Sex differences among five sources of motivation in the motivation sources inventory: preliminary findings.
Paper reports sex differences among five sources of motivation for a sample of 208 undergraduate students who completed the Motivation Sources Inventory. t tests yielded few statistically significant sex differences for the five sources of motivation; however, Instrumental Motivation was higher among men than women, while the remaining four motives showed no sex difference. Implications and research opportunities are discussed.


The Impact of CenteringPregnancy Group Prenatal Care on Birth Outcomes in Medicaid Eligible Women.
Background: CenteringPregnancy group prenatal care (GPNC) has been shown to reduce rates of preterm birth (PTB). We evaluated the impact of GPNC on spontaneous PTB (sPTB) as a first step in exploring the possible mechanism by which GPNC may decrease rates of PTB. We also evaluated whether attending more than five GPNC sessions affected PTB risk and examined all differences by race/ethnicity. Materials and Methods: We conducted a retrospective cohort study among women delivering at a single institution between April 2009 and March 2014. Birth outcome data from vital statistics records were appended to patient records, and detailed chart abstraction was used to determine spontaneous versus indicated PTB. The association between GPNC and attending more than five GPNC sessions and birth outcomes (i.e., PTB, sPTB, low birth weight [LBW], and neonatal intensive care unit [NICU] admissions) was analyzed using generalized estimating equation log binomial regression models. We examined effect modification of the associations by race/ethnicity. Results: The analysis included 1,292 women in GPNC and 8,703 in traditional individual prenatal care (IPNC). After controlling for potential confounders, the risk of PTB (risk ratio [RR] 0.38; 95% confidence interval [CI] 0.31-0.47), sPTB (RR 0.49; 95% CI 0.38-0.63), LBW (RR 0.46; 95% CI 0.37-0.56), and NICU admissions (RR 0.46; 95% CI 0.37-0.57) was lower in GPNC compared to IPNC women. Results differed by maternal race/ethnicity, with the strongest associations among non-Hispanic white mothers and the weakest associations among Hispanic mothers, especially for sPTB. Similarly, the risk of PTB, LBW, and NICU admissions was lower among GPNC women who attended more than five sessions. Conclusion: Participation in GPNC demonstrated a decreased risk for sPTB, as well as other adverse birth outcomes. In addition, participation in more than five GPNC sessions demonstrated a decreased risk for adverse birth outcomes. Prospective longitudinal studies are needed to further explore mechanisms associated with these findings.


Transcriptional control of ribosome biogenesis in yeast: links to growth and stress signals.
Ribosome biogenesis requires prodigious transcriptional output in rapidly growing yeast cells and is highly regulated in response to both growth and stress signals. This minireview focuses on recent developments in our understanding of this regulatory process, with an emphasis on the 138 ribosomal protein genes (RPGs) themselves and a group of >200 ribosome biogenesis (RiBi) genes whose products contribute to assembly but are not part of the ribosome. Expression of most RPGs depends upon Rap1, a pioneer transcription factor (TF) required for the binding of a pair of RPG-specific TFs called Fhl1 and Ifh1. RPG expression is correlated with Ifh1 promoter binding, whereas Rap1 and Fhl1 remain promoter-associated upon stress-induced down regulation. A TF called Sfp1 has also been implicated in RPG regulation, though recent work reveals that its primary function is in activation of RiBi and other growth-related genes. Sfp1 plays an important regulatory role at a small number of RPGs where Rap1-Fhl1-Ifh1 action is subsidiary or non-existent. In addition, nearly half of all RPGs are bound by Hmo1, which either stabilizes or re-configures Fhl1-Ifh1 binding. Recent studies identified the proline rotamase Fpr1, known primarily for its role in rapamycin-mediated inhibition of the TORC1 kinase, as an additional TF at RPG promoters. Fpr1 also affects Fhl1-Ifh1 binding, either independently or in cooperation with Hmo1. Finally, a major recent development was the discovery of a protein homeostasis mechanism driven by unassembled ribosomal proteins, referred to as the Ribosome Assembly Stress Response (RASTR), that controls RPG transcription through the reversible condensation of Ifh1.


Inhibition of choroidal fibrovascular membrane formation by new class of RNA interference therapeutic agent targeting periostin.
Age-related macular degeneration (AMD) is a vision-threatening disease characterized by choroidal fibrovascular membrane (FVM) formation, choroidal neovascularization (CNV) and choroidal fibrosis. No safe and effective therapeutic method has been developed for the choroidal fibrosis, although anti-vascular endothelial growth factor therapy can partially shrink the CNV. We recently reported that periostin (POSTN), which is produced by retinal pigment epithelial cells, has an important role in the formation of preretinal FVMs, but its role in choroidal FVMs has not been determined. In this study, we used Postn knockout mice to investigate the role played by POSTN in choroidal FVM formation. In addition, we used a new class of RNA interference (RNAi) agent (NK0144) that targets POSTN and determined its effect on choroidal FVM development. Genetic ablation of Postn had an inhibitory effect not only on CNV formation but also on choroidal fibrosis in a mouse CNV model. NK0144 also had a greater inhibitory effect on both the CNV and choroidal fibrosis than control RNAi with no apparent adverse effects. These findings suggest a causal relationship between POSTN and choroidal FVM formation, and also a potential therapeutic role of intravitreal NK0144 for AMD.


Virtual reality simulation training in stroke thrombectomy centers with limited patient volume-Simulator performance and patient outcome.
Virtual reality simulation training may improve the technical skills of interventional radiologists when establishing endovascular thrombectomy at limited-volume stroke centers. The aim of this study was to investigate whether the technical thrombectomy performance of interventional radiologists improved after a defined virtual reality simulator training period. As part of the quality surveillance of clinical practice, we also assessed patient outcomes and thrombectomy quality indicators at the participating centers. Interventional radiologists and radiology residents from three thrombectomy-capable stroke centers participated in a five months thrombectomy skill-training curriculum on a virtual reality simulator. The simulator automatically registered procedure time, the number of predefined steps that were correctly executed, handling errors, contrast volume, fluoroscopy time, and radiation dose exposure. The design was a before-after study. Two simulated thrombectomy cases were used as pretest and posttest cases, while seven other cases were used for training. Utilizing the Norwegian Stroke Register, we investigated clinical results in thrombectomy during the study period. Nineteen interventional radiologists and radiology residents participated in the study. The improvement between pretest and posttest cases was statistically significant for all outcome measures in both simulated cases, except for the contrast volume used in one case. Clinical patient outcomes in all three centers were well within the recommendations from multi-society consensus guidelines. Performance on the virtual reality simulator improved after training. Virtual reality simulation may improve the learning curve for interventional radiologists in limited-volume thrombectomy centers. No correlation alleged, the clinical data indicates that the centers studied performed thrombectomy in accordance with guideline-recommended standards.


Performance of the Meta-Analysis Global Group in Chronic Heart Failure Score in Black Patients Compared With Whites.
Risk stratification is critical in heart failure (HF) and the Meta-Analysis Global Group in Chronic HF (MAGGIC) score is a validated tool derived from ~40,000 patients. However, few of these patients self-identified as black, raising uncertainty regarding performance in blacks with HF. This study analyzed a racially diverse group of 4046 patients (1646 black and 2400 white) from a single center from 2007 to 2015. Baseline characteristics were collected to tabulate MAGGIC score and test its discrimination and calibration within race groups. The primary end point was all-cause mortality. Death was detected using system records and the social security death master file. Discrimination was tested using Cox models of MAGGIC score stratified by race, and combined analysis including MAGGIC, race, and MAGGIC×race. Calibration was assessed using linear regression models and plots of observed versus predicted data. Overall, 901 (21%) patients died during 1-year follow-up. MAGGIC score discrimination was similar in both race groups in terms of C statistic (0.707±0.027 versus 0.725±0.014, for black versus white; P=0.556) and the hazard ratio (HR) per MAGGIC point was 1.12 in black patients (95% CI, 1.10-1.14) and 1.13 in white patients (95% CI, 1.12-1.14). Race was a significant correlate of survival, with better survival in black patients compared with white (HR, 0.66; 95% CI, 0.56-0.78), but the interaction of MAGGIC×race was not significant (β=-0.013; P=0.16), and adding race to the model did not improve discrimination (C statistic for MAGGIC versus MAGGIC+race, 0.721 versus 0.722; P=0.79). In calibration testing, the slope was not significantly different from 1 in either group, but the groups differed from each other, and it was closer to unity among black patients (0.94 versus 1.4; P=0.004). These data support the use of the MAGGIC score to risk stratify black patients with HF.


Poly(A)+ RNA from the mucosa of rat jejunum induces novel Na(+)-dependent and Na(+)-independent leucine transport activities in in oocytes of Xenopus laevis.
Complementary DNA clones have been isolated recently from rat (D2) and rabbit kidney (rBAT) which induce increased Na(+)-independent Leu and Lys transport activities (System b0, +) when expressed in oocytes of Xenopus laevis. These cDNAs encode type II membrane glycoproteins which show significant homology to the heavy chain of the human and mouse 4F2 surface antigen (4F2hc). Injection of human 4F2hc cRNA into oocytes also results in induction of Leu/Lys transport activity, but with differing cation requirements for the two amino acids (Na(+)-dependent for Leu, Na(+)-independent for Lys: system y+L). System y+L is a newly discovered zwitterionic/cationic amino acid transporter first described in human erythrocytes. Here we have examined the characteristics of Leu transport in Xenopus oocytes microinjected with mRNA from the mucosa of rat jejunum. L-Leu uptake during 10 min (0.2 mM, 20 degrees C) reached 20 pmol/oocyte compared with endogenous uptake by water-injected oocytes of typically 3-4 pmol/oocyte. The expressed transport activity was 80% Na(+)-dependent. The Na(+)-dependent component of the expressed flux was saturable (Km app 0.20 mM) and inhibited by Lys, but not by Ala or Phe. The minor Na(+)-independent component of expressed Leu transport activity was also saturable (Km app 0.10 mM). Amino acid inhibition studies resolved this flux into two main components, one of which was inhibited by Lys, Ala and Phe and another which was only inhibited by Lys. There was a small residual component of Na(+)-independent Leu transport which was insensitive to inhibition by Lys. Experiments utilizing polymerase chain reaction (PCR) demonstrated the presence of both D2 and 4F2hc message in rat jejunum. Hybrid-depletion of jejunal mRNA with an antisense oligonucleotide complementary to D2 had no effect on the expression of Na(+)-linked Leu transport activity, but reduced the smaller Na(+)-independent component of Leu transport by 40%, suggesting only a minor role of D2 in the expression of rat intestinal Leu transport activity. Although the properties of Na(+)-dependent Leu transport were, with the exception of a lack of inhibition by Ala and Phe, consistent with erythrocyte y+L, hybrid-depletion of jejunal mRNA with an antisense oligonucleotide complementary to 4F2hc had no detectable effect on the expressed transport activity. We conclude, therefore, that mRNA from rat jejunum encodes novel Na(+)-dependent and Na(+)-independent transport activities unrelated to the D2/4F2hc glycoproteins.(ABSTRACT TRUNCATED AT 400 WORDS)


Bilateral locked facets in the thoracic spine.
Two cases of traumatic bilateral locked facets in the thoracic spine are reported. Both patients had only minor neurological signs. They both made a full neurological recovery after surgical reduction of the locked facets. Bilateral locked facets are very uncommon in the thoracic spine. The diagnosis should be considered in any patient with a fracture-dislocation of the thoracic spine. In these cases additional lateral tomographs are required. Early open reduction of bilateral locked facets and internal fixation are mandatory.


