Machine Learning in Differentiating Gliomas from Primary CNS Lymphomas: A Systematic Review, Reporting Quality, and Risk of Bias Assessment.
Differentiating gliomas and primary CNS lymphoma represents a diagnostic challenge with important therapeutic ramifications. Biopsy is the preferred method of diagnosis, while MR imaging in conjunction with machine learning has shown promising results in differentiating these tumors. Our aim was to evaluate the quality of reporting and risk of bias, assess data bases with which the machine learning classification algorithms were developed, the algorithms themselves, and their performance. Ovid EMBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. From 11,727 studies, 23 peer-reviewed studies used machine learning to differentiate primary CNS lymphoma from gliomas in 2276 patients. Characteristics of data sets and machine learning algorithms were extracted. A meta-analysis on a subset of studies was performed. Reporting quality and risk of bias were assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) and Prediction Model Study Risk Of Bias Assessment Tool. The highest area under the receiver operating characteristic curve (0.961) and accuracy (91.2%) in external validation were achieved by logistic regression and support vector machines models using conventional radiomic features. Meta-analysis of machine learning classifiers using these features yielded a mean area under the receiver operating characteristic curve of 0.944 (95% CI, 0.898-0.99). The median TRIPOD score was 51.7%. The risk of bias was high for 16 studies. Exclusion of abstracts decreased the sensitivity in evaluating all published studies. Meta-analysis had high heterogeneity. Machine learning-based methods of differentiating primary CNS lymphoma from gliomas have shown great potential, but most studies lack large, balanced data sets and external validation. Assessment of the studies identified multiple deficiencies in reporting quality and risk of bias. These factors reduce the generalizability and reproducibility of the findings.


Polyamines and polyamino acids regulation of cytosolic tyrosine protein (Tyr-P) kinase from human erythrocytes.
In vitro regulation of cytosolic tyrosine protein (Tyr-P) kinase from human erythrocytes by polyamines, polyamino acids, negative charged compounds or by insulin using angiotensin II or poly (Glu-Tyr)4:1 as substrates was studied. All the three polyamines, putrescine (Put), spermidine (Spd) and spermine (Spm) stimulated the Tyr-P kinase activity in a dose dependent manner. Spm stimulated Tyr-P kinase activity higher than Put and Spd whether the substrate was angiotension II or poly (Glu-Tyr)4:1. Polyamino acids (polyornithine, polyarginine, polyglutamic acid and polyaspartic acid) did not affect significantly the Tyr-P kinase phosphorylation except polylysine which significantly stimulated the Tyr-P kinase activity. Negative charged compounds (chondroitin sulfate A, B and C) and heparin inhibited the Tyr-P kinase phosphorylation while insulin did not influence the enzyme activity in the presence of either substrates.


Characterization of an ex vivo model for the assessment of root canal disinfection.
Root canal bacteria in teeth with apical periodontitis were enumerated after extraction and incubation. Canals in 36 teeth were sampled after: S1, incubation for 2 hours (group A), 2 days (group B), 4 days (group C), and 6 days (group D); S2, subsequent incubation for 1 week; S3, canal disinfection; and S4, final incubation for 1 week. Bacterial concentrations were determined by culture (colony-forming unit [CFU]) and epifluorescence-microscopy (EFM) and compared by using pairwise and exact-permutation tests (p < 0.05). CFU counts were lower than EFM counts. CFU counts in S1 were higher in Gp(A) than in Gp(C) (p < 0.004) and Gp(D) (p < 0.02). EFM counts in S1 were higher in Gp(A) than in Gp(C) (p < 0.02). Both enumeration methods showed bacterial counts decreasing from S1 to S2 (p < 0.04). EFM was superior to culture in this ex vivo model. The indigenous flora survived incubation for 6 days, but the adverse effect of initial access would preclude testing of disinfection protocols that require two sessions.


Management of hyperlipidemia in women with diabetes.
To review gender-related factors in coronary artery disease, possible mechanisms for increased atherogenesis in women with diabetes, and potential therapeutic strategies for hyperlipidemia. Pertinent published studies and personal experiences are discussed, and lipoprotein profiles are outlined. In the normal population, the increase in atherosclerotic vascular disease with aging in women lags behind that in men by 10 to 15 years. With the presence of diabetes, however, the atherosclerotic changes are similar in men and women. Several studies have substantiated that triglyceride levels are a stronger risk factor than cholesterol in men and women with diabetes who have coronary artery disease. In general, hypertriglyceridemia is a stronger risk factor for cardiovascular disease in women than in men. Gender differences in lipid levels can be explained physiologically by the presence of estrogen in female patients, which accelerates the rate of metabolism of lipoproteins and, in a setting of insulin deficiency, induces hypertriglyceridemia. Dietary measures and various classes of drugs, including reductase inhibitors, are used alone or in combination for management of the combined hyperlipidemia typically found in subjects with insulin resistance, diabetes, or both. Gender-related differences in lipoprotein-associated cardiovascular risk should be considered in choosing treatment options for patients with diabetes and hyperlipidemia.


Metabolomics Investigation of an Association of Induced Features and Corresponding Fungus during the Co-culture of Trametes versicolor and Ganoderma applanatum.
The co-culture of Trametes versicolor and Ganoderma applanatum is a model of intense basidiomycete interaction, which induces many newly synthesized or highly produced features. Currently, one of the major challenges is an identification of the origin of induced features during the co-culture. Herein, we report a 13C-dynamic labeling analysis used to determine an association of induced features and corresponding fungus even if the identities of metabolites were not available or almost nothing was known of biochemical aspects. After the co-culture of T. versicolor and G. applanatum for 10 days, the mycelium pellets of T. versicolor and G. applanatum were sterilely harvested and then mono-cultured in the liquid medium containing half fresh medium with 13C-labeled glucose as carbon source and half co-cultured supernatants collected on day 10. 13C-labeled metabolome analyzed by LC-MS revealed that 31 induced features including 3-phenyllactic acid and orsellinic acid were isotopically labeled in the mono-culture after the co-culture stimulation. Twenty features were derived from T. versicolor, 6 from G. applanatum, and 5 features were synthesized by both T. versicolor and G. applanatum. 13C-labeling further suggested that 12 features such as previously identified novel xyloside [N-(4-methoxyphenyl)formamide 2-O-beta-D-xyloside] were likely induced through the direct physical interaction of mycelia. Use of molecular network analysis combined with 13C-labeling provided an insight into the link between the generation of structural analogs and producing fungus. Compound 1 with m/z 309.0757, increased 15.4-fold in the co-culture and observed 13C incorporation in the mono-culture of both T. versicolor and G. applanatum, was purified and identified as a phenyl polyketide, 2,5,6-trihydroxy-4, 6-diphenylcyclohex-4-ene-1,3-dione. The biological activity study indicated that this compound has a potential to inhibit cell viability of leukemic cell line U937. The current work sets an important basis for further investigations including novel metabolites discovery and biosynthetic capacity improvement.


Oxidation of methanol and formaldehyde to CO2 by a photocatalyst with an energy storage ability.
A TiO(2)-Ni(OH)(2) bilayer photocatalyst is known as a photocatalyst with energy storage abilities. Oxidative energy from the UV-irradiated TiO(2) underlayer can be stored in the Ni(OH)(2) overlayer. We investigated oxidation and mineralization of methanol and formaldehyde by the stored oxidative energy by mean of gas chromatography. When the methanol concentration in air is as low as 10 ppm, the mass conversion efficiency from methanol to CO(2) is approximately 86%. Formaldehyde can also be oxidized to CO(2) by the stored energy.


A Primer on Heroin and Fentanyl.
Heroin and fentanyl use have reached epidemic proportions in the United States and are now blamed for the majority of drug-related overdose deaths. Both drugs are produced primarily in South America and Asia and enter the United States illegally. One result of smoking or injecting heroin or fentanyl is the development of a substance use disorder (SUD), which causes changes in brain chemistry and function. These changes result in negative behaviors and an inability to stop use. Yet, treatments are available and recovery is possible. Nurses have the potential to impact the heroin and fentanyl epidemic through developing therapeutic relationships with patients who are at risk or already have a SUD. Strategies for effective communication include maintaining a supportive, nonjudgmental attitude and incorporating motivational interviewing. All patients should be screened for opioid use and referred for treatment if indicated. It is important for nurses to be knowledgeable about heroin and fentanyl and available treatments. [Journal of Psychosocial Nursing and Mental Health Services, 55(6), 16-20.].


Oxidative stress induces the biosynthesis of citrinin by Penicillium verrucosum at the expense of ochratoxin.
Penicillium verrucosum is a fungus that can produce ochratoxin A and citrinin, two structurally related nephrotoxic mycotoxins. P. verrucosum usually occurs on wheat but can occasionally also be found in NaCl rich habitats such as salted cheeses or olives, indicating that this fungus can adapt to different environments. The ratio of ochratoxin A to citrinin produced by P. verrucosum is shifted to one of either mycotoxin at the expense of the other dependent on the environmental conditions. High NaCl concentrations shift secondary metabolite biosynthesis towards ochratoxin A production. P. verrucosum copes with NaCl stress by increased ochratoxin A biosynthesis, ensuring chloride homeostasis. Ochratoxin A carries chlorine in its molecule and can excrete chlorine from the cell. It was further shown that the regulation of ochratoxin A by high NaCl conditions is mediated by the HOG MAP kinase signal transduction pathway. Here it is shown that high oxidative stress conditions, evoked for example by increasing concentrations of Cu(2+) cations in the growth medium, shift secondary metabolite biosynthesis of P. verrucosum from ochratoxin A to citrinin. The production of citrinin normalizes the oxidative status of the fungal cell under oxidative stress conditions leading to an adaptation to these environmental conditions and protects against increased oxidative stress caused by increased Cu(2+) concentrations. Moreover citrinin also protects against light of short wavelength, which may also increase the oxidative status of the environment. The biosynthesis of citrinin is apparently regulated by a cAMP/PKA signaling pathway, because increasing amounts of external cAMP reduce citrinin biosynthesis in a concentration dependent manner. These conditions lead to the cross-regulation of the ochratoxin A/citrinin secondary metabolite pair and support the adaptation of P. verrucosum to different environments.


