Strangulated femoral hernia with appendicitis: A rare case of De Garengeot's hernia.
De Garengeot hernia is a rare case of a femoral hernia. It occurs when a femoral hernia contains a vermiform appendix that may be inflamed and sometimes necrotic, and this requires emergency surgery. However, the hernia is usually discovered by chance in the operating theater, which poses an additional challenge for surgeons. A 64-year-old man presented with a 1-week history of a painful right groin lump. The lump is irreducible and painful on exert a week ago. Ultrasound imaging showed a 1.5 × 2 cm loculated turbid liquid collection containing an edematous intestinal loop measuring 8 mm in diameter that was suspected to be the vermiform appendix. Therefore, appendectomy was performed through the hernia sac. After that, the hernia was repaired using the McVay technique and 2.0 nylon sutures. One day after the operation, the patient was discharged, and he returned to the clinic after 10 days without any complications. The patient has a history of chronic obstructive pulmonary disease (COPD), which is a risk factor for a hernia. He had to live with the right femoral hernia for ten years until it became painful and irreversible. Ultrasound revealed what appears to be an appendix. To avoid possible consequences of complicated appendicitis and strangulated hernia, emergency surgery was the appropriate choice for our patient case. The presence of an appendix in the femoral hernia poses a diagnostic and therapeutic challenge to surgeons, due to the atypical clinical picture and the lack of efficacy of radiographic methods in diagnosing the condition.


Correlation of apparent intrinsic clearances of simultaneously administered S (+) and d3R (-) hexobarbital in the rat.
Pseudoracemic hexobarbital (HB), consisting of equal molar fractions of S (+) HB and deuterium-labeled R (-) HB, d3 R (-) HB, was administered orally to rats in a dose of 50 mg/kg. Concentrations of both enantiomers in blood were measured by an enantioselective mass fragmentographic assay. Clearance data of S (+) HB and d3 R (-) HB were correlated in untreated rats, and in rats pretreated with 3-methylcholanthrene (MC), carbon tetrachloride (CCl4), and different doses of phenobarbital (PB). Although in the different groups some variation in the clearance ratio of S (+) HB over d3 R (-) HB was found, the clearance of S (+) HB was generally up to a factor of five higher than the clearance of d3 R (-) HB, except for the CCl4-treated rats. From the present data it can be tentatively concluded that S (+) HB and R (-) HB are metabolized by similar (PB-inducible) cytochrome P-450s in control and PB- and MC-pretreated rats and that clearance data obtained with racemic HB following different pretreatments may be employed as a reflection of (PB-inducible) cytochrome P-450 activity.


Pride-asap: automatic fragment ion annotation of identified PRIDE spectra.
We present an open source software application and library written in Java that provides a uniform annotation of identified spectra stored in the PRIDE database. Pride-asap can be ran in a command line mode for automated processing of multiple PRIDE experiments, but also has a graphical user interface that allows end users to annotate the spectra in PRIDE experiments and to inspect the results in detail. Pride-asap binaries, source code and additional information can be downloaded from http://pride-asa-pipeline.googlecode.com.This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics.


A new model of advance care planning: observations from people with HIV.
Although theoretical concepts from ethics and law have been applied, there is no conceptual model of advance care planning rooted in the perspective of individuals engaged in it. To develop a conceptual model of advance care planning by examining the perspectives of individuals engaged in it. In this qualitative research, we studied 140 individuals with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome who were engaged in advance care planning. Respondents' experience with and opinions about advance care planning were noted in interviews that were audiotaped, transcribed, and analyzed. The primary goal of advance care planning was to prepare for death, which entailed facing death, achieving a sense of control, and strengthening relationships. We have developed a conceptual model of advance care planning rooted in the perspectives of individuals engaged in it. The model has implications for theory, research, and practice regarding end-of-life care.


The evolving role of stem cell transplants in lymphomas.
Autologous stem cell transplantation (ASCT) is an established therapeutic modality in the treatment of lymphomas, especially in the relapse setting. It is also under investigation after first-line therapy, for example, in patients with mantle cell or T cell lymphomas. Each year more than 6000 autotransplants for lymphomas are reported to the European Blood and Marrow Transplantation (EBMT) registry. The number of allogeneic stem cell transplantations (alloSCT) in lymphoma patients has increased over the last decade, with about 1200 transplanted lymphoma patients annually reported to the registry. Optimal timing and indications for alloSCT are not well defined because of absence of randomized trials. Developments in the treatment of lymphomas including immunotherapy have changed the clinical scenarios in regard to ASCT, and many published studies are now outdated. On the other hand, patients relapsing after immunochemotherapy may derive less benefit from ASCT. Consequently, there is an increasing interest in using alloSCT not only in lymphoma patients relapsing after ASCT but also in earlier phases in specific circumstances. Although curative potential is higher with alloSCT compared with ASCT, its wider use has been hindered by excessive nonrelapse mortality (NRM). Along with decreasing NRM figures, popularity of alloSCT may increase in the near future, possibly with the expense of ASCT. Prospective, randomized studies are needed to evaluate feasibility and efficacy of alloSCT in several clinical settings, as most published evidence is based on retrospective registry data or single-center experiences.


The human histamine H2-receptor couples more efficiently to Sf9 insect cell Gs-proteins than to insect cell Gq-proteins: limitations of Sf9 cells for the analysis of receptor/Gq-protein coupling.
The human histamine H2-receptor (hH2R) couples to Gs-proteins to activate adenylyl cyclase and to Gq-proteins to activate phospholipase C, but phospholipase C activation has not consistently been observed. The aim of this study was to compare coupling of hH2R to insect and mammalian Gs- and Gq-proteins in Spodoptera frugiperda (Sf9) cells. Interaction of hH2R with mammalian G proteins was assessed with coexpressed proteins or receptor-Galpha fusion proteins that enhance coupling efficiency. hH2R efficiently coupled to insect Gs-proteins to activate adenylyl cyclase. However, hH2R poorly coupled to insect Gq-proteins as assessed by the lack of enhancement of histamine-stimulated steady-state GTP hydrolysis by regulators of G protein signaling (RGS proteins). In contrast, RGS-proteins efficiently enhanced GTP hydrolysis stimulated by the human platelet-activating factor receptor (PAFR) and the histamine H1-receptor (H1R) from man and guinea pig. The measurement of intracellular free Ca2+ concentration was not useful for studying receptor/Gq-protein coupling. hH2R also efficiently interacted with mammalian Gs-proteins, specifically with fused Gsalpha as assessed by guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS)-sensitive high-affinity agonist binding, agonist-stimulated [35S]GTPgammaS binding and adenylyl cyclase activation. In contrast, coupling of hH2R to coexpressed and fused mammalian Gqalpha was poor. However, our inability to reconstitute efficient coupling of PAFR and H1R to mammalian Gqalpha indicated that a large portion of the expressed G protein was functionally inactive. Taken together, our data show that hH2R couples more efficiently to insect cell Gs-proteins than to insect cell Gq-proteins. Unfortunately, there are significant limitations in the usefulness of Sf9 cells for comparing the coupling of receptors to mammalian Gs- and Gq-proteins and assessing Gq-mediated activation of effector systems.


Retinoblastoma.
Newer concepts in the diagnosis and treatment of retinoblastoma are briefly discussed. The role of ultrasonography, EMI scanning and LDH assays in the anterior chamber are evaluated. The greatest problems in differential diagnosis in recent years have been larval granulomatosis caused by Toxicara canis, Coat's disease and unclassifiable retinal dysplasias. The Ellsworth-Reese classification is discussed. The "cure rate" has been widely misinterpreted as survival and has led to many misapprehensions in the treatment of unilateral disease. The cases in group IV now do better for a variety of reasons and the results in orbital cases have been more extensively studied. The genetics of retinoblastoma have been intensively studied in our laboratory along with Dr. Kitchin and some newer concepts are briefly discussed. The relative roles of orthovoltage, external beam 60Co, linear accelerators and betatron are presented. Dosage level is distinctly related to radiation complications, especially retinal vascular necrosis and fatal radiation-induced neoplasms. The relationship of the latter to the pattern of inheritance is to be stressed. Chemotherapy has been used both as an adjuvant to radiation and for the destruction of micrometastases and a new protocol is described. The results of treatment are presented to update the 1966 report at the Gonin Club Meeting in Munich.


Pyrexia in a young infant - is height of fever associated with serious bacterial infection?
Febrile infants ≤ 90 days old make up a significant proportion of patients seeking care in the emergency department (ED). These infants are vulnerable to serious bacterial infections (SBIs) and early identification is required to initiate timely investigations and interventions. We aimed to study if height of an infant's temperature on presentation to the ED is associated with SBI. We performed a retrospective chart review on febrile infants ≤ 90 days old presenting to our ED between 31st March 2015 and 28th February 2016. We compared triage temperature of febrile infants with and without SBIs. We presented sensitivity, specificity, positive and negative predictive values (PPV and NPV) of fever thresholds at triage. A multivariable regression was performed to study the association between height of temperature and the presence of SBI, and presented the adjusted odds ratio (aOR) with corresponding 95% confidence intervals (CI). Among 1057 febrile infants analysed, 207 (19.6%) had a SBI. Mean temperature of infants with a SBI was significantly higher than those without (mean 38.5 °C, standard deviation, SD 0.6 vs. 38.3 °C, SD 0.5, p < 0.005). For temperature ≥ 39 °C, sensitivity, specificity, PPV and NPV for SBI was 15.5% (95%CI 10.8-21.1%), 90.4% (95%CI 88.2-92.3%), 28.1% (95%CI 21.1-36.3%) and 81.4% (95%CI 80.5-82.4%) respectively. The height of fever was consistently associated with SBI after adjusting for age, gender and SIS (aOR 1.76, 95% CI 1.32-2.33, p < 0.001). However, 32 (15.5%) infants with SBIs had an initial triage temperature ≤ 38 °C. A higher temperature at triage was associated with a higher risk of SBI among febrile infants ≤ 90 days old. However, height of temperature must be used in conjunction with other risk factors to identify SBIs in young infants.


Measuring In-Air and Underwater Hearing in Seabirds.
Electrophysiological methods were used to measure the in-air hearing of 10 species of seabirds. There are currently no measures of the underwater hearing abilities of diving birds. In preparation for constructing a behavioral audiogram both in-air and underwater hearing, several species of diving ducks were raised. Because there is a considerable amount of literature on bird hearing in air, the technical setup and training methods were modeled on similar studies, with modifications to address the nature of the underwater sound field and the difficulty of the task for the birds.