Targeted Drug Therapy to Overcome Chemoresistance in Triple-negative Breast Cancer.
Triple-negative Breast Cancer (TNBC) is the most aggressive and prevailing breast cancer subtype. The chemotherapeutics used in the treatment of TNBC suffer from chemoresistance, dose-limiting toxicities and off-target side effects. As a result, conventional chemotherapeutics are unable to prevent tumor growth, metastasis and result in failure of therapy. Various new targets such as BCSCs surface markers (CD44, CD133, ALDH1), signaling pathways (IL-6/JAK/STAT3, notch), pro and anti-apoptotic proteins (Bcl-2, Bcl-xL, DR4, DR5), hypoxic factors (HIF-1α, HIF-2α) and drug efflux transporters (ABCC1, ABCG2 and ABCB1) have been exploited to treat TNBC. Further, to improve the efficacy and safety of conventional chemotherapeutics, researchers have tried to deliver anticancer agents specifically to the TNBCs using nanocarrier based drug delivery. In this review, an effort has been made to highlight the various factors responsible for the chemoresistance in TNBC, novel molecular targets of TNBC and nano-delivery systems employed to achieve sitespecific drug delivery to improve efficacy and reduce off-target side effects.


Prevalence and determinants of concurrent wasting and stunting and other indicators of malnutrition among children 6-59 months old in Kersa, Ethiopia.
Malnutrition is the leading cause of poor child health in Ethiopia, and progress to avert it is unacceptably slow. In addition, little is known about the magnitude and factors associated with concurrent wasting and stunting (WaSt). Therefore, this study aimed to assess the prevalence and factors associated with WaSt, wasting, stunting and underweight among children 6-59 months in Kersa Health and Demographic Surveillance System, Ethiopia. Data from a total of 1091 children and their parents' were analysed from a cross-sectional study. Household questionnaires and anthropometric measurements were used for data collection. Height-for-age, weight-for-height and weight-for-age indices are expressed as standard deviation units from the mean for the reference group. Multivariate analyses were conducted to identify factors associated with WaSt, wasting, stunting and underweight. Statistical significance was declared at p < 0.05. The prevalence of indicators of malnutrition was WaSt (5.8%), wasting (16.8%), stunting (53.9%) and underweight (36.9%). Children aged 6-17 months had a higher odds of wasting (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.12-2.75) compared with those aged 36-59 months, whereas children aged 18-35 months (aOR 2.4, 95% CI 1.65-3.47) and 36-59 months (aOR 1.6, 95% CI 1.07-2.37) had higher odds of stunting compared with those aged 6-17 months. Similarly, children aged 18-35 months (aOR 1.6, 95% CI 1.07-2.37) and 36-59 months (aOR 2.2, 95% CI 1.52-3.10) had higher odds of underweight compared with children aged 6-17 months. Households that did not treat drinking water at point of use were at higher odds of WaSt (aOR 3.3, 95% CI 1.16-9.27) and stunting (aOR 1.9, 95% CI 1.31-2.85) compared with those who did treat drinking water. Boys were more likely to be WaSt, wasted, stunted and underweight. Cough was associated with WaSt, wasting and underweight. Furthermore, maternal education, maternal occupation and maternal age were significantly associated with wasting. Maternal body mass index (BMI) of less than 18.5 kg/m2 and maternal BMI between 18.5 and 25 kg/m2 were associated with child stunting. In Kersa, the prevalence of WaSt, wasting, stunting and underweight is very high and requires urgent public health intervention. This study highlights point-of-use water treatment, maternal education, hygiene and sanitation, child health service utilization and maternal BMI as important areas to improve to target child malnutrition. Furthermore, a community-based programmatic and policy direction for early identification and management of WaSt in addition to other indicators of malnutrition is recommended.


Preschool vision screening: update on guidelines and techniques.
To discuss the current preschool vision screening (PVS) guidelines and review some of the newest vision screening techniques. The different vision screening practices and barriers to screening are discussed. Vision screening guidelines, which have been developed in response to the advances in technology and increased understanding of the developing visual system, have been recently updated by some of the major medical organizations that endorse vision screening. With advances in vision screening technology, there is a growing trend for screening at younger ages. PVS has been widely endorsed by various medical organizations as an effective way to detect preventable and treatable vision problems of childhood. Although PVS is widely recommended, actual screening rates remain low. There are several real and perceived barriers to screening which often prevents successful screening programs. Current vision screening guidelines take into account the recent advances in technology. With the development of new devices, vision screening can effectively be performed at younger ages.


Dynamics of the effects of levoprotiline and maprotiline on EEG in patients with major depressive episodes (DSM-III-R).
The presented study compares the effect of the well-tested antidepressant maprotiline and a new antidepressant with an atypical pharmacological profile, levoprotiline, on EEG during repeated assessment after single dose administration. From the original number of 34 patients fulfilling the criteria of a major depressive episode (DSM-III-R) on account of a low-voltage record or pathological findings 11 were eliminated. To 12 of the remaining patients levoprotiline was administered and to 11 maprotiline, after a one-week placebo period, in doses of 150 mg. The EEG was recorded after an accommodation session immediately before, 1.5, 3, 4.5, 6 and 24 hours after a single dose administration. The record was taken on a 16-channel average reference montage at rest with closed eyes. Two-minute intervals were divided into 30 four-second periods at a sampling frequency of 128 Hz. From the signal by means of FFT the spectra were estimated and the mean spectrum for the entire recording was calculated. This was then divided into 10 frequency bands. The new method of frequency analysis of alpha-entropy was also used which is a global measure of the difference between two spectra. Three hours after administration of a single dose levoprotiline had an EEG profile corresponding to the profile of tricyclic antidepressants, i.e. it increased the values of the power spectra density in the region of 5-8.5 Hz and in the entire beta band; the decline of power in the alpha band was, however, absent. As regards maprotiline, 3 hours after administration a profile typical for antidepressants was not found; obviously because of the great variance of values of power spectra density as a result of great interindividual differences in the ingestion phase. Changes of the EEG spectrum expressed as values of alpha-entropy during different periods of apparently assessment are not incidental. After the initial rise of values a decline occurs.


Augmentation and impulsive behaviors in restless legs syndrome: Coexistence or association?
To assess the frequency of impulse control disorders (ICDs) in patients with restless legs syndrome (RLS) with and without augmentation under dopaminergic therapy in a case-control study. Augmentation and ICDs are both serious complications of dopaminergic treatment of RLS but little is known about possible associations between these drug-induced disorders. In total, 58 patients with idiopathic RLS diagnosed according to the International Restless Legs Syndrome Study Group criteria were recruited. Of these, 35 patients had augmentation. The frequency of ICD symptoms was assessed using semi-structural interviews. Demographic variables did not differ between patients with RLS with and without augmentation but those with augmentation took higher dopaminergic medication than patients without augmentation. Twenty-three patients with RLS (39.7%) had ICD symptoms, with 12 patients (20.7%) having definitive ICDs. Patients with augmentation had an increased risk of expressing ICD symptoms (p = 0.007, odds ratio 5.64, 95% confidence interval 1.59-20.02). Patients with RLS with augmentation have an almost 6-fold increased risk of exhibiting ICD symptoms. This implies that augmentation and ICDs are related and may share a common pathophysiology. Moreover, our results have clinical implications, suggesting that patients with RLS with augmentation should be screened for ICD symptoms.


On the mechanism of an asymmetric alpha,beta-unsaturated carboxylic acid hydrogenation: application to the synthesis of a PGD2 receptor antagonist.
Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of alpha,beta-unsaturated ene acid 1-E to give 2, a prostaglandin D2 (PGD2) receptor antagonist. With [(S-BINAP)Ru(p-cymene)Cl2]2 (3, S-BINAP = (S)-(+)-2,2'-bis(diphenylphospino)-1,1'-binapthyl), it was discovered that low hydrogen pressures (<30 psi) were essential to achieve high enantioselectivities (92% ee). A detailed mechanistic study was undertaken to elucidate this pressure dependence. It was determined that compound 1-E is in a ruthenium-catalyzed equilibrium with endocylic isomer 1-Endo and in photochemical equilibrium with Z isomer 1-Z. Each isomer could be hydrogenated to give 2, albeit with different rates and enantioselectivities. Hydrogenation of 1-Endo with 3 was found to give 2 in high enantiomeric excess, regardless of pressure and at a rate substantially faster than that of hydrogenation of 1-E and 1-Z. In contrast, isomers 1-E and 1-Z exhibited pressure-dependent enantioselectivities, with higher enantiomeric excesses obtained at lower pressures. A rationale for this pressure dependence is described. Deuterium labeling studies with 1-Endo and tiglic acid were used to elucidate the mechanism of hydride insertion and product release from ruthenium. Under neutral conditions, protonolysis was the major pathway for metal-carbon cleavage, while under basic conditions, hydrogenolysis of the metal-carbon bond was predominant.


Scaffolds as Structural Tools for Bone-Targeted Drug Delivery.
Although bone has a high potential to regenerate itself after damage and injury, the efficacious repair of large bone defects resulting from resection, trauma or non-union fractures still requires the implantation of bone grafts. Materials science, in conjunction with biotechnology, can satisfy these needs by developing artificial bones, synthetic substitutes and organ implants. In particular, recent advances in materials science have provided several innovations, underlying the increasing importance of biomaterials in this field. To address the increasing need for improved bone substitutes, tissue engineering seeks to create synthetic, three-dimensional scaffolds made from organic or inorganic materials, incorporating drugs and growth factors, to induce new bone tissue formation. This review emphasizes recent progress in materials science that allows reliable scaffolds to be synthesized for targeted drug delivery in bone regeneration, also with respect to past directions no longer considered promising. A general overview concerning modeling approaches suitable for the discussed systems is also provided.


