Mechanisms and implications of ADAR-mediated RNA editing in cancer.
Adenosine deaminases acting on RNA (ADARs) are enzymes that catalyze the conversion of adenosine (A) to inosine (I) in double-stranded RNAs. Inosine exhibits similar properties as guanosine. As a result, A-to-I editing has a great impact on edited RNAs, not only affecting the base pairing properties, but also altering codons after translation. A-to-I editing are known to mediate and diversify transcripts. However, the overall biological effect of ADARs are still largely unknown. Aberrant ADAR activity and editing dysregulation are present in a variety of cancers, including hepatocellular carcinoma, chronic myelogenous leukemia, glioblastoma and melanoma. ADAR-mediated A-to-I editing can influence uncontrolled nucleotide changes, resulting in susceptibility of cells to developmental defects and potential carcinogenicity. A deeper understanding of the biological function of ADARs may provide mechanistic insights in the development of new cancer therapy. Here, we discuss recent advances in research on ADAR in detail including the structure and function of ADARs, the biochemistry of ADAR-mediated RNA editing, and the relevance of ADAR proteins in cancer.


CLAIM (CLinical Accounting InforMation)--an XML-based data exchange standard for connecting electronic medical record systems to patient accounting systems.
With the evolving and diverse electronic medical record (EMR) systems, there appears to be an ever greater need to link EMR systems and patient accounting systems with a standardized data exchange format. To this end, the CLinical Accounting InforMation (CLAIM) data exchange standard was developed. CLAIM is subordinate to the Medical Markup Language (MML) standard, which allows the exchange of medical data among different medical institutions. CLAIM uses eXtensible Markup Language (XML) as a meta-language. The current version, 2.1, inherited the basic structure of MML 2.x and contains two modules including information related to registration, appointment, procedure and charging. CLAIM 2.1 was implemented successfully in Japan in 2001. Consequently, it was confirmed that CLAIM could be used as an effective data exchange format between EMR systems and patient accounting systems.


Beyond Janzen's Hypothesis: How Amphibians That Climb Tropical Mountains Respond to Climate Variation.
Janzen's hypothesis (JH) posits that low thermal variation selects for narrow physiological tolerances, and thus small species distributional ranges and high species turnover along tropical elevational gradients. Although this hypothesis has been intensely revisited, it does not explain how many tropical species may exhibit broad distributions, encompassing altitudinal gradients. Moreover, the physiological responses of tropical species remain largely unknown, limiting our understanding on how they respond to climate variation. To fill these knowledge gaps, we tested a major component of JH, the climate variability hypothesis (CVH), which predicts broader thermal tolerance breadth (Tbr = CTmax - CTmin) with broader temperature variation. Specifically, we sampled populations of five amphibian species distributed in two mountain ranges in Brazil's Atlantic Forest to test how CTmin and CTmax vary along elevational gradients. Since both thermal and water balance traits are pivotal to the evolutionary history of amphibians, we also measured rates of dehydration and rehydration and their relations with thermal tolerances. We found that broader temperature variation with increasing altitude did not always lead to broader Tbr, since changes in CTmin and CTmax were species-specific. In addition, we found that water balance did not show consistent variation with altitude, also with low correlations between hydric and thermal traits. While we also found that highland populations are at lower risk of thermal stress than lowland counterparts, both are living far from their upper thermal limits. As a consequence of intraspecific variation in physiological traits and spatial variation in climate along altitude, responses to climate variation in tropical amphibian species were context-dependent and heterogeneous. Together with recent studies showing thermal tolerances of some tropical amphibians comparable to temperate taxa, our findings highlight that several responses to climate variation in tropical species may not conform to predictions made by either the CVH or other important hypotheses concerning physiological variation. This reinforces the need to overcome geographical bias in physiological data to improve predictions of climate change impacts on biodiversity. (Portuguese abstract) Resumo A Hipótese de Janzen (JH) postula que a baixa variação térmica seleciona tolerâncias fisiológicas estreitas e, portanto, amplitudes restritas de distribuição das espécies e alta substituição de espécies ao longo de gradientes altitudinais tropicais. Embora intensamente revisitada, essa hipótese não explica como espécies tropicais podem exibir amplas distribuições geográficas, abrangendo gradientes altitudinais. Além disso, as respostas fisiológicas das espécies tropicais permanecem amplamente desconhecidas, limitando nossa compreensão sobre como elas respondem à variação climática. Para preencher essas lacunas de conhecimento, testamos um componente importante da JH, a Hipótese de Variabilidade Climática (CVH), que prevê uma maior amplitude de tolerância térmica (Tbr = CTmax - CTmin) quando a variação da temperatura ambiental é mais ampla. Especificamente, amostramos populações de cinco espécies de anfíbios distribuídas em duas cadeias montanhosas na Mata Atlântica do Brasil para testar como CTmin e CTmax variam ao longo de gradientes de altitude. Dado que parâmetros térmicos e do balanço hídrico são fundamentais para a história evolutiva dos anfíbios, também medimos as taxas de desidratação e reidratação e suas relações com as tolerâncias térmicas. Encontramos que uma variação de temperatura ambiental mais ampla com o aumento da altitude nem sempre conduz a uma Tbr mais ampla, uma vez que as mudanças em CTmin e CTmax foram espécie-específicas. Além disso, encontramos que o balanço hídrico não apresentou variação consistente com a mudança de altitude, e que as correlações entre parâmetros hídricos e térmicos foram baixas. Embora populações das maiores altitudes apresentaram menor risco de estresse térmico do que populações da mesma espécie em altitudes menores, ambas estão vivendo longe de seus limites térmicos superiores. Em consequência da variação intraespecífica em parâmetros fisiológicos e variação espacial no clima ao longo da altitude, as respostas à variação climática em espécies de anfíbios tropicais foram contexto-dependentes e heterogêneas. Juntamente com estudos recentes indicando tolerâncias térmicas de alguns anfíbios tropicais comparáveis a de táxons temperados, nossas descobertas destacam que várias respostas à variação climática em espécies tropicais podem não estar de acordo com as previsões feitas pela CVH ou outras hipóteses importantes sobre a variação fisiológica. Isso reforça a necessidade de superar o viés geográfico em dados fisiológicos para aperfeiçoar previsões dos impactos das mudanças climáticas sobre a biodiversidade. (Spanish abstract) Resumen La hipótesis de Janzen (JH) postula que la baja variación térmica selecciona tolerancias fisiológicas estrechas y, por lo tanto, rangos de distribución de especies restringidos con alta rotación de especies a lo largo de gradientes de elevación tropicales. Aunque esta hipótesis ha sido intensamente discutida, no explica cómo várias especies tropicales pueden exhibir distribuciones amplias, abarcando gradientes altitudinales. Además, las respuestas fisiológicas de las especies tropicales siguen siendo bastante desconocidas, lo que limita la comprensión de cómo responden a la variación climática. Para llenar estos vacíos de conocimiento, examinamos un componente importante de JH, la Hipótesis de Variabilidad Climática (CVH), que predice mayor amplitud de tolerancia térmica (Tbr = CTmax - CTmin) cuando la variación de temperatura es más amplia. Específicamente, tomamos muestras de poblaciones de cinco especies de anfibios distribuidas en dos cadenas montañosas en el Bosque Atlántico de Brasil para verificar cómo CTmin y CTmax varían a lo largo de este gradiente de elevación. Dado que los rasgos de equilibrio térmico y hídrico son fundamentales para la historia evolutiva de los anfibios, también medimos las tasas de deshidratación y rehidratación y sus relaciones con las tolerancias térmicas. Encontramos que una variación de temperatura más amplia con el aumento de la altitud no siempre conduce a una Tbr más amplia, ya que los cambios en CTmin y CTmax son específicos de la especie. Además, encontramos que el balance hídrico no muestra variación consistente con la altitud, con bajas correlaciones también entre los rasgos hídricos y térmicos. Si bien las poblaciones de las tierras altas tienen un menor riesgo de estrés térmico que las contrapartes de las tierras bajas, ambas se encuentran lejos de sus límites térmicos superiores. Como consecuencia de la variación intraespecífica en los rasgos fisiológicos y la variación espacial en el clima a lo largo de la altitud, las respuestas a la variación climática en las especies de anfibios tropicales fueron dependientes del contexto y heterogéneas. Junto con estudios recientes que muestran tolerancias térmicas de algunos anfibios tropicales comparables a los taxones de zonas templadas, nuestros hallazgos resaltan que varias respuestas a la variación climática en especies tropicales pueden no ajustarse a las predicciones hechas por el CVH u otras hipótesis importantes sobre la variación fisiológica. Esto refuerza la necesidad de superar el sesgo geográfico en los datos fisiológicos para mejorar las predicciones de los impactos del cambio climático en la biodiversidad.


Comparison of the reliability of parental reporting and the direct test of the Thai Speech and Language Test.
To find reliability of parental or caregiver's report and testing of the Thai Speech and Language Test for Children Aged 0-4 Years Old. Five investigators assessed speech and language abilities from video both contexts: parental or caregivers' report and test forms of Thai Speech and Language Test for Children Aged 0-4 Years Old. Twenty-five normal and 30 children with delayed development or risk for delayed speech and language skills were assessed at age intervals of 3, 6, 9, 12, 15, 18, 24, 30, 36 and 48 months. Reliability of parental or caregivers' testing and reporting was at a moderate level (0.41-0.60). Inter-rater reliability among investigators was excellent (0.86-1.00). The parental or caregivers' report form of the Thai Speech and Language test for Children aged 0-4 years old was an indicator for success at a moderate level. Trained professionals could use both forms of this test as reliable tools at an excellent level.


Tuberoinfundibular peptide of 39 residues modulates the mouse hypothalamic-pituitary-adrenal axis via paraventricular glutamatergic neurons.
Neurons in the subparafascicular area at the caudal border of the thalamus that contain the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39) densely innervate several hypothalamic areas, including the paraventricular nucleus (PVN). These areas contain a matching distribution of TIP39's receptor, the parathyroid hormone receptor 2 (PTH2R). Frequent PTH2R coexpression with a vesicular glutamate transporter (VGlut2) suggests that TIP39 could presynaptically regulate glutamate release. By using immunohistochemistry we found CRH-ir neurons surrounded by PTH2R-ir fibers and TIP39-ir axonal projections in the PVN area of the mouse brain. Labeling hypothalamic neuroendocrine neurons by peripheral injection of fluorogold in PTH2R-lacZ knock-in mice showed that most PTH2Rs are on PVN and peri-PVN interneurons and not on neuroendocrine cells. Double fluorescent in situ hybridization revealed a high level of coexpression between PTH2R and VGlut2 mRNA by cells located in the PVN and nearby brain areas. Local TIP39 infusion (100 pmol) robustly increased pCREB-ir in the PVN and adjacent perinuclear zone. It also increased plasma corticosterone and decreased plasma prolactin. These effects of TIP39 on pCREB-ir, corticosterone, and prolactin were abolished by coinfusion of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonopentanoic acid (AP-5; 30 pmol each) and were absent in PTH2R knockout mice. Basal plasma corticosterone was slightly decreased in TIP39 knockout mice just before onset of their active phase. The present data indicate that the TIP39 ligand/PTH2 receptor system provides facilitatory regulation of the hypothalamic-pituitary-adrenal axis via hypothalamic glutamatergic neurons and that it may regulate other neuroendocrine systems by a similar mechanism.


