A study for the cause of ferulic acid-induced quenching of tyrosine fluorescence and whether it is a reliable marker of intermolecular interactions or not.
Intrinsic fluorescence of peptides and proteins is extensively used to monitor their specific interactions with several natural and synthetic molecules known to have wide-ranging beneficial or detrimental effects on health. A consequence of these interactions would be a significant decrease of the fluorescence emission intensity of Tyrosine (Tyr) and/or Tryptophan (Trp) residues in the protein due to structural rearrangements of proteic microenvironment. However fluorescence quenching can be also caused by "trivial" artefacts. In this study we examined the effect of Ferulic acid (FA) on Tyr fluorescence. FA is a natural anti-oxidant suggested to bind to and to modify the structural properties of several proteins thus altering their biological activities. Fluorescence spectroscopy experiments on Tyr and on proteins containing Tyr and no Trp like beta amyloid peptides and Insulin were performed. Our results suggest that Tyr fluorescence loss can mainly result from an inner filter effect rather than from specific interactions with FA.


Why Are Indian Children So Short? The Role of Birth Order and Son Preference.
Child stunting in India exceeds that in poorer regions like sub-Saharan Africa. Data on over 168,000 children show that, relative to Africa, India's height disadvantage increases sharply with birth order. We posit that India's steep birth order gradient is due to favoritism toward eldest sons, which affects parents' fertility decisions and resource allocation across children. We show that, within India, the gradient is steeper for high-son-preference regions and religions. The gradient also varies with sibling gender as predicted. A back-of-the-envelope calculation suggests that India's steeper birth order gradient can explain over one-half of the India-Africa gap in average child height.


Malformations among 289,365 Births Attributed to Mutations with Autosomal Dominant and Recessive and X-Linked Inheritance.
The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders. The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well. One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents. It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc.


Comparison of enzyme and DNA analysis in a Tay-Sachs disease carrier screening program.
Tay-Sachs disease (GM2 gangliosidosis, type 1; TSD) is an autosomal recessive GM2 gangliosidosis resulting from the deficient activity of the lysosomal hydrolase beta-hexosaminidase A (Hex A). With a carrier frequency estimated at 1 in 25, it is a common lysosomal disorder in the Ashkenazi Jewish population. Tay-Sachs disease has provided the prototype for the prevention of severe recessive genetic diseases. Molecular analysis of the Hex A gene (HEXA) of Ashkenazi Jewish individuals affected with Tay-Sachs disease revealed that three common mutations cause the infantile and adult onset forms of the disease; a four base insertion in exon 11, a splice junction mutation in intron 12 and a point mutation in exon 7 (G269S). A study was undertaken to determine whether mutation analysis would be useful in TSD screening programs in identifying carriers and clarifying the status of individuals whose enzyme assays are inconclusive. Ashkenazi Jewish individuals who had been diagnosed as carriers, inconclusives by enzyme assay and non-carriers with low normal enzyme levels in the Mount Sinai Tay-Sachs Disease Prevention Program were examined for the presence of the three mutations using polymerase chain reaction (PCR) and allele specific oligonucleotide (ASO) hybridization. The insertion mutation was present in 29 of 34 carriers and 2 of 36 inconclusive individuals, the splice junction mutation was found in 4 of 34 carriers and the G269S mutation was found in 1 of 34 carriers. Of the 313 non-carrier individuals with normal enzyme activity in the lower normal range, one was positive for the splice junction mutation.(ABSTRACT TRUNCATED AT 250 WORDS)


Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins.
The ability of iron to catalyze formation of reactive oxygen species significantly contributes to its toxicity in cells and animals. Iron uptake and distribution is regulated tightly in mammalian cells, in part by iron regulatory protein 2 (IRP2), a protein that is degraded efficiently by the proteasome in iron-replete cells. Here, we demonstrate that IRP2 is oxidized and ubiquitinated in cells before degradation. Moreover, iron-dependent oxidation converts IRP2 into a substrate for ubiquitination in vitro. A regulatory pathway is described in which excess iron is sensed by its ability to catalyze site-specific oxidations in IRP2, oxidized IRP2 is ubiquitinated, and ubiquitinated IRP2 subsequently is degraded by the proteasome. Selective targeting and removal of oxidatively modified proteins may contribute to the turnover of many proteins that are degraded by the proteasome.


Fast Separation and Sensitive Quantitation of Polymethoxylated Flavonoids in the Peels of Citrus Using UPLC-Q-TOF-MS.
A rapid, sensitive, and efficient ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) method has been developed to analyze polymethoxylated flavonoids (PMFs) in 14 Citrus peels, including 7 Citrus reticulata (C. reticulata) and 7 Citrus sinensis (C. sinensis). In this study, fast separation can be achieved within 12 min and 42 PMFs have been identified including 33 flavones and 9 flavanones. Most C. reticulata were shown to contain more than 20 PMFs, except Guangxihongpisuanju (GX) containing only 12 PMFs, while most C. sinensis contained fewer than 20 PMFs, except Edangan (EG) containing as many as 32 PMFs. To our knowledge, there are few reports about the quantitation of PMFs using the MS response. Here, a MS quantitative method was established and systematically validated in linearity, precision, and recovery. The linearity was from 1.25 ng/mL to 1.0 μg/mL with the limit of detection (LOD) as low as 75 pg/mL and the limit of quantitation (LOQ) as low as 0.25 ng/mL. Up to 13 PMFs, more types than ever before, were undoubtedly identified and quantitated according to the PMF standards. The results showed that the contents of PMFs in the C. reticulata were generally higher than those in the C. sinensis. This study is systematic for analyzing PMFs and is of great significance because it can provide guidance on utilization of both PMFs and citrus germplasm resources in the future.


Growth of mold on fiberglass insulation building materials--a review of the literature.
An exhaustive search of the literature on the growth of mold on fiberglass insulation materials was conducted. Because of the paucity of published material, both peer-reviewed and non-peer-reviewed articles were included. The literature indicates that fiberglass can serve as a support matrix for the collection of debris which, when moist, have the capability of supporting the growth of mold. Further, binding and paper-based moisture barriers from fiberglass resins are also capable of supporting the growth of mold when moist.


Insulin Delivery Method and Admission for Glycemic Control in Pregnant Women with Type 1 Diabetes Mellitus.
To determine if there was a difference in glycemic control admissions or perinatal outcomes in women with type 1 diabetes mellitus (DM) treated with multiple daily injections (MDIs) versus continuous subcutaneous insulin infusion (CSII). This was a retrospective cohort study of women with type 1 DM with a singleton gestation who delivered between 2006 and 2014 at a tertiary hospital and received care at a dedicated DM clinic. Women who used MDI were compared with those who used CSII. The primary outcome was glycemic control admission during pregnancy. Secondary outcomes included adverse perinatal outcomes. There were a total of 156 women; 107 treated with MDI and 49 with CSII. Women treated with MDI had higher rates of glycemic control admissions versus those treated with CSII (68.2 vs. 30.6%, p < 0.001). Adjusting for age, ethnicity, public insurer, duration of DM, first recorded hemoglobin A1c (HbA1c), and DM comorbidities, the likelihood of admission remained higher in women on MDI versus CSII (AOR 5.9 [1.7-20.6]). Women treated with MDI had higher rates of postprandial hypoglycemia. Other perinatal outcomes were similar between the groups. Women with type 1 DM treated with MDI were more likely to have glycemic control admissions and postprandial hypoglycemia than those treated with CSII.


Immune cells link obesity-associated type 2 diabetes and periodontitis.
The clinical association between obesity-associated type 2 diabetes (T2D) and periodontitis, coupled with the increasing prevalence of these diseases, justifies studies to identify mechanisms responsible for the vicious feed-forward loop between systemic and oral disease. Changes in the immune system are critical for both obesity-associated T2D and periodontitis and therefore may link these diseases. Recent studies at the intersection of immunology and metabolism have greatly advanced our understanding of the role the immune system plays in the transition between obesity and obesity-associated T2D and have shown that immune cells exhibit similar functional changes in obesity/T2D and periodontitis. Furthermore, myeloid and lymphoid cells likely synergize to promote obesity/T2D-associated periodontitis despite complexities introduced by disease interaction. Thus the groundwork is being laid for researchers to exploit existing models to understand immune cell dysfunction and break the devastating relationship between obesity-associated T2D and oral disease.


Directing quadruplex-stabilizing drugs to the telomere: synthesis and properties of acridine-oligonucleotide conjugates.
Conjugates containing quadruplex-stabilizing acridines linked to oligonucleotides that are complementary to the G-rich human telomere sequence were synthesized. Acylation of 3,6-diaminoacridine followed by two Michael reactions provided derivatives suitable for conjugation, which were coupled to resin-linked amine-modified oligonucleotides by activating the carboxyl group with pentafluorophenyl 4-nitrobenzenesulfonate. After deprotection with aqueous ammonia at room temperature, conjugates incorporating different acridines, linkers, and oligonucleotide sequences were obtained. These were tested for their ability to stabilize intramolecular DNA quadruplexes that are based on the human telomeric repeat sequence (GGGTTA)(n).


Gene factories, microfunctionalization and the evolution of gene families.
Gene duplication has long been considered an important force in genome evolution. In this article, I consider families of tandemly duplicated genes that show 'microfunctionalization' - genes encoding similar proteins with subtly different functions, such as olfactory receptors. I discuss the genomic processes giving rise to such microfunctionalized gene families and suggest that, like sites of chromosomal rearrangement and breakage, they are associated with relatively high concentrations of repetitive elements. I suggest that microfunctionalized gene families arise within gene factories: genomic regions rich in repetitive elements that undergo increased levels of unequal crossing-over.


The challenge of "sperm ships": the need for the global regulation of medical technology.
This paper discusses the notion of using international shipping legislation to provide healthcare technologies to inhabitants of a country on a ship in international waters based just outside the country's border. This allows technologies that would otherwise be unavailable, regulated or banned to the citizens of a particular nation to be available, just offshore. This is because in international waters ships are governed by the laws of their home nation not those they are nearby. We focus on the example suggested recently in the UK of "sperm ships", flying Danish flags to circumvent IVF regulation in the UK. While we acknowledge that this general strategy could be used to do good by providing healthcare where it would not be otherwise available, it also provides a significant challenge to the effective sovereignty of the state and its ability to regulate healthcare technologies for the benefit of its citizens. We discuss this challenge to the regulation of healthcare and suggest a few tentative solutions.