A Rapid Epidemiological Tool to Measure the Burden of Norovirus Infection and Disease in Resource-Limited Settings.
Rapid, cost-effective tools are needed to estimate the disease burden of acute gastroenteritis (AGE) and norovirus (NoV) in resource-limited settings. Households with children (6 weeks-17 years) in rural Guatemala were randomly enrolled into 2 parallel AGE surveillance systems: (1) a prospective cohort, which included an enrollment visit followed by 1 year of prospective observation using a smartphone-based weekly symptom diary; and (2) 2 sequential cross-sectional rapid active sampling (RAS) surveys. Norovirus testing was performed during enrollment (all subjects) and for prospective AGE episodes (prospective cohort only). The prospective cohort enrolled 207 households (469 children) from April to September 2015 followed by 471 person-years of observation; RAS survey 1 enrolled 210 households (402 children) during October to November 2015, and RAS survey 2 enrolled 210 separate households (368 children) during January to February 2016. The prospective cohort detected a NoV+ AGE prevalence of 11% and a population-attributable fraction (PAF) of -1.6% at enrollment, followed by an incidence of 1.4 episodes/100 person-years. Rapid active sampling surveys 1 and 2 identified a NoV+ AGE prevalence of 14%-21% and a PAF of 3.2%-12.4%. Rapid active sampling surveys were practical and identified more cases of NoV infection and disease compared with a parallel prospective cohort in rural Guatemala.


Endotoxic activity in teeth with necrotic pulps.
From root canals of 13 teeth with necrotic pulps, samples were taken for analysis of endotoxin content by means of the Limulus by lysate technique. The results were related to the viable bacteria count of root canal samples, phenol/water-extracted lipopolysaccharides (LPS) from different gram-negative anaerobic bacteria, and to different fractions of inflammation exudate. It was found that the endotoxic activity of the root canal samples was correlated with the presence and the number of gram-negative bacteria in the root canal.


Cardiac Hemodynamics Abnormalities Induced by Intermittent Left Bundle-branch Block: A Case Report.
The left bundle-branch block (LBBB) is related to worsening cardiac performance. We describe a case of a patient with an intermittent left bundle-branch block who underwent biventricular pacemaker implantation. We noted a detrimental effect on the performance of her left ventricle with the presence of the LBBB as compared to the performance after she underwent biventricular pacing or after reversal of LBBB (i.e., native rhythm with narrow QRS). Her LBBB was accompanied by increased isovolumetric contraction time, longer pre-ejection period, and increased myocardial performance index (i.e., the Tei index) compared to her sinus rhythm with a narrow QRS complex with or under biventricular pacing.


Mapping Atmospheric Moisture Climatologies across the Conterminous United States.
Spatial climate datasets of 1981-2010 long-term mean monthly average dew point and minimum and maximum vapor pressure deficit were developed for the conterminous United States at 30-arcsec (~800m) resolution. Interpolation of long-term averages (twelve monthly values per variable) was performed using PRISM (Parameter-elevation Relationships on Independent Slopes Model). Surface stations available for analysis numbered only 4,000 for dew point and 3,500 for vapor pressure deficit, compared to 16,000 for previously-developed grids of 1981-2010 long-term mean monthly minimum and maximum temperature. Therefore, a form of Climatologically-Aided Interpolation (CAI) was used, in which the 1981-2010 temperature grids were used as predictor grids. For each grid cell, PRISM calculated a local regression function between the interpolated climate variable and the predictor grid. Nearby stations entering the regression were assigned weights based on the physiographic similarity of the station to the grid cell that included the effects of distance, elevation, coastal proximity, vertical atmospheric layer, and topographic position. Interpolation uncertainties were estimated using cross-validation exercises. Given that CAI interpolation was used, a new method was developed to allow uncertainties in predictor grids to be accounted for in estimating the total interpolation error. Local land use/land cover properties had noticeable effects on the spatial patterns of atmospheric moisture content and deficit. An example of this was relatively high dew points and low vapor pressure deficits at stations located in or near irrigated fields. The new grids, in combination with existing temperature grids, enable the user to derive a full suite of atmospheric moisture variables, such as minimum and maximum relative humidity, vapor pressure, and dew point depression, with accompanying assumptions. All of these grids are available online at http://prism.oregonstate.edu, and include 800-m and 4-km resolution data, images, metadata, pedigree information, and station inventory files.


Changes in MEPP frequency during depression of evoked release at the frog neuromuscular junction.
1. Endplate potentials (EPPs) and miniature endplate potentials (MEPPs) were recorded from frog neuromuscular junctions bathed in Ringer solutions containing normal (1.8 mM) or high (3.6 mM) Ca2+. The peptide toxin mu-conotoxin GIIIA was added to the Ringer solution to prevent muscle action potentials and contraction. 2. The nerve was stimulated with conditioning trains of 200-4800 impulses applied at 20 impulses s-1 to characterize the effects of repetitive stimulation on changes in EPP amplitude and MEPP frequency under high quantal conditions. 3. MEPP frequency was dramatically increased during and immediately following repetitive stimulation under high quantal conditions, whereas EPP amplitude was greatly depressed. There was no effect of repetitive stimulation on MEPP amplitude. 4. Following the conditioning stimulation the increase in MEPP frequency decayed back to the control level with a time course that could be described by four exponentials. The time constants of these exponentials were very similar to those that describe the components of stimulation-induced increases in EPP amplitude and MEPP frequency observed under low quantal conditions when depression is absent. 5. The results of this study indicate that depression and the components of stimulation-induced increases in release (facilitation, augmentation and potentiation) can be present at the same time, suggesting that the mechanism of depression involves different underlying factors from the mechanism(s) responsible for increases in release. They also indicate either that depression selectively affects only those quanta destined to be released in direct response to the nerve action potential, which would suggest that EPPs and MEPPs arise from different pools of transmitter, or that depression in some way affects a step in the release process involved only in evoked release, and not asynchronous (spontaneous) release.


Nursing process, student attributes, and teaching methodologies.
This study investigated the relationship among methodologies used in teaching the nursing process, nursing students' ability to use nursing process, and the following student attributes of: field-related perceptual functioning, impulsiveness, locus of control, convergent-divergent thinking ability, and scholastic aptitude. Data were collected from 201 students at the beginning and at the end of their first clinical nursing course in six institutions. Mean scores on the Group Embedded Figures Test, Different Uses Test, and Inference Test increased significantly. The most-used teaching methodology was teacher-dominated presentation; the least-used, individual conference. Findings regarding methods were based on replies from 77 faculty teaching the clinical course. A significant predictive relationship was found between the ability to use nursing process and inference ability, locus of control, and minimal time spent in small group discussion.


Molecular identification, antifungal susceptibility, and resistance mechanisms of pathogenic yeasts from the China antifungal resistance surveillance trial (CARST-fungi) study.
To have a comprehensive understanding of epidemiology and antifungal susceptibilities in pathogenic yeasts, the China Antifungal Resistance Surveillance Trial (CARST-fungi) study was conducted. All yeast isolates were identified by ribosomal DNA sequencing. Antifungal susceptibilities were performed using CLSI M27-A4 broth microdilution method. Sequence and expression level of resistant-related genes in resistant/non-wide-type (NWT) Candida isolates were analyzed. Totally 269 nonduplicate yeast isolates from 261 patients were collected. About half of the yeast isolates (127, 47.2%) were recovered from blood, followed by ascetic fluid (46, 17.1%). C. albicans remained the most prevalent (120, 44.6%), followed by C. parapsilosis complex (50, 18.6%), C. tropicalis (40, 14.9%), and C. glabrata (36, 13.4%). Fourteen (11.7%) C. albicans isolates and 1 (2.0%) C. parapsilosis isolate were resistant/NWT to triazoles. Only 42.5% (17/40) C. tropicalis were susceptible/WT to all the triazoles, with 19 (47.5%) isolates NWT to posaconazole and 8 (20%) cross-resistant to triazoles. Among C. glabrata, 20 (55.6%) and 8 (22.2%) isolates were resistant/NWT to voriconazole and posaconazole, respectively, and 4 (10.3%) isolates were cross-resistant to triazoles. Isavuconazole was the most active triazole against common Candida isolates. Except for 2 isolates of C. glabrata cross-resistant to echinocandins which were also NWT to POS and defined as multidrug-resistant, echinocandins exhibit good activity against common Candida species. All isolates were WT to AMB. For less common species, Rhodotorula mucilaginosa exhibited high MICs to echinocandins and FLC, and 1 isolate of Trichosporon asahii showed high MICs to all the antifungals except AMB. Among triazole-resistant Candida isolates, ERG11 mutations were detected in 10/14 C. albicans and 6/23 C. tropicalis, while 21/23 C. tropicalis showed MDR1 overexpression. Overexpression of CDR1, CDR2, and SNQ2 exhibited in 14, 13, and 8 of 25 triazole-resistant C. glabrata isolates, with 5 isolates harboring PDR1 mutations and 2 echinocandins-resistant isolates harboring S663P mutation in FKS2. Overall, the CARST-fungi study demonstrated that although C. albicans remain the most predominant species, non-C. albicans species accounted for a high proportion. Triazole-resistance is notable among C. tropicalis and C. glabrata. Multidrug-resistant isolates of C. glabrata and less common yeast have been emerging.


Lipidomics: quest for molecular lipid biomarkers in cardiovascular disease.
Lipidomics is the comprehensive analysis of molecular lipid species, including their quantitation and metabolic pathways. The huge diversity of native lipids and their modifications make lipidomic analyses challenging. The method of choice for sensitive detection and quantitation of molecular lipid species is mass spectrometry, either by direct infusion (shotgun lipidomics) or coupled with liquid chromatography. Although shotgun lipidomics allows for high-throughput analysis, low-abundant lipid species are not detected. Previous separation of lipid species by liquid chromatography increases ionization efficiency and is better suited for quantifying low abundant and isomeric lipid species. In this review, we will discuss the potential of lipidomics for cardiovascular research. To date, cardiovascular research predominantly focuses on the role of lipid classes rather than molecular entities. An in-depth knowledge about the molecular lipid species that contribute to the pathophysiology of cardiovascular diseases may provide better biomarkers and novel therapeutic targets for cardiovascular disease.


A solvothermal route to size- and phase-controlled highly luminescent NaYF4:Yb,Er up-conversion nanocrystals.
Size-controlled hexagonal- and cubic-phase NaYF4:Yb,Er nanocrystals with bright fluorescent emission were successfully synthesized via a solvothermal approach at a relatively low temperature (< 300 degrees C). A mixture of ethanol and ethylene glycol or pure ethylene glycol was used as a solvent, whereby changing the ethanol concentration. It is found that, besides reaction temperature and time, the reactant concentration is an important factor to control crystal phase. High reactant concentration, high reaction temperature, high concentration of ethanol and long reaction durations are favorable to the formation of brightly emitting hexagonal-phase nanocrystals. The effects of these reaction conditions on the size and the luminescent properties of the as-prepared nanocrystals are discussed. It is found that 30-120 nm hexagonal NaYF4:Yb,Er nanoparticles can be prepared using 0.04 M reactant concentration in 0-60% ethanol solution at 220 degrees C for 24 h.