High Tolerability, Favorable Safety, and Subjects' Preference for a Single 200 mg/2 mL Tildrakizumab Injection: A Phase I, Open-Label, Randomized Crossover Trial in Healthy Volunteers.
Tildrakizumab 200 mg/2 mL pre-filled syringe is a new preparation of tildrakizumab that is developed to facilitate patients' compliance. This phase I clinical trial compares the local tolerability, safety, and subjects' preferred method of administration of tildrakizumab when administered as a new single 200 mg/2 mL subcutaneous injection or as two 100 mg/1 mL subcutaneous injections in healthy subjects. Visual analogue scores were used to self-assess injection site pain immediately (< 1 min) after each administration and at 1 h and 48 h after each administration. Treatment injection site reactions were assessed at 1 h and 48 h after each administration. Treatment safety was monitored throughout the study period. Subjects' preferred method of administration was assessed 4 weeks after the last administration (day 56). No statistically significant difference in visual analogue scores and injection site reactions was detected between the two treatments. Treatment-emergent adverse events were mild, and there were no deaths or serious adverse events. Most subjects (61.5%) preferred the treatment when administered as a single 200 mg/2 mL subcutaneous injection rather than as two 100 mg/mL subcutaneous injections. Administration of 200 mg tildrakizumab as a single 2 mL subcutaneous injection was safe, well tolerated, and preferred over two separate 100 mg/1 mL subcutaneous injections by healthy subjects. Eudract No. 2020-000183-37.


Regional brain injury on conventional and diffusion weighted MRI is associated with outcome after pediatric cardiac arrest.
To assess regional brain injury on magnetic resonance imaging (MRI) after pediatric cardiac arrest (CA) and to associate regional injury with patient outcome and effects of hypothermia therapy for neuroprotection. We performed a retrospective chart review with prospective imaging analysis. Children between 1 week and 17 years of age who had a brain MRI in the first 2 weeks after CA without other acute brain injury between 2002 and 2008 were included. Brain MRI (1.5 T General Electric, Milwaukee, WI, USA) images were analyzed by 2 blinded neuroradiologists with adjudication; images were visually graded. Brain lobes, basal ganglia, thalamus, brain stem, and cerebellum were analyzed using T1, T2, and diffusion-weighted images (DWI). We examined 28 subjects with median age 1.9 years (IQR 0.4-13.0) and 19 (68 %) males. Increased intensity on T2 in the basal ganglia and restricted diffusion in the brain lobes were associated with unfavorable outcome (all P < 0.05). Therapeutic hypothermia had no effect on regional brain injury. Repeat brain MRI was infrequently performed but demonstrated evolution of lesions. Children with lesions in the basal ganglia on conventional MRI and brain lobes on DWI within the first 2 weeks after CA represent a group with increased risk of poor outcome. These findings may be important for developing neuroprotective strategies based on regional brain injury and for evaluating response to therapy in interventional clinical trials.


Stimulatory effect of TGF-beta on anionic glycoconjugate synthesis by rat calvarial cells: specificity, uncoupling of cell density dependence, and modulation by chondroitin sulfate.
Anchorage-dependent cultures of a population of cells derived from the outer part of the rat calvaria demonstrated decreased net accumulation of radiolabeled chondroitin sulfate (CS) and hyaluronic acid (HA) per cell as the cell density of the cultures increased. The addition of TGF-beta 1 resulted in large stimulations of the net CS, but not of the net HA, accumulating in the medium at all cell densities and an abolition of the density-dependent effect. These effects were largely due to increases in newly synthesized CS appearing in the medium. Supplementation of the culture media with CS had complex but relatively small effects on the stimulation of the net accumulation of radiolabeled medium CS by TGF-beta 1. The addition of TGF-beta 1 also resulted in a biphasic effect on cell growth that depended on the plating density, but cell growth differences could not account for the marked stimulation of CS synthesis by TGF-beta 1. Experiments with cycloheximide and beta-xyloside and isolation of the intact anionic glycoconjugates (AG) indicated that although synthesis of core protein was the limiting factor in CS synthesis, TGF-beta 1 stimulated the synthesis of CS chain when sufficient beta-xyloside acceptor was available. The overall results suggest that, in this cell system, the action of TGF-beta 1 on the synthesis of the major extracellular AGs is characterized by a relatively specific upregulation of CS proteoglycan (PG) synthesis and an uncoupling of the inhibitory effect of high cell density on CS PG synthesis.


Twenty-four hour pH monitoring during pregnancy and at postpartum: a preliminary study.
To quantify the amount of acid refluxed in symptomatic pregnant women and compare this to the postpartum period. Eight non complicated symptomatic pregnant women were enrolled. The mean age was 28+/-6.3 years and gestational age 26+/-4.4 weeks at inclusion. Repeated measurements were done at 9.8+/-6.5 weeks postpartum. Esophageal manometry and 24h pH monitoring were performed at each time period. Heartburn (HB), regurgitation and dysphagia were the main presenting symptoms, however only regurgitation was significantly more frequent during pregnancy (P=0.01). Lower esophageal sphincter (LES) pressure was significantly lower during pregnancy (P=0.001). Twenty-four hour pH monitoring variables were worse and the number of reflux episodes and the upright reflux reached statistical significance (P=0.03, and 0.01, respectively). Pregnancy is associated with decreased LES pressure, more frequent episodes of reflux and upright reflux.


Impaired thermoregulation and beneficial effects of thermoneutrality in the 3×Tg-AD model of Alzheimer's disease.
The sharp rise in the incidence of Alzheimer's disease (AD) at an old age coincides with a reduction in energy metabolism and core body temperature. We found that the triple-transgenic mouse model of AD (3×Tg-AD) spontaneously develops a lower basal body temperature and is more vulnerable to a cold environment compared with age-matched controls. This was despite higher nonshivering thermogenic activity, as evidenced by brown adipose tissue norepinephrine content and uncoupling protein 1 expression. A 24-hour exposure to cold (4 °C) aggravated key neuropathologic markers of AD such as: tau phosphorylation, soluble amyloid beta concentrations, and synaptic protein loss in the cortex of 3×Tg-AD mice. Strikingly, raising the body temperature of aged 3×Tg-AD mice via exposure to a thermoneutral environment improved memory function and reduced amyloid and synaptic pathologies within a week. Our results suggest the presence of a vicious cycle between impaired thermoregulation and AD-like neuropathology, and it is proposed that correcting thermoregulatory deficits might be therapeutic in AD.


[Evaluation of a portable device for measuring maximal inspiratory pressure (Pimax)].
Pimax measurement is useful for quantifying the fatigue of the respiratory muscles (the "respiratory pump" of the mechanics of respiration), for controlling the therapeutic effect of artificial respiration performed at home, and assessment of the possibility of relieving a patient from artificial respiration. So far, such measurement had required complicated set-ups. A portable alternative is now available for Pimax measurement (MPM, distributed by Medanz, Starnberg, Germany). In a prospective study we compared the Pimax values measured via the mouth pressure measuring instrument under test, with the standard laboratory method. Statistical comparison of the measured data yielded a high degree of correlation (r = 0.97) with slight scatter of the individual data around the identity line. The portable instrument tested in this manner thus represents a mobile method yielding reliable Pimax values both on an inpatient and an outpatient basis.


The relationship between combat exposure and suicide risk in U.S. military veterans: Exploring the role of posttraumatic stress symptoms and religious coping.
Rising suicide rates in the U.S. veteran population are a growing concern. Combat exposure has been identified as a potential predictor of suicide risk, but factors that may mediate the relation between combat exposure and suicide risk, and the role of potential coping mechanisms remain largely understudied. To address this gap, this study examined the association between lifetime combat exposure and current suicide risk; whether this association is mediated by posttraumatic stress disorder (PTSD) symptoms; and whether direct and/or indirect associations with combat exposure are moderated by organizational, non-organizational, and intrinsic religiosity. Data were analyzed from the National Health and Resilience in Veterans Study (2019-2020; n = 3843). Ordinary least squares and conditional process analyses were conducted to evaluate the conditional direct and indirect predictors of suicide risk. PTSD symptoms significantly mediated the association between combat exposure and suicide risk. Intrinsic religiosity showed significant moderation and reduced the coefficient of PTSD symptoms predicting suicide risk but increased the coefficient of combat exposure predicting PTSD symptoms. In this cross-sectional, observational study, no conclusions can be made regarding causality. Results of this study suggest a multifaceted relationship between combat exposure, PTSD, religiosity/spirituality, and suicide risk in U.S. veterans, and underscore the importance of PTSD and religious coping as part of ongoing suicide prevention efforts in this population.


Very low frequency blood pressure variability is modulated by myogenic vascular function and is reduced in stroke-prone rats.
Cerebrovascular myogenic function, which protects the brain from hemorrhagic stroke, is impaired in stroke-prone spontaneously hypertensive rats. Furthermore, myogenic function contributes to very low frequency blood pressure variability and dynamic autoregulation of cerebral blood flow is most effective at very low frequency in rats. Therefore, we hypothesized that very low frequency blood pressure variability is reduced in stroke-prone spontaneously hypertensive rats compared with stroke-resistant spontaneously hypertensive rats. In addition, we investigated if myogenic function also contributes to very low frequency blood pressure variability in conscious dogs. In 8-week-old normotensive Wistar-Kyoto rats, 8-week-old and 15-week-old stroke-prone spontaneously hypertensive rats and stroke-resistant spontaneously hypertensive rats, and dogs, blood pressure variability was studied during control conditions, inhibition of myogenic function (nifedipine) and hypotension induced by sodium nitroprusside. In dogs, transfer function analysis between blood pressure and total peripheral resistance was performed to study the contribution of myogenic function to blood pressure variability. Inhibition of myogenic function, but not hypotension induced by sodium nitroprusside, significantly reduced very low frequency variability of systolic blood pressure (rats: 0.02-0.2 Hz; dogs: 0.02-0.075 Hz) in conscious rats and dogs. In dogs, the gain of the transfer function was high (0.28 +/- 0.04 min/l) in the very low frequency band and was decreased to 0.11 +/- 0.01 min/l (P < 0.05) by nifedipine but not by sodium nitroprusside (0.26 +/- 0.02 min/l). Very low frequency blood pressure variability was significantly smaller in stroke-prone spontaneously hypertensive rats than in stroke-resistant spontaneously hypertensive rats (8 weeks of age: 7.8 +/- 1.1 vs. 13.1 +/- 2.2 mmHg; P < 0.05; 15 weeks of age: 7.1 +/- 1.2 vs. 16.5 +/- 3.6 mmHg; P < 0.05). Myogenic function affects very low frequency blood pressure variability in conscious rats and dogs. The smaller very low frequency blood pressure variability in stroke-prone spontaneously hypertensive rats compared with stroke-resistant spontaneously hypertensive rats suggests that impaired cerebrovascular myogenic function is reflected in reduced very low frequency blood pressure variability.


