Improvement of the fatty acid composition of an oil-producing filamentous fungus, Mortierella alpina 1S-4, through RNA interference with delta12-desaturase gene expression.
An oleaginous fungus, Mortierella alpina 1S-4, is used commercially for arachidonic acid production. Delta12-Desaturase, which desaturates oleic acid (18:1n-9) to linoleic acid (18:2n-6), is a key enzyme in the arachidonic acid biosynthetic pathway. To determine if RNA interference (RNAi) by double-stranded RNA occurs in M. alpina 1S-4, we silenced the Delta12-desaturase gene. The silenced strains accumulate 18:2n-9, 20:2n-9, and Mead acid (20:3n-9), which are not detected in either the control strain or wild type strain 1S-4. The fatty acid composition of stable transformants was similar to that of Delta12-desaturation-defective mutants previously identified. Thus, RNAi occurs in M. alpina and could be used to alter the types and relative amounts of fatty acids produced by commercial strains of this fungus without mutagenesis or other permanent changes in the genetic background of the producing strains.


Bacterial diversity and community structure in the rhizosphere of the halophyte Halocnemum strobilaceum in an Algerian arid saline soil.
Hypersaline ecosystems host a particular microbiota, which can be specifically recruited by halophytes. In order to broaden our knowledge of hypersaline ecosystems, an in natura study was conducted on the microbiota associated with the halophyte Halocnemum strobilaceum from alkaline-saline arid soil in Algeria. We collected and identified a total of 414 strains isolated from root tissues (RT), root-adhering soil (RAS), non-adhering rhizospheric soil (NARS) and bulk soil (BS) using different NaCl concentrations. Our data showed that halophilic and halotolerant bacterial isolates in BS and the rhizosphere belonged to 32 genera distributed in Proteobacteria (49%), Firmicutes (36%), Actinobacteria (14%) and Bacteroidetes (1%). Bacterial population size and species diversity were greatly increased in the rhizosphere (factor 100). The reservoir of diversity in BS was dominated by the genera Bacillus and Halomonas. Bacillus/Halomonas ratio decreased with the proximity to the roots from 2.2 in BS to 0.3 at the root surface. Salt screening of the strains showed that species belonging to nine genera were able to grow up to 5.1 M NaCl. Thus, we found that H. strobilaceum exerted a strong effect on the diversity of the recruited microbiota with an affinity strongly attributed to the genus Halomonas.


Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis.
To study the role of Mer receptor tyrosine kinase (mertk) in atherosclerosis. We irradiated and reconstituted atherosclerosis-susceptible C57Bl/6 low-density lipoprotein receptor-deficient female mice (ldlr(-/-)) with either a mertk(+/+) or mertk(-/-) (tyrosine kinase-defective mertk) bone marrow. The mice were put on high-fat diet for either 8 or 15 weeks. Mertk deficiency led to increased accumulation of apoptotic cells within the lesions, promoted a proinflammatory immune response, and accelerated lesion development. Mertk expression by bone marrow-derived cells is required for the disposal of apoptotic cells and controls lesion development and inflammation.


The pharmacology of propofol.
A review of the pharmacology of propofol, a new IV anesthetic agent, is presented. Solubilized in a soybean emulsion, propofol is one of a series of sterically hindered phenols that exhibit anesthetic activity. Induction of anesthesia with propofol may be associated with pain on injection, apnea, and a reduction in arterial blood pressure (BP) and cardiac output. Caution should be ascribed to its use in patients with coronary artery disease, where these effects may have the potential for producing myocardial ischemia. The hemodynamic responses to laryngoscopy and intubation are attenuated. The pharmacokinetic profile suggests suitability as an infusion for either maintenance of anesthesia or sedation. Use of propofol as an infusion during surgery may result in a further reduction in cardiac output, particularly with the concomitant administration of adjuvant increments of fentanyl. The ventilatory response to CO2 is depressed during such an infusion. The high clearance of propofol suggests that even after a prolonged infusion, recovery should be rapid. This finding has been confirmed in a series of studies establishing propofol as an ideal agent for use in a total IV anesthetic technique. Both the quality and speed of recovery, together with the absence of emetic sequelae, support the use of propofol in an outpatient setting. Propofol appears to have no long-term effect on adrenocortical function and appears safe for use in patients with acute intermittent porphyria and susceptibility to malignant hyperpyrexia.


Effect of clonidine on sleep patterns in man.
Clonidine (300 microgram orally) increased in man the total duration of sleep and strikingly reduced the duration of REM sleep. Yohimbine (10 mg per os) did not alter the sleep patterns in man but antagonized the effects of clonidine. These results provide evidence that an alpha sympathomimetic mechanism could suppress REM sleep and increased the total duration of sleep.


[Initial experiences of an orthogeriatric unit].
To report the design and outcomes obtained during the first operational years of the Orthogeriatric Unit (OGU) established in the Zaragoza-1 (Spain) Health-Sector. A total of 494 patients >70 years old treated in the OGU from February 2009 to December 2012. An analysis was performed using the following variables: demography, previous functional level, comorbidities, surgical delay, fracture type and surgical technique, complications, hospital stay, functional outcomes, destination after hospital discharge, and short and long term mortality. Mean age 85.22 years. High incidence of comorbidities (Charlson Index): 24.3%. Dementia: 38.5%. Surgical delay: 2.57 days. Mean hospital stay between admission and discharge/transfer to convalescence unit, 20.9 days (Traumatology 6.45+OGU 14.49). More than a third (34.6%) of patients suffered from delirium. Mean functional improvement (Barthel index at hospital discharge-Barthel index at hospital admission): 27.25 points. Montebello index: 0.49. In-hospital mortality: 6.9%. Hip fracture is such a frequent and disabling pathology among the geriatric population that its treatment requires an interdisciplinary approach. This must be managed by the geriatrician, who has to assure the continuity and integration of the diverse treatment and care schedules, with the participation of the entire professional team in the decision-making process. We are very satisfied with the creation of our interdisciplinary Unit that enables us to report competitive outcomes. We believe that the progression of this Unit from providing subacute to acute care will improve the general outcomes in the future.


The use of the H reflex in serial evaluation of nerve conduction velocity.
Conduction velocity (CV) in the H pathway, expressed by a mixed (sensorimotor) index (HCV), showed a very reduced intra-individual variability when compared to conventional conduction parameters in normal subjects. HCV, tested serially over increasing intervals of time, was about 4 times more stable than motor CV in deep peroneal nerve and about 6 times more stable than the sensory CV in sural nerve. The HCV was so accurate in showing marginal conduction changes that it clearly revealed, in normal persons, a circadian rhythm of conduction velocity, well correlated with circadian variations of body temperature, which totally escaped conventional conduction parameters. owing to its reduced variability, this conduction parameter represents, within the limits in which it can be reliably used in clinical application, a first choice tool for longitudinal conduction studies.


Immunodominant peptide epitopes of allergen, Asp f 1 from the fungus Aspergillus fumigatus.
Aspergillus fumigatus ribotoxin Asp f 1 is a major allergen with IgE binding activity to serum of a majority of patients with allergic bronchopulmonary aspergillosis (ABPA). The IgE binding epitopes or the T-cell stimulatory peptides of this molecule have not been studied. In the present investigation, we have synthesized linear decapeptides spanning the whole molecule of Asp f 1 and analyzed their IgE binding properties. We have also synthesized peptides based on their possible T-cell stimulatory properties and studied the stimulation of peripheral blood mononuclear cells from ABPA patients and normal controls. Several peptides demonstrated distinct IgE antibody binding response against sera from ABPA patients and proliferative response against peripheral blood mononuclear cells from the patients. From the results, it can be concluded that the carboxy-terminal region of Asp f 1 representing amino acid residues 115-149 involved in both humoral and cell mediated immunoresponses in ABPA.


Fanconi's anaemia and unilateral thumb polydactyly--don't miss it.
Fanconi's anaemia (FA) is a rare, life threatening inherited syndrome. Patients usually present late in the first decade of life with aplastic anaemia or acute myeloid leukaemia. FA children are also at high risk of solid organ tumours, anogenital squamous cancers, and endocrinopathies. These patients can present with unilateral radial abnormalities including thumb duplication. Hand surgeons can help achieve early diagnosis and improved survival in this group by early referral for screening. In a retrospective study of 202 children with radial ray anomalies seen over a 20 year period seven children had FA. Of these seven with FA, four had bilateral thumb hypoplasia and three had unilateral thumb anomalies--two unilateral thumb hypoplasias and one thumb duplication. The three children with unilateral anomalies were diagnosed late, presenting with bone marrow failure. All three have subsequently died following late bone marrow transplants. This study highlights the link between unilateral radial anomalies, including thumb duplication and FA and the importance of early genetic referral for diagnosis and surveillance.


Dilated cardiomyopathy in 151 Irish Wolfhounds: Characteristic clinical findings, life expectancy and causes of death.
Dilated cardiomyopathy (DCM) is an important cause of morbidity in Irish Wolfhounds (IW), a breed also predisposed to neoplastic and orthopedic diseases that shorten life expectancy. The objective of this study was to investigate survival and causes of death in IW with DCM and to characterise the clinical findings of DCM over time. Data from cardiovascular examinations performed in 1591 IW, including echocardiography and electrocardiography, were retrospectively evaluated. IW with DCM on medical therapy with long term longitudinal follow-up were included in this study (n=151; 95 males, 56 females). Based on their clinical status at initial diagnosis, IW were classified into one of three groups: preclinical DCM with sinus rhythm (PC-DCM-SR, n=35), preclinical DCM with atrial fibrillation (PC-DCM-AF, n=87), and congestive heart failure with DCM and AF (CHF-DCM-AF, n=29). Survival data were analyzed using cumulative incidence functions, Kaplan-Meier and Cox regression. CHF was predominantly characterized by chylous pleural and mild pericardial effusions. Causes of death were cardiac (CD) in 73/151 and non-cardiac (non-CD) in 62/151; 16 dogs remained alive at study end. The majority of deaths in both preclinical DCM groups were non-CD (PC-DCM-AF=51.9% non-CD, 48.1% CD; PC-DCM-SR, 65.5% non-CD, 34.5% CD). In the CHF-DCM-AF group most dogs (89.6%) experienced a CD. Median survival of the CHF-DCM-AF group (7.3 months) was significantly shorter than in the PC-DCM-AF group (21.9 months) or PC-DCM-SR group (29.1 months, P=0.001). CHF-DCM-AF in IW was associated with reduced life expectancy and CD, while most IW with preclinical DCM died from non-cardiac causes.