The DEF data base of sequence based protein fold class predictions.
A new method for predicting protein fold-classes and protein domains from sequence data is constructed and used for generating a data base of protein fold-class assignments. Any given sequence of amino acids is assigned a specific prediction of one out of 45 typical protein fold-classes, a prediction of one out of 4 super fold-classes for the content of secondary structures and a profile of fold-class predictions along the sequence. The prediction accuracy for the super fold-classes is around 91% correct and 82% correct for the specific fold-classes. This accuracy is maintained down to a few percent of sequence identity.


Coronary heart disease in the elderly.
In 1984, 435,759 deaths were attributed to CHD among persons greater than or equal to 65 years of age. CHD was the leading cause of death in this group. Death rates rose steeply with age among the elderly. Men had higher death rates than women, but the male-to-female ratio declined with increasing age. Considerable geographic variation in CHD mortality in the elderly was noted. Since 1968, CHD death rates have declined in persons greater than or equal to 65 years of age in each age, sex, and race group. However, prevalence of self-reported CHD in the elderly population has increased. Prevalence rates increased with age except for a slight decrease above age 75 in men. In 1985, 436,000 persons aged greater than or equal to 65 years were discharged with a principal diagnosis of acute MI. The hospital case fatality rate was 21.8%. Since 1970, hospitalization rates for acute MI have generally increased, while hospital fatality rates have decreased for persons greater than or equal to 65 years of age. Since 1979, utilization of coronary artery bypass surgery and coronary arteriography have dramatically increased among the elderly. In 1980 and 1981, elderly persons made six million visits to physicians' offices for chronic CHD. CHD contributed importantly to the 1980 expenditures of 3.3 billion dollars in men and 4.8 billion dollars in women greater than or equal to 65 years of age for heart disease care. Although mortality rates from CHD in the elderly have decreased since 1968, increasing hospitalization rates and utilization of other health care services emphasize the need for more vigorous efforts at prevention.(ABSTRACT TRUNCATED AT 250 WORDS)


Developing a UHPLC-QTOF-MS and Automated Library Search Method for Screening Drugs and Toxic Compounds in Postmortem Specimens.
Screening and confirming the presence of drugs and toxic compounds in various matrices are important and challenging tasks routinely faced by forensic and clinical laboratories. Recent advances in the liquid chromatographic and mass spectrometric technologies have provided an opportunity for the development of more specific and effective approaches to achieve the "screening" and "confirmation" goals in a single analytical step. The objectives of this study are: (i) the establishment of an ultra-high performance liquid chromatographic, quadrupole time-of-flight mass spectrometric mass spectrometric and MS-MS spectral database, including 1,200 compounds of interest; and (ii) the development of an effective protocol, using this database and three searching algorithms, for general unknown screening of these compounds. The established database and protocol were evaluated through the analysis of 30 external proficiency test and 100 postmortem samples and found to be significantly more effective than the LC-IT-MS and GC-MS approaches previously established in our laboratory.


Hand-foot syndrome due to hepatitis C therapy.
Direct-acting antivirals are new drugs for chronic hepatitis C treatment. They are usually safe and well tolerated, but can sometimes cause serious adverse effects and there is no consensus on how to treat or prevent them. We described a case of hand-foot syndrome due to hepatitis C virus interferon-free therapy. We report the case of a 49-year-old man with compensated liver cirrhosis due to chronic hepatitis C genotype 1, treatment-naïve, who started viral treatment with sofosbuvir, simeprevir and ribavirin for 12 weeks. At the sixth week of treatment he had anemia, requiring a lower dose of ribavirin. At the tenth week, he had erythematous, pruritic, scaly and flaky lesions on hands and feet, which showed a partial response to oral antihistamines and topical corticosteroids. It was not necessary to discontinue antiviral treatment, but in the first week after the end of treatment, there was worsening of injuries, including signs of secondary infection, that required hospitalization, antibiotics and oral corticosteroid, with progressive improvement. Biopsy of the lesions was consistent with pharmacodermia. The patient had sustained a virological response, despite the side effect. He had a history of pharmacodermia one year ago attributed to the use of topiramate, responsive to oral corticosteroid. Interferon-free therapies can rarely lead to severe adverse reactions, such as skin lesions. Patients receiving ribavirin combinations and those who had a history of pharmacodermia or skin disease may be more susceptible. There is no consensus on how to prevent skin reactions in these patients.


[Phase II study of carboplatin in genitourinary cancer. Urological Cooperative Study Group on Carboplatin].
Carboplatin was evaluated in a phase II study involving 109 patients with genitourinary cancer. A total of 21 cases of advanced testicular tumor, 38 of transitional cell carcinoma (TCC) of the urinary tract and 25 of prostatic cancer were evaluable for response. The response rate in testicular tumors was 48%, with 70% in seminomas and 27% in nonseminomas. Three responses were observed in patients previously treated with cisplatin. In TCC, the response rate was 18%. No response was observed in prostatic cancer. Carboplatin was well tolerated with no significant renal impairment and ototoxicity detected. Nausea and vomiting were experienced by 50% of patients but the severity was low. Severe myelosuppression, thrombocytopenia and leukopenia were observed. In conclusion, carboplatin has demonstrated activity in both testicular tumors and TCC of the urinary tract and is worthy of further study, especially in combination with other active drugs.


A DNA methylation network interaction measure, and detection of network oncomarkers.
Epigenetic processes--including DNA methylation--are increasingly seen as having a fundamental role in chronic diseases like cancer. DNA methylation patterns offer a route to develop prognostic measures based directly on DNA measurements, rather than less-stable RNA measurements. A novel DNA methylation-based measure of the co-ordinated interactive behaviour of genes is developed, in a network context. It is shown that this measure reflects well the co-regulatory behaviour linked to gene expression (at the mRNA level) over the same network interactions. This measure, defined for pairs of genes in a single patient/sample, associates with overall survival outcome independent of known prognostic clinical features, in several independent data sets relating to different cancer types. In total, more than half a billion CpGs in over 1600 samples, taken from nine different cancer entities, are analysed. It is found that groups of gene-pair interactions which associate significantly with survival identify statistically significant subnetwork modules. Many of these subnetwork modules are shown to be biologically relevant by strong correlation with pre-defined gene sets, such as immune function, wound healing, mitochondrial function and MAP-kinase signalling. In particular, the wound healing module corresponds to an increase in co-ordinated interactive behaviour between genes for worse prognosis, and the immune module corresponds to a decrease in co-ordinated interactive behaviour between genes for worse prognosis. This measure has great potential for defining DNA-based cancer biomarkers. Such biomarkers could naturally be developed further, by drawing on the rapidly expanding knowledge base of network science.


Fluorescence Cross-correlation Spectroscopy (FCCS) to Observe Dimerization of Transcription Factors in Living Cells.
Fluorescence cross-correlation spectroscopy (FCCS) is an established spectroscopic method to observe the interaction between the different fluorescent molecules. Using FCCS, researchers can assess the interaction of target molecules in the aqueous condition, and can apply the technique in cultured cells. Here, we describe the method of FCCS to demonstrate direct observation of dimerization between transcription factors in a living cell.


Somatomedin C immunoreactivity in the Achilles tendon varies in a dynamic manner with the mechanical load.
Distribution of the trophic peptide somatomedin C (Sm-C; insulin-like growth factor I; IGF-I) immunoreactivity was mapped in normal Achilles and tibialis anterior tendons. The spindle-shaped tendon fibroblasts showed faint perinuclear staining. Fibroblasts in the paratenon mostly had a more intense IGF-I immunoreactivity, i.e. faint to moderate. When analysing either tendon in detail, areas with more intense IGF-I immunoreactivity could be recognized and seemed to correlate with areas of high mechanical stress. Increased mechanical load induced over 3 days elevated IGF-I immunoreactivity throughout the cytoplasm of tendon fibroblasts. Peak intensity was reached in 7 days, and thereafter the IGF-I immunoreactivity seemed to decrease irrespective of persistent high mechanical load. Training the animals on a treadmill for from 20 up to 60 min per day for 5 days induced after 3-5 days increased IGF-I immunoreactivity throughout the cytoplasm of the tendon and paratenon fibroblasts. Sudden curtailment of loading the Achilles tendon resulted in a marked reduction of the IGF-I immunoreactivity in most fibroblasts within 3 days. After a week only a small number of tendon fibroblasts showed any IGF-I immunoreactivity. The IGF-I immunoreactivity of tendon fibroblasts thus correlates to mechanical loading of the tendon. It is proposed that IGF-I may have a trophic influence on tendon and paratenon cells by autocrine and/or paracrine mechanisms.


Recurrent abdominal pain caused by a toothpick in a CAPD patient.
A 27-year-old patient on CAPD presented with febrile illness and abdominal pain suggestive of peritonitis. Dialysis fluid culture yielded Enterococcus. Response to treatment was slow, with pain persisting. Laparotomy revealed a toothpick, which was causing peritoneal irritation. It was unclear how the foreign object entered the peritoneum.


Real-world incidence of monofocal toric intraocular lens repositioning: analysis of the American Academy of Ophthalmology IRIS Registry.
To determine the 12-month incidence of reoperation to realign 2 commercially available types of implanted monofocal toric acrylic intraocular lenses (IOLs). American Academy of Ophthalmology IRIS (Intelligent Research in Sight) Registry. Registry retrospective study. Eyes that underwent cataract extraction and were implanted with a TECNIS or AcrySof monofocal toric IOL in 2016 and 2017 were identified. The rate of reoperation for IOL realignment (Current Procedural Terminology code 66825) within 365 days of implantation was determined for each IOL group. Risk factors for repositioning were evaluated using logistic regression modeling. A total of 6482 eyes were implanted with a monofocal toric IOL, including 2013 (31.06%) with a TECNIS and 4469 (68.94%) with an AcrySof IOL. During the first postoperative year, 87 (1.3%) eyes underwent surgical IOL repositioning. The incidence of repositioning was significantly higher (P < .0001) for TECNIS-implanted (3.1%, 62/2013) than for AcrySof-implanted (0.6%, 25/4469) eyes (odds ratio [OR] 5.6; 95% CI, 3.5-8.9). Younger age (OR 0.76; 95% CI, 0.67-0.86 per 5-year increase) was associated with a higher risk for IOL repositioning. Real-world analysis of U.S. patients in the IRIS Registry revealed that the rate of surgical IOL repositioning was 5 times higher in eyes implanted with TECNIS than with AcrySof monofocal toric IOLs for astigmatic correction at the time of cataract surgery. These findings should be considered when selecting a toric IOL for correction of astigmatism in cataract patients, particularly in younger patients with a higher risk for misalignment requiring repositioning.