[Immune modulatory and therapeutic effect of BCG polysaccharides nucleic acid on perennial allergic rhinitis].
To observe the immune modulatory and therapeutic effect of BCG polysaccharides nucleic acid (BCG-PSN) on patients with perennial allergic rhinitis. Sixty patients with perennial allergic rhinitis were randomly divided into two groups, 30 in the test group were treated with BCG-PSN plus ketotefen and 30 in the control group were treated with ketotefen respectively. All patients were followed up and assessed for 3 months, and the blood samples were collected before treatment and 3 months after treatment for measuring the blood IgA, IgG, IgM, IgE, CD3, CD4 and CD8. In the test group, the total effective rate was significantly higher comparable to that in the control group. After treatment of BCG-PSN, blood CD3, CD4 and CD4/CD8 were significantly increased. IgE significantly reduced (P < 0.05). BCG polysaccharides nucleic acid can modulate the cellular immunofunction of patients with perennial allergic rhinitis and can increase the curative rate on perennial allergic rhinitis.


[Consciousness disorders and severe haemolytic anaemia in a patient coming from overseas].
A 54-years-old patient coming from Guinea, who presented fever, diarrhoea, consciousness disorders and severe haemolytic anaemia, was admitted to resuscitation unit in France. Despite many explorations carried out (evaluation of traumatic causes, infection, neoplasia, vascular, toxic causes, vitamin deficiency), it was not possible to explain neurological symptomatology. Besides, haemolytic anaemia was due to the ingestion of metamizole in a context of glucose-6-phosphate dehydrogenase deficit. This drug's marketing has been suspended in France since 2006. Despite appropriate treatment, after seven days of hospitalization, the patient died of multi-organ failure and hemophagocytic syndrome. This clinical case illustrates the difficulties encountered to set a diagnosis and manage patients coming from overseas. Uncommon aetiologies for French healthcare professionals should be evoked in the absence of comprehensive clinical information.


Effect of catabolic hormone infusion on organ amino acid uptake.
Elevated plasma levels of the so-called catabolic hormones (glucocorticoid, epinephrine, glucagon) have been observed in severely injured patients, and infusion of these hormones to normal subjects has reportedly simulated several metabolic aberrations characteristic of severe trauma and sepsis. We recently reported that amino acid uptake was reduced in soleus muscle, heart, and diaphragm, and increased in the liver, of septic rats. The purpose of the present study was to investigate organ amino acid uptake in nonseptic rats infused with catabolic hormones. Central venous catheters were placed in male Sprague-Dawley rats (100-150 g) and after 24 hr hormones (glucagon 5 micrograms/kg/hr, epinephrine 6 micrograms/kg/hr, corticosterone 4.2 mg/kg/hr) or vehicle (saline, ascorbic acid 1 mg/ml, albumin 3 mg/ml) was infused for 72 hr. Animals were housed in metabolic cages and allowed food and water ad lib. One hour prior to sacrifice, alpha-[3H]aminoisobutyric acid (AIB) (2.5 microCi), a nonmetabolized amino acid analog mainly transported by system-A, was injected intravenously. Animals were killed and organs were removed, weighed, and dissolved in tissue solubilizer for measurement of radioactivity. AIB uptake was significantly elevated in all organs of catabolic hormone-infused animals studied. The results suggest that catabolic hormones may be involved in the pathogenesis of increased amino acid uptake in the liver during sepsis. Inhibited amino acid uptake in skeletal muscle during sepsis, however, is probably not primarily mediated by catabolic hormones.


Heart sarcolemmal Ca2+ transport in endotoxin shock: I. Impairment of ATP-dependent Ca2+ transport.
Effects of endotoxin administration on the ATP-dependent Ca2+ transport in canine cardiac sarcolemma were investigated. The results show that the sidedness of the sarcolemmal vesicles was not affected but the ATP-dependent Ca2+ transport in cardiac sarcolemma was decreased by 22 to 46% (p less than 0.05) at 4 h following endotoxin administration. The kinetic analysis indicates that the Vmax for ATP and for Ca2+ were decreased by 50% (p less than 0.01) and 32% (p less than 0.01), respectively, while the Km values for ATP and Ca2+ were not significantly affected after endotoxin administration. Magnesium (1-5 mM) stimulated while vanadate (0.25-3.0 microM) inhibited the ATP-dependent Ca2+ transport, but the Mg(2+)-stimulated and the vanadate-inhibitable activities remained significantly lower in the endotoxin-treated animals. These data demonstrate that endotoxin administration impairs the ATP-dependent Ca2+ transport in canine cardiac sarcolemma and that the impairment is associated with a mechanism not affecting the affinity towards ATP and Ca2+. Additional experiments show that the Ca2+ sensitivity of the Ca(2+)-ATPase activity was indifferent between the control and endotoxic groups suggesting that endotoxic injury impairs Ca2+ pumping without affecting Ca(2+)-ATPase activity. Since sarcolemmal ATP-dependent Ca2+ transport plays an important role in the regulation of cytosolic Ca2+ homeostasis, an impairment in the sarcolemmal ATP-dependent Ca2+ transport induced by endotoxin administration may have a pathophysiological significance in contributing to the development of myocardial dysfunction in endotoxin shock.


Neuroendocrine carcinoma in a mediastinal teratoma as a rare variant of somatic-type malignancy.
Somatic-type malignancy (STM), defined as any sarcoma, carcinoma, leukemia or lymphoma developing in a germ cell tumor, occurs in approximately 2% of all germ cell tumors. Neuroendocrine carcinoma developing in a mediastinal germ cell tumor has not been previously reported. We here describe a 22-year-old man who underwent resection of a 11-cm mediastinal teratoma which consisted of components of all three germ cell layers with prominent foci of fetal-like liver tissue. The liver areas were surrounded by primitive neuroendocrine structures with ductal and solid growth pattern with a high proliferation rate. We diagnosed an immature mediastinal teratoma with STM, specifically neuroendocrine carcinoma arising in a background of immature liver tissue. Comparative genomic hybridization of dissected tumor tissue revealed chromosomal gains at 12 in the teratoma and neuroendocrine carcinoma component. In summary, clinicians and pathologists should be aware of neuroendocrine carcinoma as a rare type of STM complicating mediastinal germ cell tumors.


Malignant lymphoma of follicular center cell origin in humans. IV. Small transformed (noncleaved) cell lymphoma of the non-Burkitt's type.
Small transformed cell lymphoma (STC) is the least common follicular center cell neoplasm in the Lukes-Collins classification system. If the cells are homogenous in size and shape, Burkitt's lymphoma (STC-BL) is diagnosed; otherwise STC lymphoma of the non-Burkitt's type (STC-nBL) is present. The authors have reviewed their experience with 17 cases of STC-nBL. This neoplasm affects all ages, both sexes equally, and most commonly is Stage IV based either on a visceral abdominal mass or bone marrow involvement. Surface immunoglobulin analysis revealed IgM in all cases tested. In spite of aggressive treatment protocols, there were only 5 of 17 (29%) clinical complete responses. Four of these five have continuous remission from 8 to 23 months after diagnosis; all four of these patients were treated with regimens containing high-dose cyclophosphamide. Future analyses including viral studies, chromosomal analyses, and uniform treatment protocols will help determine whether STC-nBL and Burkitt's lymphoma are truly distinct entities.


Partial Laryngectomy for pT4a Laryngeal Cancer: Outcomes and Limits in Selected Cases.
A large multi-institutional case series of laryngeal cancer (LC) T4a was carried out, including 134 cases treated with open partial horizontal laryngectomies (OPHL) +/- post-operative radiation therapy (PORT). The goal was to understand better whether OPHL can be included among the viable options in selected pT4a LC patients who refuse a standard approach, represented by total laryngectomy (TL) + PORT. All 134 patients underwent OPHL type I (supraglottic), II (supracricoid), or III (supratracheal), according to the European Laryngological Society Classification. Comparing clinical and pathological stages showed pT up-staging in 105 cases (78.4%) and pN up-staging in 19 patients (11.4%). Five-year data on overall survival, disease-specific survival, disease-free survival, freedom from laryngectomy, and laryngo-esophageal dysfunction-free survival (rate of patients surviving without a local recurrence or requiring total laryngectomy and without a feeding tube or a tracheostomy) were, respectively, 82.1%, 89.8%, 75.7%, 89.7%, and 78.3%. Overall, complications were observed in 22 cases (16.4%). Sequelae were observed in 28 patients (20.9%). No patients died during the postoperative period. This large series highlights the good onco-functional results of low-volume pT4a laryngeal tumors, with minimal or absent cartilage destruction, treated with OPHLs. The level of standardization of the indication for OPHL should allow consideration of OPHL as a valid therapeutic option in cases where the patient refuses total laryngectomy or non-surgical protocols with concomitant chemo-radiotherapy.


The inhibitory action of glycine on rat cortical neurons.
The action of glycine (Gly) on rat cortical neurons was studied. Gly, iontophoretically applied, hyperpolarized the membrane potential, blocked the firing rate and decreased the amplitude of EPSP-IPSP sequences. Generally the membrane resistance during the aminoacid ejection decreased. The role of Gly in the rat cortical inhibition is discussed.


Tumor microenvironment conditions that favor vessel co-option in colorectal cancer liver metastases: A theoretical model.
Vessel co-option is an alternative strategy by which tumour cells vascularize and gain access to nutrients to support tumour growth, survival and metastasis. In vessel co-option, the cancer cells move towards the pre-existing vasculature and hijack them. Vessel co-option is adopted by a wide range of human tumours including colorectal cancer liver metastases (CRCLM) and is responsible for the effectiveness of treatment in CRCLM. Furthermore, vessel co-option is an intrinsic feature and an acquired mechanism of resistance to anti-angiogenic treatment. In this review, we describe the microenvironment, the molecular players, discovered thus far of co-opting CRCLM lesions and propose a theoretical model. We also highlight key unanswered questions that are critical to improving our understanding of CRCLM vessel co-option and for the development of effective approaches for the treatment of co-opting tumours.