Structural rebuilding of pulmonary vessels at various haemodynamic shifts in the lesser circulation.
The rebuilding of pulmonary vessels at hypo- and hypertension in the lesser circulation was studied in 41 puppy dogs, in which hypotension had been induced by stenosing the pulmonary artery. Eighteen animals were successively sacrificed 6--9 months after the surgery. Histological examinations revealed atrophic and sclerotic lesions of the pulmonary arteries. In the remaining 23 animals, various anastomoses were formed between the systemic and pulmonary circulation systems, which led to the formation of hypertrophic and hyperplastic alterations in the pulmonary vessels and to pulmonary hypertension.


Clumsy children: a prognostic study.
Twenty-four clumsy children of whom 13 had matched controls were reappraised eight years after their original assessment. The findings indicate that developmental clumsiness generally has a favourable prognosis. Mild and moderate degrees of clumsiness improved to normality, but severe degrees of clumsiness had a less favourable outcome only in regard to motor proficiencies. Clumsiness seemed not to have bearing, either on social class or on the subsequent pursuit of sporting activities. Although there was a lower level of academic achievement in the clumsy children, who also chose careers which were less manually exacting, these observations did not reach statistical significance. Maturational lag might be the aetiology in mild developmental clumsiness, whereas structural lesions involving the cerebral cortex may be present in more severely afflicted children. These findings should be considered when counseling clumsy children, both academically and vocationally.


Ultrastructural evaluation of the effects of diclazuril on the endogenous stages of Eimeria maxima and E. brunetti in experimentally inoculated chickens.
The ultrastructural morphology of the different endogenous stages of Eimeria maxima and E. brunetti was evaluated after oral treatment of inoculated chickens with a single dose of 5 mg/kg diclazuril. The drug induced no ultrastructural change in the growth or differentiation of the various schizont stages of both Eimeria spp. In E. maxima, the micromorphological appearance of micro- and macrogamonts developing from the blast from to maturation also remained unaffected by drug treatment. However, in all fertilized macrogamonts the normal pattern of oocyst wall establishment was completely disturbed, resulting in the formation of an abnormally thickened, incomplete oocyst wall and the necrosis of the zygote. In E. brunetti, the growth and nuclear division during microgametogenesis were not affected but differentiation was clearly abnormal. In comparison with the controls, this abnormal differentiation was characterized by a less extensive enlargement of the parasite surface area, aberrant morphological configurations of condensed heterochromatin, intracytoplasmic flagella formation, and glycogen accumulation. Finally, the complete degeneration of all microgamonts ensued. The growth and differentiation leading to mature macrogamonts was not disturbed; however, subsequent oocyst wall formation was largely precluded and the macrogamonts proceeded to degenerate completely. We conclude that diclazuril treatment primarily affected particular stages in the sexual development of both Eimeria spp., resulting in the complete eradication of these coccidian species.


Pharmacokinetics and pharmacodynamics of physostigmine in the rat after oral administration.
The distribution, metabolism, and pharmacokinetics of physostigmine (Phy) and the time course of butyrylcholinesterase (BuChE) in plasma and cholinesterase (ChE) activity in brain and muscle and their relationship to Phy concentration were described after oral administration of 3H-Phy (650 micrograms kg-1) to rats. Physostigmine concentration vs time data was analyzed by nonlinear computer fitting program using one-compartment model. The absorption rate constant (ka) and elimination rate constant (ke) were found to be 0.1 +/- 0.07 min-1 and 0.036 +/- 0.024 min-1, respectively. Cpmax and tmax were 3.3 ng ml-1 and 16 min. The clearance (C1) was found to be 80.9 ml min-1kg-1. Half-life of Phy in brain, muscle, and liver were 33.4 min, 22.5, and 28 min, respectively. The bioavailability (F) was calculated to be 0.02 and the extraction ratio was found to be 0.98 indicating the 'first pass' effect. Butyrylcholinesterase activity in plasma was 76 per cent at 15 min and this activity did not change significantly up to 120 min. However, Phy concentration in plasma was very low; 2.89 ng ml-1 at 15 min and declined to 0.71 ng ml-1 at 90 min. Physostigmine concentration in brain peaked at 22 min to 2.85 +/- 1.09 ng g-1 and declined to 0.33 +/- 0.11 ng g-1 at 60 min. Cholinesterase activity in brain was 96 per cent, 82 per cent and 89 per cent at 10, 45, and 120 min, respectively. Physostigmine concentration in muscle was very low and the ChE activity in the muscle was 66.4 per cent of control at 45 min. The time course of Phy metabolism indicated that at 5 min most of the RA in the tissues was due to metabolites accounting for 94.6 per cent in plasma, 90 per cent in liver, 79.8 per cent in brain and 86.3 per cent in muscle. M1 appeared to be the major metabolite followed by eseroline. The results showed extremely low concentrations of Phy (200 times less in plasma and 350 times less in brain) after oral administration compared to our previous studies with the same dose after i.m. administration.


Bio-inspired, bio-degradable adenosine 5'-diphosphate-modified hyaluronic acid coordinated hydrophobic undecanal-modified chitosan for hemostasis and wound healing.
Uncontrolled hemorrhage and wound infection are crucial causes of trauma-associated death in both the military and the clinic. Therefore, developing an efficient and rapid hemostatic method with biocompatibility, easy degradation, and wound healing is of great importance and desirability. Inspired by spontaneous blood cell plug formation in the hemostasis process, an adenosine 5'-diphosphate modified pro-coagulation hyaluronic acid (HA-ADP) coordinated with enhanced antibacterial activity of undecanal-modified chitosan (UCS) was fabricated through physical electrostatic cross-linking and freeze-drying. The as-prepared hydrogel sponges showed a porous structure suitable for blood cell adhesion. In particular, the hydrogel exhibited excellent antibacterial ability and promoted the adhesion of platelets and red blood cells, thus inducing a prominent pro-coagulation ability via platelet activation, which exhibits a shorter hemostasis time (58.94% of control) in vitro. Compared with commercially available CELOX and gelatin sponge (GS), HA-ADP/UCS accelerates hemostasis and reduces blood loss in both rat tail amputation and rat artery injury models. Furthermore, all the samples exhibited superior cytocompatibility and biodegradability. Due to these performances, HA-ADP/UCS promoted full-thickness skin defect healing significantly in vivo. All the properties of HA-ADP/UCS suggest that it has great potential for translation as a clinical application material for hemostatic and wound healing.


[Is the serum level of beta 2 microglobulin a better marker of glomerular filtration than blood creatinine?].
beta 2-microglobulin (b2M) serum level assessed by radioimmunoassay), creatinine serum level and Glomerular Filtration Rate (GFR, as measured by 125I iothalamate clearance) have been simultaneously determined in 53 controls and 123 patients with chronic renal disease (100 with chronic renal failure, GFR = 80-18 ml/min). In all groups studied, correlations between beta 2M and GFR showed no improvement over creatinine and GFR. The beta 2M serum level does not appear to be a more sensitive or reliable marker of GFR than is creatinine.


Exchange of angular momentum in EMCD experiments.
In energy loss magnetic chiral dichroism (EMCD) experiments a chiral electronic transition is induced that obeys the dipole selection rule for the magnetic quantum number Deltam = +/- 1 or DeltaL(z) = +/- h. The incident plane electron wave is inelastically scattered and is detected in the diffraction plane, i.e. again in a plane wave state. Naïve reasoning suggests that the angular momentum L(z) of the probe electron has not changed in the interaction since plane waves have L(z) = 0. This leads to the seeming contradiction that angular momentum is not conserved in the interaction. A closer inspection shows that the density matrix of the probe has indeed L(z) = +/- h after a chiral interaction. However, L(z) is not conserved when the probe electron propagates further to the exit surface of the specimen because the rigid lattice breaks rotational symmetry. Thus, the angular momentum of the photo electron that is created in a chiral electronic transition stems from both the probing electron and the crystal lattice.


Ataxia telangiectasia in Chinese children. A clinical and electrophysiological study.
The clinical manifestations, immunological, chromosomal, and multimodal electrophysiological studies of five Chinese patients with ataxia telangiectasia are described. One died of hepatocellular carcinoma not associated with Hepatitis B-antigenaemia. Another died of respiratory failure. Two siblings are free of sinopulmonary infections although they are wheelchair bound. Computed tomography of the brain showed cerebellar atrophy in four cases. Nerve conduction studies showed evidence of axonal neuropathy in all cases with the earliest detection at six years. Electromyography showed mild denervation changes in two cases. Two patients had abnormal somatosensory evoked potentials and one had abnormal visual and brain stem auditory evoked potentials. The level of alpha foetal protein was elevated whereas the serum carcino-embryonic antigen was normal in all patients.


Quincke's disease of the uvula.
Upper airway compromise may be the result of numerous factors, among which a swollen uvula should be considered in the differential diagnosis. We present a case of a 21-year-old man who presented with complaints of throat discomfort, altered voice, and tachypnea secondary to acute uvular edema. The patient was treated with sympathomimetic drugs both by injection and by inhalation with complete resolution of the swelling and his symptoms within 30 minutes. The uvula is a potential cause of upper airway obstruction and should be examined in persons presenting with airway-related complaints.


The role of Cys-17 in the pyridoxal 5'-phosphate inhibition of the bovine liver low M(r) phosphotyrosine protein phosphatase.
Mammalian tissues contain two low M(r) phosphotyrosine protein phosphatase isoforms (type-1 and type-2) that differ in the 40-73 amino-acid sequence. Only one isoform (type-2) is strongly inhibited by pyridoxal 5'-phosphate, whereas the other is poorly inhibited by this compound. The mechanism of pyridoxal 5'-phosphate inhibition of the bovine liver enzyme (a type-2 isoform) has been studied by kinetic methods using a series of pyridoxal 5'-phosphate analogues. These studies indicate that pyridoxal 5'-phosphate interacts with the enzyme in both the phosphate and aldehyde groups. Active site-directed mutagenesis has been used to investigate the sites of pyridoxal 5'-phosphate binding. Our results indicate that Cys-17, essential for enzyme activity, interacts with the phosphate moiety of pyridoxal 5'-phosphate. On the other hand, Cys-12, which is also involved in the catalytic mechanism, does not participate in pyridoxal 5'-phosphate binding.