Determination of PAHs, PCBs, minerals, trace elements, and fatty acids in Rapana thomasiana as an indication of pollution.
The aim of this investigation was to introduce several analytical methods for determination of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), minerals, trace elements, and fatty acids in Rapana thomasiana as a marine pollution indicator organism. The chemical differences of the gastropod Ra. thomasiana from polluted and nonpolluted sites of the Black Sea on the Bulgarian coast were investigated. Chromatography and high-resolution inductively coupled plasma/MS analyses were used for evaluation of PAHs, PCBs, fatty acids, minerals, and trace elements. These methods can be applied to other marine products.


Characterization of cord blood stem/progenitor cells.
Based on in vitro studies, umbilical-cord blood has been used clinically to engraft the hematopoietic systems of children. To evaluate the capacity of a single collection of cord blood to engraft an adult, it is important to consider not only the number, but also the quality of stem/progenitor cells in cord blood. We demonstrate that cord blood contains multipotential progenitor cells, possibly subsets of stem cells, that have extensive self-renewal capacity, as estimated by their capacity to form numerous secondary colonies of multiple lineages in secondary replates from single multipotential colonies. This replating capacity is enhanced by a factor or factors, perhaps novel, in cord blood plasma.


Measuring Perceptions of the Therapeutic Alliance in Individual, Family, and Group Therapy from a Systemic Perspective: Structural Validity of the SOFTA-s.
This study examined the multidimensional structure of the client and therapist versions of the self-report measure, System for Observing Family Therapy Alliances (SOFTA-s; Friedlander, Escudero, & Heatherington, Therapeutic alliances in couple and family therapy: An empirically informed guide to practice. Washington, DC: American Psychological Association, 2006) across three distinct therapeutic modalities (individual, family, group). Specifically, we investigated whether the originally theorized model of four first-order factors (Engagement in the Therapeutic Process, Emotional Connection with the Therapist, Safety within the Therapeutic System, and Shared Sense of Purpose within the Family) would be reflected in a second-order factor (Therapeutic Alliance). The sample included 105 therapists who worked with 858 clients (165 individuals, 233 families, and 43 groups) in several Spanish community agencies. To control for dependent data, we used multilevel modeling. Results of the multilevel confirmatory factor analyses showed adequate reliabilities, fit indices, and factor loadings across the three therapy contexts for both versions of the measure (client and therapist). Adequate measurement invariance was also found across respondents and therapy modalities. Taken together, these results support the structural validity of the SOFTA-s, a brief and flexible self-report alliance measure that can be used reliably in clinical practice as well as in studies of individual, family, and group therapy.


Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model.
Cancer cachexia (CC) is a multifactorial disease characterized by decreased food intake and loss of body weight due to reduced musculature with or without loss of fat mass. Patients with gastric cancer have a high incidence of cachexia. We previously established a novel CC rat model induced by human gastric cancer-derived 85As2 cells in order to examine the pathophysiology of CC and identify potential therapeutics. In patients with CC, anorexia is often observed, despite elevation of ghrelin, suggesting that ghrelin resistance may develop in these patients. In this study, we aimed to clarify the occurrence of ghrelin resistance in CC rats accompanied by anorexia and we investigated whether rikkunshito (RKT), a traditional Japanese Kampo medicine that potentiates ghrelin signaling, ameliorated CC-related anorexia through alleviation of ghrelin resistance. 85As2-tumor-bearing rats developed severe CC symptoms, including anorexia and loss of body weight/musculature, with the latter symptoms being greater in cachectic rats than in non-tumor-bearing or pair-fed rats. CC rats showed poor responses to intraperitoneal injection of ghrelin. In CC rats, plasma ghrelin levels were elevated and hypothalamic anorexigenic peptide mRNA levels were decreased, whereas hypothalamic growth hormone secretagogue receptor (GHS-R) mRNA was not affected. In vitro, RKT directly enhanced ghrelin-induced GHS-R activation. RKT administrated orally for 7 days partly alleviated the poor response to ghrelin and ameliorated anorexia without affecting the elevation of plasma ghrelin levels in CC rats. The expression of hypothalamic orexigenic neuropeptide Y mRNA but not hypothalamic GHS-R mRNA was increased by RKT. Thus, the 85As2 cell-induced CC rat model developed ghrelin resistance, possibly contributing to anorexia and body weight loss. The mechanism through which RKT ameliorated anorexia in the CC rat model may involve alleviation of ghrelin resistance by enhancement of ghrelin signaling. These findings suggest that RKT may be a promising agent for the treatment of CC.


Homogeneous epitaxial growth of N,N'-di(n-butyl)quinacridone thin films on Ag(110).
The structural evolution of the ordered N-N' dibutyl-substituted quinacridone (QA4C) multilayers (3 MLs) has been monitored in situ and in real time at various substrate temperatures using low energy electron diffraction (LEED) during organic molecular beam epitaxy (MBE). Experimental results of LEED patterns clearly reveal that the structure of the multilayer strongly depends on the substrate temperature. Multilayer growth can be achieved at the substrate temperatures below 300 K, while at the higher temperatures we can only get one ordered monolayer of QA4C. Two kinds of structures, the commensurate and incommensurate one, often coexist in the QA4C multilayer. With a method of the two-step substrate temperatures, the incommensurate one can be suppressed, and the commensurate, on the other hand, more similar to the (001) plane of the QA4C bulk crystal, prevails with the layer of QA4C increasing to 3 MLs. The two structures in the multilayers are compressed slightly in comparison to the original ones in the first monolayer.


The effects of chronic alcoholism on development of ischemic cerebral infarcts following unilateral carotid artery ligation in gerbils.
To test if chronic alcoholism potentiates mortality and accentuates cerebral infarcts associated with ischemia, 32 male and 33 female Mongolian gerbils were chronically fed ethanol in their diet for 6 weeks. Cerebral ischemia was then induced by ligation and sectioning of the right common carotid artery. Postoperatively, there was a mean difference in survival in the control versus the alcoholic gerbils. Whereas 76% of controls survived the operation, only 55% of alcoholic gerbils survived. Also, the alcoholic gerbils died earlier, usually in the initial 3 postoperation days. The incidence of cerebral infarcts was identical (52%) in both control and alcohol-treated gerbils. There was, however, a difference in the extent (size) of the infarcts and tolerance to them. The alcoholic gerbils tended to develop either large infarcts which were usually lethal, or smaller infarcts but with decreased tolerance. The cerebral infarcts in the controls tended to be smaller with better survival. These findings suggest that chronic alcohol consumption contributes significantly to the risk of mortality associated with ischemic brain infarction reported in human alcoholics, and indicate that the alcoholic gerbil is a good experimental model to study the pathophysiology of this phenomenon.


Interferon stabilization and enhancement by rare earth salts.
The addition of salts of the rare earth elements (lanthanides) enhances by a factor of two or more the initial activity of human fibroblast, leukocyte and immune interferons as well as mouse L-cell interferon. Furthermore, the salts of the lanthanides (0.01 to 0.002 M) preserve the activity of human fibroblast interferon not only after 4 days of heating at 37 degrees C but also after exposure to severe shearing forces; human leukocyte interferon was stabilized to a lesser degree, albeit significantly.


Combination of hDAF-transgenic pig hearts and immunoadsorption in heterotopic xenotransplantation of immunosuppressed baboons.
Hyperacute xenograft rejection (HXR) and acute vascular rejection (AVR) after xenotransplantation are triggered by xenoreactive antibodies (XAb) and an activated complement cascade. In a heterotopic (abdominal) xenotransplantation model we combined immunoadsorption (IA, Ig-Therasorb column) and a quadruple immunosuppressive drug therapy in recipient baboons with donor pig hearts transgenic for human decay accelerating factor (hDAF). According to XAb titers between 6 and 14 cycles of IA were performed preoperatively in 4 recipient baboons (18.6 +/- 2.5 kg). Hearts of hDAF-transgenic donor pigs (6.1 +/- 1.1 kg, Imutran Ltd., a Novartis Pharma AG Company, Basel, Switzerland) were heterotopically transplanted using the abdominal technique in baboons. Immunosuppression consisted of cyclophosphamide (CyP) induction therapy, ERL080 (Novartis Pharma AG), cyclosporin A (CyA, Neoral), and steroids. Blood levels of mycophenolate, CyA, immunoglobulins (Ig), anti-pig-antibodies, complement factors, and cardiac enzymes were determined. Abdominal electrocardiography (ECG), echocardiography, and palpation were used for monitoring of the pig hearts. Myocardial tissue specimens were examined using immunohistochemistry, light microscope (LM), and electron microscope (EM). Ten cycles of IA alone removed 78% of XAb and accordingly IgM, IgG, IgA, complement C3, and C4. None of the xenografts was hyperacutely rejected, but xenograft failure occurred after 5.0 +/- 1.3 days (range, 2.4-8.0 days) because of an AVR associated with a rapid XAb increase within 24 hours. White blood cell count (10.3 +/- 2.2 G/L) showed a maximum of 13.1 +/- 2.1 (day 1) and constant levels (1.4 +/- 0.3-2.1 +/- 1.3 G/L) between day 3 and 6. Histology (LM/EM) showed massive hemorrhage, necrosis, and vascular thrombi as signs of AVR. Although HXR was prevented by using IA and hDAF-transgenic donor hearts, AVR was not avoided due to insufficient immunosuppressive regimen used and a missed postoperative IA treatment as a result of an inefficient control of XAb production.


