The three cortical membranes of the gregarines. I. Ultrastructural organization of Gregarina blaberae.
Gregarines, parasitic protozoa of invertebrates, possess a highly differentiated cell surface, with three cortical membranes and associated structures. Transmission electron microscopy and freeze-fracture reveal the presence of two cytomembranes lying uniformly under the plasma membrane. The density and the distribution of the intramembraneous particles (IMPs) in the plasma membrane of Gregarina blaberae are similar to those reported for other eukaryotic cells. The IMP density is lower in the cytomembranes than in the plasma membrane. The distribution of IMPs in the different fracture faces of the two cytomembranes suggests that they are in topological continuity, forming either side of a flattened vesicle or cisterna. The sizes of the cytomembrane IMPs show a high variability. The nature of the IMPs, both for the plasma membrane and the cytomembrane, is discussed with regard to the integral proteins and glycoproteins of the ghost. The cell surface of G. blaberae exhibits numerous longitudinal folds with three types of cortical membrane-associated structures: 12 nm filaments, an internal lamina, and homogeneous structures described as 'rippled dense structures'. The 12 nm filaments, running under the cytomembranes along the longitudinal axis of each fold, exhibit the properties of intermediate filaments. Their distribution in mature cells and during the growth process suggests a participation in cell surface morphogenesis. The internal lamina, also localized under the cytomembranes, would stabilize each fold and assure a scaffolding function between the numerous folds. The rippled dense structures, settled on the external cytomembrane, show a regular distribution at the top of each fold. The membrane-associated structures are discussed with regard to the gliding movement mechanism.


XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC.
XL-184 (BMS-907351), under development by Exelixis Inc and Bristol-Myers Squibb Co, is a pan-tyrosine kinase inhibitor for the potential oral treatment of medullary thyroid cancer, glioblastoma multiforme and NSCLC. The prinicipal targets of XL-184 are MET, VEGFR-2 and RET, but the drug is also reported to display inhibitory activity against KIT, FLT3 and TEK. Preclinical studies demonstrated that XL-184 potently inhibited multiple receptor tyrosine kinases in various cancer cell lines and animal xenograft models, and that the drug exhibited significant oral bioavailability and blood-brain barrier penetration. A phase I clinical trial in patients with advanced solid malignancies indicated that XL-184 accumulated dose-dependently in the plasma and had a long terminal half-life. A phase II trial in patients with progressive or recurrent glioblastoma revealed modest but promising median progression-free survival. Toxicity and side effects for the drug have generally been of low-to-moderate severity. At the time of publication, three additional trials of XL-184 were recruiting patients, including a phase I trial in combination with standard of care in patients with glioblastoma, a phase I/II trial in combination with erlotinib in patients with NSCLC, and a phase III trial in patients with medullary thyroid cancer.


Effects of porcine follicular fluid and oviduct-conditioned media on maturation and fertilization of porcine oocytes in vitro.
Advances in porcine in vitro fertilization have been impaired by low normal fertilization rates resulting from a high rate of polyspermy. The present study was undertaken to determine the effects of porcine follicular fluid (pFF) and oviductal explant-conditioned medium on maturation and fertilization of porcine oocytes in vitro. Oocytes and pFF were collected from small, medium, and large follicles and pooled within size category. Maturation and fertilization media were supplemented (10%) with either fetal calf serum (FCS) or pFF (either fresh or snap-frozen). Snap-frozen pFF from small (3.1-5.0 mm) and medium (5.1-7 mm) follicles, respectively, increased maturation rates of oocytes from small and medium follicles by nearly 36% (p < 0.05) compared with those treated with FCS or fresh pFF. Supplementing media with either fresh or snap-frozen pFF from medium follicles reduced (p < 0.05) polyspermy of oocytes from small follicles by 30% compared with supplemental FCS. Snap-frozen pFF increased (p < 0.05) normal fertilization compared to that in fresh pFF (29% vs. 18%). Supplementing oocytes from medium follicles with snap-frozen pFF yielded the lowest (18%, p < 0.05) polyspermy rate. Oocytes from both small and medium follicles supplemented with pFF and/or conditioned medium (CM) from oviducts of periovulatory gilts exhibited a 95% improvement in normal fertilization rate and a 34% decrease in polyspermy rate compared to those treated with FCS (p < 0.05). CM from oviducts of luteal gilts did not improve rates of polyspermy and normal fertilization (p > 0.05). We conclude that snap-frozen follicular fluid from medium follicles and CM from cultured oviducts of periovulatory gilts improve in vitro maturation, reduce polyspermy, and increase normal fertilization rates in vitro.


Will variants of uncertain significance still exist in 2030?
In 2020, the National Human Genome Research Institute (NHGRI) made ten "bold predictions," including that "the clinical relevance of all encountered genomic variants will be readily predictable, rendering the diagnostic designation 'variant of uncertain significance (VUS)' obsolete." We discuss the prospects for this prediction, arguing that many, if not most, VUS in coding regions will be resolved by 2030. We outline a confluence of recent changes making this possible, especially advances in the standards for variant classification that better leverage diverse types of evidence, improvements in computational variant effect predictor performance, scalable multiplexed assays of variant effect capable of saturating the genome, and data-sharing efforts that will maximize the information gained from each new individual sequenced and variant interpreted. We suggest that clinicians and researchers can realize a future where VUSs have largely been eliminated, in line with the NHGRI's bold prediction. The length of time taken to reach this future, and thus whether we are able to achieve the goal of largely eliminating VUSs by 2030, is largely a consequence of the choices made now and in the next few years. We believe that investing in eliminating VUSs is worthwhile, since their predominance remains one of the biggest challenges to precision genomic medicine.