Clinical status of dentine bonding agents.
Dentine bonding agents are an important clinical contribution to modern composite technology. Important differences exist between the first- and second-generation materials which offer complementary advantages. The second-generation materials offer higher dentine bond strengths at the expense of greater chairside complexity. Indications for the use of both types of material are discussed. The role of smear layer and the primed layer is discussed and the connection is made between bond mechanism and clinical techniques. The clinical criteria, such as retention, microleakage and tooth strengthening, are related to the role of the hard tissue bond.


Resolving the paradox of sex and recombination.
Sexual reproduction and recombination are ubiquitous. However, a large body of theoretical work has shown that these processes should only evolve under a restricted set of conditions. New studies indicate that this discrepancy might result from the fact that previous models have ignored important complexities that face natural populations, such as genetic drift and the spatial structure of populations.


Evaluation of nutritional status and skin condition among elderly residents in a long-term care hospital.
The availability of nutritional screening tools for older adults is limited, depending on their physical characteristics or the setting. We investigated the relationships between various nutritional indicators and skin conditions as possible screening indicators. Cross-sectional study. A long-term care hospital in Japan. 90 elderly residents who were aged ≥65 years old. The nutritional status of the residents was assessed by body mass index (BMI), involuntary weight loss, arm muscle area, and serum albumin and prealbumin levels. Leg skin condition was evaluated by: 1) functional factors including pH, hydration and transepidermal water loss; 2) skin color including L*, a*, b* and individual typology angle (ITA°) using a tristimulus colorimetric instrument; and 3) skin morphology. Repeated measures analysis of variance was employed, adjusted for demographic characteristics and room temperature, with measurement site as the repeated variable. Among the skin indicators, b* was significantly correlated with BMI (p=0.018), and weight loss over the previous month (p=0.042) and 6 months (p=0.002). Additionally, ITA° was associated with weight loss over 1 month (p=0.013). Both b* and ITA° showed the area under the receiver operating characteristic curve of 0.64 to 0.80 for weight loss >2% over 1 month. Residents with poorer nutritional status had yellower and darker skin color.


LncRNA KCNQ1OT1 contributes to hydrogen peroxide-induced apoptosis, inflammation, and oxidative stress of cardiomyocytes via miR-130a-3p/ZNF791 axis.
It has been reported that long noncoding RNA (lncRNA) KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) played an important role in myocardial infarction (MI). However, the regulatory network behind KCNQ1OT1 in MI is largely unknown. Quantitative real time polymerase chain reaction (qRT-PCR) was applied to detect the enrichment of KCNQ1OT1, microRNA-130a-3p (miR-130a-3p) and zinc finger 791 (ZNF791). The viability and apoptosis of AC16 cells were measured by (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was conducted to assess the inflammation and oxidative stress status of AC16 cells. The targeted relationship between miR-130a-3p and KCNQ1OT1 or ZNF791 was predicted by StarBase bioinformatic database, and dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out to verify these predictions. Hydrogen peroxide (H2 O2 ) stimulation caused a significant upregulation in the expression of KCNQ1OT1, while the level of miR-130a-3p showed an opposite phenomenon. KCNQ1OT1 was a crucial downstream component in H2 O2 -mediated toxic effects, and KCNQ1OT1 accelerated H2 O2 -induced toxic effects in AC16 cells. KCNQ1OT1 could sponge miR-130a-3p and down-regulate its expression. MiR-130a-3p exerted opposite effects to KCNQ1OT1, and the depletion of miR-130a-3p attenuated the protective effects of KCNQ1OT1 intervention on AC16 cells exposed to H2 O2 . MiR-130a-3p could bind to ZNF791, and ZNF791 served as the target of miR-130a-3p to promote H2 O2 -induced injury of AC16 cells. ZNF791 was modulated by KCNQ1OT1/miR-130a-3p signaling in H2 O2 -treated AC16 cells. In all, lncRNA KCNQ1OT1 deteriorated H2 O2 -mediated injury in cardiomyocytes through upregulating ZNF791 via serving as a molecular sponge for miR-130a-3p.


Pyrrolo (1,4) benzodiazepine antitumor antibiotics: Biosynthetic studies on the conversion of tryptophan to the anthranilic acid moieties of sibiromycin and tomaymycin.
Biosynthetic intermediates between tryptophan and the anthranilate moieties of tomaymycin and sibiromycin have been suggested, based upon a combination of feeding experiments with either carbon-14-labeled substrates or competition experiments between radiolabeled tryptophan and unlabeled intermediates. In the case of sibiromycin and tomaymycin, substitution of the aromatic ring most likely takes place at the kynurenine stage. Feeding experiments with the anthramycin culture were inconclusive, most likely because of the cell impermeability.


The impact of overweight on renal toxicity in patients treated with dexamethasone, high-dose cytarabine, and cisplatin.
The combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is used as salvage chemotherapy for relapsed or refractory lymphoma. It includes the administration of cisplatin in a single dose of 100 mg/m2, and renal toxicity is a common adverse event. In this study, we retrospectively analyzed the risk factors for renal toxicity (≥ grade 2) in 74 patients who received DHAP as salvage chemotherapy. Regarding maximal renal toxicities, 38 (51.4%), 6 (8.1%), and 1 (1.4%) patients had grade 2, 3, and 4 toxicities, respectively. Multivariate analyses revealed that overweight (body mass index ≥ 25) was an independent predictive factor for renal toxicity of ≥ grade 2 (odds ratio [OR] 4.08, P = 0.032). A subgroup analysis for patients with diffuse large B cell lymphoma treated with DHAP as second-line therapy (n = 44) confirmed that overweight was an independent risk factor (OR 5.28, P = 0.049). In conclusion, we demonstrated that overweight was an independent risk factor for renal toxicity of ≥ grade 2 in patients who received DHAP. Further clinical studies will be needed to identify a method to decrease renal toxicities after the administration of cisplatin.


Microwave-induced organic reactions of bile acids: esterification, deformylation and deacetylation using mild reagents.
An efficient and convenient procedure for the esterification, deformylation, and deacetylation of bile acids is described. This is achieved by the addition of a catalytic amount of methanesulfonic acid or para-toluene sulfonic acid to a solution of bile acid in methanol in the domestic microwave oven. All these reactions were completed in the microwave oven within 1-3 min at 60% power (390 W) and the desired bile acids, namely trihydroxy-5 beta-cholestanoic acid, (23R)-3 alpha,7 alpha,23-trihydroxy-5 beta-cholan-24-oic acid, ursocholic acid and 7-ketolithocholic acid were isolated in 86-94% yield.


Dataset of the crystal structures, electrical transport properties, and first-principles electronic structures of GeTe-rich GeTe-Sb2Te3 thermoelectric materials.
The data presented in this article relate to the research article entitled "Superior room-temperature power factor in GeTe systems via multiple valence band convergence to a narrow energy range" [T. Oku et al., Mater. Today Phys. 20 (2021) 100484 (10.1016/j.mtphys.2021.100484)]. Polycrystalline (GeTe) n Sb2Te3 (n = 10, 12, 16, 20, and 24) bulk samples were prepared by melting and annealing. The Ge defect concentration of each composition was estimated from Rietveld refinement of the synchrotron X-ray powder diffraction patterns. Electrical properties, such as the electrical resistivity and Seebeck coefficient, were measured from three specimens of each composition to confirm reproducibility. Electronic-band-structure parameters and electronic density-of-states of each composition were obtained by first-principles calculations.


Gastric balloon reduces food intake and body weight in obese rats.
A less invasive method than gastric reduction surgery for treating obesity was tested by inserting balloons into the stomachs of obese rats. Male Sprague-Dawley rats were placed on a high fat diet. After 4 months, the rats weighed an average of 750 g or 23% more than rats on a chow diet. Balloons were then passed orally into the stomach, inflated with 10 ml of water, and detached from the inflating tube. Eight rats had inflated balloons; six rats had no balloons. The balloons, which could be palpated, remained inflated for 12 to 49 days with a mean of 25 days. During the period of inflation, rats with balloons consumed significantly less food (p less than 0.001) relative to rats without balloons. Gastric emptying rate was significantly slowed (p less than 0.0025) in rats with inflated balloons compared to rats with balloons that had deflated and rats with no balloons. Histology of the stomachs that held inflated balloons did not reveal pathology.


Structure and function of the Mind bomb E3 ligase in the context of Notch signal transduction.
The Notch signaling pathway has a critical role in cell fate determination and tissue homeostasis in a variety of different lineages. In the context of normal Notch signaling, the Notch receptor of the 'signal-receiving' cell is activated in trans by a Notch ligand from a neighboring 'signal-sending' cell. Genetic studies in several model organisms have established that ubiquitination of the Notch ligand, and its regulated endocytosis, is essential for transmission of this activation signal. In mammals, this ubiquitination step is dependent on the protein Mind bomb 1 (Mib1), a large multi-domain RING-type E3 ligase, and its direct interaction with the intracellular tails of Notch ligand molecules. Here, we discuss our current understanding of Mind bomb structure and mechanism in the context of Notch signaling and beyond.


IgE and immunoglobulin free light chains in allergic disease: new therapeutic opportunities.
The prevalence of allergy and associated diseases has dramatically increased during the last few decades. These hypersensitivity reactions can be subdivided into IgE- and non-IgE-dependent diseases. Anti-IgE approaches, such as omalizumab, have provided a novel treatment for allergic diseases, and have demonstrated benefit in severe allergic asthma and seasonal allergies. Nevertheless, this approach does not eliminate disease and many patients do not respond to treatment. The newly described mechanism for allergic diseases based on mast cell sensitization by Ig free light chains is exciting and may provide another approach to the treatment of allergic diseases. The peptide inhibitor F-991 has demonstrated remarkable biological activity in a number of animal models of allergic diseases, and promise for the potential treatment of allergic diseases in humans.