Lack of private health insurance is associated with higher mortality from cancer and other chronic diseases, poor diet quality, and inflammatory biomarkers in the United States.
The lack of health insurance reduces access to care and often results in poorer health outcomes. The present study simultaneously assessed the effects of health insurance on cancer and chronic disease mortality, as well as the inter-relationships with diet, obesity, smoking, and inflammatory biomarkers. We hypothesized that public/no insurance versus private insurance would result in increased cancer/chronic disease mortality due to the increased prevalence of inflammation-related lifestyle factors in the underinsured population. Data from the Third National Health and Nutrition Examination Survey participants (NHANES III;1988-1994) were prospectively examined to assess the effects of public/no insurance versus private insurance and inflammation-related lifestyle factors on mortality risk from cancer, all causes, cardiovascular disease (CVD) and diabetes. Cox proportional hazards regression was performed to assess these relationships. Multivariate regression analyses revealed substantially greater risks of mortality ranging from 35% to 245% for public/no insurance versus private insurance for cancer (HR=1.35; 95% CI=1.09,1.66), all causes (HR=1.54; 95% CI=1.39,1.70), CVD (HR=1.62; 95% CI=1.38,1.90) and diabetes (HR=2.45; 95% CI=1.45,4.14). Elevated CRP, smoking, reduced diet quality and higher BMI were more prevalent in those with public insurance, and were also associated with increased risks of cancer/chronic disease mortality. Insurance status was strongly associated with cancer/chronic disease mortality after adjusting for lifestyle factors. The results suggest that inadequate health insurance coverage results in a substantially greater need for preventive strategies that focus on tobacco control, obesity, and improved dietary quality. These efforts should be incorporated into comprehensive insurance coverage programs for all Americans.


Intellectual and Behavioral Phenotypes of Smith-Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic RAI1 Variant.
Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder caused by a 17p11.2 deletion or pathogenic variant in the RAI1 gene. SMS is associated with developmental delay, intellectual disability (ID), and major sleep and behavioral disturbances. To explore how genetic variants may affect intellectual functioning and behavior, we compared intellectual and behavioral phenotypes between individuals with a 17p11.2 deletion and pathogenic RAI1 variant. We reviewed available clinical records from individuals (aged 0-45 years) with SMS, ascertained through a Dutch multidisciplinary SMS specialty clinic. We included a total of 66 individuals (n = 47, 71.2% with a 17p11.2 deletion and n = 19, 28.8% with a pathogenic RAI1 variant) for whom data were available on intellectual functioning, severity of ID (n = 53), and behavioral problems assessed with the Child Behavior Checklist (CBCL, n = 39). Median full-scale IQ scores were lower (56.0 vs. 73.5, p = 0.001) and the proportion of individuals with more severe ID was higher (p = 0.01) in the 17p11.2 deletion group. Median total CBCL 6-18 scores (73.5 vs. 66.0, p = 0.02) and scores on the sub-scales somatic complaints (68.0 vs. 57.0, p = 0.001), withdrawn/depressed behavior (69.5 vs. 55.0, p = 0.02), and internalizing behavior (66.0 vs. 55.0, p = 0.002) were higher in the RAI1 group. The results of this study suggest that 17p11.2 deletions are associated with a lower level of intellectual functioning and less internalizing of problems compared to pathogenic RAI1 variants. The findings of this study may contribute to personalized-management strategies in individuals with SMS.


Local Legal Strategies to Increase Vaccination During the COVID-19 Pandemic - Lessons from New York City.
Vaccine mandates played a critical role in the success of New York City's COVID-19 response. By relying on evidence as a substantive basis for the mandates and adhering to procedural requirements and precedent, New York City leveraged its position and expertise as a local governmental authority to devise mandatory vaccine policies that withstood numerous legal challenges. New York City's experience highlights the role of municipal government in mounting a meaningful public health response, and the strategies adopted by NYC may provide a blueprint for municipalities around the world facing the ongoing COVID-19 pandemic and the threat of future public health emergencies.


Isolation and purification of an early pregnancy factor-like molecule from culture supernatants obtained from lymphocytes of pregnant women: II. Identification of the molecule as a Fc-receptor-like molecule: a preliminary report.
Early pregnancy factor (EPF)-like activity from culture supernatants obtained from stimulated lymphocytes of pregnant women was characterized and identified. The enzyme-linked immunosorbent assay depending on the presence of "Fc" receptors on bovine spermatozoa was used to identify the EPF-like molecule purified by gel filtration and reverse-phase high-performance liquid chromatography. The results indicated that the crude lymphocyte culture supernatant, the EPF-positive G IV fraction obtained on gel filtration, and the EPF-positive reverse-phase high-performance liquid chromatography protein readily bound with the different concentrations of aggregated human gamma-globulin in a manner similar to that in which the standard control of aggregated human gamma-globulin binds to the bovine spermatozoa. EPF-like activity synthesized and secreted by lymphocytes during pregnancy may be a Fc-receptor-like molecule.


Phase II trial of weekly docetaxel and gemcitabine for previously untreated, advanced non-small cell lung cancer.
Docetaxel and gemcitabine combination chemotherapy has been reported to be active against non-small cell lung cancer (NSCLC) and myelosuppression is the most common dose-limiting toxicity. This prospective phase II study was designed to test the hypothesis that better tolerance and increased dose intensity might be achieved if patients are treated with weekly administration schedule. Thirty-five patients with stage IIIB/IV NSCLC and a performance status 0-2 received first-line chemotherapy with docetaxel 35mg/m2 and gemcitabine 600mg/m2 on days 1, 8 and 15. Treatment was repeated every 4 weeks, for up to 4 cycles. In total, 85 chemotherapy cycles were given (median, 2; range, 1-4). Other than the completion of all 4 planned cycles (n=6), the main reasons for treatment discontinuation were toxicity (n=15) and progressive disease (n=14). The most frequently encountered toxic effects were anemia (52% of patients), nausea and vomiting (60%), fatigue (71%) and anorexia (57%). One patient died of bilateral pneumonitis, which developed shortly after the administration of second cycle. Disease control (objective response and stable disease) in the intent-to-treat (ITT) population was achieved in 60% of patients and the overall response rate was 29% (95% CI, 14-44%). With a median follow-up duration of 13 months, the median progression-free survival and overall survival were 2.8 (95% CI, 0.7-4.8) months and 10.6 (95% CI, 7.0-14.3) months, respectively. In conclusion, weekly schedule of docetaxel and gemcitabine has modest activity with acceptable toxicity profile in advanced NSCLC, but as high frequency of early discontinuation occurred does not merit further study with the present regimen.


Selenoprotein MsrB1 deficiency exacerbates acetaminophen-induced hepatotoxicity via increased oxidative damage.
Acetaminophen (APAP) overdose induces acute liver damage and failure via reactive oxygen species production and glutathione (GSH) depletion. Methionine sulfoxide reductase B1 (MsrB1) is an antioxidant selenoenzyme that specifically catalyzes the reduction of methionine R-sulfoxide residues. In this study, we used MsrB1 gene-knockout mice and primary hepatocytes to investigate the effect of MsrB1 on APAP-induced hepatotoxicity. Analyses of histological alterations and serum indicators of liver damage showed that MsrB1-/- mice were more susceptible to APAP-induced acute liver injury than wild-type (MsrB1+/+) mice. Consistent with the in vivo results, primary MsrB1-/- hepatocytes displayed higher susceptibility to APAP-induced cytotoxicity than MsrB1+/+ cells. MsrB1 deficiency increased hepatic oxidative stress after APAP challenge such as hydrogen peroxide production, lipid peroxidation, and protein oxidation levels. Additionally, basal and APAP-induced ratios of reduced-to-oxidized GSH (GSH/GSSG) were significantly lower in MsrB1-/- than in MsrB1+/+ livers. Nrf2 nuclear accumulation and heme oxygenase-1 expression levels after APAP challenge were lower in MsrB1-/- than in MsrB1+/+ livers, suggesting that MsrB1 deficiency attenuates the APAP-induced activation of Nrf2. Collectively, the results of this study suggest that selenoprotein MsrB1 plays a protective role against APAP-induced hepatotoxicity via its antioxidative function.


The risk of gastrointestinal carcinoma in familial juvenile polyposis.
Familial juvenile polyposis (JP) is an autosomal dominant condition in which affected individuals develop upper or lower gastrointestinal (GI) juvenile polyps, or both, and have a predisposition to cancer of the gastrointestinal tract. The risk of GI cancer has not been well defined because of the small number of these families and the lack of follow-up. The objective of this study was to determine the prevalence and age at diagnosis of GI polyposis and cancer in a large JP kindred. Medical records were reviewed, patients were interviewed, and histories were taken. Pathology reports and slides were reviewed by our pathologists. A database was created for analysis of clinical and pathologic factors. This kindred contains 117 members, 29 of whom have had upper or lower GI polyps or cancer, or both. All those affected have had colonic juvenile polyps or cancer, except for two who died of advanced gastric cancer and never had colonic evaluation. Nine individuals have had both upper and lower GI polyps or cancer. Sixteen of 29 (55%) affected patients have developed gastrointestinal cancer. Eleven (38%) have had colon cancer, and six (21%) have had upper GI cancers. The risk of gastrointestinal malignancy in affected members of this JP kindred exceeds 50%. The high risk of GI cancer warrants frequent endoscopic screening of both affected and at-risk family members. Screening will soon be facilitated by presymptomatic genetic testing for the identification of gene carriers.


Pan-cancer analysis reveals presence of pronounced DNA methylation drift in CpG island methylator phenotype clusters.
To provide characteristics of major genomic correlates in CpG island methylator phenotype-high (CIMP-H) subgroups in relation to corresponding non-CIMP-H subgroups by use of phenotypic, DNA methylation and RNAseq data. Twenty-three datasets generated by The Cancer Genome Atlas project encompassing over 7200 unique samples were analyzed. We identified 23 CIMP-H clusters by use of unsupervised clustering. More than 90% of CIMP-H clusters were significantly associated with accelerated epigenetic mitotic clock, demethylation of enhancer sites, backbone and repetitive sequences. Pronounced epigenetic drift observed in majority of CIMP-H subgroups may be related to increased cell division rate, which leads to expansion of DNA methylation errors. This may explain pan-cancer mechanism of establishing CIMP-H in majority of tissue types.