Say you'll be there: Associations between observed verbal responses, friendship quality, and perceptions of support in young adult friendships.
Friendships are a primary source of social support during young adulthood; however, little is known about the factors associated with young adults feeling greater support during interactions with friends. We examined how micro-level verbal responses and macro-level judgments of friendship quality were associated with perceptions of support following an interaction between friends. Same-gender friend dyads (N = 132; 66.2% female; 18-24 years, M age = 19.63) took turns speaking about a problem, then participants rated their perceptions of support given and received following the task. We coded each participant's verbal responses while in the listening role. Actor Partner Interdependence Models (APIMs) revealed significant partner effects for negative engagement responses, such that greater negative engagement responses were linked with the partner perceiving poorer support both given and received. Models revealed significant actor effects for supportive responses, such that greater supportive responses predicted the actor perceiving better support both given and received. Additionally, models revealed significant actor effects of friendship quality predicting actors' perceiving better support both given and received. Finally, exploratory models revealed minimal interactions between a few types of verbal responses and positive friendship quality. Taken together, results suggest that (a) negative verbal responding styles may be more meaningfully associated with partners' perceptions of support in the moment than are supportive behaviours, whereas (b) supportive verbal responding styles may be more meaningfully associated with actors' perceptions of support in the moment, and (c) actors' judgments of friendship quality are strongly associated with their overall perceptions of support, and a critical factor to consider in future research.


Intertwining caring science, caring practice and caring education from a lifeworld perspective-two contextual examples.
This article describes how caring science can be a helpful foundation for caring practice and what kind of learning support that can enable the transformation of caring science into practice. The lifeworld approach is fundamental for both caring and learning. This will be illustrated in two examples from research that show the potential for promoting health and well-being as well as the learning process. One example is from a caring context and the other is from a learning context. In this article, learning and caring are understood as parallel processes. We emphasize that learning cannot be separated from life and thus caring and education is intertwined with caring science and life. The examples illustrate how an understanding of the intertwining can be fruitful in different contexts. The challenge is to implant a lifeworld-based approach on caring and learning that can lead to strategies that in a more profound way have the potential to strengthen the person's health and learning processes.


Hospice Care for Children With Cancer: Where Do These Children Die?
Hospice is an important provider of end of life care; many children who die of cancer enroll in hospice programs. How frequently such children remain in hospice to die at home, or disenroll from hospice and die in the hospital, has not been described. A child's location of death has important implications for quality of life and parental adaptation. This represents a subanalysis of a retrospective study of 202 consecutive oncology patients who died at a single center between January 1, 2006 and December 31, 2010. Of 95 children who enrolled in hospice, 82 had known location of death. Sixty (73%) died at home or an inpatient hospice unit, 15 (18%) died in the oncology unit, 5 (6%) died in the intensive care unit, and 2 (2%) died in the emergency department. The median length of hospice services was 41 days, twice the national median of 21 days reported in adults. One quarter of children disenrolled from hospice care, ultimately dying in an acute care setting. Further studies are warranted to explore the hospice experience in children, and to address modifiable factors that may impact a family's choice to withdraw from hospice care.


Carbon biogeochemistry of ground water, Guiyang, southwest China.
Variations in the concentrations and isotopic compositions (delta13C(DIC)) of dissolved inorganic carbon (DIC) reflect contamination and biogeochemical cycling of the carbon in ground water. In order to understand contamination and biogeochemical cycling of DIC, we carried out research on the geochemistry of ground water of Guiyang, the capital city of Guizhou Province, China. Results show that ground water is mainly characterized by SO4.HCO3-Ca.Mg and HCO3-Ca.Mg chemical compositions. The hydrochemical characteristics of these types of water are mainly controlled by lithology of the aquifers. HCO3- is the dominant species of DIC in ground water and has lower concentrations and more negative values of delta13C(DIC) in the high-flow (summer monsoon) season, as compared to the low-flow season. This indicates that DIC is relatively enriched in carbon of biological origin in the high-flow season as compared to the low-flow season and that biological activities are the predominant control on shifts of stable carbon isotope values. The evidence that the delta13C(DIC) values of ground water decrease with increasing concentrations of anthropogenic species shows that the carbon isotopic composition of DIC can be a useful tracer of contamination, in addition to biogeochemical cycling of inorganic carbon in ground water. Results from this study show that ground water is impacted by significant levels of contamination from human activities, especially in the urban areas, as well as the northeast and west suburbs, in Guiyang city, southwest China.