Genetic variants in interleukin-18 gene and risk for cervical squamous cell carcinoma.
Cervical cancer is strongly associated with infection of oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for progression to cervical cancer. It is now recognized that host immunogenetic background participates in the control of HPV infection and development of cervical cancer. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon-gamma secretion and plays a central role in antitumor immunity. The aim of this study is to determine if potentially functional polymorphisms in IL-18 gene are associated with risk of HPV-induced cervical cancer in Taiwanese women. Pre-Developed TaqMan Allelic Discrimination Assay was used to genotype IL-18 -1297 T/C, -607 C/A, -380 C/G, -137 G/C, and +105 A/C polymorphisms in a hospital-based study of 470 women with cervical squamous cell carcinoma (CSCC) and 722 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined by PCR. None of the polymorphisms or any haplotype was found to have significant differences in distribution among all subjects with CSCC, those with HPV-16 positive CSCC, and controls. Our results suggest that the IL-18 -1297 T/C, -607 C/A, -380 C/G, -137 G/C, and +105 A/C polymorphisms are not associated with susceptibility to CSCC in Taiwanese women.


Interpreting auditory brainstem evoked responses and distortion product otoacoustic emissions in diabetic patients with normal hearing.
Hearing impairment is a reported late complication of diabetes mellitus (DM). Previous studies have suggested that microangiopathic complications may cause cochlear nerve function deterioration. We evaluated the auditory brainstem evoked responses (ABRs) and distortion product otoacoustic emission (DPOAE) results according to the presence of DM in subjects with normal hearing. A cross-sectional comparative study was conducted from January 2016 to January 2018. Auditory function tests including ABR and DPOAE were performed for outpatients complaining of unilateral tinnitus. All of analyses were conducted in ears without tinnitus on contralateral side of tinnitus ears. We included subjects showing hearing thresholds within 25 dB at 0.5, 1k, 2k, and 4k on pure tone audiometry. 45 ears in patients with type 2 diabetes mellitus and 85 ears in non-diabetic patients were finally enrolled in our study. Diabetic subjects showed significantly more prolonged absolute peak latencies (I, III, V) and inter-peak latencies (I-V, III-V) than non-diabetic subjects. However, there was no significant difference in the inter-peak latency (I-III) between these two groups. Diabetic subjects also showed significantly lower amplitudes at f2 frequencies of 1001, 1200, 1587, 4004, 5042, and 6348 Hz than non-diabetic subjects. Additionally, the prevalence of a DPOAE response, defined as 3 dB above the noise floor, was significantly lower in diabetic subjects than that in non-diabetic subjects. Diabetic patients with normal hearing can still have abnormal ABR and DPOAE results due to diabetic neuroangiopathy. ABR and DPOAE assessments can help in detecting subclinical auditory dysfunction, which precedes the manifestation of hearing impairment in diabetic patients.


Could X-ray microbeams inhibit angioplasty-induced restenosis in the rat carotid artery?
Parallel, thin (<100 microm) planes of synchrotron-generated X rays, have been shown to spare normal tissues and preferentially damage tumors in animal models. The aim of the present study was to assess the effect of such microbeams directed unidirectionally on angioplasted rat carotid arteries. Three groups of Sprague-Dawley rats were studied: (a) rats with normal, untreated arteries, (b) rats treated by balloon angioplasty, but not irradiated, and (c) rats treated with balloon angioplasty and exposed to single fraction, unidirectional, parallel, microbeams an hour after angioplasty. The microbeam array, 15 mm widex7.6 mm high, consisting of 27-microm-wide beam slices, spaced 200 microm center-to-center laterally traversed the damaged artery. The in-depth in-beam dose was 150 Gy, the "valley" dose (dose midway between microbeams resulting mainly from X-ray scattering) was 4.5 Gy on average, and the "integrated" (averaged) dose was 26 Gy. Microbeam irradiation, as given in the present study, was tolerated, but was insufficient to significantly suppress the neointimal hyperplasia. The microbeam dose used is considered low. Dose escalation would be necessary to reach conclusive results regarding the X-ray microbeam efficacy to control restenosis.


High sequence diversity and evidence of balancing selection in the Pvmsp3alpha gene of Plasmodium vivax in the Venezuelan Amazon.
The genetic diversity of a defined Plasmodium vivax population from the Venezuelan Amazon was evaluated by direct sequencing of the gene encoding the P. vivax merozoite surface protein-3alpha, Pvmsp3alpha. Three allele sizes (1.9, 1.4 and 1.1kb) were amplified from 58 isolates with frequencies of 59.3%, 21.9% and 18.8%, respectively. 27 Pvmsp3alpha nucleotide sequences were determined, with nine distinct haplotypes observed. The genetic diversity (h) at this single locus was 0.774. The P. vivax population in this region exhibits significant diversity in contrast to the genetically restricted diversity of the sympatric P. falciparum population. Despite sharing vector and human hosts, different control strategies may be required for these two species in this region. Substitution patterns in the conserved C-terminus of Pvmsp3alpha showed a significant departure from neutrality, suggesting these polymorphisms are being maintained by frequency-dependent selection as the result of an effective immune response from the host. Our findings support the use of Pvmsp3alpha genotyping as a tool for monitoring interventions aimed at control of P. vivax.


Diversification of the sleepers (Gobiiformes: Gobioidei: Eleotridae) and evolution of the root gobioid families.
Eleotridae (sleepers) and five smaller families are the earliest diverging lineages within Gobioidei. Most inhabit freshwaters in and around the Indo-Pacific, but Eleotridae also includes species that have invaded the Neotropics as well as several inland radiations in the freshwaters of Australia, New Zealand, and New Guinea. Previous efforts to infer phylogeny of these families have been based on sets of mitochondrial or nuclear loci and have yielded uncertain resolution of clades within Eleotridae. We expand the taxon sampling of previous studies and use genomic data from nuclear ultraconserved elements (UCEs) to infer phylogeny, then calibrate the hypothesis with recently discovered fossils. Our hypothesis clarifies ambiguously resolved relationships, provides a timescale for divergences, and indicates the core crown Eleotridae diverged over a short period 24.3-26.3 Ma in the late Oligocene. Within Eleotridae, we evaluate diversification dynamics with BAMM and find evidence for an overall slowdown in diversification over the past 35 Ma, but with a sharp increase 3.5 Ma in the genus Mogurnda, a clade of brightly colored species found in the freshwaters of Australia and New Guinea.


"No-touch" cryosurgical enucleation: a minimal trauma technique for eyes harboring intraocular malignancy.
Current surgical approaches for cancer are emphasizing minimal trauma--the so-called no-touch technique of tumor removal. Tumor seeding through the circulatory system seems reasonable, particularly with friable and necrotic tumors. Attempts to reduce metastatic seeds should originate with the original procedure. Enucleation of nontumor eyes with simultaneous intraocular manometry has shown which surgical maneuvers elevate intraocular pressure and how ocular massage can be avoided. Our surgical procedure involves a delicate surgical technique coupled with transscleral cryocoagulation to immobilize the tumor's blood supply.


Protection of sodium dodecyl sulfate-induced aggregation of concanalvalin A by saccharide ligands.
Concanavalin A is visibly aggregated by low concentrations of sodium dodecyl sulfate, maximum aggregation being obtained at pH 4.6. Other denaturants, such as urea, guanidine hydrochloride, Triton X-100, cetyltrimethylammonium bromide, Tween 80, and Brij 35 are ineffective in promoting visible aggregation. The sodium dodecyl sulfate-induced aggregation of concanavalin A requires the presence of an intact, saccharide-ligand binding-site. Rapid and complete reversal of the detergent effect was achieved by use of saccharides which bind to the lectin. Such compounds as tryptophan and o-nitrophenyl beta-D-galactopyranoside did not inhibit the aggregation of concanavalin A by sodium dodecyl sulfate, suggesting that the detergent does not bind the hydrophobic pocket on the surface of the protein. The results suggest that concanavalin A may have an additional, ligand-binding site which is metal-dependent and which can be modified by the addition of a saccharide ligand.


Benefit of chemotherapy based on platinum with definitive radiotherapy in older patients with locally advanced esophageal squamous cell carcinoma.
There is still no definitely therapeutic evidence of a beneficial effect of chemotherapy with radiotherapy for older patients with esophageal squamous cell carcinoma (ESCC). We aim to determine the influence of chemoradiotherapy (CRT) and radiotherapy (RT) alone in patients aged 65 years or older with locally advanced ESCC. We retrospectively analyzed 581 ESCC patients who underwent CRT and RT alone. Univariate and multivariate Cox regression analysis was used to analyze the impact of clinical factors on long-term overall survival (OS) and progression-free survival (PFS). Finally, we compared the toxicity rates of these patients. The median OS and PFS of the overall population were 23.2 months (2.0-162.6 months) and 18.6 months (1.1-159.6 months). Multivariate Cox regression analysis showed that chemotherapy (p < 0.05), tumor thickness (p < 0.01), and N stage (p < 0.05) were independent prognostic factors associated with both OS and PFS. In the chemotherapy subgroup, patients who received 2-8 cycles of chemotherapy had better OS than those who received 1 cycle (p = 0.015). The results also revealed that the CRT group has better OS and PFS than RT alone group for patients aged 65-74 years (both p < 0.01). However, for patients aged 75 years or older, there was no statistically significant difference between CRT and RT alone (both p > 0.05). Besides, higher staged ESCC has the inferior OS and PFS than lower staged ESCC for patients received RT alone and aged 65-74 years (both p < 0.05). Finally, there were significantly more severe hematologic toxicities in the CRT group than in those treated with RT alone in this study (p < 0.001). The present study suggested that CRT for locally advanced ESCC in patients aged 65 years or older had a significant benefit over RT alone in terms of OS and PFS. However, for patients aged 75 years or older, there was no statistically significant difference between CRT and RT alone. CRT should be performed with special attention in patients aged 75 years or older.


Spindle formation and chromatin condensation in cells blocked at interphase by mutation of a negative cell cycle control gene.
In Aspergillus nidulans the temperature-sensitive cell cycle mutation bimE7 causes chromosome condensation and pre-anaphase spindle formation to occur at restrictive temperature. By constructing double mutants between bimE7 and S phase or G2 phase mutants and blocking DNA replication with hydroxyurea, we demonstrate that bimE7 can cause chromatin condensation and spindle formation in cells held in S or G2. Thus bimE7 overrides normal control systems that prevent mitosis from prematurely occurring during S or G2. We show that bimE7 is a loss of function mutation and propose that bimE normally functions to negatively control a positive mitotic inducing factor, possibly the cell cycle gene nimA.


Improving communication between researchers and policy makers in long-term care or "researchers are from Mars; policy makers are from Venus".
This policy brief reports the results of a study that examined how policy makers acquire information about long-term care (LTC) and why research findings in the field often don't filter through to them. It describes the "brokers" that provide LTC research information to policy makers and outlines what can be done to make certain such information reaches policy makers and is suited to their needs. It concludes by recommending that more effort be put into disseminating LTC research information, both to communicate more effectively within the resource constraints that currently exist and to encourage increased investment in research brokering activities for the future.