Role of Ets-1 phosphorylation in the effector function of Th cells.
The transcription factor Ets-1 critically regulates differentiation and function of T helper (Th) cells. In vitro studies have demonstrated that DNA binding and transcriptional activity of Ets-1 are regulated by phosphorylation. Depending on the site of phosphorylation, Ets-1 function can either be increased or inhibited. In addition, a splice variant lacking several inhibitory phosphorylation sites has been identified, raising the possibility that this splice variant may function differently from the full-length Ets-1. However, it is unclear how the activating and inhibitory phosphorylation events of Ets-1 are coordinated during Th cell activation. Furthermore, the biological consequences of Ets-1 phosphorylation and alternative splicing in regulating the function of Th cells are unknown. We report here that both activating and inhibitory phosphorylation events of Ets-1 occur simultaneously and independently of each other during Th cell activation. We further demonstrate that the effect of Ets-1 phosphorylation is very modest and that full-length Ets-1 and its splice variant are functionally interchangeable in the regulation of cytokine production in Th cells.


Quantum Zeno and Zeno-like effects in nitrogen vacancy centers.
We present a proposal to realize the quantum Zeno effect (QZE) and quantum Zeno-like effect (QZLE) in a proximal (13)C nuclear spin by controlling a proximal electron spin of a nitrogen vacancy (NV) center. The measurement is performed by applying a microwave pulse to induce the transition between different electronic spin states. Under the practical experimental conditions, our calculations show that there exist both QZE and QZLE in a (13)C nuclear spin in the vicinity of an NV center.


3D-extravasation model -- selection of highly motile and metastatic cancer cells.
Extravasation has been described as a rate-limiting step in the process of hematogeneous metastasis formation. Thereby, transendothelial migration of tumor cells consists of a complex series of events involving multiple cell-cell and cell-matrix interactions. 3D-extravasation assays are valuable tools for the identification of genes, which are the key players at switchboards of the intracellular signaling pathways. In consequence, the combination of 3D-modeling and whole genome expression analysis lead to unravel molecular parameters which descripe distinct clinical phenotypes of cancer and therefore, work as prognosticators, predictors of therapy and new therapy targets.


Bacterial interference--is deliberate colonization with Escherichia coli 83972 an alternative treatment for patients with recurrent urinary tract infection?
The increasing microbial antibiotic resistance motivates research for non-antibiotic treatment alternatives. In recurrent urinary tract infections (UTIs), 'bacterial interference' has attracted interest as a possible alternative treatment option. The observation that asymptomatic bacteriuria (ABU) protects against recurrent UTI has prompted clinical trials with deliberate colonization of the human urinary tract as an alternative approach in patients with recurrent UTI. The strain used for colonization, the ABU isolate Escherichia coli 83972, has been shown to cause symptom-free colonizations for long periods of time. Patients on long-term colonization report a subjective benefit, and UTI treatments are rare in colonized patients. This report presents an update on open long-term E. coli 83972 colonization trials and describes the design of an ongoing randomized trial.


Quality control of immunohistochemical evaluation of tumour-associated plasminogen activators and related components. European BIOMED-1 Concerted Action on Clinical Relevance of Proteases in Tumour Invasion and Metastasis.
The plasminogen activation (PA) system is involved in the breakdown and remodelling of the extracellular matrix. In the case of cancer, this is a prerequisite for invasion and metastasis. The expression of urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 in particular have been reported to be of clinical and prognostic value. This has primarily been proven in the case of breast carcinoma and colon carcinoma, using the enzyme-linked immunosorbent assay (ELISA) as a quantitative assay to determine the level of expression. Immunohistochemistry is another technique to investigate the presence of PA components. It allows assessment in a semiquantitative way and informs in addition on the specific distribution within the tissue. To take full advantage of the benefits of immunohistochemistry, it is important to aim at optimal quality in all steps influencing the final judgement of the staining results. These various steps are highlighted and discussed in this paper.


Dissociation of Recollection-Related Neural Activity in Ventral Lateral Parietal Cortex.
fMRI responses to recognition memory test items in two regions of ventral lateral parietal cortex-the angular gyrus and temporo-parietal junction (TPJ)-are enhanced when recognition is accompanied by recollection. According to the 'episodic buffer' hypothesis, ventral parietal recollection effects reflect processes involved in maintaining or representing recollected information. According to the 'attention to memory' hypothesis, however, the effects reflect attentional re-orienting to the products of recollection. The present experiment addressed the question whether these operations map on to the angular gyrus and TPJ, respectively. Subjects were scanned during a memory test that required a Remember/Know/New and a source memory judgment, allowing recollected items to be segregated by amount of contextual information recollected. Angular gyrus activity tracked amount of recollected information, whereas activity in the TPJ was enhanced for items endorsed as recollected, but was insensitive to amount of information recollected. Thus, the two regions likely support functionally dissociable processes.


Vancomycin Pharmacokinetic Parameters in Patients with Hemorrhagic Stroke.
Infections are a common medical complication in hemorrhagic stroke patients, with vancomycin commonly used as empiric therapy. The purpose of this study was to evaluate the pharmacokinetic parameters of vancomycin in hemorrhagic stroke patients. This was a retrospective study of adult patients with aneurysmal subarachnoid hemorrhage (aSAH) or intracerebral hemorrhage (ICH) admitted between May 2010 and February 2015 who received vancomycin. Predicted pharmacokinetic parameters based on population data were compared with calculated pharmacokinetic parameters based on serum trough concentrations. Eighty aSAH patients and 66 ICH patients met inclusion criteria. In the aSAH group, the mean dosing regimen was 17.6 ± 4 mg/kg every 12 (8-12) h. The mean measured trough concentration was lower than the predicted trough concentration (9.9 ± 4.1 vs. 19 ± 8.7 μg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.135 ± 0.04 vs. 0.092 ± 0.03 h(-1); p < 0.001), and the mean calculated half-life was lower than predicted (5.7 ± 1.8 vs. 8.3 ± 2.9 h; p < 0.001). In the ICH group, the mean dosing regimen was 15.9 ± 4.3 mg/kg every 12 (8-12) h. Similarly, the mean measured trough concentration was lower than the predicted trough concentration (10.7 ± 4.6 vs. 17.5 ± 8.5 μg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.106 ± 0.03 vs. 0.079 ± 0.02 h(-1); p < 0.001), and the mean calculated half-life was lower than predicted (7.2 ± 2.3 vs. 9.6 ± 3.2 h; p < 0.001). Patients with hemorrhagic stroke exhibited pharmacokinetic alterations favoring increased elimination of vancomycin when compared to predicted pharmacokinetic parameters based on population data. This may result in underexposure to vancomycin, leading to treatment failure and other medical complications.


Sector ultrasound in the diagnosis and treatment of hematometria secondary to Asherman's syndrome.
Sector ultrasound in patients with post-traumatic amenorrhea (Asherman's) performed at BBT-determined "menses" will diagnose patients with hematometria secondary to outlet obstruction. These patients can be treated in the outpatient setting using real-time ultrasound as a guide for intrauterine manipulation.


Relationship between subunit size and number of rare electrophoretic alleles in human enzymes.
Data from published sources were used to compare the numbers of different electrophoretic alleles of 29 monomeric and dimeric human enzymes to their respective subunit molecular weights. Only those human enzymes were considered for which the total sample sizes were in excess of 2000 individuals. Correlations between these two variables were determined within sample size ranges of 2000 less than or equal to n less than or equal to 3000 and 4000 less than or equal to n less than or equal to 5000 individuals, and separately by quaternary class. There was no statistically significant correlation observed for the smaller sample size range in monomers; however, the correlations for the larger sample size range in monomers and both ranges in dimers were significant. Since there is no relationship between subunit size and heterozygosity, the relationships are due primarily to the incidence of rare alleles. These findings demonstrate the effect of locus-specific mutation rates, expected as a consequence of variation of cistron sizes, and imply that other forces are responsible for the relative frequencies of common alleles at some of the loci.


Effect of desipramine on the effects of alpha-adrenoceptor inhibitors on pressor responses and release of norepinephrine into plasma of pithed rats.
The role of neuronal uptake inhibition on the efficiency of alpha 1- and alpha 2-antagonists in inhibiting pressor responses and the release of plasma catecholamines in pithed rats were studied. Prazosin, in doses which selectively blocked alpha 1-adrenoceptors (0.01-0.1 mg/kg), was more effective than yohimbine, a relatively selective alpha 2-antagonist, in inhibiting stimulation-induced pressor responses. Yohimbine (0.1-1 mg/kg) potentiated or did not alter the pressor responses to stimulation, whereas it blocked pressor responses to administered norepinephrine (NE) more effectively than did prazosin. Inhibition of uptake by desipramine (DMI), 0.3 mg/kg, did not affect prazosin inhibition of stimulation-induced pressor responses though it increased NE overflow into circulation. In yohimbine-treated rats, DMI potentiated significantly (p less than 0.001) both pressor and NE responses to stimulation. DMI partially reversed prazosin inhibition of pressor response to administered NE (p less than 0.001) and potentiated the response in yohimbine-treated rats (p less than 0.01). The results are consistent with the view that endogenously released NE acts at intrajunctional alpha 1-adrenoceptors, whereas exogenous NE acts predominantly at extrajunctional alpha 2-adrenoceptors. The neuronal uptake site appears to be functionally (and perhaps anatomically) located outside the synaptic cleft, between intrajunctional alpha 1-postsynaptic receptors and extrajunctional alpha 2-adrenoceptors.


Ventriculomegaly in schizophrenia: is the choice of controls important?
The issue of adequate controls for the study of ventriculomegaly in schizophrenia has been explored initially by Andreasen et al. (1982), who proposed that healthy volunteers, a group with presumably smaller ventricles than medical controls, be considered the optimal comparison group in this area of research. Recently, Smith and Iacono (1986) suggested that group differences may appear to be greater when controls who are patients are used, as a result of the systematic exclusion of medical patients with large though normal ventricles. We conducted a meta-analysis of 37 studies of lateral ventriculomegaly in schizophrenia to clarify this issue. The results indicate that the average effect size in studies with healthy controls does not differ significantly from that obtained in studies employing medical, neurological, or psychiatric (nonpsychotic) controls. Thus, any group without gross neurological damage or severe psychopathology may be used for establishing ventriculomegaly in schizophrenia.