Treatment of cerebral arterio-venous malformations with laser.
The surgical application of the laser in the treatment of vascular diseases of the brain is based on its characteristic to perform an immediate or delayed modification of the vessel wall either by shrinking the collagenous fibres or by intraluminal thrombosis. Personal researches have been carried out to study the histological modifications of the vessel wall in normal arteries following laser irradiation with Nd:YAG. On this basis we have treated arterio-venous malformations (AVMs) in man. The laser enables radical surgery with a complete preservation of the healthy tissue surrounding the lesion because of reduced manipulation and the absence of intraoperative haemorrhage. Doppler technique and real-time ultrasonography are mostly suitable in the identification of the small deep-seated AVMs localizing the site of the malformation and the reactive glial tissue surrounding the lesion. The main indications are small AVMs located in critical areas of the brain.


The existence of two mitochondrial isoforms of 2,4-dienoyl-CoA reductase in the rat.
Isoforms of 2,4-dienoyl-CoA reductase (EC 220.127.116.11), which is the key enzyme in the beta-oxidation of fatty acids with double bonds, have been studied in rat heart and liver. Electrofocusing and adsorption chromatography on hydroxyapatite were used to separate the reductase activity in tissue homogenates into two peaks, one peak in each experiment being identified as the previously purified mitochondrial reductase. The novel activity was partially purified from rat liver by means of ammonium sulphate precipitation, anion-exchange chromatography on DEAE-cellulose (DE-52), hydrophobic chromatography on Phenyl-Sepharose and dye-ligand binding chromatography (Blue Sepharose). Taking into account the contribution of the different reductases to the total activity in rat liver, the overall purification for the novel isoform was 1900-fold. Ultracentrifugation on a sucrose gradient gave an M(r) of 50,000 and size-exclusion chromatography on Superdex 200 an M(r) of 60,000. The antibody against the previously characterised reductase did not cross-react with this novel isoform, but the distribution of the activity peaks in heart and liver tissue, and an electrofocusing experiment with isolated mitochondria, both pointed to a mitochondrial origin. The novel reductase was estimated to account for 80% (50%) of the total reductase activity in rat heart (liver) homogenate measured with 2,4-hexadienoyl-CoA. The present results, together with those previously published, suggest that mammals have at least three reductase isoforms: two in mitochondria and a third one in peroxisomes, but the peroxisomal activity has not been characterised so far.


Physicians in health care management: 10. Managing conflict through negotiation.
The recent focus on collaborative relationships in health care means that people and groups must cooperate to accomplish clinical and management tasks. This increasing interdependence may also cause increased organizational conflict. The management of conflicts is critical to the effectiveness of an organization. Negotiating strategies, based on Fisher and Ury's method of "principled negotiation," include establishing superordinate goals, separating the people from the problem, focussing on interests, inventing options, using objective criteria and defining success in terms of gains.


Increased Na+/Ca2+ exchanger activity promotes resistance to excitotoxicity in cortical neurons of the ground squirrel (a Hibernator).
Ground squirrel, a hibernating mammalian species, is more resistant to ischemic brain stress than rat. Gaining insight into the adaptive mechanisms of ground squirrels may help us design treatment strategies to reduce brain damage in patients suffering ischemic stroke. To understand the anti-stress mechanisms in ground squirrel neurons, we studied glutamate toxicity in primary cultured neurons of the Daurian ground squirrel (Spermophilus dauricus). At the neuronal level, for the first time, we found that ground squirrel was more resistant to glutamate excitotoxicity than rat. Mechanistically, ground squirrel neurons displayed a similar calcium influx to the rat neurons in response to glutamate or N-methyl-D-aspartate (NMDA) perfusion. However, the rate of calcium removal in ground squirrel neurons was markedly faster than in rat neurons. This allows ground squirrel neurons to maintain lower level of intracellular calcium concentration ([Ca2+]i) upon glutamate insult. Moreover, we found that Na+/Ca2+ exchanger (NCX) activity was higher in ground squirrel neurons than in rat neurons. We also proved that overexpression of ground squirrel NCX2, rather than NCX1 or NCX3, in rat neurons promoted neuron survival against glutamate toxicity. Taken together, our results indicate that ground squirrel neurons are better at maintaining calcium homeostasis than rat neurons and this is likely achieved through the activity of ground squirrel NCX2. Our findings not only reveal an adaptive mechanism of mammalian hibernators at the cellular level, but also suggest that NCX2 of ground squirrel may have therapeutic value for suppressing brain ischemic damage.


Correlation of relative permeability and relative cerebral blood volume in high-grade cerebral neoplasms.
The purpose of this study was to correlate the degree of contrast enhancement on dynamic contrast-enhanced T1-weighted MRI and the relative cerebral blood volume (rCBV) values on T2*-weighted MRI in patients with high-grade brain neoplasms. Ten patients with biopsy-proven high-grade gliomas underwent dynamic contrast-enhanced MRI using T1-weighted fast spoiled gradient-echo technique (TR/TE, 8.3/1.5) during i.v. infusion of 0.1 mmol/kg of MR contrast medium. This sequence was followed within 5 minutes by dynamic susceptibility contrast (DSC) imaging (1,500/80) during i.v. infusion of 0.2 mmol/kg of MR contrast medium. Dynamic contrast-enhanced analysis was performed using the maximum-signal-intensity algorithm, and DSC analysis was performed using the negative enhancement integral program. For each tumor, we performed two comparisons: first, the average dynamic contrast-enhanced and rCBV values within a region of interest drawn around the entire contrast-enhancing tumor on a single image through the center of the lesion and, second, the highest dynamic contrast-enhanced and highest rCBV values within each tumor. Statistical analyses of the first comparison were performed using Pearson's correlation coefficient, R2 correlation coefficient, and Spearman's rank correlation and for the second comparison using Kendall's tau correlation. The mean signal intensity values ranged between 3.48 and 7.16 SDs above baseline values (mean, 4.89 SDs). The mean rCBV values ranged between 57.9% and 122.7% of the normal lentiform nucleus (mean, 76.6%). The Pearson's correlation coefficient was 0.867, the R2 correlation coefficient was 0.752, and the Spearman's rank correlation was 0.794 (p = 0.001). Dynamic contrast-enhanced values from the region of highest signal intensity ranged between 7.7 and 48.6 SDs above baseline values (mean, 17.3 SDs). The highest rCBV values ranged between 105% and 400% of the normal lentiform nucleus (mean, 292%). The correlation was estimated to be 0.7778 and was statistically significant at the 0.01 level of statistical significance (p = 0.0035). We found a high correlation between degree of contrast enhancement on dynamic contrast-enhanced images and rCBV values in whole tumors and in regions having the highest degree of contrast enhancement in this small study. Our findings, which suggest that relative permeability and rCBV values may be correlated in high-grade glial neoplasms, deserve further study in a larger patient population.


Resource use and costs of exenatide bid or insulin in clinical practice: the European CHOICE study.
CHOICE (CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy) assessed patterns of exenatide bid and initial insulin therapy usage in clinical practice in six European countries and evaluated outcomes during the study. CHOICE was a 24-month, prospective, noninterventional observational study. Clinical and resource use data were collected at initiation of first injectable therapy (exenatide bid or insulin) and at regular intervals for 24 months. Costs were evaluated from the national health care system perspective at 2009 prices. A total of 2515 patients were recruited. At the 24-month analysis, significant treatment change had occurred during the study in 42.2% of 1114 eligible patients in the exenatide bid cohort and 36.0% of 1274 eligible patients in the insulin cohort. Improvements in glycemic control were observed over the course of the study in both cohorts (P < 0.001 for both), but mean weight was reduced in the exenatide bid cohort (P < 0.001) and increased in the insulin cohort (P < 0.001) by 24 months. Across all countries, total per patient health care costs for the 24 months post baseline were €3997.9 in the exenatide bid cohort and €3265.5 in the insulin cohort (€1791.9 versus €2465.5 due to costs other than those of injectable therapy). When baseline direct cost and patients' and disease characteristics were controlled for, mean direct costs differed by country (P < 0.0001), irrespective of treatment initiated, and the mean cost difference between treatments varied by country (P < 0.0001). Much of the higher mean cost of exenatide bid, compared with insulin, therapy was compensated for by lower mean costs of other health service utilization. Costs associated with exenatide bid or insulin initiation varied across countries, highlighting the need to avoid generalization of resource use and cost implications of a particular therapy when estimated in specific country settings.


Multi-omics insights into potential mechanism of SGLT2 inhibitors cardiovascular benefit in diabetic cardiomyopathy.
Metabolic and energy disorders are considered central to the etiology of diabetic cardiomyopathy (DCM). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) can effectively reduce the risk of cardiovascular death and heart failure in patients with DCM. However, the underlying mechanism has not been elucidated. We established a DCM rat model followed by treatment with empagliflozin (EMPA) for 12 weeks. Echocardiography, blood tests, histopathology, and transmission electron microscopy (TEM) were used to evaluate the phenotypic characteristics of the rats. The proteomics and metabolomics of the myocardium in the rat model were performed to identify the potential targets and signaling pathways associated with the cardiovascular benefit of SGLT2i. The diabetic rat showed pronounced DCM characterized by mitochondrial pleomorphic, impaired lipid metabolism, myocardial fibrosis, and associated diastolic and systolic functional impairments in the heart. To some extent, these changes were ameliorated after treatment with EMPA. A total of 43 proteins and 34 metabolites were identified as targets in the myocardium of diabetic rats treated with EMPA. The KEGG analysis showed that arachidonic acid is associated with the maximum number of related pathways and may be a potential target of EMPA treatment. Fatty acid (FA) metabolism was enhanced in diabetic hearts, and the perturbation of biosynthesis of unsaturated FAs and arachidonic acid metabolism was a potential enabler for the cardiovascular benefit of EMPA. SGLT2i ameliorated lipid accumulation and mitochondrial damage in the myocardium of diabetic rats. The metabolomic and proteomic data revealed the potential targets and signaling pathways associated with the cardiovascular benefit of SGLT2i, which provides a valuable resource for the mechanism of SGLT2i.


[Combined effect of gamma-irradiation and sodium nitrite on the oxidative sensitivity of rat hemoglobin].
gamma-Irradiation has been defined to increase in the rats blood the methemoglobin level providing for shortening the initiation phase and accelerates the autocatalytic phase initiation, reduces the period of half transforming hemoglobin into methemoglobin and increases the velocity of its oxidation. Alongside with the latter there is observed a violation of methemoglobin concentration growth dependence on the animals irradiation dose (in the range of 0.16-0.50 Gr). The hemoglobin oxygenation reaction kinetics with the initial level of hemoglobin unexceeding 3% has been determined as having a biexponential character. The reaction kinetics parameters don't depend on ionizing radiation and number of sodium nitrite oxidized subunits formed in the process of reaction in the case if their composition unexceeds 50% of the total level.