Montreal Cognitive Assessment score correlates with regional cerebral blood flow in post-stroke patients.
Valid and reliable measures are needed to assess post-stroke cognitive impairment. The Montreal Cognitive Assessment (MoCA) has been considered a superior screening test to the Mini-Mental State Examination (MMSE) for patients with post-stroke cognitive impairment, particularly in executive function, which may be related to reduction in regional cerebral blood flow (rCBF). In this study, we determined whether MoCA and MMSE scores correlate with rCBF assessed with SPECT in the subacute phase after ischemic stroke. We retrospectively enrolled 28 patients who were admitted to the Red Cross Otsu Hospital with acute cerebral infarction, which was confirmed by magnetic resonance imaging (MRI), if they underwent cognitive assessment (MoCA/MMSE) and 123I-IMP SPECT imaging within 3 weeks post-stroke during a study period of 5 months. Correlation analyses between rCBF and MoCA or MMSE scores were performed by statistical parametric mapping (SPM) and volume-of-interest (VOI) analyses. Total MoCA score correlated with the rCBF in the prefrontal cortex, cingulate cortex, caudate nucleus and thalamus by SPM analysis (uncorrected p < 0.001; cluster-level corrected p < 0.05). Among the subtest scores of MoCA, visuoexecutive function, attention, language and delayed recall scores were positively correlated with rCBF in the prefrontal cortex by VOI analysis (p < 0.05). However, total MMSE score did not correlate significantly with any of the rCBF measures. Post-stroke cognitive performance assessed with MoCA positively correlated with rCBF in brain regions mainly comprising the prefrontal-subcortical circuits. The findings of this hypothesis-generating study support the notion that MoCA is useful for assessing post-stroke cognitive status.


In-line leukoreduction filters: A new source of microparticle for human and animal study.
The isolation of microparticles (MPs) from leukoreduction filters (LRFs) during cell extraction process introduced LRFs as a precious source of MPs for animal and human study. LRFs were collected from Tehran Blood Transfusion Center. The back-flushing method was used for leukocyte extraction from the LRFs. MPs were isolated through double-step centrifugation. Dynamic light scattering (DLS), electron microscopy (EM), and flow cytometry were performed for the evaluation of MPs size, morphology, and structural properties respectively. Statistical analyses were carried out to evaluation of differences between test and control groups. a p-value less than 0.05 indicates significant differences. DLS analysis showed that the average MP size in the test and control groups was 654.83 nm and 233.68 nm respectively. SEM images showed the spherical, oval, cell fragment, and micro-aggregate particles and TEM images demonstrated the mitochondrial-like body in the MPs. Flow cytometry studies also showed a significant increase in the percent of CD41, and CD14, and a significant decrease in the percent of CD235a in the test group compared to control (P value=0.029, P value=0.035, P value= 0.001 respectively). Moreover, the percentage of CD34 MPs indicated a borderline difference between the two groups (P value= 0.075). Finally count of MPs in the test and control groups was 1202095.34 and 280948.64, respectively and the difference was significant (P value=0.008). It is concluded that LRFs are a potential source of the large volume of various cell MPs with different phenotypical and structural properties for animal and human phase studies. Moreover, the investigation of LRFs as a source of different types of exosomes can shed new light on extracellular vesicle studies.


Hand reconstruction using the thin anterolateral thigh flap.
Perforator flaps have been introduced for various kinds of reconstruction and resurfacing; in particular, the free thin anterolateral thigh flap is becoming one of the most preferred options for reconstruction of soft-tissue defects. Between 1999 and 2002, the authors used this flap as a free flap for nine cases for covering hand defects after burn, crushing injuries, or severe scar contracture release. There were eight men and one woman, the mean age of the patients was 31 years, and the size of the flaps ranged from 7 x 3.5 cm to 15 x 9 cm; thinning was performed in all flaps. All flaps survived completely, and the donor site was closed directly in seven cases; in two cases, the exposed muscle was covered with split-thickness skin graft. The anterolateral thigh flap was thin enough for defects on the dorsum and/or palm of the hand and for first web reconstruction after scar contracture release. It has many advantages in free flap surgery including a long pedicle with a suitable vessel diameter, and the donor-site morbidity is acceptable. The thin anterolateral thigh flap is a versatile soft-tissue flap that achieves good hand contour with low donor-site morbidity.


Isolation and characterization of anti-inflammatory and analgesic compounds from Uapaca staudtii Pax (Phyllanthaceae) stem bark.
Uapaca species including Uapacastaudtii Pax (Phyllanthaceae) are used in West Africa ethnomedicine to treat diverse ailments including pile, rheumatism, oedema and wound healing. However, the anti-inflammatory and analgesic potential as well as constituents of the Uapacastaudtii stem bark has not been investigated. The study was designed to evaluate the anti-inflammatory, analgesic, and antioxidant activities of extract and fractions ofU. staudtii stem bark, and to isolate the bioactive constituents. The anti-inflammatory, analgesic and antioxidant activities of the ethanol extract, dichloromethane, ethyl acetate, butanol, and aqueous fractions of U. staudtii stem bark, as well as protocatechuic acid and betulinic acid isolated from the bioactive ethyl acetate fraction were evaluated in different mice models of inflammation and pain; furthermore, antioxidant assays were carried out. Chemical structures of isolated compounds were established based on spectroscopic studies and comparison with literature data. The ethanol extract and ethyl acetate fraction exhibited good anti-inflammatory, analgesic, and antioxidant capacity in all studied models, comparable with those of the standard drugs used. Protocatechuic acid also gave significant (p < 0.05) anti-inflammatory (83%and 88% inhibition for egg-albumin induced and xylene induced oedema, respectively), analgesic (56% inhibition and 22 s of pain suppression for acetic acid-induced and hot plate-induced pain, respectively), and antioxidant effects (97% inhibition and absorbance of 2.516 at 100 μg/mL for DPPH and FRAP assay, respectively) in all the models, whereas betulinic acid only exhibited significant (p < 0.05) anti-inflammatory and antioxidant activity. The result supports the medicinal uses of the U. staudtii stem bark in the management of pain and inflammatory disease. This is the first report on the biological activities and characterization of compounds inU. staudtii, and presence of protocatechuic acid in Uapaca genus.


Prevalence and Factors Associated with Depression among Medical Students at Makerere University, Uganda.
Depression affects about a third of medical students worldwide. There is paucity of data on depression among medical students in Uganda. The purpose of this study was to establish the prevalence and factors associated with depression among medical students at Makerere University College of Health Science (MakCHS), Uganda. A cross-sectional study was conducted among students pursuing a Bachelor of Medicine and Surgery at MakCHS in May and July 2019. Students were enrolled by consecutive sampling, both online using Google Forms and in person for those unable to access internet. The self-reported Patient Health Questionnaire 9 (PHQ9) was administered to assess depression, defined as a PHQ9 score ≥10. Microsoft Excel 2016 and Stata 16 were used for data analysis. Overall, 331 valid responses (mean age 23.1±3.3 years) were submitted (response rate 93.8%). In a majority of participants, the prevalence of depression was 21.5% (n=71) of which 64.1% had moderate depression (n=50). On bivariate analysis, year of study, worrying about academic performance, and lectures were significantly associated with depression. On multivariate analysis, worrying about academic performance (aOR 2.52, 95% CI 1.50-4.22; P<0.001) and lectures (aOR 1.89, 95% CI 1.11-3.22; P=0.018) were significantly associated with depression. Depression affects a significant number of medical students at MakCHS. About one in five medical students have depression. Year of study and academic performance were significantly associated with depression. Efforts aimed at identification and evaluation of students at risk, administering appropriate interventions, and follow-up of affected students are vital. Analytical studies aimed at establishing the causative factors and the effects of depression on medical students are recommended.


Forceful balloon dilation: an outpatient procedure for achalasia.
The initial treatment of choice in patients with achalasia is balloon dilation. Heretofore, this procedure was performed on an in-hospital basis resulting in high patient cost. This study evaluated the safety and efficacy of pneumatic dilation as an outpatient procedure. Sixty-one procedures were performed on 50 patients at two centers. An overall treatment success rate of 95% (47 of 50 patients) was achieved. Two patients had elective surgical treatment and a third underwent surgery for perforation secondary to dilation. A total of three patients complained of post-procedure chest pain within 4 hours and were hospitalized. Two had perforations; one required surgical repair. The third patient had resolution of symptoms. We conclude that performing balloon dilation as an outpatient procedure is safe, efficacious, and cost effective.


Serving homeless veterans in the VA Desert Pacific Healthcare Network: a needs assessment to inform quality improvement endeavors.
This report describes a needs assessment of VA programs for homeless Veterans in Southern California and Nevada, the geographic region with the most homeless Veterans in the nation. The assessment was formulated through key informant interviews. Current service provisions are discussed, along with salient unmet needs for this vulnerable population.


Fibroblast-dependent growth of mouse mast cells in vitro: duplication of mast cell depletion in mutant mice of W/Wv genotype.
In spite of the apparent depletion of mast cells in tissues of mutant mice of W/Wv genotype, cells with many features of mast cells do develop when bone marrow cells of W/Wv mice are cultured in the presence of pokeweed mitogen-stimulated spleen cell-conditioned medium (PWM-SCM). In order to resolve this discrepancy and facilitate the analysis of the W mutation, we attempted to establish an in vitro system in which the in vivo defect of W/Wv mice can be reproduced. Cultured mast cells (CMC) were developed from bone marrow cells of either W/Wv or congenic +/+ mice, and then co-cultured with NIH/3T3 mouse fibroblasts in media supplemented only with fetal calf serum (i.e., in the absence of PWM-SCM). Under this condition, CMC from +/+ mice continued to divide and were maintained for more than 4 weeks. The supportive effect of NIH/3T3 cells required close-range interactions with CMC and was not due to synthesis of the known mast cell growth factors, interleukins 3 and 4. By contrast, CMC from W/Wv mice were not maintained, and the number of mast cells remaining after 4 weeks of co-culture was only 1% of the normal +/+ counterparts. Thus, the humoral factor-independent and cell contact-dependent system presented here revealed the intrinsic defects in growth and differentiation of CMC derived from W/Wv mice and might be useful for biochemical and molecular analysis of the gene product(s) encoded at the W locus.