A mechanistic and kinetic investigation on the oxidative thermal decomposition of decabromodiphenyl ether.
The thermal processes of materials containing decabromodiphenyl ether (BDE-209) normally result in the exposure of BDE-209 to high-temperature environments, generating a series of hazardous compounds. However, the evolution mechanisms of BDE-209 during oxidative thermal processes remain unclear. Thus, this paper presents a detailed investigation on the oxidative thermal decomposition mechanism of BDE-209 by utilizing density functional theory methods at the M06/cc-pVDZ theoretical level. The results show that the barrierless fission of the ether linkage dominates the initial degradation of BDE-209 at all temperatures, with branching ratio over 80%. The decomposition of BDE-209 in oxidative thermal processes is mainly along BDE-209 → pentabromophenyl and pentabromophenoxy radicals → pentabromocyclopentadienyl radicals → brominated aliphatic products. Additionally, the study results on the formation mechanisms of several hazardous pollutants indicate that the ortho-phenyl-type radicals created by ortho-C-Br bond fission (branching ratio reached 15.1% at 1600 K) can easily be converted into octabrominated dibenzo-p-dioxin and furan, which require overcoming the energy barriers of 99.0 and 48.2 kJ/mol, respectively. The O/ortho-C coupling of two pentabromophenoxy radicals also acts as a non-negligible pathway for the formation of octabrominated dibenzo-p-dioxin. The synthesis of octabromonaphthalene involves the self-condensation of pentabromocyclopentadienyl radicals, followed by an intricately intramolecular evolution. Results presented in this study can enhance our understanding of the transformation mechanism of BDE-209 in thermal processes, and offer an insight into controlling the emissions of hazardous pollutants.


Low dose aminophylline accelerates recovery from diazepam premedication for digestive endoscopy.
The value of intravenous aminophylline in accelerating recovery from premedication with diazepam was assessed against placebo in a randomized, double-blind trial. One hundred ten patients undergoing routine diagnostic upper gastrointestinal endoscopy received diazepam intravenously in a dosage sufficient to achieve adequate sedation. On completion of the endoscopy, patients received either aminophylline (1.5 mg/kg) or placebo. Recovery from sedation was assessed on clinical grounds by a nurse, objectively using a serial reaction time test, and by the patient on a visual analogue scale. The number of patients judged to be fully alert at 30 and 60 min after the procedure was significantly greater in the aminophylline group than in the placebo group. Compared with values obtained before sedation, the placebo group had significantly prolonged reaction times 30 min after completion of the endoscopy, whereas patients who received aminophylline did not. However, according to their self-assessments, patients in both groups felt more uncoordinated following sedation. Aminophylline appears to hasten recovery from sedation with diazepam, and its use may permit earlier mobilization of patients after endoscopy.


Characterization and quantification of methyl-benzotriazoles and chloromethyl-benzotriazoles produced from disinfection processes in wastewater treatment.
Wastewater treatment plants (WWTPs) are one of the major sources of contaminants of emerging concern (CECs) in the environment. Benzotriazole corrosion inhibitors are a class of CECs that are resistant to biodegradation and have been reported in waters varying from WWTP effluent to groundwater and drinking water. This study examined wastewater influent and effluent grab samples over three years using Comprehensive Two-Dimensional Gas Chromatography (GC × GC) to discover six target benzotriazoles, four of which have never been properly characterized in water prior to this work. The six benzotriazoles were two methyl isomers (4-methyl-1H-benzotriazole and 5-methyl-1H-benzotriazole) as well as four chloromethyl isomers (previously unidentified). Using targeted analysis, the benzotriazoles were quantified and semi-quantified in the wastewater. In all seasons sampled but one, the concentration of three of the four chloromethyl-benzotriazoles increased from the influent to effluent waters. For the first time, it was observed that the 4 and 5-methyl-benzotriazoles interact with the sodium hypochlorite in the tertiary treatment step of the WWTP leading to the formation of the four chloromethyl-benzotriazoles. This was confirmed with lab scale synthesis of the reaction where the products were chromatographically analyzed and matched mass spectral and retention time data of the water samples. Assisted by the mass spectral fragmentation information, the four chloromethyl-benzotriazole isomers were tentatively identified as 4-chloromethyl-2H-benzotriazole, 5-chloromethyl-1H-benzotriazole, 4-chloromethyl-1H-benzotriazole, and 5-chloromethyl-2H-benzotriazole, in order of elution. No analytical standards are available for the chloromethyl-benzotriazole compounds and this is the first attempted identification of them in waters. The yearly mass loadings of total benzotriazoles were estimated to average between 148.86 and 394.64 kg/year at this particular facility. The WWTP studied reuses all effluent water for irrigation of crop and forested land so this high value of benzotriazoles entering the environment is concerning and the impacts need to be further studied.


An antibody chimera technique applied to enzyme immunoassay for human alpha-1-fetoprotein with monoclonal and polyclonal antibodies.
A 2-step enzyme immunoassay (EIA) for human alpha-1-fetoprotein (AFP) is proposed, which uses covalently coupled anti-AFP IgG and anti-horseradish peroxidase (HRP) IgG (antibody chimera) binding HRP as the marker enzyme immunologically. The use of polyclonal and monoclonal anti-AFP linked to anti-HRP antibodies was compared with a conventional 2-site binding EIA with HRP covalently bound to anti-AFP IgG. The sensitivity of the conventional EIA is increased by the use of an antibody chimera comprising a molar ratio of anti-AFP IgG: anti-HRP IgG of 1:8, especially if monoclonal antibodies are employed. This improved sensitivity may be achieved by a very simple coupling procedure without purification of conjugate and with very crude HRP preparations.


DNA supercoiling facilitates the assembly of transcriptionally active chromatin on the adenovirus major late promoter.
Assembly of nucleosomes on the adenovirus major late promoter blocked initiation of transcription by RNA polymerase II. However, the formation of transcription preinitiation complexes prevented subsequent assembly of promoter sequences into nucleosomes and allowed transcription on the chromatin templates. When the formation of preinitiation complexes was in competition with nucleosome assembly, transcription on linear or relaxed closed circular DNA was inactivated by nucleosome assembly over the promoter region. However, transcription on partially supercoiled DNA (mean superhelical density of -0.036) remained active because the rapid formation of preinitiation complexes prevented subsequent assembly of promoter sequences into nucleosomes.


Risk factors for conversion to snare resection during colorectal endoscopic submucosal dissection in an expert Western center.
There are limited data regarding the risk factors and consequences of conversion to endoscopic mucosal resection (rescue EMR) during colorectal endoscopic submucosal dissection (ESD) in Western centers. This was a retrospective analysis of a prospectively collected database, from which 225 consecutive ESDs performed between 2013 and 2017 were selected. Of the included patients, 39 (18.6 %) required rescue EMR. Pre- and per-procedure characteristics were evaluated to determine the features associated with the need for rescue EMR. Outcomes and complications were also assessed. 210 patients were included, with median tumor size of 40 mm (range 20 - 110) and most tumors being in a non-rectal location (66.2 %). When compared with full ESD, rescue EMR was significantly associated with lower rates of en bloc resection (43.6 % vs. 100 %) and complete resection (R0 status; 28.2 % vs. 88.9 %), and with a higher rate of recurrence (5.1 % vs. 0 %) and more need for surgery (15.4 % vs. 3.5 %). In multivariable analysis, non-lifting (adjusted odds ratio [ORa] 3.06, 95 % confidence interval [CI] 1.23 - 7.66; P = 0.02), nongranular-type laterally spreading tumor (LST-NG; ORa 2.56, 95 %CI 1.10 - 5.99; P = 0.03), and difficult retroflexion (OR 3.22, 95 %CI 1.01 - 10.28; P = 0.049) were independent risk factors associated with conversion to rescue EMR, while tumor size and location were not. During ESD, the presence of poor lifting, LST-NG morphology, and a difficult retroflexed approach were factors associated with the need to convert to rescue EMR. Conversion to rescue EMR remains a valuable strategy.


Enterochromaffin cell hyperplasia in the gut: Factors, mechanism and therapeutic clues.
Enterochromaffin (EC) cell is the main cell type that responsible for 5-hydroxytryptamine (5-HT) synthesis, storage and release of the gut. Intestinal 5-HT play a key role in visceral sensation, intestinal motility and permeability, EC cell hyperplasia and increased 5-HT bioavailability in the gut have been found to be involved in the symptoms generation of irritable bowel syndrome and inflammatory bowel disease. EC cells originate from intestinal stem cells, the interaction between proliferation and differentiation signals on intestinal stem cells enable EC cell number to be regulated in a normal level. This review focuses on the impact factors, pathogenesis mechanisms, and therapeutic clues for intestinal EC cells hyperplasia, and showed that EC cell hyperplasia was observed under the condition of physiological stress, intestinal infection or intestinal inflammation, the disordered proliferation and/or differentiation of intestinal stem cells as well as their progenitor cells all contribute to the pathogenesis of intestinal EC cell hyperplasia. The altered intestinal niche, i.e. increased corticotrophin releasing factor (CRF) signal, elevated nerve growth factor (NGF) signal, and Th2-dominant cytokines production, has been found to have close correlation with intestinal EC cell hyperplasia. Currently, CRF receptor antagonist, nuclear factor-κB inhibitor, and NGF receptor neutralizing antibody have been proved useful to attenuate intestinal EC cell hyperplasia, which may provide a promising clue for the therapeutic strategy in EC cell hyperplasia related diseases.


[The evolution of the human species: a long journey for the respiratory system].
Evolution has involved important changes in hominids, particularly in relation to the process of encephalization and the transition to bipedalism. Some of these changes involved structures related to the respiratory system and altered its functional behavior. Changes affecting the relationship between the skull and the spinal column, together with an improved laryngeal structure (allowing vocalization), resulted in a soft and elongated oropharynx, with part of the tongue integrated into its anterior wall, and thus in an increased tendency towards upper airway collapse during sleep. Vertebral bodies moved inwards into the thorax, which became slightly shorter and went from a bell-shaped appearance to that of a flatter barrel-shaped one. This resulted in respiratory muscle mechanics that were more efficient for upright posture. The pulmonary ventilation and perfusion gradients moved from a dorsoventral to a craniocaudal axis, while the structural organization of the respiratory muscles underwent only minor changes.