Characterizing demographics, injury severity, and intubation status for patients transported by air or ground ambulance to a rural burn center.
Our study was designed to characterize intubation status among patients transported by air or ground ambulance to a rural burn center. A retrospective chart review of patients arriving at our burn center from January 1, 2005 to December 31, 2009 was completed. Descriptive and multivariate analyses were performed. During the study period, 259 air and 590 ground ambulance patients met inclusion criteria. Air ambulance patients were older and had higher total body surface area burned, lower Glasgow Coma scores, longer lengths of stay, and more frequent inhalation injuries. Approximately 10% of patients arriving by air were intubated after burn center admission, and 49% of intubated patients were extubated within 24 hours of admission. These values were 2% and 40%, respectively, for patients transported by ground. Increasing age and air ambulance transport increased the overall likelihood of change in intubation status. The likelihood of intubation by burn center providers increased with age, with suspicion of inhalation injury, and for patients transported by air. The likelihood of extubation within 24 hours of burn center admission increased with age, decreased with suspected inhalation injury, and was independent of transport mode. Among our patient population, more severely injured patients were being transported by air ambulance. However, age, suspicion of inhalation injury, and mode of transport showed a complex pattern of associations with changes in intubation status, and illustrate the need to develop better prehospital guidelines for intubation in burn patients.


[Antidepressive action, pharmacokinetic characteristics and biochemical properties of cimoxatone, a new reversible MAO-A inhibitor].
Cimoxatone is a new monoamine oxidase inhibitor (MAOI) in comparison to the existing non-selective and irreversible MAOIs used in the therapy of depression. A clinical study has been carried out in 10 depressed patients. Cimoxatone was given from 0.32 to 0.78 mg/kg/day for 28 days. The drug was shown to be effective against depression and well tolerated at the given doses. The inhibition of monoamine oxidase and its reversibility were assessed by urinary excretion of 3-methoxy-4-hydroxy- phenylethyleneglycol sulphate. The treatment had no effect on the plasma prolactin levels. The plasma concentrations of cimoxatone reached a plateau after 3 to 4 days of therapy. The study confirmed earlier findings in healthy volunteers that the principal metabolite is also active as a type A MAOI. The plasma elimination of cimoxatone and its metabolite is almost complete 4 days after the last dosing.


The birth of viromics: an interview with Forest Rohwer.
The editor of Future Microbiology, Alice Greenway, speaks to Forest Rohwer from San Diego State University (CA, USA) following his talk entitled 'Counting all the world's phage' at ASM Microbe 7-11 June 2018.


Selective block of albumin gene expression in chick embryo hepatocytes cultured without hormones and its partial reversal by insulin.
Rates of synthesis of albumin and transferrin were compared with the levels of their cognate mRNAs in primary monolayer cultures of chick embryo hepatocytes over a period of 72 h. These liver cells were exposed, from the onset of culture, only to a chemically defined medium devoid of hormonal or macromolecular supplement. Synthesis of transferrin was constant whereas synthesis of albumin diminished to near 0 in 3 days. RNA prepared from hepatocyte monolayers, maintained for various lengths of time in culture, was translated in wheat germ extracts and Xenopus oocytes. Translation products were immunoprecipitated and analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. In addition, total RNA from the cultured cells was hybridized to labeled cDNA probes to determine the number of sequences specific for each protein. Albumin mRNA was found to decrease with time in culture in all three assay systems, while transferrin mRNA remained constant. Analysis of the kinetics suggests a selective decay, with a half-life of 7 h, of the amount of albumin-specific RNA present at the beginning of culture. Apparently, in the hormone-deprived hepatocytes, there is little or no further transcription of the albumin gene. After addition of insulin to the cultures, albumin mRNA levels increased, suggesting an effect of this hormone on albumin gene utilization.


Plasma disposition and faecal excretion of netobimin metabolites and enantiospecific disposition of albendazole sulphoxide produced in ewes.
Netobimin (NTB) was administered orally to ewes at 20 mg/kg bodyweight. Blood and faecal samples were collected from 1 to 120 h post-treatment and analysed by high-performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of albendazole sulphoxide (ABZSO) enantiomers produced was also determined. Neither NTB nor albendazole (ABZ) was present and only ABZSO and albendazole sulphone (ABZSO(2)) metabolites were detected in the plasma samples. Maximum plasma concentrations (C(max)) of ABZSO (4.1 +/- 0.7 microg/ml) and ABZSO(2) (1.1 +/- 0.4 microg/ml) were detected at (t(max)) 14.7 and 23.8 h, respectively following oral administration of netobimin. The area under the curve (AUC) of ABZSO (103.8 +/- 22.8 (microg h)/ml) was significantly higher than that ABZSO(2)(26.3 +/- 10.1 (microg h)/ml) (p < 0.01). (-)-ABZSO and (+)-ABZSO enantiomers were never in racemate proportions in plasma. The AUC of (+)-ABZSO (87.8 +/- 20.3 (microg h)/ml) was almost 6 times larger than that of (-)-ABZSO (15.5 +/- 5.1 (microg h)/ml) (p < 0.001). Netobimin was not detected, and ABZ was predominant and its AUC was significantly higher than that of ABZSO and ABZSO(2), following NTB administration in faecal samples (p > 0.01). Unlike in the plasma samples, the proportions of the enantiomers of ABZSO were close to racemic and the ratio of the faecal AUC of (-)-ABZSO (172.22 +/- 57.6 (microg h)/g) and (+)-ABZSO (187.19 +/- 63.4 (microg h)/g) was 0.92. It is concluded that NTB is completely converted to ABZ by the gastrointestinal flora and absorbed ABZ is completely metabolized to its sulphoxide and sulphone metabolites by first-pass effects. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver that are responsible for sulphoxidation and sulphonation of ABZ.


Functional antagonism of β-arrestin isoforms balance IGF-1R expression and signalling with distinct cancer-related biological outcomes.
With very similar 3D structures, the widely expressed β-arrestin isoforms 1 and 2 play at times identical, distinct or even opposing roles in regulating various aspects of G protein-coupled receptors (GPCR) expression and signalling. Recent evidence recognizes the β-arrestin system as a key regulator of not only GPCRs, but also receptor tyrosine kinases, including the highly cancer relevant insulin-like growth factor type 1 receptor (IGF-1R). Binding of β-arrestin1 to IGF-1R leads to ligand-dependent degradation of the receptor and generates additional MAPK/ERK signalling, protecting cancer cells against anti-IGF-1R therapy. Because the interplay between β-arrestin isoforms governs the biological effects for most GPCRs, as yet unexplored for the IGF-1R, we sought to investigate specifically the regulatory roles of the β-arrestin2 isoform on expression and function of the IGF-1R. Results from controlled expression of either β-arrestin isoform demonstrate that β-arrestin2 acts in an opposite manner to β-arrestin1 by promoting degradation of an unstimulated IGF-1R, but protecting the receptor against agonist-induced degradation. Although both isoforms co-immunoprecipitate with IGF-1R, the ligand-occupied receptor has greater affinity for β-arrestin1; this association lasts longer, sustains MAPK/ERK signalling and mitigates p53 activation. Conversely, β-arrestin2 has greater affinity for the ligand-unoccupied receptor; this interaction is transient, triggers receptor ubiquitination and degradation without signalling activation, and leads to a lack of responsiveness to IGF-1, cell cycle arrest and decreased viability of cancer cells. This study reveals contrasting abilities of IGF-1R to interact with each β-arrestin isoform, depending on the presence of the ligand and demonstrates the antagonism between the two β-arrestin isoforms in controlling IGF-1R expression and function, which could be developed into a practical anti-IGF-1R strategy for cancer therapy.


Practical management of toxicities associated with bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia.
Bosutinib (SKI-606) is an oral, dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) that is resistant or intolerant to prior TKI therapy or for whom other TKIs are not appropriate choices. The objective of this review is to provide a longitudinal summary of toxicities that may arise during treatment with second-line or later bosutinib in patients with Ph+ chronic phase CML and to provide strategies for managing these toxicities. As bosutinib is not currently indicated for newly diagnosed CML, toxicities associated with first-line treatment are not reviewed. Recognition and optimal management of these toxicities can facilitate patient compliance and affect treatment outcomes.


Selection of obstetrics and gynecology residents on the basis of medical school performance.
The purpose of this study was to determine whether United States Medical Licensing Examination scores during medical school predict resident-in-training examination scores and whether other criteria of medical student performance correlate with the faculty's subjective evaluation of resident performance. United States Medical Licensing Examination step I and II scores for 24 residents were compared to their scores on in-training examinations. Faculty evaluated 20 graduated residents by rating both their cognitive and noncognitive clinical performance. Scores from these evaluations were compared with several criteria of their medical school performance. Statistical analysis for all comparisons was linear regression. United States Medical Licensing Examination scores positively correlated with in-training examination scores. United States Medical Licensing Examination scores, honor grades in student clinical rotations, and student interview scores did not correlate with the faculty evaluation of resident performance. Standardized tests of medical student cognitive function predict the resident's performance on standardized tests. Selection criteria that are based on other medical school achievements do not necessarily correlate with overall performance as residents in obstetrics and gynecology.