Penetration of cefamandole, cephalothin, and desacetylcephalothin into fibrin clots.
The conversion of cephalothin into a less active metabolite (desacetylcephalothin) might influence its distribution in tissues. An experimental rabbit model devised to determine concentrations of antibiotics in subcutaneous fibrin clots was used in this study. Groups of five to six animals received 100-mg/kg intravenous injections of either cefamandole or cephalothin. One hour after the injection, the concentration of cefamandole in serum was 20 times higher than that of cephalothin. Whereas cephalothin was undetectable at 4 h, cefamandole was still detectable at the end of the experiment. The half-lives of cephalothin and cefamandole in serum were 16 and 27 min, respectively. The concentration of cefamandole found in fibrin clots was severalfold higher than that of cephalothin. The half-life of cefamandole in clots (81 min) was superior to that of cephalothin (38 min). Although concentrations of both antibiotics were higher in serum than in clots at 1 h, the concentrations of these drugs in the clots persisted at higher levels throughout the next 5 h of the experiment. The extent of binding of cefamandole (87%) to rabbit serum was greater than that of cephalothin (50%). At least 55% of cephalothin was metabolized in vivo into its less active metabolite desacetylcephalothin. This metabolite was found in higher proportion in the serum (75%) than in the clots (55%). Whereas only 12% of the free (unbound) cephalothin reached the clots, 78% of the free cefamandole was found in the clots. This lower level of penetration of unbound cephalothin might be explained by the short half-life of this antibiotic, not permitting equilibrium to occur.


Shift in GATA3 functions, and GATA3 mutations, control progression and clinical presentation in breast cancer.
GATA binding protein 3 (GATA3) is a regulator of mammary luminal cell differentiation, and an estrogen receptor (ER) associated marker in breast cancer. Tumor suppressor functions of GATA3 have been demonstrated primarily in basal-like breast cancers. Here, we focused on its function in luminal breast cancer, where GATA3 is frequently mutated, and its levels are significantly elevated. GATA3 target genes were identified in normal- and luminal cancer- mammary cells by ChIP-seq, followed by examination of the effects of GATA3 expressions and mutations on tumorigenesis-associated genes and processes. Additionally, mutations and expression data of luminal breast cancer patients from The Cancer Genome Atlas were analyzed to characterize genetic signatures associated with GATA3 mutations. We show that some GATA3 effects shift from tumor suppressing to tumor promoting during tumorigenesis, with deregulation of three genes, BCL2, DACH1, THSD4, representing major GATA3-controlled processes in cancer progression. In addition, we identify an altered activity of mutant GATA3, and distinct associated genetic signatures. These signatures depend on the functional domain mutated; and, for a specific subgroup, are shared with basal-like breast cancer patients, who are a clinical group with regard to considerations of mode of treatment. The GATA3 dependent mechanisms may call for special considerations for proper prognosis and treatment of patients.


Inhibition of human neutrophil chemotaxis and chemiluminescence by amphotericin B.
The effect of the antifungal drugs amphotericin B, fluocytosine, miconazole, griseofulvin, and nystatin on the chemotactic responsiveness of human neutrophils was studied. Amphotericin B in a concentration of 2 mug/ml inhibited chemotatic responsiveness, and in a concentration of 5 mug/ml it also inhibited chemiluminescence. The inhibition of chemotaxis could be reversed by washing the cells. The other antifungal drugs did not inhibit chemotaxis even in concentrations much higher than those obtained in human serum during treatment.


Challenged by complexity: my twentieth century in immunology.
My research career has focused on complex experimental systems, principally virus-induced infectious processes. I have always run my own experimental program and never had a major mentor, although I have had many great colleagues. After graduating from the School of Veterinary Science at the University of Queensland, Australia, I worked for nine years on diseases of domestic animals. During that interval I completed a part-time PhD at the University of Edinburgh while employed as an experimental neuropathologist. Returning to the John Curtin School of Medical Research in Canberra, I focused on cell-mediated immunity, started to work seriously with mice, and thus became both an immunologist and a basic medical scientist. It was there in 1973 that Rolf Zinkernagel and I discovered MHC I-restricted CD8(+) T cell recognition, a finding that, together with the "single T cell receptor/altered self" hypothesis that we developed to explain our results, led to the 1996 Nobel Prize for Physiology or Medicine. Part of my focus since then has been to communicate the societal value and power of science to the broader community. As my scientific life is not yet over, I confine the present historical account to the twentieth century.


Magnesium deprivation affects cellular circuitry involved in drug resistance and virulence in Candida albicans.
Candida albicans has to struggle for the limited micronutrients present in the hostile host niche, including magnesium (Mg). The aim of this study was to examine the effect of Mg deprivation on drug resistance mechanisms and virulence traits of C. albicans. The drug susceptibility of C. albicans strain SC5314 was determined by broth microdilution and spot assay. Efflux pump activity was measured using the substrate rhodamine 6G. Membrane intactness was studied by propidium iodide influx, and ergosterol levels were determined by the alcoholic KOH method. Metabolic flexibility was examined by studying the activity of glyoxylate cycle enzymes. Virulence factors were assessed by yeast-to-hyphae transition, biofilm formation and cell adherence. An in vivo study was also performed in a Caenorhabditis elegans infection model. Mg chelation leads to potentiation of membrane-targeting antifungals. The role of Mg on membrane homeostasis was explored and significant differences in ergosterol levels were found. Interestingly, it was also observed that Mg deprivation impedes the metabolic flexibility of C. albicans SC5314 by inhibiting glyoxylate cycle enzymes. Furthermore, Mg deprivation inhibited potential virulence traits, including morphological transition, biofilm formation and buccal epithelial cell adherence. All of the disrupted gene targets were validated by reverse transcription PCR. Lastly, enhanced survival of C. elegans infected with C. albicans SC5314 under Mg deprivation was observed. In view of the restricted growth of C. albicans in a Mg-deficient environment, approaches could be utilised to boost the effectiveness of existing antifungals thereby improving the management of fungal infections.


Photocatalytic xanthate-based radical addition/cyclization reaction sequence toward 2-biphenyl isocyanides: synthesis of 6-alkylated phenanthridines.
A photocatalytic xanthate-based radical addition/cyclization reaction cascade toward 2-biphenylisocyanides is described as a practical and modular approach to 6-alkylated phenanthridines. The use of xanthates as radical precursors allowed the synthesis of diversely 6-substituted phenanthridines. Electrophilic radicals derived from nitriles, aromatic and aliphatic ketones, malonates, and amide derivatives, as well as radicals derived from phthalimidomethyl and benzylic derivatives were successfully introduced. The reaction proceeds under mild conditions without a stoichiometric amount of oxidant. Thirty novel phenanthridine scaffolds were synthesized with yields ranging from 24 to 76%.


Subcellular localization of intercellular adhesion molecule-1 in colonic mucosa in ulcerative colitis.
Intercellular adhesion molecule-1 (ICAM-1) mediates the firm adhesion of leukocytes to endothelial cells. In ulcerative colitis (UC), ICAM-1 is suggested also to be involved in the further migration of leukocytes toward the epithelial lining, and in colonic tissue it has been reported to be expressed by cell types other than endothelial cells. This study aimed at determining the ultrastructural localization of ICAM-1 on cells belonging to the colonic mucosa from patients with UC. Colonic biopsies from 3 UC patients and 3 control subjects were examined ultrastructurally by immunogold labeling of ICAM-1. ICAM-1 was expressed on the luminal cell membranes of endothelial cells in both controls and inflamed and noninflamed UC colon, although the density was significantly increased in UC (p < .0001). Labeling was observed on the basal endothelial cell membranes and on macrophages and plasma cells in inflamed UC colon only. Epithelial cells did not express ICAM-1. ICAM-1 appears to be constitutively upregulated on the luminal endothelial membrane in UC, and the expression on basal endothelial membranes in active UC only suggests that ICAM-1 is more extensively involved in the leukocyte migration than previously acknowledged.


The treatment of biliary atresia in Europe 1969-1995.
European studies of biliary atresia have suggested that the aetiology is heterogeneous. Histological studies of the liver and biliary remnants excised at portoenterostomy have failed to identify any prognostic features except for the size of bile ductules in the porta hepatis. Most of the major series have confirmed that there is a relationship between age at portoenterostomy and clearance of jaundice which has been achieved in more than 67% of infants under 10 weeks of age. Cholangitis reduced survival and bleeding from esophageal varices has occurred in more than 19% of long-term survivors. The 5-year jaundice-free survival rate after portoenterostomy is 37% and the 10 year rate is 18%. It is predicted that these survival rates will improve. Orthotopic transplantation now results in long-term survival in 70% of patients who fail the portoenterostomy operation and long-term survival is now achieved in a majority of children born with biliary atresia.


[The effect of oxytocin and dihydrostilbestrol on various uterine cations (author's transl)].
The effect of dihydrostilbestrol diacetate and oxytocin on the Na+, K+, Ca++ and Mg++ content in uterine Wistar rats has been studied. A bilateral ovariectomy on the animals was performed. After seven days dihydrostibestrol (0.25 mg/kg a day) and oxytocine (0.025 U.I./kg a day) were administered separately and simultaneously i.p. during a period of five days. Twenty four hours after the first, third and fifth administration, five rats from each group were decapited and the above uterine cation content was determined by atomic absorption spectrometry. Dihydrostibestrol induced a marked increase and a slight decrease in K+ and Na+ contents respectively, lowering the Na/K ration. It also increased greatly Ca++ and Mg++ content. Oxytocin induced a Na+ and K+ increase, a Ca++ decrease, and slight changes in Mg++. These results partially confirmed the bioelectric and biomechanic alterations produced by the above hormones on the uterine cells.


Effect of aging on color stability and bond strength of dual-cured resin cement with amine or amine-free self-initiators.
This study aimed to evaluate the effect of aging on the color stability and bond strengths of dual-cured resin cements containing amine or amine-free self-initiators. Three dual-cured and one light-cured resin cements were used. The covered (by lithium disilicate ceramic disks) and uncovered groups (n=10) were included. Color measurements were tested after 24 h, 10,000 and 20,000 thermal cycles (TCs). Micro-shear bond strengths (µSBS) were tested after 24 h, 10,000 and 20,000 TCs, and failure modes were analyzed (n=14). Two-way ANOVA and Tukey's test were implemented for color difference (ΔE*ab) and µSBS (α=0.05). The mean ΔE*ab difference was significant among groups (p<0.001). The lowest ΔE*ab values were obtained for dual-cured resin cement with amine-free self-initiators dual-cured cement after aging in all dual-cured resin cements, and the µSBS of the dual-cured resin cements on ceramic was significantly higher than that of the light-cured ones after aging (p<0.001).