Risk factors for xerophthalmia among mothers and their children and for mother-child pairs with xerophthalmia in Cambodia.
To characterize the risk of xerophthalmia among nonpregnant women and their children and the risk factors for households in which both mother and child have xerophthalmia. In case-control analyses of more than 15 000 households in the National Micronutrient Survey of Cambodia, univariate and multivariate logistic regression were used to estimate odds ratios (ORs) for nonpregnant mothers, children, and mother-child pairs with xerophthalmia. Risk factors for xerophthalmia. Of 10 942 children aged 18 to 60 months and 9587 nonpregnant women, the adjusted prevalence of xerophthalmia was 0.7% and 1.9%, respectively. In multivariate analyses, a child was at higher risk of xerophthalmia when the mother had xerophthalmia (OR = 4.36; 95% confidence interval [CI], 2.25-8.46), and a mother was at higher risk of xerophthalmia when a child had the disease (OR = 9.21; 95% CI, 3.56-23.82). Households were at higher risk for having both mother and child with xerophthalmia if there was a history of diarrhea in the mother (OR = 6.48; 95% CI, 1.49-28.23) or in a child younger than 60 months (OR = 10.16; 95% CI, 1.55-66.62) in the last 2 weeks. Xerophthalmia clusters among mothers and children in Cambodia and is associated with diarrheal disease. Interventions are needed to address vitamin A deficiency and diarrheal disease at the household level.


Stimulation of the pathway of porphyrin synthesis in the liver of rats and mice by griseofulvin, 3,5-Diethoxycarbonyl-1,4-dihydrocollidine and related drugs: evidence for two basically different mechanisms.
Griseofulvin and isogriseofulvin cause, like 3,5-diethoxycarbonyl-1,4-dihydrocollidine, a fall in the activity of the hepatic enzyme porphyrin-metal chelatase and accumulation of protoporphyrin in the liver. Analogues of either griseofulvin or 3,5-diethoxycarbonyl-1,4-dihydrocollidine which do not decrease the chelatase activity are not porphyrogenic on their own, but can potentiate the porphyria caused by 3,5-diethoxycarbonyl-1,4-dihydrocollidine. This suggests the existence of two basically different mechanisms by which drugs stimulate the pathway of porphyrin synthesis in the liver.


Sertraline treatment of post-stroke major depression: an open study in patients with moderate to severe symptoms.
First-ever stroke patients (n=20) with a DSM-IV diagnosis of major depressive disorder (MDD) were included in an open-label study and received a single oral dose (50-100 mg) of the selective serotonin reuptake inhibitor sertraline. At days 0, 7, 14, 28, 42, and 56, a psychometric test battery comprising the Hamilton rating scales for depression and anxiety, the Mini Mental State Examination and the Barthel Index was administered. At the endpoint, 9 (45%) of the subjects were no longer depressed, 4 (20%) presented minor depression, and 7 (35%) still suffered from MDD. Considering the whole group of treated patients, depression and anxiety symptoms were found to decrease continuously and cognitive and functional performances to improve continuously during the treatment. Furthermore, differences between the values recorded by the treatment responders and non responders at the end of follow up were highly significant (p<0.02 for all comparisons). This report suggests that sertraline treatment of post-stroke MDD could be effective and well tolerated. However, non responders to the treatment are at risk of poor outcome. Double blind studies with a greater number of patients are necessary to confirm these preliminary results.


Changes in extracellular dopamine during cocaine self-administration in squirrel monkeys.
Environmental cues are thought to play a role in drug craving, leading to the high relapse rate observed in cocaine abusers. Cocaine-paired cues can reinstate cocaine-maintained behavior in rodents and nonhuman primates and can induce changes in dopamine levels in the rodent striatum. In the present study, squirrel monkeys were trained to self-administer cocaine under a second-order schedule, and then were implanted with guide cannulae targeted at the caudate nucleus. Caudate dopamine levels were measured while the animals performed the behavioral task, self-administering cocaine or saline under extinction conditions. In addition, animals received noncontingent (passive) cocaine infusions yoked to the drug self-administration sessions. Cocaine administration increased dopamine levels 2-fold, but a leftward shift was seen in the peak effect in animals self-administering cocaine as compared to animals passively receiving cocaine. Moreover, dopamine levels began to decline during the experimental session when animals were self-administering cocaine, even though they continued to receive cocaine injections. In contrast, dopamine levels declined below baseline during the session when animals were given access to saline. The results suggest that the environmental context associated with drug self-administration can modulate cocaine-induced elevations in extracellular dopamine.


XMRF: an R package to fit Markov Networks to high-throughput genetics data.
Technological advances in medicine have led to a rapid proliferation of high-throughput "omics" data. Tools to mine this data and discover disrupted disease networks are needed as they hold the key to understanding complicated interactions between genes, mutations and aberrations, and epi-genetic markers. We developed an R software package, XMRF, that can be used to fit Markov Networks to various types of high-throughput genomics data. Encoding the models and estimation techniques of the recently proposed exponential family Markov Random Fields (Yang et al., 2012), our software can be used to learn genetic networks from RNA-sequencing data (counts via Poisson graphical models), mutation and copy number variation data (categorical via Ising models), and methylation data (continuous via Gaussian graphical models). XMRF is the only tool that allows network structure learning using the native distribution of the data instead of the standard Gaussian. Moreover, the parallelization feature of the implemented algorithms computes the large-scale biological networks efficiently. XMRF is available from CRAN and Github ( https://github.com/zhandong/XMRF ).