A new rat model for orthotopic abdominal wall allotransplantation.
Abdominal wall, one of the most commonly transplanted composite tissues, is less researched and lacking animal models. Its clinical necessities were emphasized in multiple case series to reconstruct large abdominal defects. Previous animal models have only studied components of the abdominal wall transplant. We describe findings from a new model that more likely reflect clinical transplantation. Full-thickness hemiabdominal wall flap was procured from Brown Norway (BN) rats and transplanted to an orthotopic defect on Lewis rats. Three groups were studied: group 1: Lewis to Lewis syngeneic; group 2: BN to Lewis control; and group 3: BN to Lewis with postoperative cyclosporine. Vascular imaging and cross vessel section were performed along with full-thickness abdominal wall. Immune cell profiling with flow cytometry at different time points was studied in all groups. Syngeneic group had no rejection. Control group consistently showed rejection around postoperative day 6. With cyclosporine treatment, however, transplant and recipient tissue integration was observed. Flow cytometry revealed that innate immunity is responsible for the initial inflammatory events following abdominal wall engraftment. Adaptive immunity cells, specifically interferon-γ-producing T helper (Th) 1 and interleukin-17-producing Th17 cells, dramatically and positively correlate with rejection progression of abdominal wall transplants. Technical, histological, and immunological aspects of a new rat model are described. These results give clues to what occurs in human abdominal wall transplantation. In addition, Th1, a proinflammatory cell, was found to be a potential biomarker for allograft rejection.


[Polish health care system].
The purpose of the discussion is to evaluate certain aspects of the Polish health care system - its ability to respond to contemporary dynamic social, economic and epidemiological changes (including the spread of chronic diseases, aging population or family crisis - its possibilities for providing care of the sick). The analysis of such a problem was based on a critically-oriented perspective that is developed in the field of the sociology of health and illness. The text pays particular attention to the problem of deepening social inequalities, which can be considered as one of the major factors that hinder access to health care and influence poorer health condition: In this context the mechanism of "saving health" and borrowing in order to satisfy the health needs in the face of financial difficulties was mentioned. Moreover, the text includes the attempt to evaluate the effectiveness of health promo- tion programs in our country as potentially the most effective way of raising the level of public health. There is also the issue of public confidence in health care institutions and the approval of attempts towards reforming the medical system in our country. A separate part of the discussion was devoted to criticism of the idea of reducing the role of the state in the health care sector.


Raman characterization of monolayers formed from mixtures of sodium 2-mercaptoethanesulfonate and various aromatic mercapto-derivative bases.
Metal electrodes covered with organic (mono)layers containing pi-delocalized structures have many potential applications, for example, in construction of bioelectronic elements with high efficiency of electron transfer. In this contribution, a silver surface was modified with mixed monolayers formed from sodium 2-mercaptoethanesulfonate (MES) and four model (stable and easily available) aromatic thiols with strong basic properties: 4,6-diamino-2-mercaptopyrimidine (APY), 1H-1,2,4-triazole-3-thiol (HTR), 4-methyl-1,2,4-triazole-3-thiol (MTR), and 3-amino-1,2,4-triazole-5-thiol (ATR). The structure of the formed monolayers was determined from surface-enhanced Raman scattering (SERS) measurements. These studies showed that, despite significant differences in the molecular structures, MES is a very promising candidate for making mixed monolayers with mercapto-derivative aromatic bases that are relatively homogeneous (without large one-component domains) in broad pH range. At high pH, in a one-component ATR monolayer, a significant amount of molecules are in the anionic form and adopt a flat orientation versus the metal surface. At the same pH, in mixed ATR+MES monolayers, a significantly larger part of ATR molecules than for the respective one-component monolayer is adsorbed in the neutral form with the aromatic ring(s) oriented perpendicularly to the metal surface. Also in the mixed APY+MES and HTR+MES monolayers, a significantly smaller part of HTR or APY molecules than for the respective one-component HTR and APY monolayers is deprotonated. The structure of the MTR monolayer practically does not depend on the pH of the surrounding solution. Increase of the ratio of acidic dissociation and reorientation of ATR molecules from the perpendicular to the parallel orientation is also observed during storage of the respective one-component and mixed monolayers in water, phosphorus buffers, and in the solutions of model peptides (bovine serum albumin or laccase). In some cases, the reorientation of ATR molecules forming the linkage monolayer when immersed in the peptide solution is very large. Significant spectral changes during soaking in water and solutions of model peptides has also been observed for APY monolayers. All studied mixed monolayers practically prevent the direct adsorption of peptides on the metal surface for at least 30 min.


Galectin-1 is a poor prognostic factor in patients with glioblastoma multiforme after radiotherapy.
Galectin-1, a radioresistance marker, was found in our previous study to be a prognostic factor for cervical cancer. The aim of current study is to determine the prognostic significance of the galectin-1 expression level in patients with glioblastoma multiforme (GBM) undergoing adjuvant radiotherapy (RT). We included 45 patients with GBM who were treated with maximal safe surgical resection or biopsy alone followed by adjuvant RT of EQD2 (equivalent dose in 2-Gy fractions) > or = 60 Gy for homogeneous treatment. Paraffin-embedded tissues acquired from the Department of Pathology were analyzed using immunohistochemical staining for galectin-1 expression. The primary endpoint was overall survival (OS). Patients with weak expression had a better median survival (27.9 months) than did those with strong expression (10.7 months; p = 0.009). We compared characteristics between weak and strong galectin-1 expression, and only the expression level of galectin-3 showed a correlation. The group with weak galectin-1 expression displayed a 3-year OS of 27.3% and a 3-year cancer-specific survival (CSS) of 27.3%; these values were only 5.9% and 7.6%, respectively, in the group with strong galectin-1 expression (p = 0.009 and 0.020, respectively). Cox regression was used to confirm that the expression level of galectin-1 (weak vs. strong) is a significant factor of OS (p = 0.020) and CSS (p = 0.022). Other parameters, such as the expression level of galectin-3, Eastern Cooperative Oncology Group (ECOG) performance, gender, surgical method, age ≥ 50 years, tumor size, or radiation field were not significant factors. The expression level of galectin-1 affects survival in patients with GBM treated with adjuvant RT. Future studies are required to analyze the effect of other factors, such as O(6)-methylguanine-DNA methyltransferase (MGMT)-promoter methylation status, in patients with weak and strong galectin-1 expression.


Amyl nitrite alters human in vitro immune function.
Effects on the human immune system of volatile nitrite inhalation were studied in 18 male volunteers. While nitrite inhalation decreased the absolute number of CD3+ T lymphocytes during the period of inhalation, cell numbers returned to pre-treatment levels within one week after cessation of the drug. Nitrite inhalation did not alter the percentage of CD3+, CD4+, CD8+ or CD19+ lymphocytes. Natural killer (NK) cell activity against K562 target cells was depressed by nitrite administration but returned to pre-inhalation or greater levels after nitrite discontinuation. Cell proliferation following cell activation by PHA, ConA and PWM was unaffected by amyl nitrite inhalation. We conclude that in humans inhalation of volatile nitrites causes cycles of modest immunosuppression, particularly in NK activity, followed by gradual recovery when the drug is not inhaled for several days.


BRAF mutation in endometrial carcinoma and hyperplasia: correlation with KRAS and p53 mutations and mismatch repair protein expression.
Although several gene abnormalities have been reported in endometrial carcinoma, the genetic alterations have not fully been elucidated. Recent studies have revealed frequent activating mutations of the gene for BRAF, an effector of Ras protein in the mitogen-activated protein kinase pathway, in several malignancies. However, the prevalence and significance of BRAF mutations in endometrial carcinoma remain unclear. We examined BRAF mutations in exons 11 and 15 in 97 cases of endometrial carcinoma (endometrioid type, 78; nonendometrioid type, 19), 9 cases of atypical endometrial hyperplasia, and 20 cases of normal endometrium by direct sequencing. In addition, mutations of KRAS and p53 and the immunohistochemical expression of hMLH1 and hMSH2 were also examined. Of the 97 carcinomas and 9 hyperplasias, 20 (21%) and 1 (11%) had BRAF mutations, most of them at previously unreported sites. Twenty samples of normal endometrium and 21 samples of normal endometrium obtained from sites adjacent to neoplastic lesions had no BRAF mutations. There was no apparent difference in the prevalence of BRAF mutation among stages, histologic subtypes, or grades. Mutations of KRAS and p53 were found in 18 (19%) and 22 (23%) cases, and 65 (67%) and 92 (95%) cases showed positive immunostaining for hMLH1 and hMSH2, respectively. BRAF mutation was more frequently found in hMLH1-negative cases (12 of 32, 41%) than in hMLH1-positive cases (7 of 65, 11%; P = 0.008), suggesting that it is associated with an abnormal mismatch repair function. These findings suggest that mutations of the BRAF gene are partly involved in the malignant transformation of the endometrium.


Changes in lipidomic profile of aqueous humour in Fuchs endothelial dystrophy.
To identify and determine differences in lipid profile of aqueous humour (AH) in patients with Fuchs endothelial corneal dystrophy (FECD). Lipidomic profile of eight AH samples of FECD patients and 10 control samples was analysed. Patients with previous history of anterior segment surgery, anterior segment pathology or intraocular injections were excluded. Topical ocular medications within the last 6 months were reported. Aqueous humour (AH) was obtained during the first step of Descemet membrane endothelial keratoplasty in FECD patients and during refractive lensectomy in the control group. Lipidomic ultra-performance liquid chromatography mass spectrometry was used to perform an optimal profiling of glycerolipids, sterol lipids, sphingolipids and glycerophospholipids. Metabolite extraction was accomplished by fractionating the samples into pools of species with similar physicochemical properties. The levels of 27 of 110 lipids change significantly in the AH of FECD eyes when compared to control samples. The concentration of most diacylglycerophosphocholines and 1-ether, 2-acylglycerophosphocholines increases in the AH of FECD eyes when compared to healthy controls. In addition, eight sphingomyelins and up to two long-chain highly unsaturated cholesteryl esters present higher levels in FECD samples when compared to controls. The lipid composition of AH in FECD patients differs from that of healthy subjects. Those changes may reflect oxidative stress-related changes in the lipid metabolism of the corneal endothelial cells in FECD.