Behavioural and anatomical characterization of mutant mice with targeted deletion of D1 dopamine receptor-expressing cells: response to acute morphine.
Considerable topographic overlap exists between brain opioidergic and dopaminergic neurons. Pharmacological blockade of the dopamine D(1) receptor (Drd1a) reverses several behavioural phenomena elicited by opioids. The present study examines the effects of morphine in adult mutant (MUT) mice expressing the attenuated diphtheria toxin-176 gene in Drd1a-expressing cells, a mutant line shown previously to undergo post-natal striatal atrophy and loss of Drd1a-expression. MUT and wild-type mice were assessed behaviourally following acute administration of 10 mg/kg morphine. Treatment with morphine reduced locomotion and rearing similarly in both genotypes but reduced total grooming only in MUT mice. Morphine-induced Straub tail and stillness were heightened in MUT mice. Chewing and sifting were decreased in MUT mice and these effects were not modified by morphine. Loss of striatal Drd1-positive cells and up-regulated D(2)-expression, as reflected in down-regulated D(1)-like and up-regulated D(2)-like binding, respectively, is not uniform along the cranio-caudal extent in this model but appears to be greater in the caudal striatum. Preferential caudal loss of µ-opioid-expression, a marker for the striosomal compartment, was seen. These data indicate that Drd1a-positive cell loss modifies the exploratory behavioural response elicited by morphine, unmasking novel morphine-induced MUT-specific behaviours and generating a hypersensitivity to morphine for others.


Concordance in physical growth for monozygotic and dizygotic twins.
Heights and weights were analysed for 636 twins who had been repeatedly measured from birth to 4 years. MZ twins were less concordant for birth weight than DZ twins, principally as a result of a few MZ pairs who exhibited very large differences. By one year of age, however, MZ twins had become more concordant for weight (Rmz = 0-87) while DZ twins moved further apart (Rdz = 0-55). For height, at birth, the MZ correlation was 0-58 while the DZ correlation was 0-82, but by 2 years, the MZ correlation reached 0-89 and the DZ correlation regressed to 0-58. The actual size differences within pairs followed a parallel course--for MZ twins, the differences became smaller following birth, whereas DZ differences became larger. The results are discussed in terms of (a) prenatal influences that differntially affect birth size within MZ pairs and DZ pairs, and (b) the rapid convergence of each twin on his genetic growth curve.


A cross-cultural comparison of British and Japanese lay theories of schizophrenia.
Nearly 300 matched British and Japanese participants completed an equivalent three-part questionnaire in their native language. The questionnaire covered general beliefs or conceptions about schizophrenia, causal explanations for the aetiology of schizophrenia, as well as the role of hospitals in particular, and society in general, in helping schizophrenics recover from their illness. It was predicted that the Japanese, who have more taboos about mental illness than the British, would see schizophrenics as more difficult, dangerous and "morally insane". Factor analysis of each of the three parts of the questionnaire yielded a clearly interpretable structure. The British were more concerned with the rights of schizophrenics and believed them to be less dangerous and abnormal than did the Japanese. The Japanese favoured sociological (stress) explanations more than the British for the cause of schizophrenia. Whereas the Japanese saw micro- and macro-society change as the best way to help schizophrenics, the British stressed individual care and consideration as more relevant.


Fluorescent light-induced DNA crosslinkage and chromatid breaks in mouse cells in culture.
A single 20-hr exposure of mouse cells derived from embryonic or lung tissue to cool-white fluorescent light (4.6 W/m2) causes both DNA damage and chromosome aberrations including chromatid breaks, exchanges, and minutes. In Kohn's alkaline elution technique, the DNA from exposed cells elutes more slowly than that from shielded cells. Because larger molecular weight DNA elutes slower than smaller, we interpret these results to mean that the DNA in cells exposed to light is crosslinked. The estimated frequency of crosslinks is sufficient to account for the number of chromatid breaks observed. The types of chromosome aberrations produced by light indicate that the primary lesion results in chromatid rather than chromosome breaks, and the results suggest an influence of cell density in that cells in densely populated cultures showed few or no chromatid breaks after irradiation. The present results, together with observations from the literature, suggest that the DNA crosslinkage and the chromosome aberrations produced by light may be related.


Irinotecan/IR-820 coloaded nanocomposite as a cooperative nanoplatform for combinational therapy of tumor.
To enhance synergistic therapeutic effects in breast cancer therapy. Here, we used hollow mesoporous silica nanoparticles as a biocompatible carrier to coload chemotherapy drugs Irinotecan and near-infrared IR-820 dye, which enhanced antitumor efficacy by combining chemotherapy and phototherapy. The successful synthesis of hollow mesoporous silica nanoparticles/Irinotecan/IR820 (HMII) nanocomplex was confirmed by Fourier transform infrared spectroscopy and Fluorescence spectra. The photothermal conversion efficiency and antitumor efficiency in murine breast cancer cells (EMT-6) bearing mice were further evaluated. The results demonstrated that HMII enhanced the delivery of Irinotecan and IR-820 into EMT-6 cells. HMII generated a high temperature upon a near-infrared laser irradiation (808 nm), and showed higher therapeutic efficacy in EMT-6-bearing mice compared with either HMII without laser or free drug with a laser. HMII is a desired drug codelivery system to efficiently inhibit the growth of breast cancer.


Bcr-Abl Tyrosine Kinase Inhibitors in the Treatment of Pediatric CML.
The therapeutic approach to Chronic Myeloid Leukemia (CML) has changed since the advent of the tyrosine kinase inhibitor (TKI) imatinib, which was then followed by the second generation TKIs dasatinib, nilotinib, and, finally, by ponatinib, a third-generation drug. At present, these therapeutic options represent the first-line treatment for adults. Based on clinical experience, imatinb, dasatinib, and nilotinib have been approved for children even though the studies that were concerned with efficacy and safety toward pediatric patients are still awaiting more specific and high-quality data. In this scenario, it is of utmost importance to prospectively validate data extrapolated from adult studies to set a standard therapeutic management for pediatric CML by employing appropriate formulations on the basis of pediatric clinical trials, which allow a careful monitoring of TKI-induced adverse effects especially in growing children exposed to long-term therapy.


Organochlorine and mercury residues in the harp seal (Pagophilus groenlandicus).
Samples of blubber, liver, kidney and brain, obtained from 10 male, 6 female neonatal, and 4 lactating female harp seals (Pagophilus groenlandicus), were analysed for DDT, dieldrin, PCB, and total mercury. Methyl mercury levels in blood were also determined. Biocide deposition was not significantly different in female and male ten day old pups. There were no significant differences in biocide levels in the liver of the 14/+ day old males, but in blubber there were significant differences in dieldrin and DDT. There was no clear relationship between biocide levels in the 6-18 year old lactating adults and their pups. Younger adult seals (6 and 7 years) were found to have higher levels of PCB and sigmaDDT levels in their blubber than did older females (10 and 18 years). Wide intraspecific variation was noted in organochlorine and mercury residue levels. Pups taken in 1973 were found to have lower organochlorine residues than pups taken in the same area in 1971. Preliminary investigation indicates that detectable amounts of organochlorine and mercury residues are capable of crossing the placenta in the harp seal.


Characterization of tissue chromogranin A (CgA) immunostaining and clinicohistopathological changes for the 125 Chinese patients with primary small cell carcinoma of the esophagus.
The rarity of primary small cell carcinoma of the esophagus (PSCE) has limited the clinical feature and survival analysis with large sample size. Tissue chromogranin A (CgA) protein expression has been reported to be a useful biomarker for diagnosing PSCE. Interestingly, recent studies have indicated tissue CgA as a significant prognostic marker in multiple human cancers, but without PSCE. The present study, thus, was undertaken to characterize the clinicopathological changes and to evaluate the associations of tissue CgA expression with clinical response on Chinese PSCE patients. All the 125 PSCE patients were enrolled from our 500,000 esophageal and gastric cardia carcinoma databases (1973-2015), constructed by the cooperative team from more than 700 hospitals in China and established by Henan Key Laboratory for Esophageal Cancer Research in Henan, China. Immunostaining for CgA showed that CgA was mainly located in cytoplasm of tumor cells with a positive detection rate of 44.6%. The CgA positive expression rate in PSCE at lower segment of the esophagus (72.2%) was higher than that at middle segment (41.5%) (P = 0.001). However, CgA protein expression did not correlated with lymph node metastasis (P = 0.767), TNM staging (P = 0.740), tumor invasion (P = 0.253), gender (P = 0.262), and age (P = 0.250). Multivariate survival analysis showed that the patients with higher CgA protein expression had a superior long survival than those without CgA expression (P = 0.037). The clinicopathological analysis showed that PSCE occurred predominantly in male (M:F = 1.9:1) at the middle segment (68%) of the esophagus. Histologically, 89.6% were pure PSCE and 10.4% were mixed type with either squamous cell carcinoma (8%) or adenocarcinoma (2.4%). It was noteworthy that, with the in-depth invasion from T1 to T2 and T3, the positive lymph node metastasis rate increased dramatically from 38%, 56% to 74%, respectively. The survival rates of 1-, 2-, 3-, and 5-year were 64%, 35%, 18%, and 7%, respectively. The Kaplan-Meier survival analysis showed that the young patients (≤60 years) had longer survival than the elderly (P = 0.011). Interestingly, multivariate survival analysis revealed that the patients with mixed PSCE had a significantly better survival than those with pure PSCE (P = 0.015). Furthermore, the median survival time for the patients with and without lymph node metastasis was 1.16 and 2.03 years, respectively. But, the difference was not significant (P = 0.143). Univariate analysis did not show any survival influence by gender, tumor location, tumor invasion depth, and TNM staging. It was noteworthy that, of the 13 early PSCE patients (T1N0M0), only one patient had more than 5 year survival, the others died with less than one or two year (65%). The present study indicates that the PSCE is of badly worsen prognosis, even in the pathological early stage. Tissue CgA protein expression is a promising maker not only for diagnosis and also for prognosis. Further assessment is needed to establish specific PSCE pathological staging system and to clarify the mechanisms of CgA protein in PSCE progression and prognosis.