Comparison of the accuracy of multidetector computed tomography versus two-dimensional echocardiography to measure left atrial volume.
Left atrial (LA) volume is an important prognostic factor in cardiovascular disease. Multidetector computed tomography (MDCT) is an emerging cardiac imaging modality; however, its accuracy in measuring the LA volume has not been well studied. The aim of our study was to determine the accuracy of MDCT in quantifying the LA volume. A total of 48 patients underwent MDCT and 2-dimensional (2D) echocardiography (2DE) on the same day. The area-length and Simpson's methods were used to obtain the 2D echocardiographic LA volume. The LA volume assessment by MDCT was obtained using the modified Simpson's method. Four artificial phantoms were created, and their true volume was assessed by an independent observer using both imaging modalities. The correlation between the LA volume by MDCT and 2DE was significant (r = 0.68). The mean 2D echocardiographic LA volume was lower than the LA volume obtained with MDCT (2DE 79 +/- 37 vs MDCT 103 +/- 32, p <0.05). In the phantom experiment, the volume obtained using MDCT and 2DE correlated significantly with the true volume (r = 0.97, p <0.05 vs r = 0.96, p <0.05, respectively). However, the mean 2D echocardiographic phantom volume was 16% lower than the true volume (2DE, Simpson's method 53 +/- 24 vs the true volume 61 +/- 24, p <0.05). The mean volume calculated using MDCT did not differ from the true volume (MDCT 60 +/- 21 vs true volume 61 +/- 24, p = NS). 2DE appeared to systematically underestimate the LA volume compared to phantom and cardiac MDCT, suggesting that different normal cutoff values should be used for each modality. In conclusion, LA volume quantification using MDCT is an accurate and feasible method.


Antigenic and genetic stability of bovine immunodeficiency virus during long-term persistence in cattle experimentally infected with the BIV(R29) isolate.
Experimental infection of cattle with bovine immunodeficiency virus (BIV) is characterized by persistent, low levels of virus replication in the absence of clinical disease. A virus neutralization (VN) assay was developed to examine the role of VN antibodies in controlling virus replication in cattle experimentally infected with the BIV(R29) isolate of BIV. All animals developed VN antibody, but there was no correlation between VN titres and restriction of virus replication in vivo. BIV infection did not induce high-titred, cross-neutralizing antibody and there was no evidence for antigenic variation through more than 4 years in vivo. Genetic comparisons among the BIV(R29) inoculum virus and viruses isolated from infected animals identified only limited genetic variation during 4 years in vivo. Moreover, there was no evidence that the observed variation was due to selection. Analyses of genetic diversity in the virus stock used for inoculation indicated a fairly homogeneous population. In the absence of high levels of virus replication and overt clinical disease, there appeared to be little selection of virus variants, resulting in antigenic and genetic stability of BIV(R29) during long-term, persistent infection.


Effect of dehydroepiandrosterone on hypoxic pulmonary vasoconstriction: a Ca(2+)-activated K(+)-channel opener.
In the present study, we investigated the effects of the naturally occurring hormone dehydroepiandrosterone (DHEA) on hypoxic pulmonary vasoconstriction (HPVC) in isolated ferret lungs and on K+ currents in isolated and cultured ferret pulmonary arterial smooth muscle cells (FPSMCs). Severe alveolar hypoxia (3% O2-5% CO2-92% N2) caused an initial increase in pulmonary arterial pressure (Ppa) that was followed by a reversal in pulmonary hypertension. Maintaining alveolar hypoxia caused a sustained secondary increase in Ppa. Pretreating the lungs with the K(+)-channel inhibitor tetraethylammonium (TEA) caused a small increase in baseline Ppa, potentiated HPVC, and prevented the reversal of HPVC during the sustained alveolar hypoxia. Treating the lungs with DHEA caused a near-complete reversal of HPVC in control lungs and in lungs that were pretreated with TEA. DHEA also reversed the KCl-induced increase in Ppa. In FPSMCs, DHEA caused an adenosine 3',5'-cyclic monophosphate- and guanosine 3',5'-cyclic monophosphate-independent increase in activity of the Ca(2+)-activated K+ (KCa) current. In a cell-attached configuration, DHEA caused a mean shift of -22 mV in the voltage-dependent activation of the KCa channel. We conclude that DHEA is a novel KCa-channel opener of the pulmonary vasculature.


[Sinusoidal cells of the liver and their role in pathologic processes].
The review summarizes the data on morphofunctional properties and histogenesis of 4 types of sinusoidal cells of the liver: stellate reticuloendotheliocyte (SR), endotheliocyte, lipocyte and Pit-cells. It is suggested that they be considered as a single structural-functional system forming the hematotissue barrier, the connective tissue skeleton of the lobule and taking part in neurohumoral regulations of the local processes. Most attention is given to SR which are the main element of the hepatic reticuloendothelial system. The participation of SR in the pathogenesis of hepatitis, cirrhosis of the liver, and some extrahepatic diseases has been shown to be connected not only with the disturbance of their phagocytic function but also with the deficiency in formation and correction of local immune reactions as well as the entire immune system. It is assumed that uncompensated insufficiency of the hepatic reticuloendothelial system may facilitate chronization of the pathological process in the liver as well as the development of some of its complications.