Teaching cell biology to nonscience majors through forensics, or how to design a killer course.
Nonscience majors often do not respond to traditional lecture-only biology courses. However, these students still need exposure to basic biological concepts. To accomplish this goal, forensic science was paired with compatible cell biology subjects. Several topics such as human development and molecular biology were found to fulfill this purpose. Another goal was to maximize the hands-on experience of the nonscience major students. This objective was fulfilled by specific activities such as fingerprinting and DNA typing. One particularly effective teaching tool was a mock murder mystery complete with a Grand Jury trial. Another objective was to improve students' attitudes toward science. This was successful in that students felt more confident in their own scientific abilities after taking the course. In pre/post tests, students answered four questions about their ability to conduct science. All four statements showed a positive shift after the course (p values ranging from.001 to.036, df = 23; n = 24). The emphasis on experiential pedagogy was also shown to increase critical thinking skills. In pre/post testing, students in this course significantly increased their performance on critical thinking assessment tests from 33.3% correct to 45.3% (p =.008, df = 4; n = 24).


[Application of femtosecond laser in corneal refractive surgery].
The function of photo-decomposing of femtosecond laser makes it useful in creating precise "cuts" at arbitrary locations within the corneal of almost any conceivable geometry. The applications of femtosecond laser include intrastromal photorefractive keratectomy, creating the pre-cut channels for intra-corneal ring segment, creating lamellar flaps for laser in situ keratomileusis, performing femtosecond lamellar keratoplasty, which represent an entirely new approach for the correction of refractive errors.


Distribution of Aujeszky's disease virus in experimentally infected mink (Mustela vison).
Eight Mink (Mustela vison) were inoculated orally with Aujeszky's disease virus (ADV). Three mink were killed at the onset of clinical signs and the other mink died spontaneously after inoculation. The incubation period ranged from 72 to 96 hours and was followed by a short illness characterised by increasing salivation, vomiting and retching, depression and coma. Microscopically, lesions were confined to the brain stem and consisted of a discrete non-suppurative encephalitis. Viral antigen was detected by an immunoperoxidase technique predominantly in association with specific lesions, although sometimes it was found within non-altered areas in the brain stem. Virus isolation confirmed the presence of ADV in the central nervous system. Fibrinoid degeneration of vessel walls was present in pharynx, larynx and myocardium in association with haemorrhages. Microthrombi were observed in heart and brain.


Streptococcal cellulitis of the scrotum and penis with secondary skin gangrene.
Cellulitis of the scrotum and penis is caused, in the majority of instances, by a beta hemolytic streptococci without a discernible portal of entry. Clostridium, occasionally, will result in this disease as a manifestation of a perirectal abscess. In either instance, fluid accumulates rapidly in the closed space between Colles' and Buck's fascia, producing intense swelling of the scrotum. If this compartment is not immediately decompressed by linear incisions, devascularization of the scrotal and penile skin will often occur, resulting in gangrene. Immediate treatment of the bacterial infection with penicillin also is essential. If gangrene does develop, radical debridement of the necrotic tissue as well as a wide margin of adjacent inflamed skin must be undertaken. Continual monitoring of the microflora of the debrided would is essential for the selection of the appropriate antibiotic against any secondary intruders. Coverage of the granulating would is accomplished when the would bacterial count is below 10-5 per gram of tissue.


Don't go 'way, it's time to play ... the safety game!
In an attempt to decrease the amount of time and dollars spent while increasing positive staff response, Emanual Hospital in Portland, Oregon, developed a game format to review required safety information. The game was piloted, then presented to the hospital's safety committee where it was approved as part of the hospital's education program. The game has significantly increased the percentage of staff participation in required classes. At the same time, cost of presenting the classes has decreased significantly.


The study of surface segregation of Re(3)Pt polycrystalline alloy with photoelectron spectroscopy.
The surface segregation and electronic structure of Re(3)Pt polycrystalline alloy were investigated via x-ray photoelectron spectroscopy (XPS). The results from angle-resolved core-level XPS show the enrichment of Pt at the top surface layer upon annealing at T=1200 K. The experimental results show excellent agreement with a theoretical model calculation, providing the element-specific depth profiles upon the high temperature annealing process. The presence of strong electron hybridization between Re and Pt is evident in the valence-band density-of-states ultraviolet photoemission spectra.


Encountering a cartwheeling princess: relational psychoanalytic therapy of a child with attachment difficulties and ADHD.
This study was conducted to demonstrate the use and process of contemporary relational psychoanalytic child therapy to address the interpersonal implications of attention deficit hyperactivity disorder and interlinked insecure attachment processes. This therapy case study explicates the seven-month therapeutic process of a seven-year-old girl child highlighting the need for the child therapist to balance interventions aimed at both the internal and external world of the child. In essence, this account traces therapeutic scenarios of both painful and joyful material by means of paying close attention to the entwined transference and countertransference dynamics as well as creatively and authentically engaging with the child's way of making sense of self-states, others and even medication. Key features of this account include the foundational role of assessment and the compelling mediating role of a puppet as a co-therapist within the analytic space between psychotherapist and patient. Uniquely, as an inclusive psychoanalytic therapy, relational psychoanalytic child therapy reconfigures internal object relations of the child while simultaneously ushering changes into their familial and school context by utilising the mutuality established between the child and therapist as a central pivot.


Correlation between adiponectin and reduction of cell adhesion molecules after pitavastatin treatment in hyperlipidemic patients with type 2 diabetes mellitus.
The aim of this study was to determine whether pitavastatin may prevent the progression of atherosclerotic changes in hyperlipidemic patients. Seventy-five hyperlipidemic patients with and without type 2 diabetes were enrolled to receive pitavastatin 2 mg daily. Cell adhesion molecules (sCD40L, sP-selectin, sE-selectin, and sL-selectin), chemokines (MCP-1 and RANTES) and adiponectin were measured at baseline and after 3 and 6 months of pitavastatin treatment. Adiponectin levels prior to pitavastatin treatment in hyperlipidemic patients with and without diabetes were lower than levels in normolipidemic controls. Both total cholesterol and the LDL-cholesterol (LDL-C) decreased significantly after pitavastatin administration. Additionally, hyperlipidemic patients with type 2 diabetes exhibited a significant increase in adiponectin levels after pitavastatin treatment (before vs. 3 months, 6 months, 2.81+/-0.95 vs. 3.84+/-0.84 microg/ml (p<0.01), 4.61+/-1.15 mug/ml (p<0.001)). Furthermore, hyperlipidemic diabetics exhibited significant decreases in sE-selectin and sL-selectin levels after 6 months of pitavastatin treatment (sE-selectin, before vs. 6 months, 74+/-21 vs. 51+/-10 ng/ml, p<0.05; sL-selectin, before vs. 6 months, 896+/-141 vs. 814+/-129 ng/ml, p<0.05). In addition, adiponectin showed significant correlation with sE-selectin and sL-selectin in diabetic hyperlipidemia. However, MCP-1, RANTES and sCD40L did not exhibit any differences before or after pitavastatin administration. These results suggest that pitavastatin possesses an adiponectin-dependent anti-atherosclerotic effect in hyperlipidemic patients with type 2 diabetes in addition to its lowering effects on total cholesterol and LDL-C.


Toxicologic and marrow transplantation studies in rhesus monkeys given dimethyl myleran.
The hematologic and pathologic effects of single doses of dimethyl myleran (DMM) were evaluated in rhesus monkeys with and without the infusion of marrow. DMM 3 to 5 mg/kg produced severe but reversible myelotoxicity and no non-marrow toxicity. All animals given DMM 10 mg/kg died of marrow failure which was consistently reversed by the infusion of cryopreserved autologous marrow. At higher doses of DMM the protective effect of autologous marrow was less consistent due to increased gastrointestinal toxicity. Allogeneic engraftment was not achieved following administration of 10 mg/kg of DMM. In two animals receiving 15 mg/kg, proliferating allogeneic donor cells were present in recipient marrow seven days after marrow infusion.


Design, synthesis and insecticidal activity of novel phenylpyrazoles containing a 2,2,2-trichloro-1-alkoxyethyl moiety.
A series of novel phenylpyrazoles containing a 2,2,2-trichloro-1-alkoxyethyl moiety were designed and synthesized via the key intermediate 5-trichloroethylideneimino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-alkylsulfenylpyrazole (5). The addition reaction of the imine 5 was closely related with the nature of the alcohol. The target compounds were confirmed by (1)H NMR and elemental analysis. The results of bioassays indicated that the target compounds possessed excellent activities against a broad spectrum of insects such as bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens) and diamondback moth (Plutella xylostella). Especially, the foliar contact activity against bean aphid of compound 7h at 2.5 mg kg(-1) was 89%, the larvacidal activity against mosquito of compound 6c at 2.5 microg kg(-1) was 100%, the activity against diamondback moth of compound 7a at 5 mg kg(-1) was 87%, and all of these activities were much higher than the contrast ethiprole. The results of insecticidal activities showed that the two pairs of enantiomers 7d-1 and 7d-2 gave activities without distinctive difference, and it was the similar situation for 7e-1 and 7e-2. Interestingly, the target compounds exhibited high selectivity between diamondback moth and oriental armyworm, both of which are of the order Lepidoptera. The 2,2,2-trichloro-1-alkoxyethyl moiety was essential for high insecticidal activities.


Epidemiology, etiology, diagnosis, and treatment of schizophrenia.
The epidemiology, etiology, diagnosis, and treatment of schizophrenia are reviewed. In the United States, at least 1 in every 100 persons is afflicted with schizophrenia. The theory that schizophrenia is a biochemical disorder has gained wide acceptance, although none of the etiological theories are conclusive. Criteria contained in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, are most commonly used to diagnose schizophrenia. Accuracy in diagnosing schizophrenia is critical because the treatments and prognoses for different types of psychoses can vary considerably. Treatment primarily involves the use of antipsychotic drugs, which are thought to act by blocking central dopamine receptors. The classical antipsychotics are the phenothiazines; of these, the prototype is chlorpromazine. Other classes of antipsychotics are the thioxanthenes, butyrophenones, dihydroindolones, dibenzoxazepines, diphenylbutylpiperidines, and dibenzodiazepines. Selecting an appropriate agent involves consideration of adverse effects, dosage forms, and the agent's ability to relieve target symptoms. Adverse effects of these agents include sedation, extrapyramidal effects, and anticholinergic effects. Tardive dyskinesia is a serious, irreversible condition associated with long-term antipsychotic therapy. Clozapine, a newer atypical antipsychotic, has been shown to be more effective than chlorpromazine and haloperidol and seems to cause few neurological adverse effects. Treatment of schizophrenia has not changed much since the advent of antipsychotic drug use nearly 30 years ago. Newer atypical antipsychotics show promise in improving target symptoms while causing fewer adverse effects.