Divergent Protocol for the Synthesis of Isoquinolino[1,2-b]quinazolinone and Isoquinolino[2,1-a]quinazolinone Derivatives.
The development of robust and step-economic strategies to access structurally diverse drug-like compound collections remains a challenge. A distinct structural option that constitutes the core scaffold of many biologically significant molecules is the quinazolinone ring system. Several members of this family of privileged substructures have gained attention due to their diverse biological activities. In this context, the development of an efficient strategy for their access is needed. Herein, we report a divergent metal-free operation to access a diverse collection of C6-substituted pyrrolo[4',3',2':4,5]isoquinolino[1,2-b]quinazolin-8(6H)-one and pyrrolo[4',3',2':4,5]isoquinolino[2,1-a]quinazolin-12(6H)-one architectures. The described cascade unites Friedel-Crafts and aza-Michael addition reactions. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the cascade features a promising approach for the design of unique compound libraries for drug design and discovery programs.


[Are the cytostatic drugs and their metabolites, excreted by patients during chemotherapy, hazardous for the family environment?].
In recent years the problem concerning adverse effects of excreted drugs and their active metabolites on other people and the environment has been found to be an important aspect of clinical pharmacology and environmental health. It is commonly known that antineoplastic drugs are hazardous to medical personnel who handle them, but cytostatics administered during ambulatory care are always transferred via the patient's organism to his home and hypothetically generate potential risk to other family members. The patient s home is a sub-set of the family environment where genetically determined predisposition to neoplastic disease could additionally appear. This could intensify the effect of exogenous factors responsible for carcinogenesis (e.g. cytostatics), and increase late consequences (e.g. mutations). To assess the risk the authors elaborated an algorithm for hazard identification and assessment of consequences of the hazard. Preliminary results indicated passage a/significant amounts of excreted cytostatics and their metabolites to the natural, hospital and also family environment. After excretion, mutagenic properties of these drugs were still observed. Chemical inactivation of the excreta of patients on chemotherapy completely eliminates or strongly reduces their mutagenicity. At the present time it is difficult to assess the total risk level of cytostalic drugs and their metabolites excreted by patients on chemotherapy, for their home environment. Risk identification based on dose-response and exposure assessment, will allow to determine the health, social and economic hazards and to establish standards of procedures with regard to the risk factor.


Anti-inflammatory effects of triptolide on IgA nephropathy in rats.
IgA nephropathy (IgAN) is the finding of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. Recently studies show that inflammation may involve in the progression of renal glomerulosclerosis and tubulointerstitial scarring in IgAN. This study was designed to evaluate the renoprotective effect of triptolide on IgAN rat model. IgAN was induced in Sprague-Dawley rats by oral and intravenous immunization with BSA for 12 weeks. Rats were treated with triptolide (200 μg/kg/d intragastrically) from 12 to 28 weeks. At Week 28, the rats was sacrificed, kidneys and blood samples were collected for further analysis. Our data shown that IgAN rat model showed marked deterioration of proteinuria together with higher levels of the urine protein:creatinine ratio compared to the normal control. Animals that underwent intermittent exposure to triptolide treatment exhibited significant improvements in the functional parameters without severe side effects. Rats developing IgAN had profound mesangial proliferation and mesangial expansion, intense and diffuse glomerular IgA deposition, while triptolide treatment significantly attenuated it. We also observed that treatment with triptolide significantly decreases serum levels of IL-1β and IL-18, and may exerted anti-inflammatory effects by down-regulating NLRP3 and TLR4 expression. Our study clearly demonstrated that triptolide prevents IgAN progression via an amelioration of inflammasome-mediated proinflammatory cytokine production, thus brought a light of hope for treatment of IgAN.


[(E)-1-[123I]Iodo-1-penten-5-yl]triphenylphosphonium iodide: convenient preparation of a potentially useful myocardial perfusion agent.
A rapid iodination method has been developed for the synthesis of the new 123I-labeled phosphonium cation [(E)-1-iodo-1-penten-5-yl]triphenylphosphonium iodide by I+ treatment of the corresponding trans-vinylboronic acid. This new model myocardial perfusion agent is obtained after purification in 25-50% yield in less than 1 h. High myocardial uptake (5 min, 2.38% dose/g) with prolonged retention (3 h, 2.21% dose/g) was observed in rats. In addition, heart/blood ratios were high and continued to increase over a 1-day period (5 min, 17:1; 60 min, 23:1; 3 h, 27:1; 1 day, 158:1). In rats, the liver uptake was moderate (5 min, 1.40% dose/g; 60 min; 0.25% dose/g). Excellent myocardial images were obtained in a dog.


A pragmatic clinical effectiveness trial of a novel alternative to punishment for school-based substance use infractions: study protocol for the iDECIDE curriculum.
Adolescents who use alcohol and other drugs on school campuses are at heightened risk for adverse consequences to their health and wellbeing. Schools have historically turned to punitive approaches as a first-line response to substance use. However, punishment is an ineffective deterrent for substance use and may cause harm and increase inequities. iDECIDE (Drug Education Curriculum: Intervention, Diversion, and Empowerment) was developed as a scalable and youth-centered drug education and diversion program that can be used as a skills-based alternative to punishment. We aim to evaluate the effectiveness of the iDECIDE curriculum as an alternative to punishment (ATP) for school-based substance use infractions in the context of a large pragmatic clinical effectiveness study. We will conduct a Type 1, hybrid effectiveness-implementation trial. Using a stepped wedge design with approximately 90 middle and high schools in Massachusetts, we will randomly allocate the timing of implementation of the iDECIDE curriculum compared to standard disciplinary response over approximately 36 months. We will test the overarching hypothesis that student-level outcomes (knowledge of drug effects and attitudes about substance use; frequency of substance use; school connectedness) improve over time as schools transition from a standard disciplinary response to having access to iDECIDE. The secondary aims of this trial are to (1) explore whether change in student-level outcomes vary according to baseline substance use, number of peers who use alcohol or other drugs, age, gender, and school urbanicity, and (2) determine the acceptability and feasibility of the iDECIDE curriculum through qualitative stakeholder interviews. Substance use continues to be a major and rapidly evolving problem in schools. The importance of moving away from punishment to more restorative approaches is widely accepted; however, scalable alternatives have not yet been identified. This will be the first study to our knowledge to systematically evaluate an ATP for students who violate the school substance use policy and is well poised to have important implications for policy making.


Single, double and triple deprotonation of a beta-diketimine bearing pendant pyridyl group and the corresponding rare-earth metal complexes.
A new beta-diketimine bearing the pendant pyridyl group, CH(3)C(2,6-((i)Pr)(2)C(6)H(3)NH)CHC(CH(3))(NCH(2)-C(5)NH(4)) (L1), was synthesized. The reaction of L1 with one equivalent of Sc(CH(2)SiMe(3))(3)(THF)(2) at room temperature gave a singly deprotonated product (L1-H)Sc(CH(2)SiMe(3))(2) (1). Y(CH(2)SiMe(3))(3)(THF)(2) under the same conditions led to the unexpected dimer [(L1-H(3))Y(THF)](2) (2), in which the ligand precursor L1 was triply deprotonated. The reaction of L1 with Y(CH(2)SiMe(3))(3)(THF)(2) at -35 degrees C provided a mixture of singly deprotonated product (L1-H)Y(CH(2)SiMe(3))(2) (3) and doubly deprotonated product (L1-H(2))Y(CH(2)SiMe(3))(THF)(2) (4). The reactions of L1 with Ln[N(SiMe(3))(2)](3) gave only singly deprotonated products (L1-H)Ln[N(SiMe(3))(2)](2) (5: Ln = Y; 6: Ln = La). The complexes 1, 2 and 4-6 have been characterized by single-crystal X-ray diffraction.


Positron emission tomography in the detection of malignant degeneration of low-grade gliomas.
The management of low-grade gliomas represents a challenge to the physician as a significant proportion may undergo malignant degeneration to a high-grade tumor. We present the positron emission tomography (PET) scans, using [18F] fluorodeoxyglucose (FDG), of 12 patients who have histological and/or clinical evidence of malignant degeneration of a low-grade glioma. Each scan displays a focal area of hypermetabolism similar to that of malignant gliomas which arise de novo. Three patients also underwent PET scanning prior to malignant degeneration. When the initial scan is compared with the postmalignant degeneration study, a difference in tumoral glucose uptake can be recognized. A region previously shown to be hypometabolic develops focal hypermetabolism as malignant changes evolve. This study displays the utility of FDG-PET in the evaluation of malignant degeneration of low-grade gliomas. The knowledge that a neoplasm has altered its biological behavior may influence subsequent therapeutic options. If these findings can be confirmed in larger series and by other investigators, it is possible that FDG-PET may be adopted as one of the diagnostic tools for guiding the management of low-grade gliomas.


Central neurocytoma--case report.
A 29-year-old male was admitted with chronic headache on February 26, 1987, when there were no neurological deficits or physical abnormalities. Computed tomographic (CT) scans showed a mixed-density mass with no evidence of calcification in the left lateral ventricle, which was irregularly enhanced by contrast medium. Under a diagnosis of an intraventricular glial tumor, surgery was performed via a left transcortical-transventricular approach on March 31. The highly vascular, nodular tumor, originated from the lateral wall of the left lateral ventricle near the foramen of Monro, was successfully removed. The postoperative course was uneventful and he was discharged 3 months after postoperative irradiation. Light microscopic examination revealed the tumor cells with the clear cytoplasm and perinuclear halos characteristic of an oligodendroglioma. However, electron microscopy showed neuronal elements identical with central neurocytoma as reported by Hassoun et al. in 1982. These included large numbers of dense-core or clear vesicles in the cell processes and synaptic structures.


Defining the consensus sequences of E.coli promoter elements by random selection.
The consensus sequence of E.coli promoter elements was determined by the method of random selection. A large collection of hybrid molecules was produced in which random-sequence oligonucleotides were cloned in place of a wild-type promoter element, and functional -10 and -35 E.coli promoter elements were obtained by a genetic selection involving the expression of a structural gene. The DNA sequences and relative levels of function for -10 and -35 elements were determined. The consensus sequences determined by this approach are very similar to those determined by comparing DNA sequences of naturally occurring E.coli promoters. However, no strong correlation is observed between similarity to the consensus and relative level of function. The results are considered in terms of E.coli promoter function and of the general applicability of the random selection method.