Strategies of Echinococcus species responses to immune attacks: implications for therapeutic tool development.
Echinococcus species have been studied as a model to investigate parasite-host interactions. Echinococcus spp. can actively communicate dynamically with a host to facilitate infection, growth and proliferation partially via secretion of molecules, especially in terms of harmonization of host immune attacks. This review systematically outlines our current knowledge of how the Echinococcus species have evolved to adapt to their host's microenvironment. This understanding of parasite-host interplay has implications in profound appreciation of parasite plasticity and is informative in designing novel and effective tools including vaccines and drugs for the treatment of echinococcosis and other diseases.


Novel THAP1 missense variant with incomplete penetrance in a case of generalized young onset dystonia showing good response to deep brain stimulation.
We describe a case of young onset generalized dystonia, harboring a previously unreported likely pathogenic THAP1 missense variant (c.109 G > A; p.Glu37Lys) that was inherited from her unaffected father. Moreover, we report a positive effect of deep brain stimulation, particularly on the cervical component of dystonia.


Improving acceptance of naltrexone in community addiction treatment centers: a pilot study.
Alcoholism pharmacotherapies are underused in community addiction treatment settings, in part because individuals who practice in these settings--nonmedical addiction counselors and administrators--lack knowledge about and confidence in the value of adjunctive alcohol pharmacotherapies. We developed and tested an intervention to improve knowledge and attitudes about naltrexone. A team of researchers, physicians, addiction treatment counselors, and administrators collaborated to develop a naltrexone educational intervention designed for nonmedical addiction professionals. The intervention was compared with a control condition in a pilot study with 6 addiction treatment agencies (3 agencies per group). Participants (counselors and administrators, N = 84) were assessed before and 6 months after the intervention. Results revealed that the intervention significantly improved naltrexone knowledge, and participants who received the intervention reported greater satisfaction with the education they received, as well as greater use of the information. The effect of the intervention on attitudes about naltrexone was encouraging but did not to reach statistical significance. This study is the first reported attempt to develop and test an intervention specifically to improve acceptance of adjunctive medications for alcoholism among nonmedical addiction professionals.


Regulatory and innovative mechanisms of bacterial quorum sensing-mediated pathogenicity: a review.
Quorum sensing (QS) is a system of bacteria in which cells communicate with each other; it is linked to cell density in the microbiome. The high-density colony population can provide enough small molecular signals to enable a range of cellular activities, gene expression, pathogenicity, and antibiotic resistance that cause damage to the hosts. QS is the basis of chronic illnesses in human due to microbial sporulation, expression of virulence factors, biofilm formation, secretion of enzymes, or production of membrane vesicles. The transfer of antimicrobial resistance gene (ARG) among antibiotic resistance bacteria is a major public health concern. QS-mediated biofilm is a hub for ARG horizontal gene transfer. To develop innovative approach to prevent microbial pathogenesis, it is essential to understand the role of QS especially in response to environmental stressors such as exposure to antibiotics. This review provides the latest knowledge on the relationship of QS and pathogenicity and explore the novel approach to control QS via quorum quenching (QQ) using QS inhibitors (QSIs) and QQ enzymes. The state-of-the art knowledge on the role of QS and the potential of using QQ will help to overcome the threats of rapidly emerging bacterial pathogenesis.


Temporal variation of residential pesticide use and comparison of two survey platforms: a longitudinal study among households with young children in Northern California.
Pesticide use patterns are essential inputs into human pesticide exposure models. Currently, data included for modeling purposes have mostly been collected in cross-sectional surveys. However, it is questionable whether responses to one-time surveys are representative of pesticide use over longer periods, which is needed for assessment of health impact. This study was designed to evaluate population-wide temporal variations and within-household variations in reported residential pesticide use patterns and to compare alternative pesticide data collection methods - web surveys versus telephone interviews. A total of 481 households in Northern California provided up to 3 annual telephone interviews on residential pesticide use; 182 of these households provided up to 6 quarterly web surveys that covered the same topics for some of the same time periods. Information on frequency and areas of application were collected for outdoor and indoor sprays, indoor foggers, professional applications, and behind-the-neck treatments for pets. Population-wide temporal variation and within-household consistency were examined both within telephone surveys and within web surveys, and quantified using Generalized Estimating Equations and Mixed Effect Modeling. Reporting between the two methods, the telephone survey and the web survey, was also compared. Use prevalence of outdoor sprays across the population reported in both the annual telephone surveys and the quarterly web surveys decreased over time, as did behind-the-neck treatment of pets reported in the quarterly web survey. Similarly, frequencies of use of these products decreased in the quarterly web surveys. Indoor sprays showed no statistically significant population-wide temporal variation in either survey. Intraclass correlation coefficients indicated consistent use within a household for behind-the-neck treatment on pets and outdoor sprays but great variability for the use of indoor sprays. Indoor sprays were most consistently applied in the bathroom and kitchen. Outdoor sprays were consistently more often applied by male household members, while indoor sprays were not. The two survey approaches obtained fairly similar results on the prevalence of using pesticides, but found discrepancies in use frequencies. In addition, the number of products purchased was positively correlated with application frequency for outdoor sprays (R = 0.51, p = 0.0005) but not for indoor sprays. In this population, repeated surveys are necessary either to obtain a reliable estimate of the average household use of pesticides or to project potential temporal changes of pesticide use. Web surveys could collect comparable data to traditional telephone surveys for some information. However, researchers need to consider the internet acceptability among the target population and balance lower participant burden against the need for sufficiently accurate time-varying measurement, to improve subject retention in longitudinal surveys.


The Gastrocnemius Flap for Lower Extremity Reconstruction.
The gastrocnemius flap is a versatile flap when muscle, or, muscle and skin is desired for coverage of bone of the proximal one-third of the leg, and about the knee. Both the medial and lateral heads, or both combined, may be used as flaps. Typically, the reach of only the muscle will restrict reach to just below the knee. Release off the medial femoral condyle permits increased reach, and a bit more is obtained by scoring the deep fascia and gently slow expansion of the muscle.


[Tauro-ursodeoxycholic acid vs. ursodeoxycholic acid in the dissolution of biliary calculi. Results of a single blind study].
Out of 34 patients enrolled and randomized, 31 completed the 6 months study period. Fifteen were treated with TUDCA, and 16 with UDCA. Dosage for both drugs was 10 mg/kg body weight daily. Superiprisingly, TUDCA was not found to be more active than UDCA in dissolving, totally or partially, the gallbladder stones; indeed, total dissolution was more frequent in the UDCA group. Since the two groups were similar as to number and size of the stones, the better results with UDCA cannot be attributed to the characteristics of the calculosis but must be ascribed to the molecule used. Both drugs induced an improvement in dyspeptic symptoms, but from this point of view, too, UCDA was more effective than TUDCA (p < 0.01). Finally, tolerability was also significantly better for UDCA, although TUDCA was altogether acceptable.


A novel water-soluble benzothiazole derivative BD926 inhibits human activated T cell proliferation by down-regulating the STAT5 activation.
Immunosuppressants are widely used for treatment of T cell-mediated autoimmune diseases and allogeneic graft rejection. However, because of the toxicity and tolerance of these drugs, novel immunosuppressants are urgently needed. We synthesized a series of novel water-soluble benzothiazole derivatives and found that BD926 [sodium 2-(benzo[d]thiazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-olate] had potent immunosuppressive activity. Treatment with BD926 significantly inhibited anti-CD3/anti-CD28 and alloantigen-induced human T cell proliferation as well as IL2-stimulated activated T cell proliferation in a dose-dependent manner in vitro. BD926 had no obvious cytotoxicity against human resting T cells, IL-4 treated activated T cells and fibroblast-like synoviocytes in our experimental conditions. Furthermore, BD926 induced cell cycle arrest at G0/G1 phase and inhibited the cyclin D3 and CDK 6 expression in activated T cells. BD926 inhibited the STAT5, but not Akt and p70S6K, phosphorylation in a dose-dependent manner in the IL-2-treated activated T cells. Interestingly, BD926 inhibited IFN-γ, IL-6 and IL-17, but not IL-2, IL-4 and IL-10, production in activated T cells. Finally, treatment with BD926 reduced delayed-type hypersensitivity in mice in a dose-dependent manner. Collectively, these data suggest that BD926 may be a lead compound for the design and development of new immunosuppressants for the intervention of allograft rejection and autoimmune diseases.


Radiation dose and image quality of high-pitch emergency abdominal CT in obese patients using third-generation dual-source CT (DSCT).
In this third-generation dual-source CT (DSCT) study, we retrospectively investigated radiation dose and image quality of portal-venous high-pitch emergency CT in 60 patients (28 female, mean age 56 years) with a body mass index (BMI) ≥ 30 kg/m2. Patients were dichotomized in groups A (median BMI 31.5 kg/m2; n = 33) and B (36.8 kg/m2; n = 27). Volumetric CT dose index (CTDIvol), size-specific dose estimate (SSDE), dose length product (DLP) and effective dose (ED) were assessed. Contrast-to-noise ratio (CNR) and dose-independent figure-of-merit (FOM) CNR were calculated. Subjective image quality was assessed using a five-point scale. Mean values of CTDIvol, SSDE as well as normalized DLP and ED were 7.6 ± 1.8 mGy, 8.0 ± 1.8 mGy, 304 ± 74 mGy * cm and 5.2 ± 1.3 mSv for group A, and 12.6 ± 3.7 mGy, 11.0 ± 2.6 mGy, 521 ± 157 mGy * cm and 8.9 ± 2.7 mSv for group B (p < 0.001). CNR of the liver and spleen as well as each calculated FOM CNR were significantly higher in group A (p < 0.001). Subjective image quality was good in both groups. In conclusion, third-generation abdominal high-pitch emergency DSCT yields good image quality in obese patients. Radiation dose increases in patients with a BMI > 36.8 kg/m2.


Concentration-dependent tetramerization of bovine visual arrestin.
The oligomeric states of bovine visual arrestin in solution were studied by small-angle x-ray scattering. The Guinier plot of arrestin at the concentration ranging from 0.4 mg/ml to 11.1 mg/ml was approximated with a straight line, and the apparent molecular weight was evaluated by the concentration-normalized intensity at zero angle (I(0)/conc). Using ovalbumin as a molecular weight standard, it was found that arrestin varied from monomer to tetramer depending on the concentration. The I(0)/conc decreased at high-salt concentration, but was independent of temperature. The simulation analysis of the concentration-dependent increase of I(0)/conc demonstrated that the tetramerization is highly cooperative, and arrestin at the physiological concentration is virtually in the equilibrium between monomer and tetramer. The concentration of arrestin monomer, which is considered to be an active form, remains at an almost constant level even if the total concentration of arrestin fluctuates within the physiological range. The scattering profile of arrestin tetramer in solution was in good agreement with that in the crystal, indicating that the quaternary structure in solution is essentially identical to that in crystal. Small-angle x-ray scattering was applied to a binding assay of phosphorylated rhodopsin and arrestin in the detergent system, and we directly observed their association as the increase of I(0)/conc.


