increase Hb F production in erythroid cells in vitro and in animal models in vivo. However, butyrates are also known to inhibit the proliferation of many cell types, including erythroid cells. Experience with the use of butyrate in animal models and in early clinical trials demonstrated that the Hb F response may be lost after prolonged administration of high doses of butyrate. We hypothesized that this loss of response may be a result of the antiproliferative effects of butyrate. We designed a regimen consisting of intermittent or pulse therapy in which butyrate was administered for 4 days followed by 10 to 24 days with no drug exposure. This pulse regimen induced fetal globin gene expression in 9 of 11 patients. The mean Hb F in this group increased from 7.2% to 21.0% (P <.002) after intermittent butyrate therapy for a mean duration of 29.9 weeks. This was associated with a parallel increase in the number of F cells and F reticulocytes. The total hemoglobin levels also increased from a mean of 7.8 g/dL to a mean of 8.8 g/dL (P <.006). The increased levels of Hb F were sustained in all responders, including 1 patient who has been on pulse butyrate therapy for more than 28 months. This regimen, which resulted in a marked and sustained increase in Hb F levels in more than two thirds of the adult sickle cell patients enrolled in this study, was well tolerated without adverse side effects. These encouraging results require confirmation along with an appropriate evaluation of clinical outcomes in a larger number of patients with sickle cell disease.


Dietary resilience among hunter-gatherers of Tierra del Fuego: Isotopic evidence in a diachronic perspective.
The native groups of Patagonia have relied on a hunter-gatherer economy well after the first Europeans and North Americans reached this part of the world. The large exploitation of marine mammals (i.e., seals) by such allochthonous groups has had a strong impact on the local ecology in a way that might have forced the natives to adjust their subsistence strategies. Similarly, the introduction of new foods might have changed local diet. These are the premises of our isotopic-based analysis. There is a large set of paleonutritional investigations through isotopic analysis on Fuegians groups, however a systematic exploration of food practices across time in relation to possible pre- and post-contact changes is still lacking. In this paper we investigate dietary variation in hunter-gatherer groups of Tierra del Fuego in a diachronic perspective, through measuring the isotopic ratio of carbon (∂13C) and nitrogen (∂15N) in the bone collagen of human and a selection of terrestrial and marine animal samples. The data obtained reveal an unexpected isotopic uniformity across prehistoric and recent groups, with little variation in both carbon and nitrogen mean values, which we interpret as the possible evidence of resilience among these groups and persistence of subsistence strategies, allowing inferences on the dramatic contraction (and extinction) of Fuegian populations.


VTT-006, an anti-mitotic compound, binds to the Ndc80 complex and suppresses cancer cell growth in vitro.
Hec1 (Highly expressed in cancer 1) resides in the outer kinetochore where it works to facilitate proper kinetochore-microtubule interactions during mitosis. Hec1 is overexpressed in various cancers and its expression shows correlation with high tumour grade and poor patient prognosis. Chemical perturbation of Hec1 is anticipated to impair kinetochore-microtubule binding, activate the spindle assembly checkpoint (spindle checkpoint) and thereby suppress cell proliferation. In this study, we performed high-throughput screen to identify novel small molecules that target the Hec1 calponin homology domain (CHD), which is needed for normal microtubule attachments. 4 million compounds were first virtually fitted against the CHD, and the best hit molecules were evaluated in vitro. These approaches led to the identification of VTT-006, a 1,2-disubstituted-tetrahydro-beta-carboline derivative, which showed binding to recombinant Ndc80 complex and modulated Hec1 association with microtubules in vitro. VTT-006 treatment resulted in chromosome congression defects, reduced chromosome oscillations and induced loss of inter-kinetochore tension. Cells remained arrested in mitosis with an active spindle checkpoint for several hours before undergoing cell death. VTT-006 suppressed the growth of several cancer cell lines and enhanced the sensitivity of HeLa cells to Taxol. Our findings propose that VTT-006 is a potential anti-mitotic compound that disrupts M phase, impairs kinetochore-microtubule interactions, and activates the spindle checkpoint.