Individualized medication assessment and planning: optimizing medication use in older adults in the primary care setting.
To test the feasibility and effectiveness of an individualized Medication Assessment and Planning (iMAP) program integrated within a primary care practice on the number and prevalence of medication-related problems (MRPs) and acute health services utilization, defined as combined hospitalizations and emergency department visits. Six-month, prospective, observational pilot study. Community-based primary care medical practice. Convenience sample of 64 patients aged 65 years and older who were taking at least five medications. Each patient was enrolled in the iMAP program-a collaborative, multifaceted intervention facilitated by a clinical pharmacist whereby patients receive comprehensive medication therapy management at baseline and 3 and 6 months as part of routine clinical care. MRPs were assessed and recommendations proposed using the previously published MRP classification tool; physician acceptance of recommendations served to validate the assessments. There was a significant reduction in mean number of MRPs/patient (4.2 at baseline vs 1.0 at 6 mo, p<0.0001) when adjusted for number of medications, race, and pharmacist. The prevalence of MRPs at 6 months compared with baseline was also significant (p<0.0008). Acute health services utilization was assessed by medical record abstraction. The 64 patients experienced a rate of 8.3 events/100 person-months (64 total events) during the 12-month prestudy period. During the 6-month study period, the same patients experienced 5.4 events/100 person-months (20 total events). Thus, we noted a reduction in acute health services utilization of 35%. Physicians were enthusiastically supportive of iMAP. iMAP has the potential to address a significant and timely issue affecting older adults and primary care practices: the burden of managing and continuously monitoring multiple medications in medically complex older adults. A more rigorous evaluation of iMAP is warranted and planned to demonstrate sustained effectiveness and cost-benefit.


Metabolism of benzo(a)pyrene in animals with high aryl hydrocarbon hydroxylase levels and high rates of spontaneous cancer.
Ambystoma tigrinum found in a sewage polluted pond had high levels of aryl hydrocarbon hydroxylase (AHH) activity that decreased to the basal level of control animals after being held several months in clean water. The qualitative formation of benzo(a)pyrene (BP) metabolites by salamander hepatic microsomes was similar to those seen for other species. Inhibition of epoxide hydrase activity did not alter the total metabolite production but did change the ratio of metabolites. A correlation appears to exist between high AHH induction, the presence of polycyclic hydrocarbon pollutants, and the high rate of spontaneous cancer in salamanders.


Season-of-birth as a risk factor for the seasonality of suicidal behaviour.
Despite implicating the same biological systems, the relationship between suicide seasonality and season-of-birth has not been examined previously. The purpose of this study was to investigate the interaction between season-of-birth and the seasonality of suicidal behaviour. All adult suicides (N = 2923) and deliberate self harm (DSH) hospitalizations (N = 33321) in Western Australia (1970-96) were examined. A variable population at risk approach was used to determine season-of-birth. Seasonality was established by spectral analysis. We found that DSH has a significant season-of-birth (p = 0.047) and seasonality of occurrence, both peaking in spring. Individuals born in the 90 days centred on the peak birth period, however, show no DSH seasonality. In contrast, suicide has no season-of-birth (p = 0.53). We also found a season-of-birth effect among the DSH group that eliminates any seasonality of DSH among the high-risk by birth group. Further work is needed to identify the possible biological and environmental determinants of this interaction.


Denoising Algorithm for Event-Related Desynchronization-Based Motor Intention Recognition in Robot-assisted Stroke Rehabilitation Training with Brain-Machine Interaction.
Rehabilitation robots integrated with brain-machine interaction (BMI) can facilitate stroke patients' recovery by closing the loop between motor intention and actual movement. The main challenge is to identify the patient's motor intention based on large training datasets with noise contamination in the Electroencephalogram (EEG) signal. To address this problem, this paper proposed a self-adaptively denoised Event-Related Desynchronization (ERD)-based motor intention recognition algorithm (DeERD) in order to enable BMI training with a small sample of calibration data. This study recruited 8 stroke patients. Each patient was required to execute paralyzed upper-limb motor attempt for 20 trials and remain in resting state for 20 trials randomly. ERD-based motor intention recognition algorithm, Common spatial filter algorithm (CSP) and Directed Transfer Function analysis (DTF) were used to extract features for classification respectively and compared with the proposed DeERD analysis. DeERD can filter the noise and extract the average lines as the principal trends. With denoising processing, Accuracy (ACC) was up to 70% for all 8 patients and they could be included in this BMI system effectively. The proposed DeERD model generated statistically significant increase in True Positive Rate (TPR) and in ACC than the DTF model. TPR and ACC standard deviation of DeERD was smaller than that of CSP. The proposed DeERD model can eliminate the principal noise and extract the principal trend of the time-frequency analysis. It provides a practical method to recruit more stroke patients into BMI training with fewer calibration trainings.


A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial.
Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC. Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate. A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%. Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.


Gamete preservation: knowledge, concerns and intentions of Israeli and Danish students regarding egg and sperm freezing.
What do Danish and Israeli students of both sexes know about age in relation to fertility and gamete preservation, and what are their concerns and intentions for the future in this regard? A cross-sectional comparative study of male and female Danish and Israeli students was conducted between November 2018 and April 2019. A total of 1010 students, 508 from Denmark and 502 from Israel, completed questionnaires assessing knowledge, perceptions and intentions regarding gamete preservation. More than 70% of both genders in Israel thought that women start experiencing fertility decline at age 35 and up. A total of 60% of Danish women and 51% of Danish men chose 29-34 as the time where fertility decline starts. Some 95% of Danish students chose 20-29 as the best age for egg freezing, while the corresponding number in Israel was 85%, regardless of gender. In total, 51% of Israeli women said they are extremely or very worried about future infertility, compared with 31% of Danish women, 26% of Israeli men and 12% of Danish men. Regarding preservation intentions, no gender differences were found. Some 3% of Israeli students said they would consider gamete preservation, as compared with 14% of Danish students. These findings suggest a widespread worry among Danish and Israeli women about their future fertility. Danish students report more awareness of age-related fertility decline. Unique to this study is the inclusion of male students. The preliminary findings reveal that men are less worried about their reproductive future.


Expanding the genetic and phenotypic spectrum of CHD2-related disease: From early neurodevelopmental disorders to adult-onset epilepsy.
CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged.


Studies on intercellular LETS glycoprotein matrices.
Intercellular matrices secreted by chick embryo fibroblasts in culture were studied by scanning electron microscopy. Cell-cell contact is a prerequisite for the expression of such matrices. The smallest fiber detected by transmission electron microscopy is 5--10 nm in diameter. These matrix fibers tend to cluster to form bundles. Immunofluorescence and immunoferritin procedures reveal that LETS protein is one of the components of the matrices. The matrices are isolated from other cellular organelles by detergent treatment. More than 90% of the proteins in cell-free matrices are LETS protein, suggesting that the matrices are probably made of only one component--LETS protein. Since the solubilization of matrices requires beta-mercaptoethanol, LETS protein matrices may be the first known polymer system in nature to use disulfide linkage as an intermolecular polymerization vehicle. Collagen does not appear to be involved in such matrices. The LETS protein matrix supports the morphological conversion of rounded cells into spindle-shaped, and also promotes myoblast fusion. It does not, however, exert an effect upon cell growth, the rate of glucose uptake or protease production.


New diagnosis of mother-to-child transmission of HIV in 8 Latin-American countries during 2018.
Important prevention efforts have led to a reduction in mother-to-child transmission of HIV (MTCT) globally. However, new cases of paediatric HIV infections still occur. Early diagnosis of new HIV infections is essential to start an appropriate antiretroviral treatment to avoid childhood morbidity and mortality related to infection. The aim of this study was to describe the new cases of MTCT in Latin-American referral hospitals. A retrospective, multicentre and descriptive study of the new cases of MTCT diagnosed during 2018 in 13 referral hospitals from 8 Latin-American countries (Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Panama) belonging to PLANTAIDS (Paediatric Network for Prevention, Early Detection and Treatment of HIV in Children), was conducted. PLANTAIDS is included in CYTED (Ibero-American Programme of Science and Technology for Development). Eighty-one children (40.7% males) were included, median age at diagnosis of 2.33 years (IQR:0.7-4.7). Less than 3% of women knew their HIV diagnosis before pregnancy. More than 80% of them were diagnosed after delivery, 8.7% during pregnancy, and 2.9% at delivery. Only one patient underwent antiretroviral therapy (ART) prior to pregnancy. At diagnosis, 50.0% of the children presented with an advanced stage of disease (stage C following the current CDC classification for HIV infection), and 34.4% had less than 15% CD4+ cells/mm3. The time elapsed between delivery and the maternal diagnosis was correlated with the age of children at diagnosis, ρ = 0.760, p < 0.001. Younger age at diagnosis (p = 0.03), a smaller number of previous hospitalizations (p < 0.01), and better immunovirological status (p < 0.01) were found in children whose mothers knew their HIV status at delivery, compared to mothers who were not aware of it. Although MTCT in Latin America has declined in recent years, our series shows there are still cases that indicate some failures in prevention, being a critical point to improve an earlier diagnosis of pregnant women. Half of the children were diagnosed in an advanced stage of disease and the delay in maternal diagnosis entailed a worse clinical and immunological child' prognosis.


Identification of M(1) muscarinic receptor subtype in rat stomach using a tissue segment binding method, and the effects of immobilization stress on the muscarinic receptors.
Distinct muscarinic acetylcholine receptor subtypes widely distribute in stomach tissues and are involved in many physiological functions. Although mRNA of M(1) subtype was found in gastric mucosa, the M(1) subtype has not been detected by conventional membrane binding assays. In the present study, muscarinic receptor subtypes in the rat stomach were reevaluated by using the tissue segment binding technique recently developed to recognize the inherent/native profiles of receptors without receptor environment perturbation. [(3)H]-N-methylscopolamine (NMS) bound to muscarinic receptors in the intact segments of rat gastric mucosa and muscle layers. The muscarinic receptors in the mucosal segments were composed of M(1), M(2) and M(3) subtypes, among which the M(1) subtype selectively showed high affinity for pirenzepine. However, in the membrane preparations, binding sites with high affinity for pirenzepine could not be detected. In the muscle layer, M(2) and M(3) subtypes, but not M(1), were identified in tissue segment and conventional membrane binding assays. Western blotting analysis recognized the M(1) subtype in the membrane preparations of mucosal but not muscle layers. Chronic immobilization stress increased the M(3) subtype in mucosal and muscle layers and decreased the M(2) subtype in the muscle layer, whereas M(1) and M(2) subtypes in mucosal layer did not change after the stress. The current study shows that M(1) subtype occurs as a pirenzepine-high affinity entity in intact segments of rat gastric mucosa, but that it loses the affinity for pirenzepine upon homogenization. Careful identification of native in vivo muscarinic receptors may further elucidate their functions in stomach.