Operationalizing integrated care on a clinical level: the INTERMED project.
During the last 10 years the INTERMED method has been developed as a generic method for the assessment of bio-psychosocial health risks and health needs and for planning of integrated treatment. The INTERMED has been conceptualized to counteract divisions and fragmentation of medical care. Designed to enhance the communication between patients and the health providers as well as between different professions and disciplines, the INTERMED is a visualized, action-oriented decision-support tool. This article presents various aspects of the INTERMED, such as its relevance, description, scoring, the related patient interview and treatment planning, scientific evaluation, implementation, and support for the method.


15-deoxy-Delta(12,14)-prostaglandin J(2) and curcumin modulate the expression of toll-like receptors 4 and 9 in autoimmune T lymphocyte.
Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model for multiple sclerosis (MS). We have shown earlier that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and curcumin ameliorate EAE by modulating inflammatory signaling pathways in T lymphocytes. Toll-like receptors (TLRs), expressed primarily in innate immune cells, play critical roles in the pathogenesis of EAE. T lymphocytes also express TLRs and function as costimulatory receptors to upregulate proliferation and cytokine production in response to specific agonists. In this study, we show that naïve CD4(+) and CD8(+) T cells express detectable levels of TLR4 and TLR9 and that increase after the induction of EAE in SJL/J and C57BL/6 mice by immunization with PLPp139-151 and MOGp35-55 antigen, respectively. It is interesting to note that in vivo treatment with 15d-PGJ2 or curcumin results in a significant decrease in TLR4 and TLR9 expression in CD4(+) and CD8(+) T cells in association with the amelioration of EAE. Although the exact mechanisms are not known, the modulation of TLR expression in T lymphocytes by 15d-PGJ(2) and curcumin suggests new therapeutic targets in the treatment of T cell-mediated autoimmune diseases.


Using the learning disability screening questionnaire to help identify people with an intellectual disability in homeless services.
We explored the accuracy of using the learning disability screening questionnaire (LDSQ) in services for people experiencing homelessness in the United Kingdom. We examined the concordance between the LDSQ outcomes and assessments of intellectual disability. Seventy adults experiencing homelessness completed the LDSQ. Staff completed the LDSQ and a measure of adaptive functioning for 38 of this group. Nine participants received an intellectual assessment. Sensitivity and specificity for the LDSQ when completed by staff was 83% and 96% respectively and 50% and 92% when completed by the individual. Seven people had intellectual and adaptive functioning in the intellectual disability range. The results suggest that the LDSQ would be an appropriate and beneficial screening tool to use within services for people experiencing homelessness. More accurate results would be likely if it were completed by staff.


Cpmer: A new conserved eEF1A2-binding partner that regulates Eomes translation and cardiomyocyte differentiation.
Previous studies have shown that eukaryotic elongation factor 1A2 (eEF1A2) serves as an essential heart-specific translation elongation element and that its mutation or knockout delays heart development and causes congenital heart disease and death among species. However, the function and regulatory mechanisms of eEF1A2 in mammalian heart development remain largely unknown. Here we identified the long noncoding RNA (lncRNA) Cpmer (cytoplasmic mesoderm regulator), which interacted with eEF1A2 to co-regulate differentiation of mouse and human embryonic stem cell-derived cardiomyocytes. Mechanistically, Cpmer specifically recognized Eomes mRNA by RNA-RNA pairing and facilitated binding of eEF1A2 with Eomes mRNA, guaranteeing Eomes mRNA translation and cardiomyocyte differentiation. Our data reveal a novel functionally conserved lncRNA that can specifically regulate Eomes translation and cardiomyocyte differentiation, which broadens our understanding of the mechanism of lncRNA involvement in the subtle translational regulation of eEF1A2 during mammalian heart development.


Simultaneous discrimination of the three genomes in hexaploid wheat by multicolor fluorescence in situ hybridization using total genomic and highly repeated DNA probes.
Common wheat, Triticum aestivum, is an allohexaploid species consisting of three different genomes (A, B, and D). The three genomes were simultaneously discriminated with different colors. Biotinylated total genomic DNA of the diploid A genome progenitor Triticum urartu, digoxigenin-labeled total genomic DNA of the diploid D genome progenitor Aegilops squarrosa, and nonlabeled total genomic DNA of one of the possible B genome progenitors Ae. speltoides were hybridized in situ to metaphase chromosome spreads of Triticum aestivum cv. Chinese Spring. For detection, only two fluorochromes, fluorescein and rhodamine, were used. The A, B, and D genomes were simultaneously detected by their yellow, brown, and orange fluorescence, respectively. The genomic fluorescence in situ hybridization pattern of chromosome 4A of cv. Chinese Spring wheat showed that the distal 32% of the long arm was derived from a B genome chromosome. Furthermore, by using two highly repeated sequence probes, pSc 119.2 and pAsl, and two fluorochromes simultaneously, we were able to identify all B and D genome chromosomes and chromosomes 1A, 4A, and 5A of wheat.


An ethnobotany of the Lukomir Highlanders of Bosnia & Herzegovina.
This aim of this study is to report upon traditional knowledge and use of wild medicinal plants by the Highlanders of Lukomir, Bjelašnica, Bosnia and Herzegovina (B&H). The Highlanders are an indigenous community of approximately 60 transhumant pastoralist families who speak Bosnian (Bosanski) and inhabit a highly biodiverse region of Europe. This paper adds to the growing record of traditional use of wild plants within isolated communities in the Balkans. An ethnobotanical study using consensus methodology was conducted in Lukomir in Bjelašnica's mountains and canyons. Field work involved individual semi-structured interviews during which informants described plants, natural product remedies, and preparation methods on field trips, garden tours, while shepherding, or in settings of their choice. Plant use categories were ranked with informant consensus factor and incorporated into a phylogenetic tree. Plants cited were compared to other ethnobotanical surveys of the country. Twenty five people were interviewed, resulting in identification of 58 species (including two subspecies) from 35 families, which were cited in 307 medicinal, 40 food, and seven material use reports. Individual plant uses had an average consensus of five and a maximum consensus of 15 out of 25. There were a number of rare and endangered species used as poisons or medicine that are endemic to Flora Europaea and found in Lukomir. Ten species (including subspecies) cited in our research have not previously been reported in the systematic ethnobotanical surveys of medicinal plant use in B&H: (Elymus repens (L.) Gould, Euphorbia myrsinites L., Jovibarba hirta (L.) Opiz, Lilium bosniacum (Beck) Fritsch, Matricaria matricarioides (Less.) Porter ex Britton, Phyllitis scolopendrium (L.) Newman, Rubus saxatilis L., Silene uniflora Roth ssp. glareosa (Jord.) Chater & Walters, Silene uniflora Roth ssp. prostrata (Gaudin) Chater & Walters, Smyrnium perfoliatum L.). New uses not reported in any of the aforementioned systematic surveys were cited for a total of 28 species. Thirteen percent of medicinal plants cited are endemic: Helleborus odorus Waldst. et Kit., Gentiana lutea L., Lilium bosniacum (Beck) Fritsch, Silene uniflora Roth ssp. glareosa (Jord.) Chater & Walters., Silene uniflora Roth ssp. prostrata (Gaudin) Chater & Walters, Salvia officinalis L., Jovibarba hirta (L.) Opiz, and Satureja montana L. These results report on the cohesive tradition of medicinal plant use among healers in Lukomir, Bosnia and Herzegovina. This work facilitates the community's development by facilitating local and international conversations about their traditional medicine and sharing insight for conservation in one of Europe's most diverse endemic floristic regions, stewarded by one of Europe's last traditional Highland peoples.


Prevalence of self-reported fatigue in intensive care unit survivors 6 months-5 years after discharge.
Prolonged stays in intensive care units (ICU) are responsible for long-lasting consequences, fatigue being one of the more debilitating. Yet, fatigue prevalence for patients that have experienced ICU stays remains poorly investigated. This study aimed to evaluate fatigue prevalence and the level of physical activity in ICU survivors from 6 months to 5 years after ICU discharge using the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) and Godin questionnaires, respectively. Data from 351 ICU survivors (out of 1583 contacted) showed that 199 (57%) and 152 (43%) were considered as fatigued and non-fatigued, respectively. The median FACIT-F scores for fatigued versus non-fatigued ICU survivors were 21 (14-27) and 45 (41-48), respectively (p < 0.001). Time from discharge had no significant effect on fatigue prevalence (p = 0.30) and fatigued ICU survivors are less active (p < 0.001). In multivariate analysis, the only risk factor of being fatigued that was identified was being female. We reported a high prevalence of fatigue among ICU survivors. Sex was the only independent risk factor of being fatigued, with females being more prone to this symptom. Further studies should consider experimental approaches that help us understand the objective causes of fatigue, and to build targeted fatigue management interventions.


A comparative ultrastructural study of the mitotic chondrogenic cells in the mandibular condyle and tibial growth plate of the rat.
Mitotic cells in the rat mandibular condyle (proliferative mandibular cells) were compared with mitotic cells in the rat tibial growth plate (proliferative tibial cells). In the tibial proliferative cells, the rough endoplasmic reticulum mostly became vacuolated during the latter stage of mitosis, whereas the rough endoplasmic reticulum of the proliferative mandibular cells rarely underwent disorganization. Further, a wide area remained outside of the mitotic spindle in the proliferative tibial cells at the metaphase, while only a narrow area remained in the proliferative mandibular cells. This finding might account for the difference of disorganization of the rough endoplasmic reticulum.


Cefotaxime treatment of gram-negative enteric meningitis in infants and children.
18 infants and children (1 week to 3 months of age) were treated with cefotaxime 200 mg/kg/day for Gram-negative enteric bacillary meningitis. 17 of these patients (94.4%) survived, with a complication rate of 23.5% (4/17 patients). The follow-up cerebrospinal fluid cultures at 24 hours were sterile in all patients. Cefotaxime was safe and effective in treating Gram-negative enteric bacillary meningitis in infants and children and should be considered as a potential drug of choice in Gram-negative neonatal meningitis due to susceptible organisms.