Antibiotic prescribing practice in the management of cough or diarrhea among children attending hospitals in Addis Ababa: a cross-sectional study.
Irrational use of antibiotics is a global problem. Failure to follow clinical guidelines is one of the main reasons for irrational use of antibiotics. Cough and/or diarrhea are the main childhood illnesses in Ethiopia, and health care providers are expected to follow the national guideline while managing these illnesses. This study tried to assess the extent of adherence to the guideline while managing cases of childhood diarrhea and/or cough. The study was conducted in 23 hospitals in Addis Ababa. Data were collected prospectively from April to June 2016 using a structured questionnaire. A total of 1,073 children aged 2-59 months who visited the hospitals for cough or diarrhea during the study period were included in the study. Equal number of cases were allocated to each hospital and consecutive cases were included in the study until the calculated sample size was attained for each hospital. Data collectors approached cases after they were seen by the health care provider. SPSS version 20 was used to analyze the data. Of the total number of cases, an antibiotic was prescribed for 794 (74.0%) of the children. Cotrimoxazol 209 (26.3%), amoxicillin 185 (23.3%), and cephalosporines 174 (21.9%) were the three most commonly prescribed antibiotics. Six hundred eighty-eight (86.6%) of the prescriptions were determined to be inappropriate. Of the inappropriate prescriptions, 631 (91.7%) were for prescribing antibiotics when not necessary and 57 (8.3%) were for prescribing the wrong spectrum of antibiotics. Using multivariate analysis, a child not having diarrhea was independently associated with appropriate antibiotic prescription (adjusted odds ratio =0.261, 95% confidence interval: 0.095-0.714). The prescriber being qualified as a pediatrician was an independent predictor of inappropriate antibiotic prescription (adjusted odds ratio =9.967, 95% confidence interval: 4.221-23.532). The magnitude of inappropriate antibiotic prescription while managing cough and/or diarrhea in our setting was high. It needs urgent action to prevent emergence of antibiotic-resistant microorganisms.


Aligned, ultralong single-walled carbon nanotubes: from synthesis, sorting, to electronic devices.
Aligned, ultralong single-walled carbon nanotubes (SWNTs) represent attractive building blocks for nanoelectronics. The structural uniformity along their tube axis and well-ordered two-dimensional architectures on wafer surfaces may provide a straightforward platform for fabricating high-performance SWNT-based integrated circuits. On the way towards future nanoelectronic devices, many challenges for such a specific system also exist. This Review summarizes the recent advances in the synthesis, identification and sorting, transfer printing and manipulation, device fabrication and integration of aligned, ultralong SWNTs in detail together with discussion on their major challenges and opportunities for their practical application.


Camphorquinone-10-sulfonic acid and derivatives: convenient reagents for reversible modification of arginine residues.
Camphorquinone-10-sulfonic acid hydrate was prepared by the action of selenous acid on camphor-10-sulfonic acid. Camphorquinone-10-sulfonylnorleucine was prepared either from the sulfonic acid via the sulfonyl chloride or by selenous acid oxidation of camphor-10-sulfonylnorleucine. These reagents are useful for specific, reversible modification of the guanidino groups of arginine residues. Camphorquinonesulfonic acid is a crystalline water-soluble reagent that is especially suitable for use with small arginine-containing molecules, because the sulfonic acid group of the reagent is a convenient handle for analytical and preparative separation of products. Camphorquinonesulfonylnorleucine is more useful for work with large polypeptides and proteins, because hydrolysates of modified proteins may be analyzed for norleucine to determine the extent of arginine modification. The adducts of the camphorquinone derivatives with the guanidino group are stable to 0.5 M hydroxylamine solutions at pH 7, the recommended conditions for cleavage of the corresponding cyclohexanedione adducts. At pH 8-9 the adducts of the camphorquinone derivatives with the guanidino group are cleaved by o-phenylenediamine. The modification and regeneration of arginine, of the dipeptide arginylaspartic acid, of ribonuclease S-peptide, and of soybean trypsin inhibitor are presented as demonstrations of the use of the reagents. The use of camphorquinonesulfonyl chloride to prepare polymers containing arginine-specific ligands is discussed.


Attentional Modulation of Change Detection ERP Components by Peripheral Retro-Cueing.
Change detection is essential for visual perception and performance in our environment. However, observers often miss changes that should be easily noticed. A failure in any of the processes involved in conscious detection (encoding the pre-change display, maintenance of that information within working memory, and comparison of the pre and post change displays) can lead to change blindness. Given that unnoticed visual changes in a scene can be easily detected once attention is drawn to them, it has been suggested that attention plays an important role on visual awareness. In the present study, we used behavioral and electrophysiological (ERPs) measures to study whether the manipulation of retrospective spatial attention affects performance and modulates brain activity related to the awareness of a change. To that end, exogenous peripheral cues were presented during the delay period (retro-cues) between the first and the second array using a one-shot change detection task. Awareness of a change was associated with a posterior negative amplitude shift around 228-292 ms ("Visual Awareness Negativity"), which was independent of retrospective spatial attention, as it was elicited to both validly and invalidly cued change trials. Change detection was also associated with a larger positive deflection around 420-580 ms ("Late Positivity"), but only when the peripheral retro-cues correctly predicted the change. Present results confirm that the early and late ERP components related to change detection can be functionally dissociated through manipulations of exogenous retro-cueing using a change blindness paradigm.


Assessment of body composition in pediatric overweight and obesity: A systematic review of the reliability and validity of common techniques.
Accurate measurement of body composition is required to improve health outcomes in children and adolescents with overweight or obesity. This systematic review aimed to summarize the reliability and validity of field and laboratory body composition techniques employed in pediatric obesity studies to facilitate technique selection for research and clinical practice implementation. A systematic search in MEDLINE (via PubMed), EMBASE, CINAHL, and SPORTDiscus from inception up to December 2019 was conducted, using a combination of the following concepts: body composition, pediatric overweight/obesity, and reliability/validity. The search strategy resulted in 66 eligible articles reporting reliability (19.7%), agreement between body composition techniques cross sectionally (80.3%), and/or diagnostic test accuracy (10.6%) in children and adolescents with overweight or obesity (mean age range = 7.0-16.5 years). Skinfolds, air-displacement plethysmography (ADP), dual-energy X-ray absorptiometry (DXA), and ultrasound presented as reliable techniques. DXA, ADP, and isotope dilution showed similar and the best agreement with reference standards. Compared with these laboratory techniques, the validity of estimating body composition by anthropometric equations, skinfolds, and BIA was inferior. In conclusion, the assessment of body composition by laboratory techniques cannot be replaced by field techniques due to introduction of measurement errors, which potentially conceal actual changes in body components.


Ionogels of Sugar Surfactant in Ethylammonium Nitrate: Phase Transition from Closely Packed Bilayers to Right-Handed Twisted Ribbons.
In the simplest ionic liquid, ethylammonium nitrate (EAN), ionogels with high mechanical strength were prepared from a surfactant with a disaccharide polar head. Phase structures from closely packed bilayers to right-handed twisted ribbons were determined via freeze-fracture transmission electron microscopy (FF-TEM) observations. The phase transition mechanism was investigated deeply and systematically. The temperature contributes to suitable tail chain conformations of surfactant molecules for adapting to different self-assembled structures including right-handed twisted ribbons and bilayers. Two different arrays were revealed for different bilayers by the small-angle X-ray scattering (SAXS) measurements. The rheological and tribological properties of the ionogels were investigated. The better lubricating property and antiwear capability of the ionogels compared to the EAN may be attributed to the structure characteristics and the good thixotropic properties.


Molecular genetic characterization of different isolates of Echinococcus granulosus in east and southeast regions of Turkey.
We used PCR-RFLP analysis of ribosomal ITS1 fragment using four different restriction enzymes and DNA sequencing of mitochondrial CO1 gene to investigate the genetic characteristics of isolates of Echinococcus granulosus obtained from different hosts (179 sheep, 19 cattle, 7 goat, 1 camel, 1 dog and 1 human) and regions (Elazig, Malatya, Erzurum, Van, Diyarbakir and Sanliurfa) of Turkey. The report represents the most comprehensive genotypic investigation of E. granulosus isolates undertaken in Turkey, with Turkish samples of cattle, goat, camel and dog origin being characterized for the first time. We show that the predominant genotype involved in E. granulosus transmission in Turkey is the common sheep strain (G1 genotype) infecting humans, cattle, sheep, goats, camels as well as the dog definitive host. Nevertheless, we urge that coordinators of local control programs in Turkey should take into consideration the potential occurrence and risk of additional strains of E. granulosus infecting humans and animal hosts, and plan accordingly.


ACTH Infusion Impairs Baroreflex Sensitivity-Implications for Cardiovascular Hypoglycemia-Associated Autonomic Failure.
Hypoglycemia attenuates cardiovascular homeostatic autonomic control. This attenuation, known as the cardiovascular component of hypoglycemia-associated autonomic failure (HAAF), is characterized most notably by decreased baroreflex sensitivity (BRS) that begins during hypoglycemia and persists until at least the next day, despite return to euglycemia. Understanding the mechanisms underlying this reduction in BRS is important because BRS attenuation is associated with increased morbidity and mortality. The objective of this work is to investigate the role of the adrenocorticotropin (ACTH)-adrenal axis in decreasing BRS. We tested the hypothesis that infusion of ACTH 1-24 (cosyntropin), as compared to placebo, would acutely suppress BRS, and that this decrease in BRS would be present the next day. A double-blind, placebo-controlled, random-order, cross-over study was conducted. This study took place in a clinical research center. Participants included healthy men and women. Interventions included an intravenous infusion of cosyntropin (70 μg/hour for 2.5 hours in the morning and again in the early afternoon) vs normal saline placebo. Outcome measures included BRS during and 16 hours after cosyntropin vs placebo infusions. Cosyntropin infusion attenuated BRS (mm Hg/ms) as compared to placebo (baseline 17.8 ± 1.38 vs 17.0 ± 2.07; during 14.4 ± 1.43 vs 17.3 ± 1.65; and next day 14.8 ± 1.42 vs 18.9 ± 2.04; P < .05, time by treatment, analysis of variance). BRS was decreased during the final 30 minutes of the morning cosyntropin infusion as compared to baseline (P < .01) and remained suppressed the next day (16 hours after afternoon infusion) (P < .025). Placebo infusion did not significantly change BRS. Corrected QT interval was not affected. ACTH attenuates BRS, raising the possibility that hypoglycemia-induced increases in ACTH may contribute to the cardiovascular component of HAAF.