[Catecholamine metabolism in patients with neurological manifestations of spinal osteochondrosis].
Catecholamines content was measured in blood plasma and urine in 104 patients presenting with different neurological syndromes of vertebral osteochondrosis. The results secured were compared to the values of vegetative cardiovascular tests in the same patients. Patients presenting with reflex vegetative muscular-and-tonic, reflex vegetovascular manifestations of vertebral osteochondrosis, and those patients presenting with radix symptomatology as well as those patients with reflex neurodystrophic manifestations (though less evident in the latter) were all diagnosed as having developed relatively high values for blood plasma content of norepinephrine at the expense of degeneration of peripheral vegetative nerve endings and reduction of the normal recapture of this mediator from the blood and its urine elimination. Diagnosing of high values for blood plasma and urine content of norepinephrine against the background of a striking inhibition of indices of vegetative cardiovascular tests in patients with vertebrogenic radix symptomatology suggest involvement into the bodily process of compensation and adaptation of suprasegmental vegetative nerve structures.


A spatiotemporal meta-analysis of HIV/syphilis epidemic among men who have sex with men living in mainland China.
Geographic differences in HIV, syphilis and condomless sex among men who have sex with men in China remained unknown. We aimed to elucidate these spatiotemporal changing patterns in China. We conducted a spatiotemporal meta-analysis. We searched four databases for studies conducted between 2001 and 2015. We included studies that reported original data of HIV/syphilis prevalence in China, the study's area/province, and period of data collection. We grouped studies into six regions and four time periods. We examined the changing patterns of national and regional prevalence of HIV, syphilis and condomless sex. Search results yielded 2119 papers, and 272 were included in the meta-analysis. The sample sizes of the studies ranged from 19 to 47,231. National HIV prevalence increased from 3.8% (95% CI 3.0-4.8) in 2001-07 to 6.6% (5.6-7.7) in 2013-15. In most regions, the rise occurred before 2010 and the HIV prevalence remained relatively stable afterwards, except for the Northwest which showed a considerable increase since 2008. National syphilis prevalence decreased from 12.3% (10.2-14.9) in 2001-07 to 7.1% (5.6-8.9) in 2013-15. The trends of HIV and syphilis infections have been effectively curbed in MSM in most regions of China. Continuous efforts, particularly promotion of condom use, are needed to further reduce these infections.


Mammalian p55CDC mediates association of the spindle checkpoint protein Mad2 with the cyclosome/anaphase-promoting complex, and is involved in regulating anaphase onset and late mitotic events.
We have investigated the function of p55CDC, a mammalian protein related to Cdc20 and Hct1/Cdh1 in Saccharomyces cerevisiae, and Fizzy and Fizzy-related in Drosophila. Immunofluorescence studies and expression of a p55CDC-GFP chimera demonstrate that p55CDC is concentrated at the kinetochores in M phase cells from late prophase to telophase. Some p55CDC is also associated with the spindle microtubules and spindle poles, and some is diffuse in the cytoplasm. At anaphase, the concentration of p55CDC at the kinetochores gradually diminishes, and is gone by late telophase. In extracts prepared from M phase, but not from interphase HeLa cells, p55CDC coimmunoprecipitates with three important elements of the M phase checkpoint machinery: Cdc27, Cdc16, and Mad2. p55CDC is required for binding Mad2 with the Cdc27 and Cdc16. Thus, it is likely that p55CDC mediates the association of Mad2 with the cyclosome/anaphase-promoting complex. Microinjection of anti-p55CDC antibody into mitotic mammalian cells induces arrest or delay at metaphase, and impairs progression of late mitotic events. These studies suggest that mammalian p55CDC may be part of a regulatory and targeting complex for the anaphase-promoting complex.