Personnel attitudes toward people with mental illness at a psychiatric hospital in Taiwan.
The attitudes of psychiatric hospital personnel are critically related to the quality of mental health care, but few studies have investigated this issue. This study is aimed at an exploration of the attitudes of psychiatric hospital personnel toward people with mental illness and at an examination of the associated factors. A self-report questionnaire, the Mental Illness Attitude Scale (MIAS), was used to collect data from psychiatric hospital personnel in Taiwan (n = 290). The MIAS included 46 items and 4 dimensions: acceptance, rehabilitation and prognosis, social distance and recommendations for interventions. Rehabilitation and prognosis had the highest item average scores (4.03) and social distance had the lowest item average scores (3.22). Stigmatization and the number of different types of contacted clients were two significantly associated attitude factors. Psychiatric hospital personnel in Taiwan tend to have positive attitudes toward people with mental illness in general situations but hold less positive attitudes in terms of community integration-related issues and intimate relationships. More evidence-based community services should be conducted to decrease personnel concerns about the successful community integration of those who are mentally ill. Future studies can investigate the concept and impact of stigmatization more deeply.


Ultrahypofractionated Radiotherapy for Localised Prostate Cancer: How Far Can We Go?
Following adoption of moderately hypofractionated radiotherapy as a standard for localised prostate cancer, ultrahypofractioned radiotherapy delivered in five to seven fractions is rapidly being embraced by clinical practice and international guidelines. However, the question remains: how low can we go? Can radiotherapy for prostate cancer be delivered in fewer than five fractions? The current review summarises the evidence that radiotherapy for localised prostate cancer can be safely and effectively delivered in fewer than five fractions using high dose rate brachytherapy or stereotactic body radiotherapy. We also discuss important lessons learned from the single-fraction high dose rate brachytherapy experience.


Characterizing geometric distortions of 3D sequences in clinical head MRI.
Phantoms are often used to estimate the geometric accuracy in magnetic resonance imaging (MRI). However, the distortions may differ between anatomical and phantom images. This study aimed to investigate the applicability of a phantom-based and a test-subject-based method in evaluating geometric distortion present in clinical head-imaging sequences. We imaged a 3D-printed phantom and test subjects with two MRI scanners using two clinical head-imaging 3D sequences with varying patient-table positions and receiver bandwidths. The geometric distortions were evaluated through nonrigid registrations: the displaced acquisitions were compared against the ideal isocenter positioning, and the varied bandwidth volumes against the volume with the highest bandwidth. The phantom acquisitions were also registered to a computed tomography scan. Geometric distortion magnitudes increased with larger table displacements and were in good agreement between the phantom and test-subject acquisitions. The effect of increased distortions with decreasing receiver bandwidth was more prominent for test-subject acquisitions. Presented results emphasize the sensitivity of the geometric accuracy to positioning and imaging parameters. Phantom limitations may become an issue with some sequence types, encouraging the use of anatomical images for evaluating the geometric accuracy.


Antioxidant and antimicrobial activity of two Costa Rican cultivars of ber (Ziziphus mauritiana): An underexploited crop in the American tropic.
Ber is an antioxidant-rich fruit from Asia and has recently been cultured in Central America. The antioxidant capacity and antimicrobial activity of Z. mauritiana cultured of bers from Guanacaste, Costa Rica, were evaluated. Two farm locations and two cultivars were evaluated. Total polyphenolic compounds (TPC), proanthocyanidin compounds (PAC), and ascorbic acid were spectrophotometrically quantified. Antioxidant activity has been analyzed using the DPPH method. Antimicrobial susceptibility was determined using the Kirby-Bauer disk diffusion method. Ber samples contained 11-44 mg GAE/g TPC. Green fruits and leaves had the highest concentrations. The ascorbic acid concentration in ber fruits was determined between 251 and 466 mg/100 g. Ber vitamin C content is higher than most common fruits. Proanthocyanidin compounds were determined between 1.8 and 9.9 mg 4-MCG/g, and the highest concentration was observed in the leaves. Our samples showed the antioxidant activity of 90-387 μmol TE/g, which was moderate activity. The nutritional quality of ber fruits was related to maturity conditions. The ber fruits, a crop from Asia previously adapted to live in Costa Rica, are rich in vitamin C and TPC, and the concentration of those metabolites was even higher than the concentration reported in bers grown in other countries. The TPC and PACs had an interestingly wide antimicrobial spectrum. Cultivars and farm locations have a significant effect on metabolite production.


Skin autofluorescence as proxy of tissue AGE accumulation is dissociated from SCORE cardiovascular risk score, and remains so after 3 years.
Skin autofluorescence (SAF), as a proxy of AGE accumulation, is predictive of cardiovascular (CVD) complications in i.a. type 2 diabetes mellitus and renal failure, independently of most conventional CVD risk factors. The present exploratory substudy of the Groningen Overweight and Lifestyle (GOAL)-project addresses whether SAF is related to Systematic COronary Risk Evaluation (SCORE) risk estimation (% 10-year CVD-mortality risk) in overweight/obese persons in primary care, without diabetes/renal disease, and if after 3-year treatment of risk factors (change in, Δ) SAF is related to ΔSCORE. In a sample of 65 participants from the GOAL study, with a body mass index (BMI) >25-40 kg/m2, hypertension and/or dyslipidemia, but without diabetes/renal disease, SAF and CVD risk factors were measured at baseline, and after 3 years of lifestyle and pharmaceutical treatment. At baseline, the mean SCORE risk estimation was 3.1±2.6%, mean SAF 2.04±0.5AU. In multivariate analysis SAF was strongly related to age, but not to other risk factors/SCORE. After 3 years ΔSAF was 0.34±0.45 AU (p<0.001). ΔSAF was negatively related to Δbodyweight but not to ΔSCORE%, or its components. At follow-up, SAF was higher in 11 patients with a history of CVD compared to 54 persons without CVD (p=0.002). Baseline and 3-year-Δ SAF are not related to (Δ)SCORE, or its components, except age, in the studied population. ΔSAF was negatively related to Δweight. As 3-year SAF was higher in persons with CVD, these results support a larger study on SAF to assess its contribution to conventional risk factors/SCORE in predicting CVD in overweight persons with low-intermediate cardiovascular risk.


Effects of barometric pressure and lunar phases on premature rupture of the membranes.
Meteorologic events have often been blamed for premature rupture of the fetal membranes. This study analyzed the relationship of barometric pressure and lunar phase to membrane rupture and found no evidence that membrane rupture is influenced by those phenomena.


Use of the one-hour blood xylose test as an indicator of small bowel mucosal disease.
The one-hour blood xylose concentration was evaluated to determine its usefulness as a screening test for small bowel mucosal disease in infants and children. Six of 13 patients with one-hour blood xylose levels of less than 20 mg/dl had normal small bowel biopsies by light microscopy. Five of 20 children with normal one-hour xylose levels had abnormal small bowel villous architecture. Because of the significant false positive (46%) and false negative results (25%), the one-hour blood xylose concentration should not be used as the sole indicator for small bowel biopsy in infants and children with chronic diarrhea.


Morphologically distinct patterns of apoptosis correlate with size and high-grade dysplasia in colonic adenomas.
To examine the relationship of morphological patterns of apoptosis in colonic adenomas to standard pathological variables. Apoptosis patterns were evaluated in 184 consecutive colonic adenomas and 14 adenocarcinomas, using haematoxylin and eosin sections. Apoptosis identification was selectively validated by electron microscopy. There were three patterns of apoptosis: (i) confluent basal apoptosis; (ii) crypt lumen apoptosis, both assessed semiquantitatively; and (iii) scattered apoptosis (not quantified). Adenoma site, size, type, mitoses, and grade of dysplasia were also assessed. MIB-1 immunostaining was performed in 20 cases. In 142 adenomas (77%) confluent basal apoptosis (n = 124) and/or crypt lumen apoptosis (n = 69) were identified; 42 (23%) had scattered apoptosis only. Significant correlations were: (i) extensive confluent basal apoptosis with small adenomas < or =5 mm (P < 0.0001); (ii) crypt lumen apoptosis with large adenomas >5 mm (P < 0.0001) and (iii) with high-grade dysplasia (P < 0.0003); and (iv) coexistence of both patterns (n = 51) with large adenomas >5 mm (P < 0.0001). Neither apoptosis pattern correlated with other variables. Adenocarcinomas had minimal confluent basal apoptosis (5/14), conspicuous crypt lumen apoptosis (14/14), intraglandular coagulative necrosis, and scattered apoptotic tumour cells. Confluent basal apoptosis is maximal early in colonic tumorigenesis. The 'switch' to a predominant crypt lumen apoptosis pattern suggests that a different apoptosis induction mechanism might be associated with the transition to adenocarcinoma.


Frequency of Human papillomavirus in women attending cervical cancer screening program in Chile.
Human papillomavirus (HPV) is the etiological factor for cervical cancer and its precursor lesions. The characterization of HPV genotypes in preneoplastic lesions and cervical cancer could establishes the effectiveness of vaccination plan in Chilean population. The aim of this study was to determine HPV frequency in a group of women including in a cervical screening program in the public health care system in Chile. We analyzed 985 cervical smears samples from women with different histological diagnosis, attending to public health care in Temuco-Chile between 2004 and 2012, to detect HPV genotypes, through PCR followed by reverse line blotting assay. HPV was found present in 80.8% (n = 796) of samples. Only a 5.6% of 985 samples were infected with a low-risk HPV, considering multiple infections. 10.5% (n = 8/76) of normal cervical epithelia, 83.5% (n = 208/249) and 87.6% (n = 557/636) of low and high grade squamous intraepithelial lesions, respectively, and 95.8% (n = 23/24) of squamous cervical carcinomas tested positive for HPV. HPV 16 was the most frequent genotype found (Overall 44.9%, n = 442/985; SCC: 62.5%, n = 15/24). A high variability of HPV types was also found in preneoplastic lesions, whereas there was a selection of genotypes in neoplasia. Also, there was a higher risk of infection with HPV 16 in women ≤26 years and 34-41 years old (p < 0.05), meanwhile infections with HPV 16 or HPV 18 have related with cancer development (p < 0.01). These data provide further information about the frequency of HPV genotypes in women with cervical lesions in Chile, and the introduction of new targeted vaccines against a wider spectrum of HPV is suggested.