Do cancer incidence and mortality rates differ among ethnicities in Canada?
Cancer incidence rates have been shown to vary by ethnicity, and the increasing awareness of and interest in reporting ethnic health inequalities have been growing internationally. The objective of this study was to assess cancer incidence and mortality rates by ethnicity in Canada. The study used the 2006 Canadian Census Health and Environment Cohort, linked to the Canadian Cancer Registry and the Canadian Vital Statistics-Death Database, to determine cancer cases and mortality from 2006 to 2016. Ethnicity was categorized as non-Indigenous North American (NINA); European; Caribbean; Latin, Central and South American (LCSA); African; East Asian; South Asian; and West Central Asian and Middle Eastern. Europeans had the highest standardized incidence rates, while NINA had the highest mortality rates. Rates varied substantially by ethnicity and immigrant status. The top three cancers accounted for 46.5% to 61.9% of all new cancers, while the top three cancer deaths accounted for 36.1% to 61.9% of all deaths. The distribution of cancers within the top 10 cancers and the top 10 cancer deaths also differed; e.g., stomach cancer was found to be more prevalent in the East Asian, LCSA, African and Caribbean groups. Non-immigrant African males had the highest cancer incidence rates, and non-immigrant South Asian females had the highest mortality rates. There is considerable variability in cancer incidence and cancer mortality rates by ethnicity, and this study addresses the knowledge gap in Canada in this area. Establishing baseline indicators, such as cancer rates by ethnicity, is essential to understanding the differences within the diverse Canadian population and to informing targeted interventions that may help reduce health inequalities.


Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors.
Lipoxins are bioactive eicosanoids that are immunomodulators. In human myeloid cells, lipoxin (LX) A4 actions are mediated by interaction with a G protein-coupled receptor. To explore functions of LXA4 and aspirin-triggered 5(S),6(R),15(R)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA4) in vivo, we cloned and characterized a mouse LXA4 receptor (LXA4R). When expressed in Chinese hamster ovary cells, the mouse LXA4R showed specific binding to [3H]LXA4 (K(d) approximately 1.5 nM), and with LXA4 activated GTP hydrolysis. Mouse LXA4R mRNA was most abundant in neutrophils. In addition to LXA4 and 15-epi-LXA4, bioactive LX stable analogues competed with both [3H]LXA4 and [3H]leukotriene D4 (LTD4)-specific binding in vitro to neutrophils and endothelial cells, respectively. Topical application of LXA4 analogues and novel aspirin-triggered 15-epi-LXA4 stable analogues to mouse ears markedly inhibited neutrophil infiltration in vivo as assessed by both light microscopy and reduced myeloperoxidase activity in skin biopsies. The 15(R)-16-phenoxy-17,18, 19,20-tetranor-LXA4 methyl ester (15-epi-16-phenoxy-LXA4), an analogue of aspirin triggered 15-epi-LXA4, and 15(S)-16-phenoxy-17,18,19,20-tetranor-LXA4 methyl ester (16-phenoxy-LXA4) were each as potent as equimolar applications of the anti-inflammatory, dexamethasone. Thus, we identified murine LXA4R, which is highly expressed on murine neutrophils, and showed that both LXA4 and 15-epi-LXA4 stable analogues inhibit neutrophil infiltration in the mouse ear model of inflammation. These findings provide direct in vivo evidence for an anti-inflammatory action for both aspirin-triggered LXA4 and LXA4 stable analogues and their site of action in vivo.


PBRM1 and BAP1 as novel targets for renal cell carcinoma.
Technological advances in genome sequencing have led to the identification of novel driver genes mutated in renal cancer. Hitherto, 1 gene was known to be frequently mutated in renal cell carcinoma of clear cell type (ccRCC), the von Hippel-Lindau (VHL) gene. VHL was identified by positional cloning as the gene responsible for a familial syndrome with renal cancer predisposition, von Hippel-Lindau. Subsequently, VHL was found to be inactivated in approximately 90% of sporadic ccRCC. The discovery of VHL, together with the elucidation of its function, transformed the treatment of ccRCC leading to the introduction of 5 new drugs into the clinic. However, no other familial ccRCC predisposing genes are frequently mutated in sporadic ccRCC. With the development of massively parallel sequencing, a plethora of somatically mutated genes has been identified. Most genes are mutated at low frequencies, but 3 genes are mutated in more than 10% of ccRCC, PBRM1 (mutated in ~50%), BAP1 (~15%), and SETD2 (~15%). Like VHL, all 3 genes are 2-hit tumor suppressor genes. Furthermore, these 3 genes are within a 50-Mb region on the short arm of chromosome 3p that encompasses VHL and is deleted in ~90% of ccRCC. We discovered that PBRM1 mutations tend to anticorrelate with BAP1 mutations in ccRCC and that PBRM1- and BAP1-mutated tumors exhibit different biology and are associated with markedly different outcomes. This established the foundation for the first molecular genetic classification of sporadic ccRCC. Herein, I review the evidence that implicated PBRM1 and BAP1 as renal cancer driver genes, provide an update on the function of the gene products, and speculate on how mutations in these genes may be exploited therapeutically.


Synthesis and Characterization of Binary, Highly Endothermic, and Extremely Sensitive 2,2'-Azobis(5-azidotetrazole).
2,2'-Azobis(5-azidotetrazole) (C2N16, 3), a highly energetic nitrogen-rich binary CN compound was obtained in a three-step synthesis through the formation of 5-azidotetrazole (1), subsequent amination using O-tosylhydroxylamine to give 2-amino-5-azidotetrazole (2), and oxidative azo coupling of 2 using tBuOCl as an oxidant in MeCN. A nitrogen:carbon ratio of 8:1, eight nitrogen atoms in a row, and a nitrogen content of over 90% was unknown for a binary heterocyclic compound until now. The successful isolation was confirmed through X-ray diffraction as well as by vibrational and 13C NMR spectroscopy. C2N16 can explode instantly and shows mechanical sensitivities far higher than quantitatively measurable. Nevertheless, it features interesting energetic performances, which were calculated using different quantum-chemical methods.


Responses of mouse lymphocytes to extracellular adenosine 5'-triphosphate (ATP). Lymphocytes with cytotoxic activity are resistant to the permeabilizing effects of ATP.
The effects of extracellular ATP on plasma membrane permeability in mouse lymphocytes were studied with plasma membrane depolarization, uptake of ethidium bromide, and release of lactate dehydrogenase as indicators of increased permeability. Extracellular ATP induced sustained depolarization of plasma membrane potential as well as uptake of low m.w. fluorescent markers in mouse lymphocytes derived from thymus and spleen, and in two lymphoma lines YAC-1 and MBL-2. The fully ionized form ATP4- rather than MgATP2- mediated the increased permeability of the plasma membrane. Although prolonged exposure to exogenous ATP ultimately lysed the lymphocytes, two CTL populations (CHM-14 clone and CTLL-2 line) and IL-2-treated spleen lymphocytes with unrestricted killing activity were highly resistant to the permeabilizing action of extracellular ATP at all concentrations tested. In addition, CTL derived from primary immune peritoneal exudate and enriched by in vitro culture for 5 days in the presence of specific stimulator cells were also resistant to this permeabilizing effect. These findings show that exogenous ATP has a lytic effect on mouse lymphocytes but not on CTL, and suggest a role for ATP in cell-mediated cytotoxicity.


Isoforms of fatty-acid-binding protein in bovine heart are coded by distinct mRNA.
In the course of our studies on structure/function relationships of fatty-acid-binding proteins, we reported earlier that the two isoforms of the 15-kDa cardiac fatty-acid-binding protein (cFABP) from bovine heart only differ in one position; Asn98 in pI 5.1-cFABP; Asp98 in pI 4.9-cFABP [Unterberg, C., Börchers, T., Højrup, P., Knudsen, J. and Spener, F. (1990) J. Biol. Chem. 265, 16,255-16,261]. In the present study, we elucidate the origin for this heterogeneity. Isoelectric focusing analysis of immunoprecipitated in vitro translation products from total mRNA and positive-hybrid-selected cFABP/mRNA revealed two L-[35S]methionine-labeled proteins corresponding to pI 5.1-cFABP and pI 4.9-cFABP. In a control experiment, recombinant mRNA derived from cDNA encoding pI 5.1-cFABP was translated and produced only pI 5.1-cFABP as shown by isoelectric focusing of the translation products. We could observe co-translational acetylation but not post-translational deamidation of the cFABP isoforms. Taken together, our results demonstrate that the isoforms of cardiac fatty-acid-binding protein found in bovine heart are coded by distinct mRNA species.


Endothelial Extracellular Vesicles-Promises and Challenges.
Extracellular vesicles, including exosomes, microparticles, and apoptotic bodies, are phospholipid bilayer-enclosed vesicles that have once been considered as cell debris lacking biological functions. However, they have recently gained immense interest in the scientific community due to their role in intercellular communication, immunity, tissue regeneration as well as in the onset, and progression of various pathologic conditions. Extracellular vesicles of endothelial origin have been found to play a versatile role in the human body, since they are on the one hand known to contribute to cardiovascular diseases, but on the other hand have also been reported to promote endothelial cell survival. Hence, endothelial extracellular vesicles hold promising therapeutic potential to be used as a new tool to detect as well as treat a great number of diseases. This calls for clinically approved, standardized, and efficient isolation and characterization protocols to harvest and purify endothelial extracellular vesicles. However, such methods and techniques to fulfill stringent requirements for clinical trials have yet to be developed or are not harmonized internationally. In this review, recent advances and challenges in the field of endothelial extracellular vesicle research are discussed and current problems and limitations regarding isolation and characterization are pointed out.


Treatment of malignant germ cell tumors.
In an unselected group of 278 patients with germ cell tumors, disease-free status was obtained in 97% by a treatment program including a surveillance-only strategy for stage I testicular cancer, and low-or high-dose cisplatinum-etoposide treatment for patients with more extensive disease. The overall follow-up period was a median of 40 months (range 20-62 months). At present 100% of patients with stage I disease, 91% with stage II disease, 86% with stage III disease, 75% with extragonadal germ cell tumors, and 3 of 3 patients with germ cell tumors in the ovary are alive and without disease. Among 36 patients treated with high-dose cisplatinum and etoposide there were six toxic deaths, four of them in patients with residual malignant disease. Three patients died of progressive disease. There were no toxic deaths among 54 patients with disseminated disease but without poor prognostic features who were treated with low-dose cisplatinum-etoposide; six of these patients died of progressive disease. It is concluded: 1) that surveillance is a feasible and reasonable strategy for patients with stage I disease; 2) that excellent survival results can be achieved with standard-dose cisplatinum-etoposide in patients with disseminated disease and a favorable prognostic profile; and 3) that disease-free status can be obtained in nearly all patients with poor prognostic features at the expense of significant toxicity. Standardized criteria for selection of patients with poor prognoses are needed. Randomized trials should be carried out to define the role of high-intensity treatment and, finally, measures to decrease or prevent serious toxicity should be explored.