Preparation and photoluminescence properties of europium ions doped TiO2 nanocrystals.
In this paper, pure and Eu3+ doped TiO2 nanocrystals (NCs) have been fabricated successfully by a two steps of sol-gel and hydrothermal methods. The microstructures, morphologies and photoluminescent properties of Eu(3+)-TiO2 were investigated by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and photoluminescence spectroscopy (PL). XRD and PL results show that the existent of rare earth can inhibit the transformation of TiO2 NCs from anatase to rutile phase and can improve the luminescence intensity of the prepared samples. The room-temperature PL emission of the as-grown samples is dominated by the 5D(0)-7F(j) transitions of Eu3+ ions. But the luminescence intensity drops dramatically when the annealing temperature reaches a relatively high degree because of the formation of the rutile phase of TiO2 NCs hosts.


The sacroiliac joint: review of anatomy, mechanics, and function.
The purpose of this paper is to review the anatomy and function of the pelvis in order to enhance the clinical understanding of this closed chain kinematic complex. The relevant bony and soft tissue anatomy is discussed with an emphasis on the complex and unique features of the related parts of the pelvis. Osteokinematics of the pelvis and the sacroiliac joints are discussed relevant to functional movements of the spine and lower extremities. Intrapelvic joint surface motion is presented in light of past and more recent experimental work. Questions regarding the validity of clinical sacroiliac models and future research are posed. J Orthop Sports Phys Ther 1991;13(2):71-84.


Essential role of RVL medullary neuronal activity in the long term maintenance of hypertension in conscious SHR.
It is well established that sympathetic nervous system is responsible for the onset, development and maintenance of neurogenic hypertension. The rostroventrolateral medulla (RVLM) and medullo-cervical pressor area (MCPA) are important central sympathoexcitatory regions whose role on neurogenic hypertension remains unknown. To establish RVLM and MCPA roles in the long-term regulation of blood pressure by depressing their neuron activity through the over-expression of hKir2.1-potassium channel in conscious spontaneously hypertensive rats (SHR). In SHR, a lentiviral vector LVV-hKir2.1 was microinjected into RVLM or MCPA areas. A sham group was injected with LVV-eGFP. Blood pressure (BP) and heart rate (HR) were continuously monitored for 75 days. Baroreflex and chemoreflex functions were evaluated. Baroreflex gain, chemoreflex sensitivity, BP and HR variability were calculated. LVV-hKir2.1 expression in RVLM, but not in MCPA, produced a significant time-dependent decrease in systolic, diastolic, mean-BP and LF of systolic BP at 60-days post-injection. No significant changes were seen in LVV-eGFP RVLM injected SHR. Data show that chronic expression of Kir2.1 in the RVLM of conscious SHR caused a marked and sustained decrease in BP without changes in the baro- and peripheral chemoreceptor reflex evoked responses. This decrease was mostly due to a reduction in sympathetic output revealed indirectly by a decrease in the power density of the SBP-LF band. Our data are amongst the firsts to demonstrate the role of the RVLM in maintaining BP levels in hypertension in conscious SHR. We suggest that a decrease in RVLM neuronal activity is an effective anti-hypertensive treatment strategy.


Serum soluble CD23 level correlates with subsequent development of AIDS-related non-Hodgkin's lymphoma.
The cytokine soluble CD23 (sCD23) has been shown to act as a B cell growth factor and to be elevated in serum prior to development of AIDS-related non-Hodgkin's lymphoma (AIDS NHL). To further characterize the elevation of serum sCD23 in AIDS NHL patients and investigate its potential as a diagnostic test, a matched case-control study of AIDS NHL (n = 101) was nested within the Multicenter AIDS Cohort Study. Serum sCD23 was measured in cases' and controls' serum specimens at three different time periods (0-6, 6-12, and 12-18 months) and CD4+ thresholds (0-99, 100-199, and 200-299 cells/microl) prior to the case's NHL diagnosis. Changes in serum sCD23 over time were examined in AIDS NHL cases relative to controls, and t tests were performed to determine whether cases' serum sCD23 exceeded that of controls at each time period and CD4+ threshold. Overall, cases' median serum sCD23 levels were approximately double those of controls. Serum sCD23 concentration was positively correlated with lymphocyte counts for both cases and controls. The difference in cases' and controls' serum sCD23 levels became greater as AIDS NHL diagnosis date approached: in the 18 months preceding the case's NHL diagnosis, serum sCD23 was stable in cases but dropped in controls. Although this difference was statistically significant (P < 0.05), it was not clinically significant. It is unlikely that serum sCD23 would make a useful test for AIDS NHL because the magnitude of the difference between cases and controls was small and there was no change in serum sCD23 in cases that would indicate disease.


Fusion of phospholipid vesicles with planar phospholipid bilayer membranes. I. Discharge of vesicular contents across the planar membrane.
Multilamellar phospholipid vesicles are introduced into the cis compartment on one side of a planar phospholipid bilayer membrane. The vesicles contain a water-soluble fluorescent dye trapped in the aqueous phases between the lamellae. If a vesicle containing n lamellae fuses with a planar membrane, an n-1 lamellar vesicle should be discharged into the opposite trans compartment, where it would appear as a discernible fluorescent particle. Thus, fusion events can be assayed by counting the number of fluorescent particles appearing in the trans compartment. In the absence of divalent cation, fusion does not occur, even after vesicles have been in the cis compartment for 40 min. When CaCl2 is introduced into the cis compartment to a concentration of greater than or equal to 20 mM, fusion occurs within the next 20 min; it generally ceases thereafter because of vesicle aggregation in the cis compartment. With approximately 3 x 10(8) vesicles/cm3 in the cis compartment, about 25-50 fusion events occur following CaCl2 addition. The discharge of vesicular contents across the planar membrane is the most convincing evidence of vesicle-membrane fusion and serves as a model for that ubiquitous biological phenomenon--exocytosis.