Mechanisms contributing to the genesis of hypoglossal preinspiratory discharge.
Preinspiratory discharge manifests in the neuronal recordings of the pre-Bötzinger complex, parafacial respiratory group, retrotrapezoid nucleus, and Kölliker-Fuse nucleus, as well as the efferent neural discharge of respiratory-related nerves innervating upper airway musculature. This neural component of triphasic eupnea contemporaneously contributes to the genesis of native and originate respiratory rhythmic activity, as well as the preinspiratory component of efferent neural respiratory discharges. In the course of our investigations evaluating hypoglossal discharge in response to asphyxia, we noted a curious pattern of neural respiratory recovery following postasphyxia resuscitation in hypoglossal, vagal, and phrenic neurograms in unanesthetized decerebrate rats. Specifically, we observed a gradual return of a pseudobiphasic eupnea characterized by initial transition bursts followed by robust eupneic bursts with dynamics inclusive of a gradually and progressively increasing duration of the hypoglossal eupneic bursts and duration and amplitude of the preinspiratory component of these bursts, as well as progressively lengthening expiratory interval between these bursts in the phrenic nerve discharge. This was followed by conversion to regular triphasic eupnea. We discuss our extrapolations based on these findings regarding eupneic respiratory central pattern generation and mechanisms contributing to the genesis of preinspiratory activity in hypoglossal discharge.


A particle swarm optimizer with passive congregation.
This paper presents a particle swarm optimizer (PSO) with passive congregation to improve the performance of standard PSO (SPSO). Passive congregation is an important biological force preserving swarm integrity. By introducing passive congregation to PSO, information can be transferred among individuals of the swarm. A particle swarm optimizer with passive congregation (PSOPC) is tested with a set of 10 benchmark functions with 30 dimensions and compared to a global version of SPSO (GSPSO), a local version of SPSO (LSPSO), and PSO with a constriction factor (CPSO), respectively. Experimental results indicate that the PSO with passive congregation improves the search performance on the benchmark functions significantly.


Evidence of an isomeric pair in furan...HCl: Fourier transform infrared spectroscopy and ab initio calculations.
For the first time the coexistence of a sigma- and a pi-complex in the C(4)H(4)O:HCl system has been observed, in the same supersonic expansion of a molecular jet seeded with argon (or helium) or in a flow-cooled cell at 240 K. This is an exception to the third of the Legon-Miller rules which claims the sigma-structure to be the only one to exist. On the grounds of energetic considerations and band contour simulations, two observed bands at 2787.7 and 2795.5 cm(-1) of the nu(s) HCl stretching frequency are assigned to the two complexes, recorded as Fourier transform infrared spectra with a resolution between 0.2 and 0.5 cm(-1). Complementary calculations show that the use of the standard second-order Moller-Plesset perturbation theory may be erroneous for such a complex, due of the overestimation of the dispersion contribution with respect to the electrostatic term. It is finally established that only a balanced version of the second-order Moller-Plesset perturbation method, spin-component scaled-MP2, or a higher level of theory like a coupled-cluster approach, can provide a reliable energetic analysis for this complex.


Parallel mitral and tufted cell pathways route distinct odor information to different targets in the olfactory cortex.
Odor signals are conveyed from the olfactory bulb to the olfactory cortex (OC) by mitral cells (MCs) and tufted cells (TCs). However, whether and how the two types of projection neuron differ in function and axonal connectivity is still poorly understood. Odor responses and axonal projection patterns were compared between MCs and TCs in mice by visualizing axons of electrophysiologically identified single neurons. TCs demonstrated shorter onset latency for reliable responses than MCs. The shorter latency response of TCs was maintained in a wide range of odor concentrations, whereas MCs responded only to strong signals. Furthermore, individual TCs projected densely to focal targets only in anterior areas of the OC, whereas individual MCs dispersedly projected to all OC areas. Surprisingly, in anterior OC areas, the two cell types projected to segregated subareas. These results suggest that MCs and TCs transmit temporally distinct odor information to different OC targets.


Nitric oxide and renal function.
A wealth of evidence shows that nitric oxide can modulate the autoregulation of renal blood flow, the glomerular surface area available for filtration, the glomerulotubular feedback response, and the release of renin. From an integrative point of view, inhibition of nitric oxide synthesis will alter the function of all of these homeostatic mechanisms and impair the pressure-induced natriuresis secondary to increases in intrarenal vascular resistance and tubular sodium reabsorption. These effects, along with an elevation of both total peripheral resistance and vascular tone of the capacitance vessels, are the most likely determinants of the volume-dependent elevation of blood pressure (ie, salt-sensitive hypertension) that occurs during partial inhibition of nitric oxide synthesis. This observation has important physiological and pathologic implications because it shows for the first time that the blockade of a single endogenous vasodilator substance can produce a sustained increase in blood pressure that can be influenced by changes in blood volume. Because of these characteristics, this review emphasizes in particular the characteristics of the nitric oxide synthesis pathway and briefly describes several known methods of increasing the biologic activity of nitric oxide; these methods eventually may be modified and used as therapeutic interventions in humans with deficient nitric oxide synthesis.


Perfluorooctane sulfonate concentrations in surface water in Japan.
Perfluorooctane sulfonate (PFOS) is a class of specialty chemicals used in a variety of applications, and has been found to be globally distributed in many living organisms including humans. Several analytical methods have been developed for determination of PFOS in environmental samples and biological matrices. However, these methods employ liquid chromatography/tandem mass spectrometry (LC/MS/MS), an instrumentation which has limited accessibility because it is expensive to use and maintain. In the present study we present the development of a robust analytical method using liquid chromatography/mass spectrometry (LC/MS) in combination with solid phase extraction. The high yield and concentration of the present method enabled us to quantify PFOS as low as 0.1 ng/L. This method was applied to the determination of PFOS in 142 surface water samples collected from various geographic locations around Japan. The geometric mean (geometric standard deviation) (ng/L) for river samples (n = 126) was 2.37 (4.13), with a median of 1.68 and a range of 0.3-157 ng/L, and for coastal sea water samples (n = 16) was 1.52 (4.14), with a median of 1.21 and a range of 0.2-25.2 ng/L. However, the concentrations in most of the samples were much lower than the values reported in the US, except for those from the Jinzu (135.0 ng/L) and Tama (157 ng/L) Rivers. Because surface waters in the Ara (13.0-38.5 ng/L), Tama (0.7-157.0 ng/L), and Yodo (0.9-27.3 ng/L) Rivers, sources of drinking water for more than eight million people, were moderately contaminated with PFOS, more work is needed to assess exposure to PFOS.


Moiré Enhanced Two-Band Superconductivity in a MnTe/NbSe2 Heterojunction.
Recent advances in creating moiré periods of two-dimensional heterostructures enable diverse and compatible tunability to modulate the conventional proximity effect involving superconductivity, magnetism, and topology. Here, by constructing a MnTe/NbSe2 heterojunction via molecular beam epitaxy growth, we report on a moiré-enhanced multiband superconductivity by low-temperature scanning tunneling microscopy/spectroscopy measurements. We observe a distinct double-gap superconducting spectrum on monolayer MnTe that is absent on the NbSe2 substrate. The subgap character exhibits a moiré-related oscillation in real space, which can be well described by an effective two-band model. The restored two-gap feature and its rapid suppression under a small magnetic field are speculated to be mediated by the moiré superlattice, which is closely related to the enhanced interband coupling strength of quasiparticle scattering. Our work paves the way for engineering proximitized properties of heterostructures by a moiré landscape with spatial modulations.


Nanomaterial-Facilitated Cyclin-Dependent Kinase 7 Inhibition Suppresses Gallbladder Cancer Progression via Targeting Transcriptional Addiction.
Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract cancer, and there is a lack of effective treatment. Here, we developed a nanoparticle platform (8P4 NP) that can deliver THZ1, a cyclin-dependent kinase 7 (CDK7) inhibitor, to treat GBC. Analysis of datasets demonstrated that CDK7 was positively correlated with poor prognosis. CDK7 inhibition suppressed cell proliferation, induced apoptosis, and caused cell cycle block in GBC cells. THZ1 downregulated CDK7-mediated phosphorylation of RNA polymerase II (RNAPII), resulting in a significant downregulation of transcriptional programs, with a preferential repression of oncogenic transcription factors. To improve the tumor targeting efficiency of THZ1, 8P4 NPs were prepared and assembled with THZ1 to form THZ1@8P4 NPs. Compared with free THZ1, THZ1@8P4 NPs showed more advantages in prolonging blood circulation, escaping from lysosomes and increasing cellular uptake. Importantly, THZ1@8P4 NPs demonstrated a more significant inhibition effect on GBC cells than free THZ1 in vitro. In addition, THZ1@8P4 NPs could efficiently deliver THZ1 to tumor sites in a patient-derived xenograft model of early recurrence, leading to tumor regression and transcriptional inhibition with minimal toxicity. In summary, we conclude that THZ1@8P4 NPs provide a potent therapeutic strategy that targets CDK7-mediated transcriptional addiction in GBC.


Prognostic stratification of Dukes B colon cancer by a neoglycoprotein.
Disease progression of tumors is accompanied by structural changes of the glycan chains of cellular glycoconjugates. Within the concept of the sugar code the presence of complementary receptors such as lectins translates changes in ligand presentation into biological effects, for example in growth regulation and adhesion. By introducing neoglycoproteins to histopathological colon cancer analysis the questions are addressed as to whether specific binding sites for main N- and O-glycan components are present and whether they harbor potential for prognostic predictions. Synthetic conjugation of fucose, lactose, and mannose derivatives to a carrier protein yielded neoglycoproteins for glycohistochemical analysis. The tumor panel included routinely fixed tissue sections from 67 cancer cases (15 Dukes A, 20 Dukes B, 15 Dukes C, and 17 metastatic tumors) and 6 hepatic metastases as well as 20 normal biopsy specimens as control. Quantitative image analysis determined the labeling index and the mean optical density in each case, separating tumor and peritumoral connective tissue. Specific carbohydrate-dependent binding with inter-individual heterogeneity was observed. The distinct staining profiles were not associated with disease stage or metastasis formation. Strong expression of lactose-binding sites in the peritumoral connective tissue especially in terms of the labeling index was significantly correlated with reduced survival in Dukes B patients (p=0.02). A similar tendency was observed in the Dukes C group. In conclusion, the application of the synthetic markers aimed at lectin detection defines lactose binding as new prognostic marker. It has potential relevance for improving the benefit from adjuvant therapy in Dukes B colorectal cancer patients. Technically, chemical ligand immobilization to an inert carrier can find useful application beyond glycosciences in the quest to extend the panel of tumor markers.