Clinical applicability of Tokyo guidelines 2018/2013 in diagnosis and severity evaluation of acute cholangitis and determination of a new severity model.
To determine the diagnostic accuracy of Tokyo guidelines (TG) 2018/2013 (TG18/TG13) and predictors of poor prognosis in acute cholangitis. Retrospective 1-year study of consecutive hospital admissions for acute cholangitis. Prognosis was defined in terms of 30 d in-hospital mortality. Of the 183 patients with acute cholangitis, diagnostic accuracy based on Charcot's triad, TG07 and TG18/TG13 was 67.8, 86.9 and 92.3% (p < .001), respectively. Regarding severity based on TG18/TG13, 30.6% of cases were severe. A poor prognosis was found in 10.9% of patients. After multivariate analysis, systolic blood pressure <90 mmHg (OR 11.010; p < .001), serum albumin <3 g/dL (OR 1.355; p = .006), active oncology disease (OR 3.818; p = .006) and malignant aetiology of obstructive jaundice (OR 2.224; p = .021) were independent predictors of poor prognosis. The discriminative ability of the model with these four variables was high (AUROC 0.842; p < .001), being superior to TG18/TG13 (AUROC 0.693; p = .005). TG18/TG13 showed high diagnostic accuracy in acute cholangitis. Compared with TG18/TG13, the simplified severity model ≥2 allows easy selection of patients who will benefit from admission to the intensive care unit and early biliary decompression.


Development of nanostructures in the diagnosis of drug hypersensitivity reactions.
This article provides an overview of novel nanoscale structures potentially applicable to the field of allergy, and to discuss the required properties, advantages, and disadvantages of those nanostructures for clinical application focusing on diagnosis of drug hypersensitivity reactions. Advances in the development of different nanostructures are favoring their biomedical applications. One area of interest is the interaction between nanostructures and the immune system, including their ability to emulate carrier molecules and their potential use for the diagnosis of allergic reactions. Immunoassays are the most widely used in-vitro test for evaluating immunoglobulin E (IgE)-mediated drug hypersensitivity reactions. However, they have important technical limitations affecting their sensitivity. A wide variety of nanostructures have been designed to quantify specific IgE, with the aim of diagnosing different kinds of allergies. Nanoparticles-based colloidal immunoassay employed in microdevices and/or miniaturized systems are improving IgE detection sensitivity. Dendrimers have shown immense potential for the design and development of sensor platforms for evaluating IgE-mediated drug hypersensitivity reactions, due to the increase in hapten density and IgE accessibility. In this sense, a variety of dendritic structures as well as their hybridization to different solid supports have been shown to be successful when applied in the diagnosis of drug allergy. Moreover, the knowledge of the complete antigenic determinants would allow their inclusion and therefore further improvement of the sensitivity.


Morphological and molecular distinction of two Fridericia species (Clitellata, Enchytraeidae) having same spermatheca type.
One enchytraeid species, proved to be new to science, is described in this paper as Fridericia ventrochaetosa sp. nov. The new species is distinguished from similar species, especially from F. galba (Hoffmeister, 1843), which has almost the same type of spermatheca, on the basis of morphological characters and molecular data (nuclear ribosomal ITS region, mitochondrial cytochrome c oxidase subunit I and nuclear histone 3 gene sequences). Apart form the new species, GenBank reference sequences are provided for the first time for F. hegemon and F. regularis. The results show that, although the shape of the spermatheca is a very important marker in the case of Fridericia species, other characters can be equally important for their taxonomic identification.


Orbital tumor in acute myeloid leukemia associated with karyotype 46,XX,t(8;21)(q22;q22): a case report.
Orbital tumor formation in acute myeloid leukemia (AML) is rare as an initial symptom. Furthermore, orbital granulocytic sarcoma (myeloid sarcoma) in pediatric patients is uncommon. We describe a 5-year-old Japanese girl with a left orbital mass as an initial symptom of AML, the mass revealed by computed tomography. Peripheral blood and bone marrow pictures and a chromosomal analysis disclosing 46,XX,t(8;21)(q22;q22) showed AML (M2 according to the French-American-British classification). She was treated with antileukemic chemotherapy systemically. Three weeks after the initiation of chemotherapy, the orbital tumor regressed markedly. AML as an initial symptom of the orbital mass should be fully considered in a differential diagnosis, even in the absence of typical leukemic symptoms, and chromosomal analysis and immunophenotypical analysis may explain the pathogenesis of the extramedullary leukemic tumor.


Inhibition of Hsp90 function delays and impairs recovery from heat shock.
The induction of the heat shock response as well as its termination is autoregulated by heat shock protein activities. In this study we have investigated whether Hsp90 functional protein levels influence the characteristics and duration of the heat shock response. Treatment of cells with several benzoquinone ansamycin inhibitors of Hsp90 (geldanamycin, herbimycin A) activated a heat shock response in the absence of heat shock, as reported previously. Pretreatment of cells with the Hsp90 inhibitors significantly delayed the rate of restoration of normal protein synthesis following a brief heat shock. Concurrently, the rate of Hsp synthesis and accumulation was substantially increased and prolonged. The cessation of heat shock protein synthesis did not occur until the levels of Hsp70 were substantially elevated relative to its standard threshold for autoregulation. The elevated levels of HSPS 22-28 (the small HSPS) and Hsp70 are not able to promote thermotolerance when Hsp90 activity is repressed by ansamycins; rather a suppression of thermotolerance is observed. These results suggest that a multicomponent protein chaperone complex involving both Hsp90 and Hsp70 signals the cessation of heat shock protein synthesis, the restoration of normal translation, and likely the establishment of thermotolerance. Impaired function of either component is sufficient to alter the heat shock response.


Intracellular signal transduction and modification of the tumor microenvironment induced by RET/PTCs in papillary thyroid carcinoma.
RET gene rearrangements (RET/PTCs) represent together with BRAF point mutations the two major groups of mutations involved in papillary thyroid carcinoma (PTC) initiation and progression. In this review, we will examine the mechanisms involved in RET/PTC-induced thyroid cell transformation. In detail, we will summarize the data on the molecular mechanisms involved in RET/PTC formation and in its function as a dominant oncogene, on the activated signal transduction pathways and on the induced gene expression modifications. Moreover, we will report on the effects of RET/PTCs on the tumor microenvironment. Finally, a short review of the literature on RET/PTC prognostic significance will be presented.


Spontaneous oesophageal rupture: a diagnostic challenge in resource-limited setting.
Spontaneous oesophageal rupture after swallowing a bolus of food is a very rare condition. In resource-limited settings, it is very challenging to diagnose this condition especially when its presentation is atypical. Its prognosis is very poor when diagnosis is delayed due to risk of mediastinitis. We report a case of 37-year-old man who was admitted to our hospital complaining of sudden onset of chest tightness and pain after a meal 8 h prior to admission. Urgent chest radiograph revealed right hydropneumothorax with collapsed lung. Water-seal drainage was established gushing 1200 ml of food materials. Definitive diagnosis of oesophageal rupture was reached after post-mortem.


Feeding behavior of Mimomyia (Etorleptiomyia) luzonensis (Ludlow, 1905) (Diptera, Culicidae) in Peninsular Malaysia.
Mosquitoes are vectors of various human diseases in the tropics including yellow fever, dengue, malaria and West Nile virus. Mosquitoes can act as vectors between wildlife and humans, which is particularly important for diseases where wild animals serve as reservoirs of parasites in the absence of human infections. Research has mainly focused on the medical impacts of Anopheles, Aedes, Mansonia and Culex, however, very little attention has been directed towards other mosquito genera, especially those which act as vectors of diseases of wildlife. We have observed adults of Mimomyia (Etorleptiomyia) luzonensis (Ludlow, 1905) feeding on a toad, Ingerophrynus parvus, near an oil palm plantation settlement in Setia Alam, Selangor state, Peninsular Malaysia. Mimomyia is known to feed on reptiles and amphibians, and is a documented vector of several arboviruses, including West Nile virus. The observation of Mimomyia feeding on a common toad near a human settlement highlights a need to understand the relationships between mosquitoes, toads and humans from an ecological perspective. We report on-site observations of the feeding habit of Mimomyia; the first records from Malaysia.


Neurobehavioral alterations induced by third-trimester gestation-equivalent ethanol exposure are inhibited by folate administration.
Prenatal ethanol exposure (PEE) causes several neurobehavioral impairments in the fetus. Postnatal days (PDs) 4-9 in rodents are considered equivalent to the third trimester of gestation in humans. This period is characterized by high rates of synaptogenesis and myelination and the maturation of key structures and transmitter systems. Nutritional supplements, such as folate, have gained attention as putative treatments to mitigate detrimental effects of PEE. Folate is crucial for DNA synthesis and amino acid metabolism and heightens antioxidant defenses. The present study examined neurobehavioral effects of the concurrent administration of folate (20 mg/kg/day) and ethanol (5 g/kg/day) during PDs 4-9 in male and female Wistar rats. During PDs 16-18, the rat pups were tested for anxiety-like and exploratory activity in the light-dark box (LDB), open field (OF), and concentric square field (CSF) tests. After weaning, they were tested for sucrose preference and ethanol intake. Neonatal ethanol exposure reduced body weight in infancy but did not enhance ethanol self-administration or significantly affect performance in the OF or LDB. Neonatal ethanol exposure also reduced sucrose intake in the preference test and increased shelter-seeking in the CSF, and folate significantly inhibited these effects. The present findings suggest that folate, a treatment that is devoid of serious side effects, can ameliorate some neurobehavioral effects of PEE.


Room noise criteria--the S12.2-1995 standard raises serious technical and economic considerations.
The key issue with the S12.2-1995 standard is not the differences in the assessment of sound quality, particularly at the low frequencies, but rather the use of octave-band data to describe low-frequency equipment misbehavior. Unfortunately, the "NCB vs RC" controversy leads research efforts and technical discussions in the wrong directions, disregarding serious economic and technical considerations. This conflict can be resolved by: (1) avoiding the use of octave-band data to rate noise with abnormal (spectral and/or temporal) characteristics, (2) addressing the widespread need for the room noise criteria as a practical design tool for general use in architectural spaces, and (3) developing adequate descriptor/procedures to qualify, quantify, and determine the impact of "rumble" on human response. A further goal should be to develop integrated criteria that would apply to both HVAC and computer noise sources.