Polymorphism of glutathione S-transferase Omega gene: association with risk of childhood acute lymphoblastic leukemia.
To evaluate the association between glutathione S-transferase Omega (GSTO) genes polymorphism and the susceptibility of acute lymphoblast leukemia (ALL). The polymorphism of GSTO1 and GSTO2 genes were analyzed in 99 ALL patients compared with 100 healthy children by PCR-based restriction fragment length polymorphism (RFLP) analysis. GSTO1*A140D polymorphism was significantly associated with susceptibility to ALL (OR = 2.24, 95% CI = 1.16-4.35, P = 0.009) whereas, GSTO2*N142D genotype was significantly interacted with high risk group of childhood ALL (OR = 5.52, 95% CI = 1.72-17.71, P = 0.004). This study revealed gene polymorphism in glutathione S-transferase Omega class may be a risk factor to the development of acute childhood lymphoblastic leukemia.


The AMPK pathway triggers autophagy during CSF1-induced microglial activation and may be implicated in inducing neuropathic pain.
The development and maintenance of neuropathic pain is now given far more attention in the clinic work. Increasing evidence has shown that colony-stimulating factor 1 (CSF1) is involved in microglial activation and may further induce pain. Here, we observed the signaling events that link the CSF1-induced microglial activated and consequences for pain processing. For the in vitro study, flow cytometry showed the microglial activity was markedly increased after CSF1 stimulation. Western blot showed the increased expression of p-PRKAA1/PRKAA1, p-AMPK/AMPK, p-ULK1/ULK1, p-S6k/S6k and LC3-II/LC3-I. QRT-PCR showed the IL-1, TNF-α and BDNF were simultaneously upregulated in the activated microglia cells, whereas the specific AMPK inhibitor compound C exhibited reverse effects in microglia. Using immunofluorescence staining and electron microscopy, we found CSF1 decreased microglial p62 expression and induced the number of autophagosomes, whereas compound C significantly exhibited the reverse effects. For the in vivo study, compared with the control and AMPK-siRNA transfection, the mice under CSF1 intrathecal injection increased CSF1 receptor and LC3 expressed in the activated spinal microglia. More importantly, qRT-PCR showed CSF1 intrathecal injection substantially upregulated BDNF and c-Fos mRNA expression as well as the ensuing neuropathic pain. Our findings demonstrated that CSF1 induced a significant upregulation of microglial activation via the AMPK signaling pathway and resulted in an increasing microglial autophagic level. An increasing CSF1 level in the central nervous system can mimic and cause pain syndromes by up-regulation of AMPK-depended autophagy, thus offering a new target for the therapy of neuropathic pain.


Identifying a small set of marker genes using minimum expected cost of misclassification.
This paper presents a model independent feature selection approach to identify a small subset of marker genes. An evaluation measure, minimum expected cost of misclassification (MEMC), is used to estimate the discriminative power of a feature subset without building a model. The MECM measure is combined with sequential forward search for feature selection. This approach was applied to a breast cancer profiling problem, with the goal of identifying a small number of marker genes whose expression can be used to predict cancer molecular subtype (p53 gene status). Furthermore, the method was also applied to find a small set of single-nucleotide polymorphisms (SNPs) that can be used to predict molecular phenotype of a different type, namely alleles (genetic variants) of human leukocyte antigen genes that play an important roles in autoimmunity. Two marker genes were identified based on p53 status, which achieved a p-value of 7.53×10(-5) (vs. 6×10(-4) with 32 genes identified by previous research) in survival analysis. Six SNP loci were identified that achieved a leave-one-out cross-validation accuracy of 92.8% (vs. 90.6% and 89.5% with 18 SNPs selected using χ2 statistics and information gain, respectively). The MECM-based feature selection approach is capable of identifying a smaller subset of market genes with comparable or even better performance than that obtained using conventional filter methods.


Urban Trees and Hydrological Ecosystem Service: A Novel Approach to Analyzing the Relationship Between Landscape Structure and Runoff Reduction.
Urban stormwater runoff has posed significant challenges in the face of urbanization and climate change, emphasizing the importance of trees in providing runoff reduction ecosystem services (RRES). However, the sustainability of RRES can be disturbed by urban landscape modification. Understanding the impact of landscape structure on RRES is crucial to manage urban landscapes effectively to sustain supply of RRES. So, this study developed a new approach that analyzes the relationship between the landscape structural pattern and the RRES in Tabriz, Iran. The provision of RRES was estimated using the i-Tree Eco model. Landscape structure-related metrics of land use and cover (LULC) were derived using FRAGSTATS to quantify the landscape structure. Stepwise regression analysis was used to assess the relationship between landscape structure metrics and the provision of RRES. The results indicated that throughout the city, the trees prevented 196854.15 m3 of runoff annually. Regression models (p ≤ 0.05) suggested that the provision of RRES could be predicted using the measures of the related circumscribing circle metric (0.889 ≤ r2 ≤ 0.954) and the shape index (r2 = 0.983) of LULC patches. The findings also revealed that the regularity or regularity of the given LULC patches' shape could impact the patches' functions, which, in turn, affects the provision of RRES. The landscape metrics can serve as proxies to predict the capacity of trees for potential RRES using the obtained regression models. This helps to allocate suitable LULC through optimizing landscape metrics and management guidance to sustain RRES.


Design, synthesis, and evaluation of indeno[2,1-c]pyrazolones for use as inhibitors against hypoxia-inducible factor (HIF)-1 transcriptional activity.
HIF-1 is regarded as a promising target for the drugs used in cancer chemotherapy, and creating readily accessible templates for the development of synthetic drug candidates that could inhibit HIF-1 transcriptional activity is an important pursuit. In this study, indeno[2,1-c]pyrazolones were designed as readily available synthetic inhibitors of HIF-1 transcriptional activity. Nine compounds were synthesized in 4-5 steps from commercially available starting materials. In evaluations of the ability to inhibit the hypoxia-induced transcriptional activity of HIF-1, compound 3c showed a higher level compared with that of known inhibitor, YC-1. The compound 3c suppressed HIF-1α protein accumulation without affecting the levels of HIF-1α mRNA.


Limitations of exercise testing in critical left coronary artery disease.
Exercise testing was evaluated in 51 patients with critical left coronary artery disease (LCA) documented by coronary arteriography within two weeks of their bicycle ergometer (26 patients) or treadmill (25 patients) electrocardiographic study. Adequate tests, as defined by the patient having reached 85% of predicted maximum heart rate, were achieved in only 16 patients on the ergometer (62%) and in 21 (84%) on the treadmill. Nevertheless mean maximum double product (220 vs 232) and mean exercise time (4.6 min vs 5.0 min.) were similar (p:NS). The sensitivity for ergometry and treadmill testing was 75 and 62% respectively. If however we include those negative studies in which for various reasons patients were unable to achieve 85% of their predicted maximal heart rate (i.e., inadequate studies), sensitivity was only 46 and 52% respectively. Thus a sizable group of patients with critical LCA disease cannot adequately perform exercise tests especially on the ergometer; and over half of all such patients studied will be found for one reason or another to respond negatively, regardless of exercise protocol.


Pathological impairments induced by interstitial implantation of 125I seeds in spinal canal of banna mini-pigs.
Use a banna mini-pig to set up 125I implantation model, and investigate the consequence of radiation-related impairments. In present study, 125I seeds were implanted into spinal canal of T13 level of spine in banna mini-pigs. After operation, the pigs were raised up to 8 months, behavior changes were recorded within this period. After 8 months, spinal cords were collected for pathological analysis. In this study, a 125I brachytherapy animal model had been successfully established, in the model group, the banna pigs' Tarlov scale decreased from 5 to 2.57 ± 0.36, significant cellular impairments were noted by pathological analysis. Without any protection and operation improvement, 125I implantation can cause serious histological impairments and moving difficulty for banna mini-pigs; this present research provides an alternative tool to study spinal 125I brachytherapy.


New bis(hydroxymethyl) alkanoate curcuminoid derivatives exhibit activity against triple-negative breast cancer in vitro and in vivo.
Novel bis(hydroxymethyl) alkanoate curcuminoid derivatives were designed, synthesized and screened for in vitro antiproliferative and in vivo antitumor activity. Selected new compound 9a and curcumin were further evaluated for inhibitory activity against ER+/PR+ breast cancer (MCF-7, T47D), HER 2+ breast cancer (SKBR3, BT474, and MDA-MB-457) and triple negative breast cancer (TNBC) (HS-578T, MDA-MB-157, and MDA-MB-468) cell lines. In addition, compound 9a was evaluated in the MDA-MB-231 xenograft nude mice model. Compound 9a exhibited greater inhibitory activity than curcumin against TNBC cells and also demonstrated significant inhibitory activity against doxorubicin-resistant MDA-MB-231 cells, with ten-fold higher potency than curcumin. Furthermore, when evaluated against the MDA-MB-231 xenograft nude mice model, compound 9a alone was ten-fold more potent than curcumin. Moreover, synergistic activity was observed when 9a was used in combination with doxorubicin against MDA-MB-231 breast cancer cells.


Erdosteine salvages cardiac necrosis: Novel effect through modulation of MAPK and Nrf-2/HO-1 pathway.
Isoproterenol (ISO) induced oxidative stress and inflammation is involved in the pathogenesis of myocardial necrosis. To optimize the effect of erdosteine against myocardial necrosis, male albino Wistar rats were divided into eight groups (n = 6), that is, normal, ISO-control, erdosteine pretreatment with ISO. Rats were administered erdosteine orally for 28 days. Two doses of ISO (85 mg/kg), s.c. were given to ISO-C and erdosteine treatment groups on the 27th and 28th day. On the 29th day, hemodynamic parameters were recorded and the heart was excised for further parameters. In ISO-C rats, significantly increased levels of inflammatory markers, pro-oxidants, and structural damage were observed as compared with normal group. Furthermore, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed an increased expression of apoptotic proteins. Erdosteine at 80 mg/kg reversed the deleterious effects of ISO and normalized myocardium. Erdosteine showed anti-inflammatory, antiapoptotic, and antioxidant activities through inhibition of MAPK and Nrf-2/HO-1 pathways. To conclude, erdosteine was found protective in ISO-induced myocardial necrosis through MAPK and Nrf-2/HO-1 pathway.