Degradation of foot-and-mouth disease virus during composting of infected pig carcasses.
The objective of this study was to investigate the inactivation and degradation of foot-and-mouth disease (FMD) virus during composting of infected pig carcasses as measured by virus isolation in tissue culture and by real-time reverse transcriptase polymerase chain reaction (RRT-PCR). Three FMD-infected pig carcasses were composted in a mixture of chicken manure and wood shavings in a biocontainment level 3 facility. Compost temperatures had reached 50 degrees C and 70 degrees C by days 10 and 19, respectively. Under these conditions, FMD virus was inactivated in specimens in compost by day 10 and the viral RNA was degraded in skin and internal organ tissues by day 21. In comparison, at ambient temperatures close to 20 degrees C, FMD virus survived to day 10 in the skin tissue specimen from the pig that had the highest initial level of viral RNA in its tissues and the viral RNA persisted to day 21. Similarly, beta-actin mRNA, tested as a PCR control, persisted to day 21 in specimens held at ambient temperatures, but it was degraded in the remnants of tissues recovered from compost on day 21. Results from this study provide evidence that composting could be used for safe disposal of pig carcasses infected with FMD virus.


Maternal glucose in pregnancy is associated with child's adiposity and leptin at 5 years of age.
Exposure to maternal hyperglycaemia in pregnancy has been associated with childhood obesity. Leptin regulation might be involved in this 'adiposity programming' and may depend on timing of exposure. To investigate associations of maternal glycaemia at different periods in pregnancy with childhood adiposity and leptin levels at 5 years of age. In a prospective pre-birth cohort, we measured maternal glucose levels after a 50 g oral glucose challenge test at first trimester (9.8 ± 2.3 weeks) and during a 75 g oral glucose tolerance test at second trimester (26.5 ± 0.9 weeks). We followed up children at 5 years; we measured anthropometry and body composition using dual-energy X-ray absorptiometry (DXA). We measured fasting leptin levels using immunoassays (Luminex) in 328 children. We conducted linear regression analyses, adjusting for potential confounders. Maternal glycaemia at first trimester was associated with childhood leptin levels at 5 years, independently of maternal pre-pregnancy BMI and other confounders (β = .09 ± .04; P = .03). Higher post-load glucose levels at second trimester were associated with greater total body fat percentage measured by DXA (1 hour-glucose: β = .010 ± .004; P = .03 and 2 hours-glucose: β = .016 ± .005; P = .002), but not with leptin levels. Our results suggest that programming of leptin regulation may be sensitive to maternal hyperglycaemia specifically in early pregnancy.


[Helminth fauna of Neurergus strauchii (Steindachner, 1888) (spotted salamander) collected in Malatya and Bitlis].
Forty-one (23 females, 18 males) Neurergus strauchii (spotted salamanders) collected in Malatya and Bitlis, were examined for helminths in 2001-2002. In this study, 1 helminth species, Cosmocerca commutata (Nematoda) was found. This study is the first helminthological research on spotted salamanders in the world. Also, this is the first time the parasite of frogs has been reported in Neurergus strauchii.


A transport-dependent energy burden imposed by growth of Enterobacter cloacae in the presence of 10% sodium dodecyl sulfate.
Growth of Enterobacter cloacae in a glucose asparagine salts medium in the presence of 10% sodium dodecyl sulfate entailed an energy burden in the form of a 20% decreased cell yield, a 30% faster rate of glucose utilization, and a 70% increased rate of oxygen consumption. Similar detergent-induced decreases in cell yield were observed with 10 other sugars and sugar alcohols. Only glycerol supported equivalent cell growth in the presence and absence of sodium dodecyl sulfate. A model is presented which interprets these observations in terms of an altered membrane potential which makes active transport energetically less efficient.


Cloning and characterization of CmGPD1, the Candida magnoliae homologue of glycerol-3-phosphate dehydrogenase.
Glycerol-3-phosphate dehydrogenase (GPDH) plays a central role in glycerol metabolism. A genomic CmGPD1 gene encoding NADH-dependent GPDH was isolated from Candida magnoliae producing a significant amount of glycerol. The gene encodes a polypeptide of 360 amino acids, which shows high homology with known NADH-dependent GPDHs of other species. The CmGPD1 gene was expressed in recombinant Escherichia coli with the maltose-binding protein (MBP) fusion system and purified to homogeneity using simple affinity chromatography. The purified CmGpd1p without the MBP fusion displayed an apparent molecular mass of 40 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. The CmGpd1p enzyme exhibited a K(cat)/K(m) value of 195 min(-1) mM(-1) for dihydroxyacetone phosphate whereas K(cat)/K(m) for glycerol-3-phosphate is 0.385 min(-1) mM(-1). In a complementation study, CmGpd1p rescued the ability of glycerol synthesis and salt tolerance in a Saccharomyces cerevisiae GPD1DeltaGPD2Delta mutant strain. The overall results indicated that CmGPD1 encodes a functional homologue of S. cerevisiae GPDH.


Inter-donor variation in cell subset specific immune signaling responses in healthy individuals.
Single cell network profiling (SCNP) is a multi-parameter flow cytometry based approach that allows for the simultaneous interrogation of intracellular signaling pathways in multiple cell subpopulations within heterogeneous tissues, without the need for individual cell subset isolation. Thus, the technology is extremely well-suited for characterizing the multitude of interconnected signaling pathways and immune cell subpopulations that regulate the function of the immune system. Recently, SCNP was applied to generate a functional map of the healthy human immune cell signaling network by profiling immune signaling pathways downstream of 12 immunomodulators in 7 distinct immune cell subsets within peripheral blood mononuclear cells (PBMCs) from 60 healthy donors. In the study reported here, the degree of inter-donor variation in the magnitude of the immune signaling responses was analyzed. The highest inter-donor differences in immune signaling pathway activity occurred following perturbation of the immune signaling network, rather than in basal signaling. When examining the full panel of immune signaling responses, as one may expect, the overall degree of inter-donor variation was positively correlated (r = 0.727) with the magnitude of node response (i.e. a larger median signaling response was associated with greater inter-donor variation). However, when examining the degree of heterogeneity across cell subpopulations for individual signaling nodes, cell subset specificity in the degree of inter-donor variation was observed for several nodes. For such nodes, relatively weak correlations between inter-donor variation and the magnitude of the response were observed. Further, within the phenotypically distinct subpopulations, a fraction of the immune signaling responses had bimodal response profiles in which (a) only a portion of the cells had elevated phospho-protein levels following modulation and (b) the proportion of responsive cells varied by donor. These data exemplify the application of SCNP to provide a detailed characterization of inter-donor variation in immune signaling pathway activation in a healthy donor cohort. This dataset provides a basis for identifying cell subpopulation specific immune signaling abnormalities in cancer and immune-mediated diseases. Building upon these data in future studies may help inform on disease etiology, maintenance and therapeutic selection.


Patients' Knowledge and Perceptions of Morcellation.
Morcellation has received increased media and professional attention, but it remains unclear how much the average patient knows about this topic. We sought to evaluate patients' knowledge of morcellation, assess their perceptions of the risks and benefits, and determine how these perceptions affect their decision regarding the route of surgery. Anonymous paper surveys were administered to 500 patients attending gynecologic appointments at the University of Michigan. Survey questions gathered demographic information and assessed knowledge of various surgical approaches for hysterectomy and myomectomy. Questions regarding patients' knowledge of morcellation explored various types of morcellation and the risks and benefits of this procedure. Of the 500 surveys administered, 396 patients answered at least 1 survey question resulting in a response rate of 79.2%. The mean ± SD age of respondents was 47.0 ± 14.1 years, 80.8% were white, and 83.1% had completed some college. Only 8.3% of patients reported that they had ever heard of morcellation. Even among women who were actively considering a hysterectomy or myomectomy (n = 33) or those who had undergone a hysterectomy or myomectomy (n = 98), only 12.1 and 7.1%, respectively, had heard of morcellation. Of those who had heard of morcellation (n = 32), only 9.4% correctly identified the definition in a multiple-choice question. Only 4.0% of women would choose an abdominal approach to avoid morcellation. Patients have very little knowledge about morcellation and most patients have never heard of the procedure. Very few patients would refuse morcellation and opt for an abdominal surgery instead.


A knowledge infrastructure for occupational safety and health.
Occupational Safety and Health (OSH) professionals should use scientific evidence to support their decisions in policy and practice. Although examples from practice show that progress has been made in evidence-based decision making, there is a challenge to improve and extend the facilities that support knowledge translation in practice. A knowledge infrastructure that supports OSH practice should include scientific research, systematic reviews, practice guidelines, and other tools for professionals such as well accessible virtual libraries and databases providing knowledge, quality tools, and good learning materials. A good infrastructure connects facilities with each other and with practice. Training and education is needed for OSH professionals in the use of evidence to improve effectiveness and efficiency. New initiatives show that occupational health can profit from intensified international collaboration to establish a good functioning knowledge infrastructure.


Chronic spontaneous urticaria: new evidences on the role of autoimmunity.
The purpose of this review is to provide an overview of the recent advancements and relevance of the autoimmune theories in chronic spontaneous urticaria (CSU). Two primary types of autoimmunity, Type I and Type IIb, have emerged as major contributors to CSU, characterized by immunoglobulin E (IgE) and immunoglobulin G (IgG) autoantibodies, respectively. Genetic evidence supports the notion that CSU shares more similarities with other autoimmune diseases rather than atopic diseases. Novel autoallergens such as FcεRI and tissue transglutaminase have been identified, contributed to our understanding of autoimmune mechanisms. Furthermore, the potential overlap between Type I and Type IIb autoimmunity has been recognized. Evaluating the autoimmune status of CSU patients through biomarkers and understanding their clinical implications is vital for effective management. For instance, CSU patients with Type IIb autoimmunity, with or without coexisting Type I autoimmunity, may exhibit resistance to H1-antihistamines and omalizumab treatment but could potentially respond well to cyclosporine or Bruton's tyrosine kinase inhibitors. Further investigations are needed to explore new autoallergens and autoantibodies in CSU, establishing their connection to the development of autoimmunity. The efficacy of novel drugs targeting different mechanisms should be examined to determine their responses in both autoimmune CSU and nonautoimmunity-related CSU.


Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer.
The epithelial-mesenchymal transition (EMT) enhances cancer invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We show that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6-biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecule biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and reactive oxygen species production by suppressing mitochondrial complex I activity; this metabolic reprogramming results in an increased CSC-like property and tumorigenicity by enhancing the interaction of β-catenin with T-cell factor. Our study indicates that the loss of FBP1 is a critical oncogenic event in EMT and BLBC.