Smith-Magenis syndrome: report of one case.
Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome characterized by an interstitial deletion on the short arm of chromosome 17 involving the band p11.2. A 3-year-old girl was referred for evaluation of moderate psychomotor retardation and several behavioral problems including self-injuring behavior, hyperactivity, and sleep disturbance. Visual and hearing impairment, and brain abnormalities including ventriculomegaly and hypoplastic right transverse sinus, were detected. Routine cytogenetic study showed an apparent mosaicism of an interstitial deletion over the chromosomal region 17p11.2 in 65% metaphases. However, the microdeletion was found in all metaphases by fluorescence in situ hybridization study with the probe D17S29 (for Smith-Magenis critical region on 17p11.2). Her sleep disorder improved after the use of melatonin.


Asymptomatic foot and ankle structural injuries: a 3D imaging and finite element analysis of elite fencers.
Fencing is a highly asymmetrical combat sport, that imposes high mechanical demands over repeated exposures on the musculoskeletal structures, a primary cause of injuries in fencers. However, there are limited epidemiological studies on the structural injuries of the foot and ankle in fencers. This study aimed to investigate foot and ankle structural injuries, and explore how metatarsophalangeal joint structural changes may affect the mechanisms of foot and ankle injuries in asymptomatic fencers. 3D images of foot and ankle morphology using computed tomography were obtained from ten elite fencers. We then constructed finite element models of the first metatarsophalangeal joint in the foot of their trail legs. The validated models were used to simulate stress distribution changes from different ankle joint angles during lunging. The findings showed that stress distribution changes at the medial and lateral sesamoid may have caused sesamoid fractures, and that habitual and concentrated stress on the metatarsal bones might have flattened the sesamoid groove. This process may damage the integrity of the first metatarsophalangeal joint, and consequently affect the efficiency of the windlass mechanism in fencers. During lunging, different ankle joint angles of the trail foot increased the total stress difference of the medial and lateral foot, and thus influenced the lunging quality and its stability. Our findings revealed that the asymmetric nature of fencing might have caused asymptomatic foot and ankle structural injuries, and finite element analysis results indicated that this might increase the incidence of the serious injuries if unattended. Regular computed tomography examination should be introduced to monitor elite fencers' lower limb alterations, permitting unique angle adjustments in the trail foot without sacrificing technical or physiologic properties based on the exam results and reduce the lower limb injury risk.


Safety management in times of crisis: Lessons learned from a nationwide status-analysis on German intensive care units during the COVID-19 pandemic.
The status of Safety Management is highly relevant to evaluate an organization's ability to deal with unexpected events or errors, especially in times of crisis. However, it remains unclear to what extent Safety Management was developed and sufficiently implemented within the healthcare system during the COVID-19 pandemic. Providing insights of potential for improvement is expected to be directional for ongoing Safety Management efforts, in times of crisis and beyond. A nationwide survey study was conducted among healthcare professionals and auxiliary staff on German Intensive Care Units (ICUs) evaluating their experiences during the first wave of the COVID-19 pandemic. Error Management and Patient Safety Culture (PSC) measures served to operationalize Safety Management. Data were analyzed descriptively and by using quantitative content analysis (QCA). Results for n = 588 participants from 53 hospitals show that there is a gap between errors occurred, reported, documented, and addressed. QCA revealed that low quality of safety culture (27.8%) was the most mentioned reason for errors not being addressed. Overall, ratings of PSC ranged from 26.7 to 57.9% positive response with Staffing being the worst and Teamwork Within Units being the best rated dimension. While assessments showed a similar pattern, medical staff rated PSC on ICUs more positively in comparison to nursing staff. The status-analysis of Safety Management in times of crisis revealed relevant potential for improvement. Human Factor plays a crucial role in the occurrence and the way errors are dealt with on ICUs, but systemic factors should not be underestimated. Further intensified efforts specifically in the fields of staffing and error reporting, documentation and communication are needed to improve Safety Management on ICUs. These findings might also be applicable across nations and sectors beyond the medical field.


Everolimus restrains the paracrine pro-osteoclast activity of breast cancer cells.
Breast cancer (BC) cells secrete soluble factors that accelerate osteoclast (OC) differentiation, leading to the formation of osteolytic bone metastases. In the BOLERO-2 trial, BC patients with bone involvement who received Everolimus had a delayed tumor progression in the skeleton as a result of direct OC suppression through the inhibition of mTOR, in addition to the general suppressor effect on the cancer cells. Here, we explored the effect of Everolimus, as mTOR inhibitor, on the pro-OC paracrine activity of BC cells. Both MDA-MB-231 and MCF-7 BC cell lines were incubated with sub-lethal amounts of Everolimus, and their conditioned supernatants were assessed for their capacity to differentiate OCs from PBMC from healthy donors, as well as to interfere with their bone resorbing activity shown on calcium phosphate slices. We also measured the mRNA levels of major pro-OC factors in Everolimus-treated BC cells and their secreted levels by ELISA, and evaluated by immunoblotting the phosphorylation of transcription factors enrolled by pathways cooperating with the mTOR inhibition. Finally, the in vivo pro-OC activity of these cells was assessed in SCID mice after intra-tibial injections. We found that Everolimus significantly inhibited the differentiation of OCs and their in vitro bone-resorbing activity, and also found decreases of both mRNA and secreted pro-OC factors such as M-CSF, IL-6, and IL-1β, whose lower ELISA levels paralleled the defective phosphorylation of NFkB pathway effectors. Moreover, when intra-tibially injected in SCID mice, Everolimus-treated BC cells produced smaller bone metastases than the untreated cells. mTOR inhibition in BC cells leads to a suppression of their paracrine pro-OC activity by interfering with the NFkB pathway; this effect may also account for the delayed progression of bone metastatic disease observed in the BOLERO-2 trial.


[Immunohistochemical study on Rosenthal fibers in gliomas using anti-GFAP and anti-ubiquitin antibodies].
Immunohistochemically we investigated Rosenthal fibers (RFs) on specimen surgically removed from patients with glioma (three cerebellar astrocytomas, three optic gliomas, two spinal cord astrocytomas, one spinal ganglioglioma). Pathological diagnoses were pilocytic astrocytoma, fibrillary astrocytoma, and ganglioglioma. We utilized sections from the formalin-fixed paraffin-embedded tissues and stained them with H & E, PTAH, PAS as well as with anti-GFAP (glial fibrillary acidic protein) antibody (Ab) and two anti-ubiquitin Abs...anti-PHF (paired helical filament) monoclonal Ab (DF2) which recognizes ubiquitin (H. Mori in Science) and anti-ubiquitin polyclonal Ab provided by Dr. Haas. The primary antibodies were diluted with Tris-saline as follows: anti-GFAP (1:500), DF2 (culture medium without dilution), anti-ubiquitin (2 micrograms/ml). Sections were deparaffinized and incubated with primary antibodies overnight at room temperature. They were visualized by the avidin-biotin-peroxidase complex (ABC) procedure (Vectastain, Vector, USA) and counterstained with hematoxylin. Negative control sections were treated by omitting the primary antibodies. In the representative specimen we compared H & E, anti-GFAP and anti-ubiquitin staining on 3 microcrons serial sections. RFs were eosinophilic (bright red on H & E), purply-stained with PTAH (metachromasia), black with Heidemhein's iron-hematoxylin, and negative with PAS. Anti-GFAP Ab stained glial filaments diffusely in the cytoplasm and cell process of astrocytomas in every case. The peripheral parts of most RFs were intensely stained with anti-GFAP. The whole part of some RFs showed dark staining, and no part of a few RFs showed positive reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)


The profiling of university of Ljubljana students according to their motives for exercise participation.
The main research objective is the analysis of the grouping of the students of the University of Ljubljana, with respect to the intensity of different types of exercise participation motives, their gender, discipline and year of study, level of physical activity, status of physical education class, organization of physical activities during study, and place of residence. Data were collected using personal data sheets during enrolling students at the University of Ljubljana. Students completed The Exercise Motivations Inventory (EMI-2), with additional data about sociodemographic parameters. The results reveal that the students could be grouped in three distinctive clusters, which can be very clearly explained in terms of the prevalence of exercise participation motives in general. The students grouped in the first cluster have the lowest average values (means) in all exercise participation motives. The students grouped in the second cluster have the profile with moderate means in all exercise participation motives, while the students grouped in the third cluster have the profile with the highest means in all exercise participation motives. The results indicate overall higher motivation for physical activity in men. All the sub-samples are different in their relevant features used in clustering (e.g., male students are dominant in life sciences, etc.), which provide a guide both for the explanation of the results obtained and for practical implications.


The Brain Activity in Brodmann Area 17: A Potential Bio-Marker to Predict Patient Responses to Antiepileptic Drugs.
In this study, we aimed to predict newly diagnosed patient responses to antiepileptic drugs (AEDs) using resting-state functional magnetic resonance imaging tools to explore changes in spontaneous brain activity. We recruited 21 newly diagnosed epileptic patients, 8 drug-resistant (DR) patients, 11 well-healed (WH) patients, and 13 healthy controls. After a 12-month follow-up, 11 newly diagnosed epileptic patients who showed a poor response to AEDs were placed into the seizures uncontrolled (SUC) group, while 10 patients were enrolled in the seizure-controlled (SC) group. By calculating the amplitude of fractional low-frequency fluctuations (fALFF) of blood oxygen level-dependent signals to measure brain activity during rest, we found that the SUC patients showed increased activity in the bilateral occipital lobe, particularly in the cuneus and lingual gyrus compared with the SC group and healthy controls. Interestingly, DR patients also showed increased activity in the identical cuneus and lingual gyrus regions, which comprise Brodmann's area 17 (BA17), compared with the SUC patients; however, these abnormalities were not observed in SC and WH patients. The receiver operating characteristic (ROC) curves indicated that the fALFF value of BA17 could differentiate SUC patients from SC patients and healthy controls with sufficient sensitivity and specificity prior to the administration of medication. Functional connectivity analysis was subsequently performed to evaluate the difference in connectivity between BA17 and other brain regions in the SUC, SC and control groups. Regions nearby the cuneus and lingual gyrus were found positive connectivity increased changes or positive connectivity changes with BA17 in the SUC patients, while remarkably negative connectivity increased changes or positive connectivity decreased changes were found in the SC patients. Additionally, default mode network (DMN) regions showed negative connectivity increased changes or negative changes with BA17 in the SUC patients. The abnormal increased in BA17 activity may be a key point that plays a substantial role in facilitating seizure onset.