Interaction of G-protein βγ complex with chromatin modulates GPCR-dependent gene regulation.
Heterotrimeric G-protein signal transduction initiated by G-protein-coupled receptors (GPCRs) in the plasma membrane is thought to propagate through protein-protein interactions of subunits, Gα and Gβγ in the cytosol. In this study, we show novel nuclear functions of Gβγ through demonstrating interaction of Gβ(2) with integral components of chromatin and effects of Gβ(2) depletion on global gene expression. Agonist activation of several GPCRs including the angiotensin II type 1 receptor specifically augmented Gβ(2) levels in the nucleus and Gβ(2) interacted with specific nucleosome core histones and transcriptional modulators. Depletion of Gβ(2) repressed the basal and angiotensin II-dependent transcriptional activities of myocyte enhancer factor 2. Gβ(2) interacted with a sequence motif that was present in several transcription factors, whose genome-wide binding accounted for the Gβ(2)-dependent regulation of approximately 2% genes. These findings suggest a wide-ranging mechanism by which direct interaction of Gβγ with specific chromatin bound transcription factors regulates functional gene networks in response to GPCR activation in cells.


Post-translational modifications talk and crosstalk to class IIa histone deacetylases.
Epigenetic modifications, such as histone or DNA modifications are key regulators of gene transcription and changes are often associated with maladaptive processes underlying cardiovascular disease. Epigenetic regulators therefore likely play a crucial role in cardiomyocyte homeostasis and facilitate the cellular adaption to various internal and external stimuli, responding to different intercellular and extracellular cues. Class IIa histone deacetylases are a class of epigenetic regulators that possess a myriad of post-transcriptional modification sites that modulate their activity in response to oxidative stress, altered catecholamine signalling or changes in the cellular metabolism. This review summaries the known reversible, post-translational modifications (PTMs) of class IIa histone deacetylases (HDACs) that ultimately drive transcriptional changes in homeostasis and disease. We also highlight the idea of a crosstalk of various PTMs on class IIa HDACs potentially leading to compensatory or synergistic effects on the class IIa HDAC-regulated cell behavior.


Retinotopic and nonretinotopic field potentials in cat visual cortex.
Two types of field potentials were identified in cat visual cortex using contrast reversal of oriented bar gratings: a short-latency fast-local component with a retinotopic organization similar to that seen with single-unit discharges at the same cortical site, and a slow, nonretinotopic component with a longer peak latency. The slow-distributed component had an extensive receptive field mapped by measuring the amplitude of binary kernels and showed strong inhibitory interactions within the receptive field. The peak latency of the slow-local component increased with distance from the retinotopic center, suggesting a possible conduction delay. Both components showed some orientation bias depending on the laminar location, but the bias could be independent of the orientation preferred by single units in the immediate vicinity. The present findings indicate that locally generated field potentials reflect cortical mechanisms for nonlinear integration over wide areas of the visual field.


Minimal brain damage induced by early iron deficiency: modified dopaminergic neurotransmission.
The reports that iron-deficiency anemia in human subjects induces behavioral changes was investigated in rats made nutritionally iron-deficient. The most prominent features of these animals were: the unchanged metabolism of the neurotransmitters noradrenaline, dopamine and serotonin, profound reduction of brain nonheme iron, the selective diminution of dopamine D2 receptor number (measured by Bmax), modification of dopamine-dependent behaviors and reduction of learning processes. The induction of these changes and their recovery with iron supplementation are age- and time-dependent phenomena. In newborn rats, however, the consequences of iron deficiency are irreversible, even after long-term iron supplementation. The results point to the profound effect iron metabolism can have on the long-term development and function of dopaminergic neurotransmission. These findings may not be totally unexpected, since iron distribution in the brain is highly localized in dopaminergic-peptidergic regions, such as the globus pallidus, substantia nigra, red nucleus, thalamus, caudate nucleus and nucleus accumbens. In some regions its concentration is higher than that found in the liver, the site of iron metabolism.


Telophase-stage host ooplasts support complete reprogramming of roscovitine-treated somatic cell nuclei in cattle.
Nuclear-cytoplasmic incompatibilities are known to play a significant role in the developmental outcome of embryos produced by nuclear transfer, particularly when metaphase arrested oocytes are used as hosts for interphase donor nuclei. To further our understanding of how cell cycle coordination affects somatic cell cloning, somatic cells at different stages of the cell cycle were fused to host oocytes either before (metaphase II, M-II) or after (telophase II, T-II) activation. To obtain cells at different stages of the cell cycle, fetal fibroblast (FF) and granulosa cells (GC) were treated with roscovitine, an inhibitor of cyclin-dependent kinases (CDKs) resulting in a large percentage of cells in S/G(2)-phase. In contrast to the M-II group, which did better with confluent cells, embryos reconstructed with T-II cytoplasts resulted in higher rates of blastocyst formation when fused to cells recovered at 16-24 h after passage. Embryos reconstructed with FF treated with roscovitine and T-II cytoplasts (Rosc/T-II) resulted in similar blastocyst rate compared to those produced with confluent cells and M-II cytoplasts (Conf/M-II). Transfer of blastocysts to surrogate heifers resulted pregnancies and birth of healthy calves from Rosc/T-II and Conf/M-II reconstructed embryos. These results indicate that, when combined with nuclear donor cells at specific cell cycle stages, M-II and T-II bovine oocytes are similarly effective in supporting the reprogramming of somatic cell nuclei.


Interarytenoid notch height relative to the vocal folds. Pilot study.
We measured interarytenoid notch height (IANH) in 20 young children who required direct laryngoscopy under general anesthesia. By means of a specifically designed instrument, we found that the average IANH approximated 3 mm. Laryngeal incompetence on swallowing or in the presence of gastroesophageal reflux is associated with a low IANH (p < .0001). Therefore, IANH may be a measure of relative laryngeal incompetence.


Allopurinol prophylactic therapy and the prevention of contrast-induced nephropathy in high-risk patients undergoing coronary angiography: A prospective randomized controlled trial.
Contrast-induced nephropathy (CIN) is considered to be a possibly severe complication of radiography and thus, remains to be the main cause of acute kidney injury (AKI) for inpatients. A clinical trial was executed to measure the preventive effect of allopurinol against CIN in high-risk patients undertaking coronary angiography. Through randomized controlled trial, 140 patients with at minimum two risk factors of CIN, undertaking coronary angiography, were randomly allocated to the allopurinol (n = 70) or control group (n = 70). Those in the allopurinol group received allopurinol (300 mg) a day before their coronary angiography and intravenous hydration for 12 hours before and after their procedure, while members of the control group only received intravenous hydration. Serum creatinine (SCr), blood urea nitrogen (BUN) and uric acid were measured before and 48 hours after the procedure. CIN was defined by a 25% increase in SCr or the concentration of > 0.5 mg/dl, 48 hours after coronary angiography. CIN was observed in 8 (11.4%) patients in the allopurinol group and 11 (15.7%) patients in the control group. There was no significant difference in the incidence of CIN between the two groups at 48 hours after coronary angiography (P = 0.459). In the allopurinol group, the median SCr concentration decreased non-significantly from 1.16 mg/dl to 1.13 mg/dl, 48 hours after coronary angiography (P = 0.189). In the control group, the median SCr concentration increased significantly from 1.11 mg/dl to 1.2 mg/dl, 48 hours after coronary angiography (P < 0.001). Allopurinol presents no considerable effectiveness over the hydration protocol for development of CIN in high-risk patients.


Preventive care in the emergency department: screening for domestic violence in the emergency department.
The most effective methods for identification and management of domestic violence (DV) victims in health care settings are unknown. The objective of this study was to systematically review screening for DV in the emergency department (ED) to identify victims and decrease morbidity and mortality from DV. Using the terms "domestic violence" or "partner violence," and "identification" or "screening," and "emergency," the authors searched MEDLINE, the Cochrane Database, and Emergency Medical Abstracts from 1980-2002. They selected articles studying screening tools, interventions, or determining the incidence or prevalence of DV among ED patients. The studies were analyzed using evidence-based methodology. Three hundred thirty-nine articles resulted from the literature search. Based on selection criteria, 45 were reviewed in detail and 17 pertained to the ED. From references of these 17 articles, three additional articles were added. Screening can be conducted using a brief verbal screen and existing ED personnel. A randomized, controlled trial did not demonstrate a difference in screening rates between experimental and control hospitals. No studies assessed the effect of ED screening for DV on morbidity or mortality of domestic violence. An ED-based advocacy program resulted in increased use of shelters and counseling. Because of the paucity of outcomes research evaluating ED screening and interventions, there is insufficient evidence for or against DV screening in the ED. However, because of the high burden of suffering caused by DV, health care providers should strongly consider routinely inquiring about DV as part of the history, at a minimum for all female adolescent and adult patients.


Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia.
In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep. RNA-seq of cultured SCZ human glial progenitor cells (hGPCs) revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell autonomous. Our data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia and provide a humanized model for its in vivo assessment.


[New guidelines for cervical cancer screening in young patients: what impact? ].
The publication in 2009 of the new recom- mandations by the American College of Obstetricians and Gynaecologists (ACOG) about the screening of cervical cancer enabled us to optimize the treatment, especially in young patients. The aim of these modifications is to decrease overtreatment of low grade lesions and thereby the risk of obstetrical complica- tions. The objective of our article is to briefly recall these new guidelines together with a study conducted in our Department of Obstetrics and Gynaecology which aim is to confirm that our practice follows these instructions and to check that these procedures are safe for the future of these young patients.