Ten years of a neonatal screening program for hemoglobinopathies in Friuli-Venezia Giulia: first regional experience in Italy.
Hemoglobinopathies are the commonest genetic defect worldwide (7% of the world's population has at least one hemoglobin mutation). Although prenatal screening for hemoglobinopathies is not obligatory during pregnancy in Italy, it is offered to women by the Italian National Health Service in the pre-conception phase. The screening of newborns is a valid alternative, and has been adopted in various European countries, albeit in a piecemeal fashion. Neonatal screening has the advantage of providing early diagnosis of a hemoglobinopathy. Here we report the findings from the experience with neonatal screening in Friuli-Venezia Giulia since 2010. The hemoglobinopathy screening project in Friuli-Venezia Giulia, a Region in north Italy, began in November 2010. High-performance liquid chromatography was performed on dried blood spot samples collected by obstetric nurses from neonates within 5-8 days after birth. From 2010 to 2019, 11,956 newborns were screened, and abnormal hemoglobin was found in 519 of them (4.34%): the variants identified included HbS, HbC, HbD, HbE and HbX. More specifically, the HbS variant was observed in 347 (2.9%) newborns and the homozygous pattern was identified in 24 (0.2%) cases. The screening also detected two cases of β-thalassemia major. We report our experience of 10 years of screening newborns for hemoglobinopathies in the Region of Friuli-Venezia Giulia, in which 7.7% of people come from malaria-endemic areas. Increased mobility and migratory flows bringing in hemoglobinopathy carriers from endemic areas have led to an increase in mutations in non-malarial countries, with a current incidence of around 4% in the newborns we tested. This means that hemoglobinopathies can be described as a rare condition. Our data show that incidence rates are comparable to those of other inherited disorders such as phenylketonuria, thereby justifying the inclusion of the test for hemoglobinopathies into screening programs for rare diseases.


A National Strategy for Preventing Substance and Opioid Use Disorders Through Evidence-Based Prevention Programming that Fosters Healthy Outcomes in Our Youth.
The recently released National Drug Control Strategy (2022) from the White House Office of National Drug Control Policy (ONDCP) lays out a comprehensive plan to, not only enhance access to treatment and increase harm reduction strategies, but also increase implementation of evidence-based prevention programming at the community level. Furthermore, the Strategy provides a framework for enhancing our national data systems to inform policy and to evaluate all components of the plan. However, not only are there several missing components to the Strategy that would assure its success, but there is a lack of structure to support a national comprehensive service delivery system that is informed by epidemiological data, and trains and credentials those delivering evidence-based prevention, treatment, and harm reduction/public health interventions within community settings. This paper provides recommendations for the establishment of such a structure with an emphasis on prevention. Systematically addressing conditions known to increase liability for behavioral problems among vulnerable populations and building supportive environments are strategies consistently found to avert trajectories away from substance use in general and substance use disorders (SUD) in particular. Investments in this approach are expected to result in significantly lower rates of SUD in current and subsequent generations of youth and, therefore, will reduce the burden on our communities in terms of lowered social and health systems involvement, treatment needs, and productivity. A national strategy, based on strong scientific evidence, is presented to implement public health policies and prevention services. These strategies work by improving child development, supporting families, enhancing school experiences, and cultivating positive environmental conditions.


Ternary Model of the Speciation of I-/Br-/Cl-Trihalomethanes Formed in Chloraminated Surface Waters.
This study examined the effects of the iodide concentration and pH on yields and speciation of the entire group of 10 species of iodine-, bromine-, and chlorine-containing trihalomethanes (THMs) formed at pH values from 6.5 to 8.5 in chloraminated surface waters in the presence of bromide and iodide. Pathways of iodine, bromine, and chlorine incorporation in the active sites in dissolved organic matter (DOM) were examined on the basis of a ternary halogenation/THM speciation model. The model assumed the occurrence of sequential three-step halogenation of the active site and competition of iodine, bromine, and chlorine species at each node of the halogenation sequence. A comparison of experimentally measured and modeled speciation coefficients and also iodine and bromine incorporation factors calculated for 10 THM species showed that the developed approach was sufficient to closely model the observed trends. Interpretation of preferred iodine incorporation pathways associated with the generation of THMs in all examined conditions showed that the susceptibility of the halogenated intermediates to iodine incorporation increases rapidly with the number of iodine atoms that have already been incorporated into the reaction site. In contrast, the incorporation of bromine and chlorine atoms in the intermediates involved in the generation of THMs makes them largely inactive in iodine incorporation reactions. The presented approach allows for a further understanding of the mechanisms of DOM/halogen interactions and prediction of the speciation of THMs formed at varying pH values, iodide concentrations, and other system conditions.