International multicenter international sensitivity index (ISI) calibration of a new human tissue factor thromboplastin reagent derived from cultured human cells.
The international sensitivity index (ISI) of the first working standard of Simplastin HTF, a new human tissue factor thromboplastin derived from cultured human cells, has been assessed in a calibration exercise in two Canadian and five European laboratories. Calibrations against international reference preparations (IRP) were performed for the manual method and six types of automated coagulometers that cover the majority of clotting endpoint principles in routine use. The ISI was method-dependent and varied between 1.03 and 1.29 when calibrated against rTF/95 (human IRP). The ISI was also dependent on the route of calibration. Compared with calibration against rTF/95, the ISIs obtained by calibration against RBT/90 (rabbit IRP) were on average 4.4% higher (P < 0.005). Considering the principle of 'like vs. like', the ISIs obtained by calibration against rTF/95 should be preferred.


Heparin-induced hyperkalemia.
An 85-year-old lady with type 2 diabetes mellitus of 32 years duration with peripheral neuropathy was admitted under the vascular surgeons with extensive gangrene of her lower limb. She was on insulin for the last 7 years. Initial investigations showed normal serum electrolytes. She was started on antibiotics and unfractionated heparin, and her electrolytes showed hyperkalemia, which persisted on active treatment. Her short synacthen test showed good response, renin was normal with low aldosterone, urinary pH, sodium, potassium and osmolality was normal. On stopping heparin serum, potassium became normal. On restarting heparin (low molecular weight) during a suspected episode of pulmonary embolism, she developed hyperkalemia and heparin was stopped. Her potassium and aldosterone became normal on discontinuation of heparin. She developed hyperkalemia with both unfractionated and low molecular weight heparin.


Drift in vivo of transcutaneous dual electrodes.
TcPO2 and tcPCO2 monitoring is widely used but the in vitro drift of the new combined sensors is unknown. We tested the in vivo stability of 3 such electrodes in six adults, compared to nasal endtidal values from a mass spectrometer. Each electrode was remembraned within 5 days and had a 2 point dry gas calibration at 45 degrees C before fixing to the subjects' right arms. TcPO2, tcPCO2 and endtidal values were averaged over four minutes after 30 minutes equilibration, and then at seven subsequent 20 minute intervals. We observed that (1) Endtidal values remained stable (2) tcPCO2 differed from baseline by less than 3 torr (3) tcPO2 rose significantly in all three electrodes by an average of 16 to 21% and, (4) in vivo drift greatly exceeded separately determined in vitro changes. We discuss the possible explanations for the observed results, and conclude that skin permeability changes may play an important role. In the light of the large in vivo tcPO2 drift, transcutaneous dual electrodes are not reliable trend indicators of blood gases in adults.


Concurrent Use of Videolaryngoscope and Fiberoptic Bronchoscope in a Child with Neurofibromatosis to Facilitate Endotracheal Intubation.
In children who have craniofacial asymmetry secondary to neurofibromatosis type 1, the securing of the airway can be challenging. These patients have varying degrees of head and neck tumors that complicate endotracheal intubation. Anesthesiologists have many techniques and devices that assist us in securing adult airways and these devices are available in pediatric sizes which can also be used to safely secure the smaller airways. This 13-year-old male patient with Neurofibromatosis presented with a 2 cm mouth opening, Mallampati IV assessment, and thyromental distance of 2 cm for surgery. During the previous management of this child's airway it was found to be difficult using the fiberoptic bronchoscope or the Glidescope alone. This is a case report of improvement of intubating conditions using both devices concurrently.


Liver stiffness measurement by acoustic radiation forced impulse and transient elastography in patients with intrahepatic cholestasis.
Transient elastography (TE) and acoustic radiation force impulse (ARFI) imaging enable a noninvasive assessment of liver stiffness measurement (LSM) and liver fibrosis/cirrhosis staging. However, their use in cholestatic diseases is still scarce. The aim of this study was to evaluate the performance of TE and ARFI for the initial assessment of hepatic fibrosis in intrahepatic cholestatic (IHC) diseases and assess LSM changes after 3 months of specific therapy. This prospective study was carried out on 50 IHC patients. Assessment at baseline and after 3 months of LSM by TE and ARFI was performed. Overall, 60% of the patients were women (36.5±9.2 years). IHC etiologies were 23 (46%) autoimmune hepatitis, eight (16%) primary sclerosing cholangitis, eight (16%) drug induced, and five (10%) primary biliary cirrhosis. TE could diagnose ≥F2, ≥F3, and F4 stages at cutoffs of at least 6.7, 9.4, and 14.0 kPa, sensitivity/specificity were 100/50% for ≥F2, 88.2/83% for ≥F3, and 90/100% for F4. Moreover, the sensitivity and specificity of ARFI were 93/50% for ≥F2 (cutoff: 1.53 m/s); 71/67% for ≥F3 (cutoff 1.77 m/s); and 90/100% for F4 (cutoff: 2.43 m/s).Follow-up showed a significant decrease in TE and ARFI values by 27 and 22.3% (P<0.001 and <0.001, respectively) and, accordingly, fibrosis stages decreased significantly by both TE and ARFI (P=0.002 and <0.001, respectively). TE and ARFI represent noninvasive methods with adequate diagnostic performance for the assessment of fibrosis, and monitoring disease progression and treatment response in intrahepatic cholestasis.


Identification of the novel HLA-DQA1*01:01:01:11 and -DQA1*01:03:01:13 alleles in individuals from India.
The novel alleles HLA-DQA1*01:01:01:11 and -DQA1*01:03:01:13 were detected during the routine HLA typing process.


Tumor progression-related transmembrane protein aspartate-β-hydroxylase is a target for immunotherapy of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) has a poor survival rate due to recurrent intrahepatic metastases and lack of effective adjuvant therapy. Aspartate-β-hydroxylase (ASPH) is an attractive cellular target since it is a highly conserved transmembrane protein overexpressed in both murine and human HCC tumors, and promotes a malignant phenotype as characterized by enhanced tumor cell migration and invasion. Dendritic cells (DCs), expanded and isolated from the spleen, were incubated with a cytokine cocktail to optimize IL-12 secretion and co-stimulatory molecule expression, then subsequently loaded with ASPH protein for immunization. Mice were injected with syngeneic BNL HCC tumor cells followed by subcutaneous inoculation with 5-10×10(5) ASPH loaded DCs using a prophylactic and therapeutic experimental approach. Tumor infiltrating lymphocytes (TILs) were characterized, and their role in producing anti-tumor effects determined. The immunogenicity of ASPH protein with respect to activating antigen specific CD4+ T cells derived from human peripheral blood mononuclear cells (PBMCs) was also explored. We found that immunotherapy with ASPH-loaded DCs suppressed and delayed established HCC and tumor growth when administered prophylactically. Ex-vivo re-stimulation experiments and in vivo depletion studies demonstrated that both CD4+ and CD8+ cells contributed to anti-tumor effects. Using PBMCs derived from healthy volunteers and HCC patients, we showed that ASPH stimulation led to significant development of antigen-specific CD4+ T-cells. Immunization with ASPH-loaded DCs has substantial anti-tumor effects which could reduce the risk of HCC recurrence.


Ethanol ablation in postbiopsy liver hemorrhage following two failed embolizations.
A 42-year-old male presented with intraperitoneal hemorrhage 5days following percutaneous liver biopsy for suspected hepatocellular carcinoma. Diagnostic angiogram localized the bleeding to segment VI hepatic artery branches. Two consecutive arterial embolizations with microspheres and platinum coils failed to control the bleeding. The patient was a poor surgical candidate, so ultrasound-guided ethanol ablation of the bleeding source and surrounding liver segment was employed as salvage therapy. The patient stabilized clinically and was discharged home to begin palliative therapy.


Malalignment and cartilage lesions in the patellofemoral joint treated with autologous chondrocyte implantation.
The aim of our current study is to present the 12.6 years' follow-up results in patients with cartilage lesions of the patellofemoral joint, treated with autologous chondrocyte implantation (ACI) with the use of periosteum. Ninety-two patients having patella or trochlea lesion participated in this study. Lysholm and Tegner questionnaires were completed 12.6 years (SD 2.3 years) after the surgery. The patients were asked whether they feel better, worse or had not experienced any difference compared to previous years and whether they would undergo the operation again. Complications or subsequent surgeries were also assessed. Median Tegner score was three, improved by one level compared with preoperative values (P = 0.02). Median Lysholm score was 70, improved by nine points (n.s.). Seventy-two percent of the patients were better or unchanged while 93% would undergo the operation again. Patients with no kissing lesions appeared to have a better prognosis. Patients with malalignment or instability that had undergone a realignment procedure had comparable outcomes to the patients that did not need any additional surgery. Realignment procedures increased the incidence of serious complications but they were associated with decreased incidence of periosteal hypertrophy. No association was found between the age of the patients at the time of the ACI or the size per lesion and any of the clinical outcomes. ACI provides a satisfactory outcome for the treatment of cartilage lesions of the patellofemoral joint, even for the cases with concomitant patellar instability. It seems that correcting the coexisting background factors with realignment, stabilizing or unloading procedures, along with the treatment of cartilage lesions, is improving the clinical outcomes over time and decreases the incidence of periosteal hypertrophies although increasing the incidence of serious complications. Our study reveals the good results and the high level of patients' activities (as shown by Tegner score), were preserved 12.6 years after the implantation, in both isolated trochlea and patella lesions and also in multiple and in kissing lesions where an intervention could be considered as a salvage procedure.


Retracted: Research and Development of User Clustering-Based Content Similarity Algorithms in Dance-Assisted Choreography Techniques.
[This retracts the article DOI: 10.1155/2022/1364835.].