Does breathing pattern affect cerebrovascular reactivity?
What is the central question of this study? Is cerebrovascular reactivity affected by isocapnic changes in breathing pattern? What is the main finding and its importance? Cerebrovascular reactivity does not change with isocapnic variations in tidal volume and frequency. Deviations of arterial carbon dioxide tension from resting values affect cerebral blood vessel tone and thereby cerebral blood flow. Arterial carbon dioxide tension also affects central respiratory chemoreceptors, adjusting respiratory drive. This coincidence raises the question: does respiratory drive also affect the cerebral blood flow response to carbon dioxide? A change in cerebral blood flow for a given change in the arterial carbon dioxide tension is defined as cerebrovascular reactivity (CVR). Two studies have reached conflicting conclusions on this question, using voluntary control of breathing as a disturbing factor during measurements of CVR. Here, we address some of the methodological limitations of both studies by using sequential gas delivery and targeted control of carbon dioxide and oxygen to enable a separation of the effects of carbon dioxide on CVR from breathing vigour. We confirm that there is no detectable superimposed effect of breathing efforts on CVR.


Asymmetrical flow field-flow fractionation to probe the dynamic association equilibria of β-D-galactosidase.
Protein dynamics play a significant role in many aspects of enzyme activity. Monitoring of structural changes and aggregation of biotechnological enzymes under native conditions is important to safeguard their properties and function. In this work, the potential of asymmetrical flow field-flow fractionation (AF4) to study the dynamic association equilibria of the enzyme β-D-galactosidase (β-D-Gal) was evaluated. Three commercial products of β-D-Gal were investigated using carrier liquids containing sodium chloride or ammonium acetate, and the effect of adding magnesium (II) chloride to the carrier liquid was assessed. Preservation of protein structural integrity during AF4 analysis was essential and the influence of several parameters, such as the focusing step (including use of frit-inlet), cross flow, and injected amount, was studied. Size-exclusion chromatography (SEC) and dynamic light scattering (DLS) were used to corroborate the in-solution enzyme oligomerization observed with AF4. In contrast to SEC, AF4 provided sufficiently mild separation conditions to monitor protein conformations without disturbing the dynamic association equilibria. AF4 analysis showed that ammonium acetate concentrations above 40 mM led to further association of the dimers ("tetramerization") of β-D-Gal. Magnesium ions, which are needed to activate β-D-Gal, appeared to induce dimer association, raising justifiable questions about the role of divalent metal ions in protein oligomerization and on whether tetramers or dimers are the most active form of β-D-Gal.


Contributing to the ICNP: validating the term cultural diversity.
The specific aims of this study were to: Propose a definition of the term cultural diversity; Validate the term cultural diversity; and Submit a term and definition for international utilisation to the International Council of Nurses (ICN) for consideration for inclusion in the ICNP. South Africa was one of four African countries (Botswana, South Africa, Swaziland, and Zimbabwe) funded by the WK Kellogg Foundation to participate in the ICNP project. South Africa had 2 research groups. One of the research groups identified the term cultural diversity to define. This was a qualitative study where a philosophical perspective was used to explore, explain and describe nursing practice. The combined method proposed by the International Council of Nurses (ICN) was utilised to define and validate the term cultural diversity. Validation and literature review provided sufficient support for the defined characteristics and the term was finally defined and submitted to ICN in November 2002 as: CULTURAL DIVERSITY is a type of CULTURE with the specific characteristics: co-existence of different groups, e.g. ethnic, religious, linguistic and other groups each with their own values and belief systems, traditions and different lifestyles. The research group was informed in December 2003 of the ICNP Evaluation Committee recommendation that the term cultural diversity will be included in the ICNP.


Haploid pluripotent stem cells: twofold benefits with half the effort in genetic screening and reproduction.
Haploid pluripotent stem cells, which are capable of self-renewal and differentiation into other cell types with only one set of chromosomes, have been established in several species from haploid embryos. Compared with diploid embryonic stem cells (ESCs), haploid embryonic stem cells (haESCs) are smaller in size, have a prolonged metaphase, and undergo self-doubling during culture. The monoallelic expression of haESCs provides great convenience for recessive inheritance research. Genetically modified haESCs also provide benefits in replacement of the gamete genomes, which not only facilitates the study of the function of imprinted genes but also potentially removes barriers to same-sex reproduction. In this review, we focus on strategies for obtaining haESCs and their potential applications in genetic screening, genomic imprinting, and unisexual reproduction.


Dendrocin, a distinctive antifungal protein from bamboo shoots.
An antifungal protein, with a molecular weight of 20 kDa and an inhibitory action on mycelial growth in the fungi Fusarium oxysporum, Botrytis cincerea, and Mycosphaerella arachidicola, was isolated from fresh bamboo shoots. The protein, designated dendrocin, was unadsorbed on DEAE-cellulose and adsorbed on Affi-gel blue gel and CM-Sepharose. Dendrocin showed only limited similarity in N-terminal sequence to thaumatin-like proteins, unlike other thaumatin-like proteins which closely resemble each other. Its molecular weight was also lower than those of the previously reported thaumatin-like proteins. The protein was devoid of hemagglutinating and ribonuclease activities found in some antifungal proteins.


Comparative evaluation among different materials to replace soft tissue in oral radiology studies.
The aim of this study was to establish which materials afford better simulation of soft tissues in Oral Radiology studies. The sample was composed of four materials in eleven different thicknesses to simulate the soft tissues of the face. The mean values of the relative amounts of radiographic contrast of the materials were determined and compared to a gold standard value, which was obtained from 20 patients who were referred to have periapical radiographs taken of the left mandibular molars. Data were subjected to statistical analysis with Dunnett's test (p<0.05). The mean value of the relative amounts of contrast encountered in the patients was 0.47, with a range between 0.36 and 0.64 for all 44 material/thickness combinations. The majority of the tested materials showed values close to those of the patients' tissues, without statistically significant differences among them. The values of only three materials/thickness combinations differed statistically from those of the patients' tissues. Based on the results of the present study, it may be concluded that except for utility wax (4 mm and 8 mm) and water (4 mm), all materials tested at different thickness could be used as soft tissue substitute materials in Oral Radiology studies.


Does the gas exchange anaerobic threshold occur at a fixed blood lactate concentration of 2 or 4 mM?
The anaerobic threshold (theta an) is defined as the VO2 at which blood lactate concentration [lactate] begins to systematically increase (lactate "break point") during incremental exercise. Numerous studies have shown that gas exchange break points at the anaerobic threshold correlate highly (r congruent to 0.90) with the lactate break point. Recently, it has been suggested that the anaerobic threshold occurs at a fixed [lactate] of 2 mM or 4 mM. We therefore compared the gas exchange theta an to the three lactate criteria (break point, 2 mM, and 4 mM) for theta an estimation. Fourteen subjects performed an incremental cycle ergometer test. Ventilation and gas exchange were computed every 30 s. During the same 30-s intervals, venous blood was sampled for [lactate]. Four criteria were used for theta an determination: (1) systematic increase in VE/VO2, without a concomitant increase in VE/VCO2; (2) lactate break point; (3) 2 mM [lactate]; and (4) 4 mM [lactate]. Relative to the gas exchange criterion (i.e., #1), theta an was higher by 44, 280, and 1028 ml X min-1 for the three lactate criteria, respectively; the last two being significantly different (P less than 0.05). Thus, the anaerobic threshold discerned from gas exchange or the lactate break point does not correspond with a fixed, absolute [lactate] of 2 mM or 4 mM.


Modulation of platelet responsiveness through selective phosphorylation of plasma membrane proteins.
32P phosphorylation of plasma membranes from human blood platelets, under conditions that closely resemble physiological ones (endogeneous phosphate donors and intact platelets in homologous plasma), result in the incorporation of the label mainly in a membrane glycoprotein of apparently high molecular weight (greater than 400 000). Dibutyryl cyclic AMP, an inhibitor of platelet aggregation, specifically increases the degree of phosphorylation of this glycoprotein. Moreover, it has been found that prostaglandin E1 one of the most potent inhibitors of platelet aggregation which also increases phosphorylation of the same glycoprotein, is significantly more effective than cyclic AMP. Cyclic GMP does not have any apparent effect on platelet aggregation. However, incubation of platelet-rich plasma with both cyclic GMP and cyclic AMP results in a partial recovery of the platelet responsiveness towards ADP-induced aggregation. Coincidently, the degree of phosphorylation of the high molecular weight glycoprotein under these conditions, although still higher than in controls (no nucleotides added), is significantly decreased as compared with cyclic AMP-treated cells. Furthermore, cyclic GMP inhibits the cyclic AMP-dependent protein kinase activity in isolated platelet plasma membranes. These results suggest a central role for this membrane phosphoglycoprotein in the triggering of platelet aggregation and, furthermore, suggest that modulation of its degree of phosphorylation may be exerted through some cyclic AMP/cyclic GMP relationship, which in the basal state might be critical for platelet responsiveness.


Dehydration-rehydration vesicle methodology facilitates a novel approach to antibody binding to liposomes.
Mouse monoclonal IgG1 specific for hepatitis B surface antigen and ovine polyclonal antibody raised against digoxin were covalently coupled by a diazotisation method to small unilamellar vesicles (SUV) composed of equimolar phospholipid and cholesterol supplemented with 6 mol% aminophenylstearylamine (APSA). Up to 33% of the antibody used was associated with vesicles, depending on the phospholipid and the antibody type used. Antibody-coated SUV were mixed with carboxyfluorescein (CF) or beta-galactosidase to generate multilamellar dehydration-rehydration vesicles (DRV) containing CF or active enzyme. In contrast, coupling of antibodies directly to beta-galactosidase-containing DRV resulted in total inactivation of the enzyme. About 85% of the SUV-bound antibody was recovered in DRV and of this, 78-82% was exposed on the liposomal surface, possibly because of reorientation of the APSA-antibody complex during DRV formation. Antibody-coated DRV remained stable in the presence of plasma at 37 degrees C and also under storage at 4 degrees C. Further, antibody coupled to such liposomes was capable of efficient interaction with the respective antigen. The present method allows the attachment of antibodies to the liposomal surface independently of entrapment of solutes, the activity of which is thus preserved, and could be adapted to alternative coupling procedures or ligands.