Evaluation of Surface Treatments of PDMS Microfluidic Devices for Improving Small-Molecule Recovery with Application to Monitoring Metabolites Secreted from Islets of Langerhans.
Microfluidic devices are becoming an important tool for bioanalysis with applications including studying cell secretion, cell growth, and drug delivery. Small molecules such as drugs, cell products, or nutrients may partition into polydimethylsiloxane (PDMS), a commonly used material for microfluidic devices, potentially leading to poor recovery or inaccurate delivery of such chemicals. To decrease small-molecule partitioning, surface and bulk PDMS treatments have been developed; however, these have been tested on few analytes, or their biocompatibility are unknown. Studies often focus on one analyte, whereas a diversity of chemicals are of interest and possibly affected. In this study, 11 device treatments are tested and applied to 21 biologically relevant small molecules with a variety of chemical structures. Device treatments are characterized using water contact angle measurements and evaluated by measuring recovery of the 21 target analytes using liquid chromatography-mass spectrometry. 1,5-Dimethyl-1,5-diazaundecamethylene polymethobromide (polybrene), a positively charged polymer, produced the least hydrophilic surface and was found to provide the best recovery with most of the analytes having >50% recovery and up to 92% recovery; however, recovery varied by analyte highlighting the importance of analyte diversity rather than targeting a single analyte in evaluating treatments. A polybrene-treated device was applied to investigate secretion from pancreatic islets, which are micro-organs involved in glucose homeostasis and diabetes. Islets secrete small molecules that have been shown to modulate the secretion of islets' main functional products, glucose-regulating hormones. The polybrene treatment enabled the detection of 20 target analytes from islets-on-chip during isosmotic and hypo-osmotic glucose perfusions and resulted in detection of more significant secretion changes compared to untreated PDMS.


Activity of bis(7-hydroxycoumarin) Mannich bases against bovine viral diarrhoea virus.
Some Mannich bases of 7-hydroxycoumarins (3-6) with piperazine or other amines bearing two secondary amine groups were prepared and tested against viruses representative of RNA families. All compounds were symmetrical and possessed two identical coumarin moieties with respect to one diamine. In the series of 7-hydroxy derivatives, 3a was endowed with a significant activity against BVDV. Then, some of these double Mannich bases were alkylated and acylated. Among the propyloxy derivatives, only 3f showed a modest activity against BVDV. Among the acyl derivatives, the p-nitrobenzoyl derivative 3i emerged as the most active compound; in this series, the p-nitrobenzoyl derivative 3j also exhibited good action against BVDV and modest activity against CVB-5. On the whole, the compounds presented here show some differences, with respect to previous studies in terms of SAR from similar Mannich bases of 7-hydroxycoumarin.


Monoclonal antibody-mediated tumor regression by induction of apoptosis.
To characterize cell surface molecules involved in control of growth of malignant lymphocytes, monoclonal antibodies were raised against the human B lymphoblast cell line SKW6.4. One monoclonal antibody, anti-APO-1, reacted with a 52-kilodalton antigen (APO-1) on a set of activated human lymphocytes, on malignant human lymphocyte lines, and on some patient-derived leukemic cells. Nanogram quantities of anti-APO-1 completely blocked proliferation of cells bearing APO-1 in vitro in a manner characteristic of a process called programmed cell death or apoptosis. Cell death was preceded by changes in cell morphology and fragmentation of DNA. This process was distinct from antibody- and complement-dependent cell lysis and was mediated by the antibody alone. A single intravenous injection of anti-APO-1 into nu/nu mice carrying a xenotransplant of a human B cell tumor induced regression of this tumor within a few days. Histological thin sections of the regressing tumor showed that anti-APO-1 was able to induce apoptosis in vivo. Thus, induction of apoptosis as a consequence of a signal mediated through cell surface molecules like APO-1 may be a useful therapeutic approach in treatment of malignancy.


Isolation and characterization of small phosphorylated peptides controlling transcription "in vitro" from trout testis chromatin DNA.
Low molecular weight peptides are linked to the chromatin DNA of several tissues, from which they can be dissociated by alkaline extraction. They show very high specific activity in the control of transcription "in vitro". In this work the biochemical properties of controlling transcription peptide effectors isolated from trout testis DNA are reported. The purified peptides prevailingly contain glutamic acid, serine, aspartic acid, glycine and alanine. Studies of the peptide structure by N-terminal analysis using the dansyl chloride procedure was unsuccessful, suggesting the presence of a blocked NH2 group. At the same time the active peptides cannot be digested by carboxypeptidases. The gel filtration of the chromatin peptidic fractions on Sephadex G-25, Trisacryl GF05 or Sephadex G-15 shows that the active peptides elute as a single major peak with an elution volume corresponding to a molecular weight of about 1000. The paper electrophoresis performed at different pH and ionic strength shows that the chromatin peptides are separated in two fractions. One of them is strongly acidic and migrates towards the positive pole until pH 1.9, indicating the presence of phosphoric residues which probably exert an important role in the control of transcription "in vitro". The chromatin peptides are further purified by Sephadex G-10 and high performance liquid chromatography. The amino acid analysis of the purified peptides are reported.


The effect of cold application on pain during the chest tube removal: A meta-analysis.
In this meta-analysis, we aimed to investigate the effect of cold application on chest tube removal-related pain compared to conventional analgesic care. A systematic review and meta-analysis were conducted (PROSPERO, 2021: CRD42020179867). We searched studies in PubMed, Ovid-LWW, Scopus, Taylor & Francis, Science Direct, EBSCO, Google Scholar, Medline Complete, Cochrane Library and ULAKBIM databases and grey literature for this study. We included the articles published from January 2009 to December 2019. We limited the language to Turkish and English and the design to randomized-controlled trials. All studies were reviewed by two independent researchers. Meta-analysis was performed using the Comprehensive Meta-Analysis version 3.3 software. Heterogeneity was investigated by meta-regression. A total of 2,462 records were identified, of which 16 studies were included in a random model meta-analysis. The cold application was used in combination with a pharmacological agent in six studies and alone in 13 studies. All patients were older than 16 years and they had at least one chest tube. Cold application was found to be effective in relieving pain during chest tube removal (d=-1.265). The use of a non-pharmacological method such as cold application is helpful to reduce pain or reduce painkiller doses during chest tube removal. Its use is recommended, as it is effective, easy to use, and cost-effective without any side effects.


Rivastigmine versus placebo in hyperhomocysteinemic Parkinson's disease dementia patients.
The effects of rivastigmine versus placebo in Parkinson's disease dementia (PDD) patients with elevated or normal/low plasma homocysteine were determined. In this prospective analysis of a 24-week, randomly assigned, placebo-controlled study of rivastigmine in PDD, subpopulations comprised patients with plasma homocysteine >or=14 micromol/L (elevated) or <14 micromol/L (normal/low). Coprimary outcomes were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Alzheimer Disease Cooperative Society-Clinical Global Impression of Change (ADCS-CGIC). Secondary outcomes included additional measures of cognition, including attention and executive function, daily function, and neuropsychiatric symptoms. Adverse events (AEs) were monitored. In total, 342 of 541 patients provided samples for analysis, from which 72% had elevated plasma homocysteine. Hyperhomocysteinemic patients showed treatment differences (rivastigmine vs. placebo) of 4.0 on ADAS-cog and 0.7 on ADCS-CGIC (both P < 0.01), and significant treatment differences on secondary outcomes. Rivastigmine- and placebo-treated hyperhomocysteinemic patients (16.5% and 14.6%) discontinued the study because of AEs. Patients with normal/low homocysteine showed no treatment differences on primary or secondary outcomes (1.4 on the ADAS-cog and 0.1 on ADCS-CGIC, both P = ns); 16.7% and 10.3% rivastigmine- and placebo-treated patients discontinued because of AEs. Elevated homocysteine was associated with greater rivastigmine treatment differences than normal/low homocysteine.


Mutations in exons 2 and 3 of the FOLR1 gene in demented and non-demented elderly subjects.
We have previously reported six novel mutations in the 5'-UTR of the gene for folate receptor-alpha (FOLR1). In our search for additional mutations we screened patients, referred for investigation of suspected dementia (DGM subgroup) by SSCP and DNA sequencing from the end of exon 1 to the first bases of intron 3. We found 4 sequence variations, FOLR1 g.1314G>A, g.1816delC, g.1841G>A, and g.1928C>T. Pyrosequencing genotyping assays were developed for all of them, and 389 active seniors (AS subgroup) and the 202 DGM patients were genotyped for these mutations. The frequency q of the mutated allele was, among the AS subjects, 0.068, 0.0026, 0.0026, and 0.024 respectively, and among the DGM subjects, 0.067, 0.0076, 0.0078, and 0.023. The g.1816delC and g.1841G>A mutations thus were more frequent in the DGM than in the AS subgroup, but the difference did not reach statistical significance. The mutated alleles, FOLR1 1816(-) and 1841A, always occurred together in the same subjects, suggestive of a rare double-mutant haplotype. The two common polymorphisms, FOLR1 g. 1314G>A and g.1928C>T seemed not to raise tHcy plasma levels, whereas the double-mutated g.1816(-)-g.1841A haplotype may possibly have a slight tHcy-raising effect. Thus, so far 8 novel rare FOLR1 mutations with a combined prevalence of approximately 1.3% in Whites as well as two common polymorphisms with 5% and 13%, respectively, have been demonstrated. Only a few of the rare mutations may potentially be associated with raised plasma tHcy concentrations. No association with dementia was found.


Cell-to-flagellum attachment and surface architecture in kinetoplastids.
A key morphological feature of kinetoplastid parasites is the position and length of flagellum attachment to the cell body. This lateral attachment is mediated by the flagellum attachment zone (FAZ), a large complex cytoskeletal structure, which is essential for parasite morphogenesis and pathogenicity. Despite the complexity of the FAZ only two transmembrane proteins, FLA1 and FLA1BP, are known to interact and connect the flagellum to the cell body. Across the different kinetoplastid species, each only has a single FLA/FLABP pair, except in Trypanosoma brucei and Trypanosoma congolense where there has been an expansion of these genes. Here, we focus on the selection pressure behind the evolution of the FLA/FLABP proteins and the likely impact this will have on host-parasite interactions.