Network pharmacology analysis of the pharmacological mechanism of Artemisia lavandulaefolia DC. in rheumatoid arthritis.
The traditional She medicine is a notable type of traditional Chinese medicine, which has been applied for a long history despite the lack of sufficient mechanistic understanding. Our study revealed the possible molecular mechanism of sesquiterpene 5α-Hydroxycostic acid, active ingredient of traditional She medicine Artemisia lavandulaefolia DC., in the treatment of rheumatoid arthritis (RA). RA-fibroblast like synoviocytes (RA-FLSs) were treated with 5α-Hydroxycostic acid, Anthemidin, and methotrexate (MTX). CCK-8 and ELISA were used to measure the resultant viability of RA-FLSs and to quantify pro-inflammatory cytokines. Target genes of 5α-Hydroxycostic acid and Anthemidin, RA-related differentially expressed genes, and RA-related genes were retrieved by bioinformatics analyses, results of which were further intersected to identify candidate genes. The protein-protein interaction network was constructed to develop the pharmacophore model. The molecular docking was simulated to determine the core target androgen receptor (AR) for subsequent molecular mechanism investigation in vitro. The 5ɑ-Hydroxycostic acid, Anthemidin, or MTX of different concentrations inhibited the viability of RA-FLSs, and downregulated the levels of proinflammatory cytokines. The pharmacophore model and molecular docking of 10 candidate targets with 5α-Hydroxycostic acid were successfully established. In vitro experiments provided evidence confirming that 5α-Hydroxycostic acid elevated AR expression to inhibit inflammatory responses of RA-FLSs and degradation of extracellular matrix. Therefore, this study reveals the active ingredient sesquiterpene 5α-Hydroxycostic acid of traditional She medicine Artemisia lavandulaefolia DC., and illustrates potential molecular mechanism in RA treatment by upregulating AR expression. This study is the first to report the effect of the active ingredient sesquiterpenes in traditional She medicine A.lavandulaefolia DC on RA and elucidate the underlying molecular mechanism associated with up-regulated AR expression. This study provides new insights into the mechanistic understanding of traditional She medicine in the treatment of RA.


Amphetamine locomotor sensitization is accompanied with an enhanced high K⁺-stimulated Dopamine release in the rat medial prefrontal cortex.
In the present work, we assessed dopamine extracellular levels in the medial Prefrontal Cortex of rats repeatedly treated with amphetamine during early abstinence. Rats were injected once daily with amphetamine for five consecutive days. A sensitized locomotor response was observed in 55% of animals treated. After two days of abstinence, an amphetamine challenge dose was given to all rats and locomotor activity was measured to assess expression of sensitization. A persistence of heightened locomotor response to amphetamine was observed in rats that developed sensitization. Twenty four hours after amphetamine challenge, microdialysis experiments were carried out to evaluate basal and stimulated dopamine extracellular levels in the medial Prefrontal Cortex. Rats that developed and expressed amphetamine locomotor sensitization showed a significantly greater high potassium-stimulated dopamine release compared to Non-sensitized and Saline rats. These results show that the increased dopamine releasability in the medial Prefrontal Cortex occurs soon after development of amphetamine locomotor sensitization, and might be underlying the early expression of sensitization.


Eligibility criteria for phase I clinical trials: tight vs loose?
The purpose of the current study is to analyze a series of phase I cancer clinical trials, examine and compare trial protocols based on patients' eligibility criteria. We evaluated all dose escalation phase I trial protocols with accessible or published results performed at Institute for Drug Development, Cancer Therapy and Research Center (San Antonio) between 1991 and 2016. Study protocols were categorized as non-restrictive (NRP) or restrictive (RP) based on several eligibility parameters. Fisher's Exact and Chi-square tests were used to compare characteristics of NRP and RP. Of 284 protocols screened, 231 dose escalation phase I trial protocols (with accessible results) of solid tumors were included in this review. There were 145 NRP (involving 3190 patients) and 86 RP (involving 1892 patients). The median number of exclusion criteria for NRP and RP were 14 and 23, respectively. The most common reasons that made trial protocol to be restrictive were ECOG ≤ 1, strict requirements for renal or hepatic function (≤ 2.5 times upper limit of normal) and exclusion of subjects with brain metastases. The median accrual time for NRP was significantly shorter as compared to RP (17 vs 26 months). The median number of dose levels explored in NRP and RP were 9 and 6, respectively. RP had a higher screen failure as well as premature closure rate. The rates of DLTs, SAEs, toxicity-related death and response were not different between the two groups. Our study findings are in support of devising well thought and justified phase I study eligibility criteria.


Screening for nutritional rickets in a community.
Concern has been expressed about the rising incidence of nutritional rickets with its associated long-term sequelae in children globally. In order to address the condition worldwide, it is imperative that accurate figures of its incidence are available particularly in at-risk communities. In order to obtain these figures, various screening tools and diagnostic criteria have been used with no standardization of methodologies, resulting in varying prevalences which may under- or over-estimate the prevalence depending of the techniques used. This review discusses the advantages and disadvantages of various screening tests used to diagnose rickets in communities. Clinical signs characteristic of rachitic deformities have been used extensively, but are likely to over-estimate the prevalence and are dependent on the clinical skills of the observer. Biochemical tests such as alkaline phosphatase and 25-hydroxyvitamin D have also been proposed. There is no consensus on the usefulness of alkaline phosphatase as a screening tool, while there is general agreement that the measurement of vitamin D status is unhelpful in screening for rickets. Finally, the confirmation of the presence of active rickets in suspected infants and children is dependent on radiographic findings, although these may be less helpful in adolescents whose growth plates might be closed or nearly so. In order to obtain uniformity in screening for rickets globally, the is a need for consensus among public health specialists, paediatric endocrinologists and those interested in paediatric bone disease as to the best methods to be employed to determine the prevalence of rickets, particularly in communities with limited resources.


The Association between Opioid Discontinuation and Heroin Use: A Nested Case-Control Study.
Opioid prescribing guidelines recommend reducing or discontinuing opioids for chronic pain if harms of opioid treatment outweigh benefits. As opioid discontinuation becomes more prevalent, it is important to understand whether opioid discontinuation is associated with heroin use. In this study, we sought to assess the association between opioid discontinuation and heroin use documented in the medical record. A matched nested case-control study was conducted in an integrated health plan and delivery system in Colorado. Patients receiving opioid therapy in the study period (January 2006-June 2018) were included. Opioid discontinuation was defined as ≥45 days with no opioids dispensed after initiating opioid therapy. The heroin use onset date represented the index date. Case patients were matched to up to 20 randomly selected patients without heroin use (control patients) by age, sex, calendar time, and time between initiating opioid therapy and the index date. Conditional logistic regression models estimated matched odds ratios (mOR) for the association between an opioid discontinuation prior to the index date and heroin use. Among 22,962 patients prescribed opioid therapy, 125 patients (0.54%) used heroin after initiating opioid therapy, of which 74 met criteria for inclusion in the analysis. The odds of opioid discontinuation were approximately two times higher in case patients (n = 74) than control patients (n = 1045; mOR = 2.19; 95% CI 1.27-3.78). Among patients prescribed chronic opioid therapy, the observed increased risk for heroin use associated with opioid discontinuation should be balanced with potential benefits.


The Tn10-encoded Tet repressor blocks early but not late steps of assembly of the RNA polymerase II initiation complex in vivo.
We have studied the effect of the Tn10-encoded Tet repressor on expression from 13 cauliflower mosaic virus (CaMV) 35S promoter derivatives that contain a tet operator sequence in various positions downstream of the TATAbox. When the operator sequence was inserted less than 33 bp away from the TATAbox (position +9 with respect to the transcription start site), the repressor interfered with transcription, whereas increasing the distance to 35 bp (position +11) abolished repression. This result indicates that initiation of transcription from the CaMV 35S promoter occurs in at least two different steps: (1) binding of transcription factors, involving sequences extending to position +9; this step can be inhibited by binding of the Tet repressor protein; and (2) initiation of transcription from this complex, which is not affected by the repressor protein. We suggest that the Tet repressor can be used to investigate whether transcription conditions in vitro truly reflect the in vivo situation.


Primary vs. secondary insertion of anterior chamber lenses.
In this prospective study, patients with cataracts were divided into two groups. In Group I, intracapsular cataract extraction with anterior chamber lens insertion was performed as a one-step procedure. Patients in Group II underwent intracapsular cataract extraction followed by secondary insertion of an anterior chamber lens two to three months later. The higher incidence of CME seen with the secondary procedure seems to indicate that primary rather than secondary insertion of anterior chamber lenses is advisable.


Optimization of pigment dyeing process of high performance fibers using feed-forward bottleneck neural networks mapping technique.
Process optimization involves the minimization (or maximization) of an objective function, that can be established from a technical and (or) economic viewpoint taking into account safety of process. The basic idea of the optimization method using neural network (NN) is to replace the model equations (which traditionally obtained using, for example, the surface response design or others methods) by an equivalent NN. The feed-forward bottleneck neural network (FFBN) as a mapping technique is described and evaluated. From the 2D maps the optimal parameters of pigment dyeing of high performance fibers on the bases of poly-amide benzimidazole (PABI) and polyimide (arimid) are discussed. The studied fibers were treated in 32 experiments under the conditions as proposed by the Design of Experiment (DOE), varying five influencing factors. Neural network mapping method enables visualization of process and shows the influence of different factors on different output responses. Optimum parameters were selected upon compromise decision.


Optimal cutoff value of basal anti-mullerian hormone in iranian infertile women for prediction of ovarian hyper-stimulation syndrome and poor response to stimulation.
We intended to establish the threshold of Anti-Mullerian Hormone (AMH) for detection of Ovarian Hyper-Stimulation Syndrome (OHSS) and poor response to treatment in Iranian infertile women. Pre-stimulation menstrual cycle day-3 hormonal indices including basal AMH values were measured in 105 infertile women aged 32.5 ± 4.3 years. Patients underwent long GnRH agonist Controlled Ovarian Hyperstimulation (COH) in a referral infertility center (Tehran, Iran). The gonadotropin dose was determined based on the age and basal serum Follicular Stimulating Hormone (FSH) level. The IVF/ICSI cycles were followed and the clinical and sonographic data were recorded. Sixteen cases developed OHSS. The prevalence of PCOS was higher in subjects with OHSS [62.5 % (38.8-86.2) vs. 17 % (9.2-24.9)]. The patients with OHSS had higher ovarian follicular count [23.7 (3.2) vs. 9.1 (0.5); p < 0.05], collected oocytes [13.5 (1.9) vs. 6.9 (0.5); p < 0.05] and AMH level [7.9 (0.7) vs. 3.6 (0.3); p < 0.05]. Basal AMH level and oocyte yields (but not age, BMI, and PCOS) correlated with occurrence of OHSS; and only the AMH levels were associated with poor ovarian response (oocytes yield ≤ 4). The optimal cutoff value for the prediction of OHSS was 6.95 ng/ml (area under the receiver operating characteristics curve: 0.86; CI: 0.78-0.95; sensitivity: 75 %; specificity: 84 %; odds ratio for occurrence of OHSS: 9 and p < 0.001). The optimal cut point to discriminate poor response (oocytes ≤4) was 1.65 ng/ml ( AUC : 0.8; CI: 0.69-0.91; sensitivity: 89 % specificity : 71 %; and OR = 23.8 and P value <0.001). Iranian women with basal AMH level > 6.95 ng/ml are at high risk of developing OHSS and those with AMH level < 1.65 ng/ml are poor responders.