Mycotic aneurysm of the superior and inferior mesenteric artery.
Visceral artery aneurysms as a result of arterial degenerative disease are rare (0.1%-2%), and the superior mesenteric artery (SMA) accounts for 3.2% of all reported series. The current incidence of inferior mesenteric artery (IMA) aneurysm is unknown. However, infective causes (mycotic) of SMA and IMA aneurysm as a result of primary, secondary, and cryptogenic etiology remain a separate entity and attain fewer cases in the literature. Currently, there is no consensus on their presentation, diagnosis, and overall management. A systematic review and meta-aggregation of literature from 1944 to March 2015 in the English language and of adult subjects in MEDLINE, Ovid, CINAHL, and the Cochrane database was conducted. The median age of patients with SMA aneurysm was 36 (range, 14-92) years, with a significant male predominance (73% vs 27%). In order of prevalence, abdominal pain (n = 25; 65%), low-grade fever (n = 23; 60%), malaise (n = 10; 26%), weight loss (n = 9; 23%), and nausea and vomiting (n = 8; 20%) were the most common presenting signs and symptoms. The most common microorganism was Streptococcus (n = 18; 47%), followed by Staphylococcus (n = 11; 28%). The investigative modality of choice was computed tomography (n = 22; 57.8%), followed by ultrasonography of the abdomen (n = 9; 23%). Primary etiology was noted in 5.4%, secondary in 71%, and cryptogenic in 13% of all cases. Aneurysmectomy alone was associated with bowel resection in four cases (10.5%), whereas aneurysmectomy with interposition vein grafting required no further intervention. The inpatient mortality after surgery was 7.8%, and the overall mortality was 15%. The median follow-up was 12 months (range, 2-120 months). The median age of patients with IMA aneurysm was 48 (range, 22-64) years, with a male predominance of 2:1 and abdominal pain in all cases (n = 3; 100%). The most common microorganism was Streptococcus (n = 2; 66.6%), and the operation of choice was aneurysmectomy (n = 2; 66.6%) after computed tomography scan (n = 3; 100%) as an investigative modality of choice. The pentad of abdominal pain, pyrexia of unknown origin, malaise, weight loss, and nausea remains the most convincing presentation of mycotic aneurysms of the SMA and IMA. Computed tomography is the investigative modality of choice, and such patients are best served with aneurysmectomy alone in IMA aneurysms and interposition vein grafting in SMA aneurysms after initiation of antimicrobial therapy on suspicion of the diagnosis.


Single or repeated electroconvulsive shocks alter the levels of prodynorphin and proenkephalin mRNAs in rat brain.
The effects of single or repeated electroconvulsive shocks (ECS) on the abundance of mRNAs coding for prodynorphin (DYN mRNA) and proenkephalin (EK mRNA) in rat brain were investigated. Rats were given either a single ECS and sacrificed at 0.5, 2, 6, or 12 h post-shock (expt. I), or were subjected to ECS for 1, 3 or 6 days and killed 24 h after the last shock (expt. II). The amounts of DYN mRNA and EK mRNA were measured in several brain regions using RNA blot analysis. In expt. I, a biphasic change in the DYN mRNA level was found in the hippocampus, with an initial 49% decrease at 0.5 h followed by a 51% increase at 6 h after a single ECS. The EK mRNA content in the entorhinal cortex started to increase at 0.5 h, and continued to rise, reaching 260% of the control level at 12 h post-shock. A smaller increase in the EK mRNA level was found also in the hippocampus at 2 to 12 h post-shock. No significant increase in [Met5]-enkephalin or dynorphin A(1-8) immunoreactivity was detected by radioimmunoassay in either area. In expt. II, a dramatic reduction in the DYN mRNA level was observed in the hippocampus 24 h after a single or repeated ECS. In contrast, elevated DYN mRNA levels were seen in the striatum and hypothalamus. The EK mRNA level remained elevated in the entorhinal cortex after 6 daily ECS.(ABSTRACT TRUNCATED AT 250 WORDS)


Drug dosing error with drops: severe clinical course of codeine intoxication in twins.
In spite of the lack of evidence for its efficacy, and of sporadic reports of severe adverse events, codeine is still widely used as an antitussive agent in children. A 3-year-old boy (twin 1) was found lying in vomit and apnoeic at night; he was resuscitated and immediately transferred to our paediatric intensive care unit (PICU). Two and a half hours later, his twin brother (twin 2) was found dead in his bed at home. Twin 1 required mechanical ventilation for 3 days, but he eventually made a full recovery; autopsy in twin 2 showed massive aspiration of gastric content. History revealed that the monozygotic twins had an upper respiratory tract infection for several days and had both been given codeine at a dose of "10 drops per day" by their mother. The blood of both twins was found to contain high levels of codeine and its metabolites. The weight of "10 drops" was determined experimentally and was found to range from 494 to 940 mg. Thus, the highest possible dose given by mother was 23.5 mg of codeine instead of the recommended 10 mg. The twins had identical CYP2D6 gene polymorphisms corresponding to the "extensive metaboliser" type. Because of the variability of drop size drug dosage, dosage "by drops" is unprecise and may result in accidental overdose. The combination of repeated overdosing and extensive metabolism to morphine is likely to have caused apnoea in these twins. These cases illustrate the danger of codeine as an antitussive in young children.


A randomized, double-blind, placebo-controlled trial of paracetamol and ketoprofren lysine salt for pain control in children with pharyngotonsillitis cared by family pediatricians.
To evaluate the analgesic effect and tolerability of paracetamol syrup compared to placebo and ketoprofen lysine salt in children with pharyngotonsillitis cared by family pediatricians. A double-blind, randomized, placebo-controlled trial of a 12 mg/kg single dose of paracetamol paralleled by open-label ketoprofren lysine salt sachet 40 mg. Six to 12 years old children with diagnosis of pharyngo-tonsillitis and a Children's Sore Throat Pain (CSTP) Thermometer score > 120 mm were enrolled. Primary endpoint was the Sum of Pain Intensity Differences (SPID) of the CSTP Intensity scale by the child. 97 children were equally randomized to paracetamol, placebo or ketoprofen. Paracetamol was significantly more effective than placebo in the SPID of children and parents (P < 0.05) but not in the SPID reported by investigators, 1 hour after drug administration. Global evaluation of efficacy showed a statistically significant advantage of paracetamol over placebo after 1 hour either for children, parents or investigators. Patients treated in open fashion with ketoprofen lysine salt, showed similar improvement in pain over time. All treatments were well-tolerated. A single oral dose of paracetamol or ketoprofen lysine salt are safe and effective analgesic treatments for children with sore throat in daily pediatric ambulatory care.


Washout of small stones in the bile duct by saline infusion using a side-holed balloon catheter in patients undergoing endoscopic papillary balloon dilation.
Complete bile duct clearance of stones should be achieved in patients managed with endoscopic papillary balloon dilation. However, complete retrieval of small stones or tiny fragments sometimes proves difficult using conventional devices. We attempted the removal of fine stone fragments by saline infusion using a specially designed retrieval balloon catheter with a blind tip and a side hole located proximal to the balloon in 14 patients. Using this technique, bile duct clearance was achieved in a single attempt in 13 of 14 patients; 2 attempts were required in 1 patient. Cholecystitis occurred in 2 patients with gallstones in situ after the procedure. Saline washout using a side-holed retrieval balloon catheter effectively cleans stones and stone fragments from the bile duct in patients treated with endoscopic papillary balloon dilation.


1,25-dihydroxyvitamin D3 suppresses lipopolysaccharide-induced interleukin-6 production through aryl hydrocarbon receptor/nuclear factor-κB signaling in oral epithelial cells.
Antiinflammatory effect of 1,25-dihydroxyvitamin D3 (1,25D3) has been reported in periodontitis, but the exact mechanisms remain unclear. Oral epithelial cells are recently highlighted as an important regulator of inflammation in this disease. This in vitro study was established to investigate the effect of 1,25D3 on key proinflammatory cytokine IL-6 production and aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB) signaling in oral epithelial cells upon the stimulation of lipopolysaccharide (LPS) from periodontal pathogens. OKF6/TERT-2 oral keratinocytes were incubated with LPS and different concentrations of 1,25D3, and levels of IL-6 production were determined using enzyme-linked immunosorbent assay (ELISA). Expression of vitamin D receptor (VDR), and activation of AhR was examined using western blot analysis, and phosphorylation of NF-κB was detected using cell-based protein phosphorylation ELISA. 1,25D3 inhibited LPS-induced IL-6 overexpression in OKF6/TERT-2 cells. Additionally, 1,25D3 increased VDR expression and AhR activation, and repressed NF-κB phosphorylation. Furthermore, 1,25D3 suppressed IL-6 expression and enhanced VDR expression and regulated AhR/NF-κB signaling activation in a dose-dependent manner after 48 h treatment. These results suggest that 1,25D3 may inhibit LPS-induced IL-6 overexpression in human oral epithelial cells through AhR/NF-κB signaling. Our findings may provide an explanation for the antiinflammatory effect and therapeutic benefit of 1,25D3 in periodontitis.


Influence of confluent holding time on UV light mutagenesis in human diploid fibroblasts.
We have investigated the induction of mutants resistant to 6-thioguanine (6TG) following 254 nm ultraviolet light exposure of density-inhibited cultures of human diploid fibroblasts. Phenotypic expression of 6TG resistance was maximal within 9 days and remained stable through 19 days after irradiation. In reconstruction studies, complete recovery of 6TG-resistant mutants occurred at cell densities of up to 35 000 cells per 100-mm petri dish. The induced mutation frequency increased linearly with dose over the range of 3-9 J/m2; the D0 of the survival curve was 4.2 J/m2. Delaying subculture to low density for 1.5-24 h after irradiation produced unexpected alterations in induced mutation frequencies. An increase in UV-induced mutations of approximately 3-fold was observed in cultures maintained in confluence for 3 h. This trend was reversed with longer holding times: the mutation frequency declined sharply in cultures held for 6 h as compared to the 3-h value, and thereafter showed a steady and gradual diminution to background levels. These data suggest that the repair of potentially mutagenic damage is a complex phenomenon which can lead to an increase or decrease in mutation frequency as a function of holding time. Although the decline in mutation frequency observed following longer holding intervals is consistent with the notion of an error-free process, we hypothesize that the increased mutation frequency produced by a short holding period reflects the existence of a cell-mediated process which enhances the mutagenic potential of at least some UV-induced DNA photoproducts.