Mycobacterium haemophilum infection in canine cerebrospinal fluid.
A 4-year-old female spayed Australian cattle dog was presented to the Emergency Service at the University of Missouri Veterinary Health Center Small Animal Hospital for generalized pain and lethargy. At presentation, the dog showed severe cervical spinal pain and thoracic limb deficits consistent with a multifocal neuroanatomic localization. Magnetic resonance imaging of the cervical spine revealed T2 and T1 postcontrast intense signal extending from the level of the medulla through C5 most marked in the caudal brainstem and cranial cervical spinal cord. The suspected diagnosis was severe meningoencephalomyelitis and secondary edema. Analysis of cerebrospinal fluid (CSF) collected from the cerebellomedullary cistern revealed a marked mixed pleocytosis with intralesional structures morphologically consistent with Mycobacterium sp. Standard DNA PCR assay performed on the CSF yielded the presence of Mycobacterium haemophilum. To the authors' knowledge, this is the first reported case of CNS mycobacteriosis diagnosed on CSF analysis in a dog.


Acute gastric volvulus: an uncommon complication of a hiatus hernia.
An 80-year-old male patient with a history of a hiatus hernia presented with acute abdominal pain and vomiting. CT of his abdomen revealed extraluminal free gas consistent with a perforation. He had a large hiatus hernia. The subdiaphragmatic portion of the stomach was distended and adopted a more transverse lie. The radiological findings were in keeping with acute gastric volvulus with secondary ischaemic complications. Acute gastric volvulus is an abnormal rotation of the stomach resulting in complete obstruction. It is a surgical emergency and does not always present in its classical form. Clinicians should be mindful of this diagnosis in patients presenting with an acute surgical abdomen, especially if the presentation is non-specific, as delays in diagnosis are associated with significant morbidity and mortality.


Communication problems in hearing children of deaf parents.
Fifty-two children who had deaf parents and were thought to have normal hearing were evaluated for speech, hearing, and language problems. Standardized tests, audiological evaluations, and informal conversation and play techniques were used. Of the 52 children of deaf parents, less than half were considered to be developing speech and language normally and 12% had previously undiagnosed hearing loss. The prevalence of speech and language problems and hearing losses is higher in this population than in the population at large. The children appeared to be using two systems to communicate, one with hearing people and one with the deaf. Of the children having some speech and language difficulty, approximately half had problems that were not associated with other known physiological or environmental factors that might affect speech and language. Although there were no children of intelligible mothers who had speech and language problems, there were children developing normally who had parents whose speech intelligibility was poor. Contrary to indications in the literature, speech and language problems did not disappear after the children entered school. A large number of school-age children as well as preschoolers appeared to be having speech and language problems. The amount of time spent with hearing adults during the preschool years or the presence of older normal-hearing and -speaking siblings did not seem related to speech and language difficulty. However, when an elder sibling had speech and language difficulty, the younger siblings tended to have similar problems. The relationship between sign and oral language development is ambiguous, but there is no indication that the use of sign language deters oral language development. In view of the high incidence of communication problems in this population, annual audiological evaluations and counseling of deaf parents concerning aspects of hearing loss and normal language development are recommended. The problems encountered in providing therapy are discussed.


miRnalyze: an interactive database linking tool to unlock intuitive microRNA regulation of cell signaling pathways.
The various pathophysiological processes occurring in living systems are known to be orchestrated by delicate interplays and cross-talks between different genes and their regulators. Among the various regulators of genes, there is a class of small non-coding RNA molecules known as microRNAs. Although, the relative simplicity of miRNAs and their ability to modulate cellular processes make them attractive therapeutic candidates, their presence in large numbers make it challenging for experimental researchers to interpret the intricacies of the molecular processes they regulate. Most of the existing bioinformatic tools fail to address these challenges. Here, we present a new web resource 'miRnalyze' that has been specifically designed to directly identify the putative regulation of cell signaling pathways by miRNAs. The tool integrates miRNA-target predictions with signaling cascade members by utilizing TargetScanHuman 7.1 miRNA-target prediction tool and the KEGG pathway database, and thus provides researchers with in-depth insights into modulation of signal transduction pathways by miRNAs. miRnalyze is capable of identifying common miRNAs targeting more than one gene in the same signaling pathway-a feature that further increases the probability of modulating the pathway and downstream reactions when using miRNA modulators. Additionally, miRnalyze can sort miRNAs according to the seed-match types and TargetScan Context ++ score, thus providing a hierarchical list of most valuable miRNAs. Furthermore, in order to provide users with comprehensive information regarding miRNAs, genes and pathways, miRnalyze also links to expression data of miRNAs (miRmine) and genes (TiGER) and proteome abundance (PaxDb) data. To validate the capability of the tool, we have documented the correlation of miRnalyze's prediction with experimental confirmation studies. http://www.mirnalyze.in.


Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity.
Myeloid cells are key factors in the progression of bronchopulmonary dysplasia (BPD) pathogenesis. Endothelial monocyte-activating polypeptide II (EMAP II) mediates myeloid cell trafficking. The origin and physiological mechanism by which EMAP II affects pathogenesis in BPD is unknown. The objective was to determine the functional consequences of elevated EMAP II levels in the pathogenesis of murine BPD and to investigate EMAP II neutralization as a therapeutic strategy. Three neonatal mouse models were used: (1) BPD (hyperoxia), (2) EMAP II delivery, and (3) BPD with neutralizing EMAP II antibody treatments. Chemokinic function of EMAP II and its neutralization were assessed by migration in vitro and in vivo. We determined the location of EMAP II by immunohistochemistry, pulmonary proinflammatory and chemotactic gene expression by quantitative polymerase chain reaction and immunoblotting, lung outcome by pulmonary function testing and histological analysis, and right ventricular hypertrophy by Fulton's Index. In BPD, EMAP II initially is a bronchial club-cell-specific protein-derived factor that later is expressed in galectin-3+ macrophages as BPD progresses. Continuous elevated expression corroborates with baboon and human BPD. Prolonged elevation of EMAP II levels recruits galectin-3+ macrophages, which is followed by an inflammatory state that resembles a severe BPD phenotype characterized by decreased pulmonary compliance, arrested alveolar development, and signs of pulmonary hypertension. In vivo pharmacological EMAP II inhibition suppressed proinflammatory genes Tnfa, Il6, and Il1b and chemotactic genes Ccl2 and Ccl9 and reversed the severe BPD phenotype. EMAP II is sufficient to induce macrophage recruitment, worsens BPD progression, and represents a targetable mechanism of BPD development.


Background and Current Treatment of Squamous Cell Carcinoma of the Anus.
In this review, a summary of our current understanding of squamous cell carcinoma of the anus (SCCA) and the advances in our knowledge of SCCA regarding screening, prevention, the role of the immune system, current treatment and the potential for novel targets are discussed. The present standard of care in terms of treatment is 5-fluorouracil (5-FU) and mitomycin C (MMC) concurrently with radiation, which results in a high level of disease control for small early cancers. Preservation of the anal sphincter is achieved in the majority, although anorectal function is often impaired. Although evidence from prospective studies to support a change in the treatment strategy is lacking, patients with HPV-negative SCCA appear to be less responsive to chemoradiation (CRT) and relapse more frequently. In contrast, HPV-positive tumours usually fare better, but oncological outcomes are modified by smoking and immune incompetence. There is current interest in escalating the radiotherapy dose for larger, more advanced tumours, and de-escalating treatment for HPV-positive tumours. The use of novel immunological treatments to target the underlying different molecular pathways of HPV-positive cancers is exciting.


The Spatial Landscape of the Bacterial Community and Bile Acids in the Digestive Tract of Patients With Bile Reflux.
Bile reflux can lead to inflammation and increased intestinal metaplasia. Since bile acids can influence the gastrointestinal environment, it is possible that bile reflux may alter the gastric microbiota and potentially the oral or gut microbiota. Bile acids have a very complex interrelationship with microbiota. We aimed to explore the characteristics of the digestive tract microbiota and bile acids profile in bile reflux patients. This study included 20 chronic gastritis patients with bile reflux and 20 chronic gastritis patients without bile reflux. Saliva, gastric fluid, and fecal samples were collected for bile acid testing. Buccal mucosal swabs, gastric mucosal tissues, and feces were collected for bacteria detection. The UPLC-MS/MS examined bile acids profiles. 16S rRNA gene sequencing was used to analyze the bacterial profile. Bilirubin in the blood increased in bile reflux patients. No other clinical factors were identified to be significantly associated with bile reflux. 12-DHCA, 6,7-diketo LCA, and βHDCA decreased while TUDCA increased in saliva of bile reflux patients. Streptococcus, Capnocytophaga, Neisseria, and Actinobacillus decreased in oral mucosa of bile reflux patients while Helicobacter, Prevotella, and Veillonella increased. Gastric bile acid levels were generally higher in bile reflux patients. Gastric mucosal microbiota was highly stable. The changes in fecal bile acids were insignificant. Bifidobacterium, Prevotella_2, Ruminococcus, Weissella, Neisseria, and Akkermansia decreased in fecal samples from bile reflux patients; while Alloprevotella, Prevotella_9, Parabacteroides, and Megamonas increased. Our results demonstrate that bile reflux significantly alters the oral, gastric, and intestinal bile acids profiles but only influences the oral and gut microbiota composition. These findings indicate that bile reflux can modulate the gastrointestinal microbiota in a site-specific manner.


Cannabis: Drug of Abuse and Therapeutic Agent, Two Sides of the Same Coin.
The consumption of Cannabis sativa plant, known as marijuana in the Western world, for different purposes (therapeutic, intoxicating, and spiritual) due to its psychoactive effects, can be traced back to ancient times. Cannabis is the most used illicit drug worldwide; however, its legal status is changing rapidly. Cannabis regulation will allow a better understanding of its effects as a misused drug, including new challenges, such as the availability of highly potent Cannabis extracts. Furthermore, scientific research is making significant efforts to take advantage of the potential therapeutic uses of Cannabis active compounds. The science of Cannabis derivatives started with the identification of the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), allowing the formal study of the complex set of effects triggered by Cannabis consumption and the deciphering of its pharmacology. Δ9-THC is recognized as the compound responsible for the psychoactive and intoxicating effects of Cannabis. Its study led to the discovery of the endocannabinoid system, a neuromodulatory system widespread in the human body. CBD does not induce intoxication and for that reason, it is the focus of the search for cannabinoid potential clinical applications. This review examines the current state of knowledge about contrasting perspectives on the effects of Cannabis, Δ9-THC, and CBD: their abuse liability and potential therapeutic use; two sides of the same coin.