Noradrenergic circuits in the forebrain control affective responses to novelty.
In rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated. We sought to define the role of central NE transmission in neophilic and neophobic behaviors. We assessed dopamine β-hydroxylase knockout (Dbh -/-) mice lacking NE and their NE-competent (Dbh +/-) littermate controls in neophilic (novelty-induced locomotion; NIL) and neophobic (novelty-suppressed feeding; NSF) behavioral tests with subsequent quantification of brain-wide c-fos induction. We complimented the gene knockout approach with pharmacological interventions. Dbh -/- mice exhibited blunted locomotor responses in the NIL task and completely lacked neophobia in the NSF test. Neophobia was rescued in Dbh -/- mice by acute pharmacological restoration of central NE with the synthetic precursor L-3,4-dihydroxyphenylserine (DOPS), and attenuated in control mice by the inhibitory α2-adrenergic autoreceptor agonist guanfacine. Following either NSF or NIL, Dbh -/- mice demonstrated reduced c-fos in the anterior cingulate cortex, medial septum, ventral hippocampus, bed nucleus of the stria terminalis, and basolateral amygdala. These findings indicate that central NE signaling is required for the expression of both neophilic and neophobic behaviors. Further, we describe a putative noradrenergic novelty network as a potential therapeutic target for treating anxiety and substance abuse disorders.


Glucocorticoids protect against suppression of T cell responses in a murine model of acute ethanol exposure and thermal injury by regulating IL-6.
Previous reports by this laboratory demonstrated that acute alcohol exposure combined with a 15% body surface area dorsal scald injury results in significant reductions in delayed-type hypersensitivity (DTH) and splenocyte proliferative responses compared to either insult alone. Previous studies by this lab have also shown that these defects are mediated, in part, by increased production of interleukin-6 (IL-6). Because both alcohol exposure and thermal injury are known to modulate glucocorticoid (CORT) levels, and CORT regulates IL-6 gene expression, the relationship between circulating CORT and IL-6 production in burn + ethanol mice was examined. At 24 and 48 h post-burn, a positive correlation existed between circulating CORT levels and measurements of cellular immune function. Administration of exogenous CORT to burn + ethanol-treated mice resulted in significant restoration (to 60% of control) of DTH and splenocyte proliferative responses. This restoration was concomitant with a down-regulation of circulating and macrophage-derived IL-6. The specificity of CORT in modulating these responses was tested by assessing cellular immune function and IL-6 levels after glucocorticoid receptor blockade with RU486. Taken together, these data strongly suggest that under normal circumstances CORT protects burned mice from severe immune dysfunction, a protection that is not afforded to burn + ethanol-treated mice. Furthermore, the immune dysfunction observed in burn + ethanol mice may be due to a lack of glucocorticoid attenuation of IL-6.


The evolution of plant sexual diversity.
Charles Darwin recognized that flowering plants have an unrivalled diversity of sexual systems. Determining the ecological and genetic factors that govern sexual diversification in plants is today a central problem in evolutionary biology. The integration of phylogenetic, ecological and population-genetic studies have provided new insights into the selective mechanisms that are responsible for major evolutionary transitions between reproductive modes.


[Effects of emodin on lung fibroblast proliferation and cell cycle in vitro].
To gain a better understanding of the effect of emodin on lung fibroblast (LF) proliferation in vitro. The methods of cell cultured in vitro, 3H-TdR incorporation, flow cytometry and electron microscopy were used in research to compare LF proliferation, cell cycle and morphologic change of LF in vitro. It was found that emodin reduced the proliferation of LF in vitro (P < 0.01), and such inhibitory effect was dose-dependent. Emodin delayed the progression of LF from G1 to S and G2 phase (P < 0.01). Also, electron microscopic examination demonstrated that the ultrastructure of LF in emodin group was not markedly worse as compared with that in the control group. Emodin inhibits the proliferation of LF and delays the progression of LF cell cycle. Emodin at the dose of 100 micrograms/ml does not destroy the ultrastructure of LF cells. These findings may provide a theoretical basis for the endeavors to use emodin for preventing lung fibrosis diseases.


Associations of Adipocytokines and Early Renal Dysfunction in Young People on the Background of Dyslipidemia.
There are data supporting the idea that atherogenic dyslipidemia is a risk factor for CKD and reduced GFR. The aim was to evaluate the associations between adipocytokines and early renal dysfunction in young people with dyslipidemia. A population study was conducted in IIPM-Branch of IC&G SB RAS, in 2013-2017. Furthermore, 1033 people were included in the study (469 men (45.4%) and 564 women (54.6%)). The study included blood sampling, anthropometric data, and adipokines by multiplex analysis. Among people with reduced kidney function and DLP, men were 3.1 times more common than without DLP, women smoked 2 times less often, arterial hypertension was 7.8 times more common, and abdominal obesity was 2.7 times more common (and women with DLP were 3 times more likely than those without DLP). An increase in the level of resistin by 1 mcg/mL was associated with an increased chance of having renal dysfunction by 0.2%. An increase in the level of GIP was associated with an increased chance of having renal dysfunction by 1.1%. In young people with dyslipidemia, regardless of the presence of abdominal obesity, resistin and GIP are associated with the presence of renal dysfunction.


Uveitis in rabbits with pleural effusion disease. Clinical and histopathological observations.
Pleural effusion disease (PED) is a generalized infection of laboratory rabbits caused by a virus-like agent. The disease was first described in the late sixties as a mortality problem among rabbits used for the propagation of Nichols' pathogenic Treponema pallidum in Scandinavian laboratories using the T. pallidum immobilization (TPI) test for the serological diagnosis of syphilis. The iridocyclitis, described as a manifestation of PED, has been studied in detail in rabbits experimentally infected with the PED agent. All rabbits surviving the acute phase of infection developed a non-pyogenic, non-granulomatous anterior uveitis during the "viraemic" stage of infection. The ocular signs of disease culminated between days 3 and 6 and disappeared within 2 to 3 weeks. No recurrence of uveitis was observed during a 6-months observation period, nor by subsequent subcutaneous re-inoculation of the PED agent. Histologically, the uveal reaction was mild and regressed almost completely within 4 weeks. Discrete choroidal inflammatory foci occurred in some of the re-inoculated rabbits, but without changes in the anterior eye segment. The uveitis of pleural effusion disease in rabbits seems to be caused directly by the virus-like agent. It might possibly serve as a simple and reproducible model in further uveitis research.


Developing a simultaneously antioxidant and pH-responsive κ-carrageenan/hydroxypropyl methylcellulose film blended with Prunus maackii extract.
к-Carrageenan and hydroxypropyl methylcellulose were used as matrix materials in which the extract of Prunus maackii pomace (EPm) was added to prepare a simultaneously antioxidant and pH-responsive film. EPm effectively increased the flexibility, barrier properties, antioxidant activity and pH-responsiveness of the film. When EPm content was increased to 8%, the elongation at break, heat-sealing strength and oxygen permeability of the film could reach 43.20 ± 2.07%, 1096.39 ± 51.29 N/m and 2.23 ± 0.02 cm3 mm m-2 day-1 atm-1, respectively. Ultraviolet-visible spectra of EPm and the films color changed significantly in the range of pH 2.0-12.0. The κC/Hm/EPmy film obviously slowed the oxidation of lard compared with commercial PE film, and exhibited visible changes from red to purple when TVB-N in the pork reached 13.18 mg/100 g which was close to the freshness limit of 15.00 mg/100 g. Therefore, the κC/Hm/EPmy film can be promisingly used for extending oil shelf life and indicating the protein-rich food quality.


Primary systemic chemotherapy with sequential, dose-dense epirubicin and docetaxel for inoperable, locally advanced inflammatory breast cancer: a phase II study.
Sequential, dose-dense epirubicin plus docetaxel was evaluated as primary systemic therapy for women with inoperable, locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients (LABC n=27; IBC n=7) received 3 cycles of epirubicin 120 mg/m2 every 2 weeks followed by 3 cycles of docetaxel 100 mg/m2 every 2 weeks, with granulocyte colony-stimulating factor. Grade 3-4 toxicities were observed in 21 of 195 cycles (10.8%). Grade 3 anemia and leukopenia each occurred in 1% of cycles. Following chemotherapy, all patients underwent surgery. Eight patients (23.5%) had a clinical complete response and 15 (44.1%) had a partial response. In patients with IBC, median skin thickness decreased from 5.85 mm (range: 3.1-6.2 mm) to 4 mm (range: 2.7-5.1 mm) (p<0.005). Sequential, dose-dense epirubicin plus docetaxel achieved a high response rate among patients with LABC or IBC with only moderate toxicity.


Cloning and sequence analysis of the Escherichia coli 4.5 S RNA gene.
The structure of the Escherichia coli gene coding for the metabolically stable 4.5 S RNA has been determined by cloning and DNA sequence analysis. Results from Southern hybridization assays carried out prior to cloning show the 4.5 S DNA to be limited to a single locus in the E. coli K12 genome. A 5.4 X 10(3) base DNA fragment containing the 4.5 S DNA was cloned into plasmid pBR322 for restriction, hybridization and sequence analyses. Cells harboring the cloned gene overproduce the 4.5 S RNA by 15-fold under normal culturing conditions; however, no effect on growth rate is observed. DNA sequencing revealed only one copy of the 4.5 S RNA gene, with a deduced RNA sequence both longer at 114 bases and slightly different from the RNA sequence reported earlier. A promoter structure immediately preceding the structural gene shows good agreement with the prokaryotic consensus sequence at both the -35 and -10 regions. In addition, a G + C-rich sequence between the Pribnow box and the start of transcription agrees well with an apparent consensus sequence found for other stable RNA genes also under stringent control. No clearly recognizable termination signal was found immediately downstream from the 3' terminus of the 4.5 S DNA, although structural elements with that potential appear to occur. A potential coding sequence for a protein occurs about 100 bases downstream from the 4.5 S DNA, suggesting the possibility of a dual function 4.5 S RNA-mRNA transcript.