A nonlinear model for hippocampal cognitive prosthesis: memory facilitation by hippocampal ensemble stimulation.
Collaborative investigations have characterized how multineuron hippocampal ensembles encode memory necessary for subsequent successful performance by rodents in a delayed nonmatch to sample (DNMS) task and utilized that information to provide the basis for a memory prosthesis to enhance performance. By employing a unique nonlinear dynamic multi-input/multi-output (MIMO) model, developed and adapted to hippocampal neural ensemble firing patterns derived from simultaneous recorded CA1 and CA3 activity, it was possible to extract information encoded in the sample phase necessary for successful performance in the nonmatch phase of the task. The extension of this MIMO model to online delivery of electrical stimulation delivered to the same recording loci that mimicked successful CA1 firing patterns, provided the means to increase levels of performance on a trial-by-trial basis. Inclusion of several control procedures provides evidence for the specificity of effective MIMO model generated patterns of electrical stimulation. Increased utility of the MIMO model as a prosthesis device was exhibited by the demonstration of cumulative increases in DNMS task performance with repeated MIMO stimulation over many sessions on both stimulation and nonstimulation trials, suggesting overall system modification with continued exposure. Results reported here are compatible with and extend prior demonstrations and further support the candidacy of the MIMO model as an effective cortical prosthesis.


Replication-defective adenovirus infection reduces Helicobacter felis colonization in the mouse in a gamma interferon- and interleukin-12-dependent manner.
Helicobacter infection leads to chronic inflammation of the stomach. Although the infection persists in spite of an immune response, animal studies have shown that adjuvant-based oral vaccines can protect against infection and even eliminate established infection. These vaccines are thought to induce a Th2 immune response, counterbalancing the Th1 response seen with natural infections. As a prelude to using adenovirus vectors carrying cytokine genes to modulate the immune response to established Helicobacter felis infection, we first examined the effect of the replication-defective adenovirus (RDA) vector itself. C57BL/6 mice chronically infected with H. felis (8 to 10 weeks) received intramuscular injections of RDA. The effect of RDA on the severity of H. felis colonization and the degree of gastric inflammation was assessed 2 weeks later. RDA caused a significant decrease in H. felis colonization without significantly altering the associated inflammation. RDA did not alter the H. felis-specific immunoglobulin G1 (IgG1), IgG2a, and IgA responses in the serum but was associated with an increase in gamma interferon (IFN-gamma)-producing CD8(+) spleen cells. To determine if IFN-gamma or Th1 cytokines were involved in the response to RDA, we examined RDA treatment of H. felis infection in mice lacking either IFN-gamma or interleukin-12 (IL-12). RDA failed to alter H. felis colonization in either of these two mouse strains. Thus, viral infection of mice chronically infected with H. felis led to a significant decrease in H. felis colonization in an IFN-gamma- and IL-12-dependent manner. These results demonstrate that Th1 responses associated with systemic viral infection can influence an established H. felis infection.


Current developments in bronchoscopy. The role of the flexible fiberscope.
The development and increasing use of flexible fiberoptic bronchoscopy has added immeasurably to the potential of diagnostic and therapeutic bronchoscopy. However, neither the flexible nor rigid (open tube) bronchoscope should be regarded as the "primary instrument", but the use of one or the other in the individual case should depend on relative indications. Ideally, bronchologists should be proficient with both rigid and flexible instruments; it is preferable that those experienced only in flexible bronchoscopy work in collaboration with those who are familiar with open tube bronchoscopy as well. In any case, the need for facility in management of airway obstruction, indirect and direct laryngoscopy, and proper administration of topical anesthetics to the larynx and tracheobronchial tree should be recognized. Indications, instrumentarium and technique, special applications, contraindications and complications of flexible bronchoscopy are reviewed.


Coupled-mode theory for infrared and submillimeter wave detectors.
We present a comprehensive, spatiotemporal, modal theory of submillimeter-wave and far-infrared power detectors. The theory is based on the contraction of the coherence tensor of the light with another coherence tensor that incorporates all of the physics of the detector. The theory is extremely general and applies to detectors of any bandwidth, with light in any state of polarization and spatiotemporal coherence. The theory applies equally to quasi-monochromatic and pulsed systems. We show that the tensor associated with the detector is a measureable quantity and outline a procedure for its experimental determination. We derive expressions for the statistical properties of a detector's output, including the correlations between the outputs of different detectors, say, in an array or interferometer. The theory provides a clear conceptual understanding of how any general detector couples to the modes of an optical system and thereby provides a powerful and flexible way of modeling the behavior of detectors and instruments.