The Influence of Gender Categories and Gender Stereotypes on Young Children's Generalizations of Biological and Behavioral Characteristics.
We examined the influence of categorization and stereotyping on young children's (N = 96; 39 to 71 months of age) use of gender to make generalizations regarding novel biological and behavioral characteristics. Participants were asked to sort pictures of children according to either gender, common gender stereotypes, or shirt color. Then participants performed a triad inductive reasoning task. Children in the Stereotype condition consistently generalized on the basis of gender, but performance was inconsistent in the absence of stereotyping. Results are discussed in relation to variability in early gender cognition.


Novel molecular laser-induced photoluminscence signature with hyperspectral imaging for instant and remote detection of trace explosive materials.
Instant detection of explosive material is highly appreciated for counterterrorism activity and homeland security. Nitro group (high energy rich bond) is responsible for explosive characteristics. Nitro group includes intense competition between two highly electronegative atoms. Nitro group is frequently encountered in all explosive materials. This function group includes delocalized π bond; that could secure intense photoluminescence (fluorescence and phosphorescence) signature. In this study, the main classes of explosive materials including nitro-compounds (i.e. TNT), nitramines (i.e. RDX), and nitric esters (i.e. PETN) were stimulated with green laser source of 532 nm and 5 mW power. The photoluminescence signature of each tested material was captured via hyperspectral camera. The tested explosives demonstrated characteristic fluorescence signature at 571, 587, and 613 nm for RDX, PETN, and TNT respectively. Furthermore, TNT demonstrated characteristic phosphorescence signature at 975 nm. The customized laser induced photoluminescence technique offered facile detection of trace explosive material via clustering approach based on K-m clustering (k = 8); this technique was able to detect RDX, PETN and TNT traces on the finger nail via processed hyperspectral images at 581 nm, 797 nm and 953 nm, respectively. This study shaded the light on novel customized photoluminescence technique for facile detection and identification of trace explosive materials.


The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study.
Empagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment. This QT interval study assessed potential effects of empagliflozin on ventricular repolarisation and other electrocardiogram (ECG) parameters. A randomised, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design to reduce sample size, while maintaining full statistical power. single empagliflozin doses of 25 mg (therapeutic) and 200 mg (supratherapeutic), matching placebo and open-label moxifloxacin 400 mg (positive control). Triplicate 12-lead ECGs of 10 second duration were recorded at baseline and during the first 24 hours after dosing. The primary endpoint was mean change from baseline (MCfB) in the population heart rate-corrected QT interval (QTcN) between 1-4 hours after dosing. Thirty volunteers (16 male, 14 female, mean [range] age: 34.5 [18-52] years) were randomised. The placebo-corrected MCfB in QTcN 1-4 hours after dosing was 0.6 (90% CI: -0.7, 1.9) ms and -0.2 (-1.4, 0.9) ms for empagliflozin 25 mg and 200 mg, respectively, below the ICH E14 defined threshold of regulatory concern 10 ms. Assay sensitivity was confirmed by a placebo-corrected MCfB in QTcN 2-4 hours post-dose of 12.4 (10.7, 14.1) ms with moxifloxacin 400 mg. Empagliflozin tolerability was good for all volunteers; 23.3% experienced adverse events (AEs) with empagliflozin and 27.6% with placebo. The most frequent AE was nasopharyngitis. Single doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers. ClinicalTrials.gov: NCT01195675.


Is loneliness a predictor of the modern geriatric giants? Analysis from the survey of health, ageing, and retirement in Europe.
The modern Geriatric Giants have evolved to encompass four new syndromes, of frailty (linked to fatigue and physical inactivity), sarcopenia, anorexia of ageing, and cognitive impairment. In parallel, loneliness has been established as a risk factor for adverse mental and physical health outcomes among older adults. To analyse loneliness as a predictor of the modern Geriatric Giants in European older adults, using a longitudinal design of nationally representative data. Longitudinal population-based cohort study. Data from countries that participated in waves 5 and 6 of the Survey of Health, Ageing, and Retirement in Europe project. The sizes of the subsamples analysed ranged from 17,742 for physical inactivity to 24,524 for anorexia of ageing. Loneliness (measured from wave 5) was the independent variable of interest. The dependent variables were incidence of fatigue, physical inactivity, sarcopenia, anorexia of ageing, and cognitive impairment from wave 5 (baseline) to wave 6. Poisson regression models were used for multivariable analysis, obtaining Relative Risk (RR) and 95 % confidence intervals (CI). The prevalence of loneliness ranged from 9.2%-12.4% at wave 5. The 2-year incidence of fatigue was 16 % (95 % CI: 15.5-16.5), physical inactivity 9.8 % (95 % CI: 9.4-10.3), sarcopenia 5.6 % (95 % CI: 5.3-5.9), anorexia of aging 5.4 % (95 % CI: 5.1-5.7), and cognitive impairment 10.3 % (95 % CI: 9.9-10.8). The multivariable analysis showed that loneliness was a predictive factor for fatigue (30 %, CI: 17-45 % higher risk), physical inactivity (24 %, CI: 7-43 % higher risk) and cognitive impairment (26 %, CI: 9-46 % higher risk), adjusted by age, sex, number of chronic diseases, education level, region and depression. Loneliness is an independent risk factor for fatigue, physical inactivity, and cognitive impairment in older adults. The incidence of anorexia of ageing and sarcopenia was not associated with loneliness over the 2-year observation period.


Locoregional opening of the rodent blood-brain barrier for paclitaxel using Nd:YAG laser-induced thermo therapy: a new concept of adjuvant glioma therapy?
Nd:YAG laser-induced thermo therapy (LITT) of rat brains is associated with blood-brain barrier (BBB) permeability changes. We address the question of whether LITT-induced locoregional disruption of the BBB could possibly allow a locoregional passage of chemotherapeutic agents into brain tissue to treat malignant glioma. CD Fischer rats were subject to LITT of the left forebrain. Disruption of the BBB was analyzed using Evans blue and immunohistochemistry (IH). Animals were perfused with paclitaxel, and high-pressure liquid chromatography (HPLC) was employed to analyze the content of paclitaxel in brain and plasma samples. LITT induces an opening of the BBB as demonstrated by locoregional extravasation of Evans blue, C3C, fibrinogen, and IgM. HPLC proved the passage of paclitaxel across the disrupted BBB. LITT induces a locoregional passage of chemotherapeutic agents into the brain tissue. This is of potential interest for the treatment of brain tumors.


Cotesiacassina sp. nov. from southwestern Colombia: a new gregarious microgastrine wasp (Hymenoptera, Braconidae) reared from the pest species Opsiphanescassina Felder & Felder (Lepidoptera, Nymphalidae) feeding on Elaeis oil palm trees (Arecaceae).
A new species of microgastrine wasp, Cotesiacassina Salgado-Neto, Vásquez & Whitfield, sp. nov., is described from southwestern Colombia in Tumaco, Nariño. This species is a koinobiont gregarious larval endoparasitoid, and spins a common mass of cocoons underneath the host caterpillars of Opsiphanescassina (Felder & Felder) (Lepidoptera, Nymphalidae), feeding on oil palm trees (interspecific hybrid Elaeisoleifera × E.guineensis) (Arecaceae). While superficially similar, both morphologically and biologically, to C.invirae Salgado-Neto & Whitfield from southern Brazil, the two species are distinct based on DNA barcodes, host species, geographical range and morphological characters.


Generation of an oxidative stress precedes caspase activation during 7beta-hydroxycholesterol-induced apoptosis in U937 cells.
The oxysterol 7beta-hydroxycholesterol (7beta-OH) has been shown to induce apoptosis in a number of cell lines. Though not fully elucidated, the mechanism through which this oxysterol induces cell death is thought to involve the generation of an oxidative stress leading to perturbation of the mitochondrion and release of cytochrome c into the cytosol. Cytochrome c together with Apaf-1 causes activation of the initiator caspase, caspase-9, which in turn activates caspase-3 ultimately leading to the degradation of poly(ADP-ribose) polymerase (PARP). The objective of the present study was to investigate the signalling pathway in 7beta-OH-induced apoptosis in U937 cells, a human monocytic blood cell line known to undergo apoptosis upon treatment with 7beta-OH, over a time course of 48 h. Apoptosis was evident after 24 h incubation. Glutathione levels were decreased after 6 h and this was coupled with an increase in SOD activity. Through western blot analysis we examined expression of caspase-3, -8, and -9 and cleavage of the caspase-3 substrate PARP. The sequence proceeded with activation of caspase-9 after 9 h, caspase-3 at the 12 h timepoint, and cleavage of PARP after 24 h treatment with 7beta-OH. Caspase-8 did not appear to play a major role in this particular apoptotic pathway.


Dobutamine magnetic resonance imaging predicts contractile reserve of chronically dysfunctional myocardium: comparison with was fluorine-18 fluorodeoxyglucose positron emission tomography.
This study sought to investigate whether low-dose dobutamine-MRI can detect residual myocardial viability in patients with chronic myocardial infarction and, left ventricular dysfunction. Eleven patients with chronic myocardial infarction and left ventricular dysfunction were employed for identification of viable myocardium by cine-MRI during dobutamine infusion. All patients underwent coronary angiography and left ventriculography, 18FDG-PET, MRI at rest and stress. The systolic wall thickening measured at rest and during stress was compared with the results of 18FDG-PET, respectively. A significant difference of either dobutamine-induced systolic wall thickening (SWthstress) or dobutamine-induced contractile reserve (deltaSWth = SWthstress - SWthrest) was present between viable and scar regions (1.0 +/- 0.3 versus -0.3 +/- 0.1, P < 0.01; 1.0 +/- 0.3 versus -0.2 +/- 0.2, P < 0.01). obutamine-induced contractile reserve can be predicted in the regions of akinesia or dyskinesia at rest when systolic wall thickening was > or = 1.0 mm during dobutamine stimulation.