Physicochemical characterization of 1,2-diphytanoyl-sn-glycero-3-phosphocholine in model membrane systems.
We report here on a series of studies aimed at characterization of the structural and dynamical properties of the synthetic lipid diphytanoyl phosphatidylcholine, in multilamellar dispersions and vesicle suspensions. The lipid exhibits no detectable gel to liquid crystalline phase transition over a large temperature range (-120 degrees C to +120 degrees C). Examination of proton nuclear magnetic resonance (NMR) free induction decays obtained from multilayer dispersions of diphytanoyl phosphatidylcholine provided an estimate of the methylene proton order parameter. The estimated magnitude of 0.21 is comparable to those determined for other phospholipids. Sonication of aqueous dispersions of diphytanoyl phosphatidylcholine led to formation of bilayer vesicles as determined by the measurement of the outer/inner choline methyl proton resonances, vesicle sizes in electron micrographs, and comparison of proton NMR linewidths between multilayer and sonicated dispersions. Ultracentrifugation studies of diphytanoyl phosphatidylcholine vesicles in H2O and 2H2O media yielded a value of 1.013 +/- 0.026 ml/g for the partial specific volume of this lipid. We have measured spin lattice relaxation rates for the methyl and methylenemethyne protons of the hydrocarbon chains of diphytanoyl phosphatidylcholine in bilayer vesicles over a range of temperatures and at two NMR frequencies (100 and 220 MHz). The observed relaxation rates for the methylene protons in this system were approximately twice those previously reported for dipalmitoyl phosphatidylcholine at comparable temperatures and resonance frequencies, whereas the relaxation rates measured for the methyl protons were greater than those of the straight chain lipid by an order of magnitude. Measurement of the spin lattice relaxation rates of the hydrocarbon protons of the diphytanoyl phosphatidylcholine in a 10 mol% mixture of the branched-chain lipid in a deuterated host lipid, diperdeuteropalmitoyl phosphatidylcholine, showed a discontinuity in the temperature dependence of the proton NMR longitudinal relaxation rates of the branched-chain lipid in the region of the gel to liquid crystalline phase transition temperature of the deuterated dipalmitoyl phosphatidylcholine host lipid. This result may be taken as evidence of lateral phase separation of a liquid cyrstalline phase enriched in diphytanoyl phosphatidylcholine from a gel phase enriched in diperdeuteropalmitoyl phosphatidylcholine at temperatures below the phase transition temperature of deuterated host lipid. This conclusion is supported by the observation of an abrupt change in the hydrocarbon methylene linewidth (at 100 MHz) of 10 mol% diphytanoyl phosphatidylcholine in diperdeuteropalmitoyl phosphatidylcholine over the temperature range where lateral phase separation is taking place according to differential thermograms.


Discovery of novel JAK1 inhibitors through combining machine learning, structure-based pharmacophore modeling and bio-evaluation.
Janus kinase 1 (JAK1) plays a critical role in most cytokine-mediated inflammatory, autoimmune responses and various cancers via the JAK/STAT signaling pathway. Inhibition of JAK1 is therefore an attractive therapeutic strategy for several diseases. Recently, high-performance machine learning techniques have been increasingly applied in virtual screening to develop new kinase inhibitors. Our study aimed to develop a novel layered virtual screening method based on machine learning (ML) and pharmacophore models to identify the potential JAK1 inhibitors. Firstly, we constructed a high-quality dataset comprising 3834 JAK1 inhibitors and 12,230 decoys, followed by establishing a series of classification models based on a combination of three molecular descriptors and six ML algorithms. To further screen potential compounds, we constructed several pharmacophore models based on Hiphop and receptor-ligand algorithms. We then used molecular docking to filter the recognized compounds. Finally, the binding stability and enzyme inhibition activity of the identified compounds were assessed by molecular dynamics (MD) simulations and in vitro enzyme activity tests. The best performance ML model DNN-ECFP4 and two pharmacophore models Hiphop3 and 6TPF 08 were utilized to screen the ZINC database. A total of 13 potentially active compounds were screened and the MD results demonstrated that all of the above molecules could bind with JAK1 stably in dynamic conditions. Among the shortlisted compounds, the four purchasable compounds demonstrated significant kinase inhibition activity, with Z-10 being the most active (IC50 = 194.9 nM). The current study provides an efficient and accurate integrated model. The hit compounds were promising candidates for the further development of novel JAK1 inhibitors.


Obstetric and neonatal outcomes after programmed frozen embryo transfer with or without GnRH agonist for polycystic ovary syndrome: secondary analysis results from a randomized controlled trial.
Recent studies have reported higher risks of adverse maternal and neonatal outcomes, such as hypertensive disorders of pregnancy, after programmed frozen embryo transfer, especially in cycles with gonadotropin-releasing hormone agonist pretreatment. It remains unclear if GnRH agonist pretreatment before programmed frozen embryo transfer further increases the risk for obstetrical complications among women with polycystic ovary syndrome. This study aimed to compare the obstetrical and neonatal complications of singleton and twin pregnancies after programmed frozen embryo transfer with or without gonadotropin-releasing hormone-a pretreatment among women with polycystic ovary syndrome. This was a secondary analysis of a single-center, randomized controlled trial comparing the live birth rate and cost-effectiveness of programmed cycle-prepared frozen embryo transfers with or without gonadotropin-releasing hormone agonist pretreatment among women with polycystic ovary syndrome. The analysis was restricted to women with polycystic ovary syndrome, aged 24 to 40 years, who delivered live neonates after frozen-thawed blastocyst transfer. The obstetrical and neonatal outcomes were compared between programmed cycles with and those without gonadotropin-releasing hormone agonist pretreatment. The adjusted odds ratios with 95% confidence intervals were calculated and adjustments were made for relevant confounders. The maternal and neonatal complications associated with 177 live single births and 38 twin births (253 newborns in total) were analyzed. There were no significant differences in the frequencies of obstetrical complications, including hypertensive disorders of pregnancy, between the gonadotropin-releasing hormone agonist pretreatment and no pretreatment group for both singleton and twin pregnancies. However, there was a significantly greater incidence of having a low birthweight neonate among singleton infants born after gonadotropin-releasing hormone agonist pretreatment when compared with no pretreatment (10.2% vs 1.3%; P=0.042), and a low birthweight among singleton infants was still more likely after adjusting for confounders (relative ratio, 3.85; 95% confidence interval, 1.13-7.11; P=.024). Other neonatal complications were all comparable between the pretreatment and no pretreatment groups for both singleton and twin pregnancies. For women with polycystic ovary syndrome, programmed frozen embryo transfer cycles with gonadotropin-releasing hormone agonist pretreatment could lead to a greater risk of having a low birthweight singleton neonate.


Trauma to the esophagus.
We have classified esophageal trauma into three major categories: (1) Iatrogenic trauma including endoscopic perforation, trauma due to dilatation, surgical trauma, tube trauma, radiation trauma, and drug trauma; (2) Self-induced trauma including foreign bodies, corrosive or drug ingestion, and postemetic trauma; (3) Direct trauma including penetrating trauma and blunt trauma. Discussion and illustrative cases are presented.


Diversity, diversity indices and tropical cockroaches.
The diversity of samples of cockroaches (Blattaria) taken with light-traps in six localities in Panama is described. As a diversity index α of the log series is found to be more satisfactory than either N 2 or N 1 of Hills's series or Hurlbert's S m, even if the distribution of the relative abundances is significantly different from a log series. However, even the α-index is of only limited usefulness. A simple statistic such as the number of species per unit effort can be at least as useful. The seasonal variation in the value of the diversity indices is negatively correlated with both the number of species and the number of individuals. Mountain sites have a lower alpha-diversity than lowland sites and relatively undisturbed sites have more individuals and more species than disturbed ones, although this difference is not reflected in the value of the diversity indices. To describe the beta-diversity the NESS similarity index, here called C m, is far superior over any other indices available. The between site diversity is very high. Samples taken at the same site in successive years in most cases are significantly different from being random samples of the same fauna.


Are there any relationships between personality type, salivary total antioxidant level and academic stress?
Stress is one of the most important determinants of total antioxidant capacity (TAC). This study aimed to assess alterations in salivary TAC following academic stress according to the personality type. This descriptive study evaluated 53 dental students at Shahid Beheshti University of Medical Sciences, Tehran, Iran, who were divided into type A (n = 25) and type B (n = 28) personality groups using the Bortner questionnaire. Saliva samples were collected during the 1st week of the semester (a low-stress period) and during the 1st week of the final exams (a high-stress period). Salivary TAC was measured using a specific kit. The data was analyzed using the repeated measures analysis of variance (ANOVA), the analysis of covariance (ANCOVA), the χ2 tests, the independent t tests, and the Bonferroni adjustments. Overall, salivary TAC in the high-stress period was significantly lower than that in the low-stress period (0.27 vs 0.31 mM) (p = 0.016). The comparison of salivary TAC between the type A and type B personality groups in the low-stress period showed no significant difference (p = 0.450). During the highstress period, a reduction in salivary TAC was recorded in both groups, which was borderline significant in the type A personality group (p = 0.050), but non-significant in the type B personality group (p = 0.140). The comparison of salivary TAC between the type A and B personality groups in the high-stress period also revealed no significant difference (p = 0.780). Academic stress can decrease salivary TAC, and the personality type has no significant effect on this relationship.


The nature of Schwertmannite and Jarosite mediated by two strains of Acidithiobacillus ferrooxidans with different ferrous oxidation ability.
Jarosite and Schwertmannite are iron-oxyhydroxysulfate materials. These materials gain increasing interest in geological and metallurgical fields. Especially, for it can effectively scavenge heavy metals, less toxic ions and better biocompatibility, the application potential in environment becomes more and more intriguing. In this study, the nature of Jarosite and Schwertmannite mediates synthesized by two strains of Acidithiobacillus ferrooxidans with different ferrous oxidation ability is investigated. The precipitates are characterized by SEM, XRD, FTIR, and TG/DSC analysis. The materials are varied in color, shape, surface area, elemental composition and crystallinity. The crystallinity of precipitate produced by A. ferrooxidans 23270 with lower oxidation ability in optimized medium is significantly better than the precipitate produced by A. ferrooxidans Gf. A. ferrooxidans Gf will tend to mediate the formation of Schwertmannite with the decreasing of monovalent cation concentration in optimized medium. Cr(VI) adsorption capacity difference exists among the four materials. The adsorption efficiency of Schwertmannite is higher than Jarosite. Adsorption capacity of the materials formed by A. ferrooxidans Gf is higher than that of A. ferrooxidans 23270. Adsorption capacity decreases with the increasing of crystallinity.


Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.
The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.


Comparison of metastatic properties of a variety of mouse, rat, and human cells in assays in nude mice and chick embryos.
We have previously developed an assay to measure experimental metastatic ability of cells following intravenous injection into chorioallantoic membrane (CAM) veins of naturally immune deficient chick embryos. Here we compare metastatic properties of different cell types (ras-transformed and control NIH 3T3, LTA, and 10T1/2; melanoma; and glioma) from several species (mouse, rat, human), using chick embryos and the more commonly-used immune deficient host, nude mice. We found a good correlation between the two assays. Both hosts have advantages and disadvantages in assessing metastatic properties. We conclude that the chick embryo assay is a useful alternative host for experimental metastasis studies. This assay correlates well with and is less costly than assays using nude mice.


[Aorto-esophageal fistula: late complications following aortic graft implantation].
Aorto-esophageal fistula is a rare complication after repair of thoracic aortic aneurysm. In a review of the literature only 3 cases have been found. A fourth case is reported which was diagnosed preoperatively by endoscopy.