Lung function and exhaled nitric oxide levels in infants developing chronic lung disease.
Chronic lung disease (CLD) is a common outcome of neonatal intensive care. To determine whether the results of serial exhaled nitric oxide (eNO) measurements during the perinatal period differed between infants who did and did not develop CLD. In addition, we wished to assess whether eNO results were more predictive of CLD development than lung function test results or readily available clinical data (gestational age and birthweight). The patients were 24 infants with a median gestational age of 27 (range 25-31) weeks. Measurements of eNO levels, functional residual capacity (FRC), and compliance of the respiratory system (CRS) were attempted on postnatal days 1, 3, 5, 7, 14, and 28 days. The 12 infants who developed CLD were of significantly lower birthweight and gestational age than the rest of the cohort; in addition, they had lower median FRC (P < 0.02) and CRS (P < 0.02) results, but not higher eNO levels, in the first week after birth. Construction of receiver operator characteristic (ROC) curves demonstrated that the CRS and FRC results on Day 3 were the best predictors of CLD development; the areas under the ROC curves were 0.94 and 0.91, respectively. Early lung function test results, but not eNO levels, are useful in predicting CLD development, but are not significantly better than birthweight.


Safe storage time for reprocessed flexible endoscopes: a systematic review.
Flexible endoscopes are used to diagnose and treat gastrointestinal and pulmonary diseases. They have narrow, internal channels which are used to insert instruments, air and water into hollow organs and to remove tissues and secretions. Since endoscopes are contaminated during use and have heat sensitive components that cannot be sterilized, they are reprocessed with cleaning and high-level disinfection to destroy microorganisms. Knowing how long reprocessed endoscopes can be safely stored is essential for preventing infection and decreasing unnecessary costs. The objective was to systematically review the best available evidence related to safe storage time (in days) of flexible endoscopes that have undergone reprocessing in order to determine when they can be safely used again without posing any risk of contamination from pathogens. The types of equipment were flexible endoscopes that had been reprocessed according to recommended guidelines, stored for a specified period of time, and tested for microorganisms.The intervention was the length of time (in days) that reprocessed endoscopes were appropriately stored before use.This review included non-randomized controlled trials and prospective cohort studies.This review considered studies that included the outcome measure: microbial growth on endoscopes which was measured with microbiological cultures. The search strategy aimed to find studies in English and Spanish and included published and unpublished studies from 1990 to 2014. An initial search of CINAHL, MEDLINE/PUBMed and EMBASE was conducted followed by an analysis of the text words contained in the title and abstract and index terms used to describe the articles. Next, a search using all identified keywords and index terms was undertaken across all included databases. Then, the reference lists of all identified reports and articles were searched for additional studies. A citation search was performed in order to find additional studies that cited those already located. The Joanna Briggs Institute's critical appraisal instruments were used to assess methodological quality. Data were extracted from studies in the review using the Joanna Briggs Institute data extraction form. Since the findings were expressed using descriptive statistics, a meta-analysis was impossible. Therefore, the findings have been summarized in a narrative form with tables and a figure. Ten studies met the appraisal criteria and were included in the review. Storage time ranged from two to 56 days, and all 10 studies concluded that endoscopes could safely be stored for the time measured. Seven studies measured microbial growth in all channels; six involved storing the endoscopes for at least three days and five for at least seven days. The contamination rates were low (2% at three days and 4% at seven days) and pathogens were rare. The contamination rate remained consistent over time. Endoscopes can be stored for seven days if they have been effectively reprocessed and appropriately stored. Ongoing surveillance cultures are necessary to verify reprocessing effectiveness.


Chronology of particle emission from the E/A=61 MeV 36Ar+27Al reaction.
The emission time chronology of neutrons, protons, and deuterons from the E/A=61 MeV 36Ar+27Al reaction is deduced from two-particle correlation functions.


Behçet's syndrome: pulmonary vascular disease.
Pulmonary artery involvement (PAI) due to Behçet's syndrome, although rare, has always been a focus of interest not only in endemic areas but also in many parts of the world. This interest is shared by many disciplines other than internal medicine, such as radiology, cardiothoracic surgery, cardiology and respiratory medicine. Most importantly, our understanding of PAI has significantly changed in recent years. Recent work found the following: pulmonary artery aneurysms are not the only form of PAI. Solo 'in-situ' pulmonary artery thrombosis (PAT) can be found in up to one-third of the patients at presentation. Both pulmonary artery aneurysms and PAT present with similar clinical symptoms, whereas abundant hemoptysis is less frequent in PAT. PAI is strongly associated with thrombosis in the lower-extremity deep veins and right side of the heart. Varying and multiple pulmonary parenchymal lesions such as nodules, consolidations and cavities are part of this involvement as well. While either aneurysms or thrombosis could disappear successfully with immunosuppressives in up to 70% of the patients, the condition can be fatal still in one-fourth. Large aneurysms and high pulmonary artery pressures are associated with a poor prognosis. Although we now know the condition and its associated complications better, we need to study how we can predict development of PAI, its pathogenesis and finally what can we do to improve the survival.


Polyatomic ab Initio Complex Potential Energy Surfaces: Illustration of Ultracold Collisions.
Resonances are metastable states that decay after a finite period of time. These states play a role in many physical processes. For example, in recent cold collision experiments, autoionization from a resonance state was observed. Complementing such observations with theory provides insight into the reaction dynamics under study. Theoretical investigation of autoionization processes is enabled via complex potential energy surfaces (CPESs), where the real and imaginary parts, respectively, provide the energy and decay rate of the system. Unfortunately, calculation of ab initio polyatomic CPESs are cumbersome; hence, they are not in abundance. Here, we present an ab initio polyatomic CPES utilizing a recently developed approach, which makes such calculations feasible. This CPES helps interpret the autoionization process observed in the He(23S) + H2 collision. From the behavior of the calculated CPES we can conclusively determine the nature of the autoionization process. Moreover, this CPES was used to generate reaction rates for the collision of He with ortho- and para-H2. These reaction rates are obtained from first principles. The results show a remarkable agreement with the cold collision experimental measurements, which demonstrates the robustness of our method. Hereby, we provide a computational tool for designing and interpreting new types of experiments that involve resonance states, e.g., in nucleobase damages (DNA or RNA) or in interatomic (intermolecular) Coulombic decay.


Circulating BAFF and CXCL10 levels predict response to pegylated interferon in patients with HBeAg-positive chronic hepatitis B.
B-cell activating factor (BAFF), an essential cytokine for B lymphocytes activation, has been implicated in the pathogenesis of chronic viral hepatitis. However, the role of BAFF in patients with chronic hepatitis B (CHB) undergoing antiviral therapy is unknown. Patients with HBeAg-positive CHB treated with 48-week pegylated interferon (PEG-IFN; n = 42), who had stored plasma samples during treatment were recruited. Serial plasma levels of BAFF and C-X-C motif chemokine 10 (CXCL10) during therapy were measured. Combined response (CR), defined as HBeAg seroconversion with HBV DNA < 2,000 IU/mL plus HBsAg decline ≥ 1 log10 IU/mL at 24 weeks post-treatment, was achieved in 11 (26.2%) patients. BAFF levels were elevated during treatment but decreased to pre-treatment levels after PEG-IFN cessation in both responders and non-responders. Low baseline BAFF (< 770 pg/ml) and high CXCL10 (≥ 320 pg/ml) levels were independently associated with CR in multivariate analysis. Baseline CXCL10/BAFF ratio of ≥ 0.45 was predictive of CR with positive and negative predictive values of 61.5 and 89.7%, respectively. In summary, low baseline BAFF and high CXCL10 levels were associated with treatment response to PEGIFN. The combined measurement of these immune markers may help individualized decision-making in patients with HBeAg-positive CHB.


Meta-analysis of effects of yoga exercise intervention on sleep quality in breast cancer patients.
This study seeks to systematically evaluate and test the effects of yoga exercise intervention programs on sleep quality in breast cancer patients in order to suggest more optimized exercise programs. Computer searches of the PubMed, Embase, Cochrane Library, Web of Science and CINAHL databases are conducted from the date of their inception to June 8th, 2022 to collect randomized controlled trials on the effects of yoga exercise intervention on sleep quality in breast cancer patients. Two investigators independently carry out the inclusion and exclusion criteria literature screening, data extraction and methodological quality assessment of the included literature by applying the Cochrane risk of bias tool. Subgroup analysis is performed using RevMan 5.4.1 software, and the six moderating variables of intervention format, intervention type, weekly intervention frequency, total intervention duration, single intervention duration and intervention evaluation at different time points are set for the 782 subjects of the 12 included publications. Twelve randomized controlled trials with a total sample size of 782 subjects are included, including 393 subjects in the experimental group and 389 subjects in the control group. The meta-analysis shows that yoga exercise intervention is effective in improving sleep quality in breast cancer patients [SMD = -0.40, 95% CI: (-0.71, -0.09), P = 0.01]; yoga exercise intervention focusing on positive meditation [SMD = -0.55, 95% CI: (-1.08, -0.03), P = 0.04] is effective in improving sleep; yoga exercise intervention two or three times a week is effective in improving sleep quality [SMD = -0.69, 95% CI: (-1.19, -0.19), P = 0.007]; yoga exercise intervention for 6-8 weeks significantly improves sleep quality [SMD = -0.86, 95% CI: (-1.65, -0.08), P =0.03]; and evaluation immediately after the end of intervention improves sleep outcomes [SMD = -0.17, 95% CI: (-0.33, 0.00), P = 0.05], while differences in sleep quality improvement are not statistically significant for the remaining subgroup outcomes (P > 0.05). The available evidence suggests that yoga exercise intervention has good effects on improving sleep quality in breast cancer patients. Positive meditation intervention type, intervention frequency of two or three times per week, total intervention duration of 6-8 weeks and evaluation immediately after the end of intervention are shown to be effective in improving sleep quality.


In vivo antimalarial action of a lipophilic iron (III) chelator: suppression of Plasmodium vinckei infection by reversed siderophore.
We assessed in vivo antimalarial action of a lipophilic iron (III) chelator belonging to a new synthetic family of biomimetic siderophores previously termed reversed siderophores (RSFs). The family member, RSF ileum2, was chosen for its high membrane permeability and fast irreversible inhibition of human malaria parasite growth in vitro. [Shanzer A, et al., Proc Natl Acad Sci USA 88:6585, 1991 and Lytton SD, et al., Blood 81:214, 1993]. The lipophilic drug was administered to Swiss mice by subcutaneous route in fractionated coconut oil at a dosage of 0.37 g/kg every 8 hr with no adverse reactions observed. After 3-4 injections demonstrable suppression of Plasmodium vinckei petteri infection was observed and an additional 3-4 injections resulted in 2-3-fold lower parasitemia with prolonged survival time over sham-injected control mice.