The scope of Baker's law.
Baker's law refers to the tendency for species that establish on islands by long-distance dispersal to show an increased capacity for self-fertilization because of the advantage of self-compatibility when colonizing new habitat. Despite its intuitive appeal and broad empirical support, it has received substantial criticism over the years since it was proclaimed in the 1950s, not least because it seemed to be contradicted by the high frequency of dioecy on islands. Recent theoretical work has again questioned the generality and scope of Baker's law. Here, we attempt to discern where the idea is useful to apply and where it is not. We conclude that several of the perceived problems with Baker's law fall away when a narrower perspective is adopted on how it should be circumscribed. We emphasize that Baker's law should be read in terms of an enrichment of a capacity for uniparental reproduction in colonizing situations, rather than of high selfing rates. We suggest that Baker's law might be tested in four different contexts, which set the breadth of its scope: the colonization of oceanic islands, metapopulation dynamics with recurrent colonization, range expansions with recurrent colonization, and colonization through species invasions.


Hepatitis C co-infection is associated with an increased risk of incident chronic kidney disease in HIV-infected patients initiating combination antiretroviral therapy.
Combination antiretroviral therapy (cART) has reduced mortality from AIDS-related illnesses and chronic comorbidities have become prevalent among HIV-infected patients. We examined the association between hepatitis C virus (HCV) co-infection and chronic kidney disease (CKD) among patients initiating modern antiretroviral therapy. Data were obtained from the Canadian HIV Observational Cohort for individuals initiating cART from 2000 to 2012. Incident CKD was defined as two consecutive serum creatinine-based estimated glomerular filtration (eGFR) measurements <60 mL/min/1.73m2 obtained ≥3 months apart. CKD incidence rates after cART initiation were compared between HCV co-infected and HIV mono-infected patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression. We included 2595 HIV-infected patients with eGFR >60 mL/min/1.73m2 at cART initiation, of which 19% were HCV co-infected. One hundred and fifty patients developed CKD during 10,903 person-years of follow-up (PYFU). The CKD incidence rate was higher among co-infected than HIV mono-infected patients (26.0 per 1000 PYFU vs. 10.7 per 1000 PYFU). After adjusting for demographics, virologic parameters and traditional CKD risk factors, HCV co-infection was associated with a significantly shorter time to incident CKD (HR 1.97; 95% CI: 1.33, 2.90). Additional factors associated with incident CKD were female sex, increasing age after 40 years, lower baseline eGFR below 100 mL/min/1.73m2, increasing HIV viral load and cumulative exposure to tenofovir and lopinavir. HCV co-infection was associated with an increased risk of incident CKD among HIV-infected patients initiating cART. HCV-HIV co-infected patients should be monitored for kidney disease and may benefit from available HCV treatments.


Management of enterocutaneous fistulae in Crohn's disease.
The outcome among 39 patients with enterocutaneous fistulae complicating Crohn's disease has been reviewed. The patients were considered in two groups: (1) no disease - all were early postoperative fistulae (n = 9); (2) active disease (i) without abscess formation (n = 16), (ii) with abscess formation (n = 14). Postoperative fistulae with no evidence of active Crohn's disease healed spontaneously. Fistulae in the presence of active disease did not heal even with prolonged medical management. The only effective treatment was excision of the diseased segment from which the fistulae arose and any distal obstruction. None of the fistulae closed surgically has recurred.


Differential and sequential delivery of fluorescent lysosomal probes into phagosomes in mouse peritoneal macrophages.
It has previously been inferred that the fusion of a macrophage secondary lysosome with a phagosome delivers the entire lysosomal contents uniformly to the phagosome. We found, however, that different fluorescent lysosomal probes can enter phagosomes at remarkably different rates, even though they are initially sequestered together in the same organelles. Thus, sulforhodamine is almost exclusively delivered to yeast-containing phagosomes within 2 h of phagocytosis. But fluoresceinated, high molecular weight dextran accumulates in the same phagosomes only over a period of approximately 24 h. We postulate that the delivery of lysosomal contents may involve an intermittent and incremental process in which individual components can be selectively and sequentially transferred.


Radiopaque Resorbable Inferior Vena Cava Filter Infused with Gold Nanoparticles.
Failure to remove a retrievable inferior vena cava (IVC) filter can cause severe complications with high treatment costs. Polydioxanone (PPDO) has been shown to be a good candidate material for resorbable IVC filters. However, PPDO is radioluscent under conventional imaging modalities. Thus, the positioning and integrity of these PPDO filters cannot be monitored by computed tomography (CT) or x-ray. Here we report the development of radiopaque PPDO IVC filters based on gold nanoparticles (AuNPs). Commercially available PPDO sutures were infused with AuNPs. Scanning electron microscopy analysis confirmed the presence of AuNP on the surface of PPDO. Micro-CT and x-ray images of the AuNP-infused PPDO sutures showed significant signal enhancement compared to untreated PPDO sutures. Elemental analysis showed that gold loading exceeded 2000 ppm. Tensile strength and in vitro cytotoxicity showed no significant difference between AuNP-infused and untreated PPDO. In a 10-week stability study, neither the gold content nor the radiopacity of the infused PPDO sutures significantly changed in the first 6 weeks. The increased attenuation of AuNP-infused PPDO sutures indicates their major advantage as a radiopaque resorbable filter material, as the radiopacity allows monitoring of the position and integrity of the filter, thereby increasing its safety and efficacy.


Diagnostic Value of Carcinoembryonic Antigen in Ascites for Colorectal Cancer with Peritoneal Carcinomatosis.
Diagnostic tests for carcinoembryonic antigen (CEA) in ascites have been performed in various malignant cases, but there is only few data on the applicability of CEA for colorectal cancer (CRC) patients with peritoneal carcinomatosis. We aimed to determine the usefulness of CEA in ascites (aCEA) as a diagnostic parameter for CRC with peritoneal carcinomatosis. Between January 2000 and May 2013, the medical records of 259 patients who underwent paracentesis for the evaluation of ascites were retrospectively reviewed. CRC patients with ascites (n=82) and patients with non-malignant ascites (n=177) were evaluated. Patients who had other malignancies, including gastric or ovarian cancer, with ascites were excluded. The optimal diagnostic cut-off value of aCEA for CRC with peritoneal carcinomatosis was determined using receiver operating characteristic curve analysis. The value of aCEA for predicting the occurrence of peritoneal carcinomatosis was evaluated using a logistic regression model. The optimal cut-off value of aCEA to diagnose CRC with peritoneal carcinomatosis was 3.89 ng/mL, and the area under the curve for aCEA was 0.996 (sensitivity 96.3%, specificity 100%, positive predictive value 100%, negative predictive value 98.3%). Multivariate logistic regression analysis showed that aCEA was an independent factor predicting the occurrence of peritoneal carcinomatosis. In this study, we showed that aCEA may be a useful parameter for diagnosing CRC with peritoneal carcinomatosis, and we propose an optimal aCEA cut-off value of 3.89 ng/mL. Further study that includes patients with other malignant ascites may be necessary to validate these findings.


An integrative review of adolescent trust in the healthcare provider relationship.
To conduct an integrative review of empirical studies examining factors affecting trust in the healthcare provider (HCP) relationship among adolescents. An integrative review was conducted. The keywords adolescent, trust, healthcare provider and related words were searched in multiple online research databases. The results were limited to research published between 2004 and 2019. Seventeen primary sources were identified and synthesized in the final review. Guided by the Whittemore and Knafl integrative review method, a data-based convergent synthesis design was used to explore the key research question in both qualitative and quantitative research. This integrative review found that health care provider behaviours, such as confidentiality, honesty, respect, and empathy, promote adolescent's trust of the HCP. Notable gaps in the literature were also identified, including a lack of diversity among adolescent samples and HCP types and underdeveloped measures of adolescent trust of HCP. This integrative review informed the development of a new conceptual definition of adolescent trust of HCP, which embodies the key findings of the importance of HCP confidentiality, honesty, respect, and empathy. This definition can be used to develop instruments, interventions and policies that promote HCP trust among adolescents. Future research is needed to develop instruments to measure adolescents' trust of HCPs, evaluate trust of HCPs among diverse samples of adolescents and evaluate adolescent trust of HCPs with a variety of HCP types. The new conceptual definition of adolescent trust of HCP can be used to enhance nursing practice and design behavioural interventions to improve trust of HCP. To foster adolescent trust of HCP, policies should be enacted in healthcare institutions to explain confidentiality, provide notification of reporting mandates and formalize consent, assent and dissent for adolescents seeking health care.


Fatty Acid Methyl Ester Composition of Some Turkish Apiaceae Seed Oils: New Sources for Petroselinic Acid.
The seed oils of twenty-six species of Apiaceae belonging to the genera Bunium, Cnidium, Ferula, Ferulago, Heracleum, Hippomarathrum, Malabaila, Myrrhoides, Olymposciadium, Pimpinella, Prangos, Szovitsia, Trigonasciadium, Trinia and Zosima, collected in Turkey, were investigated for their oil content, and amount of petroselinic acid (PA), as well as for the composition of their fatty acid methyl esters (FAMEs) by GC-MS. Seed oil content ranged from 7.1% in Szovitsia callicarpa to 29.3% in Ferda haussknechtii. The results showed that the seed oils of the studied species contained high amounts of PA (1.2-72.2%), followed by significant amounts of linoleic (LA, 13.8-50.8%) and oleic (OA, 4.2-61.6%) acids. PA was found in all the analyzed species, except for Olymposciadium caespitosum, which belongs to a monotypic endemic genus of the family. According to data from our study, PA was found to be predominantly in the seed oils of Hippomarathrum cristatum (72.2%), Trinia glauca (64.9%) and Bunium microcarpum (59.7%) and, therefore these species might be considered as new sources of PA, and represent a potential oleochemical raw material. This is the first extensive study of the composition ofTurkish Apiaceae species. The high amounts of PA may also have chemotaxonomic significance.


Correlated evolution of distinct signals associated with increased social selection in female white-shouldered fairywrens.
Conspicuous female signals have recently received substantial scientific attention, but it remains unclear if their evolution is the result of selection acting on females independently of males or if mutual selection facilitates female change. Species that express female, but not male, phenotypic variation among populations represents a useful opportunity to address this knowledge gap. White-shouldered fairywrens (Malurus alboscapulatus) are tropical songbirds with a well-resolved phylogeny where female, but not male, coloration varies allopatrically across subspecies. We explored how four distinct signaling modalities, each putatively associated with increased social selection, are expressed in two populations that vary in competitive pressure on females. Females in a derived subspecies (M. a. moretoni) have evolved more ornamented plumage and have shorter tails (a signal of social dominance) relative to an ancestral subspecies (M. a. lorentzi) with drab females. In response to simulated territorial intrusions broadcasting female song, both sexes of M. a. moretoni are more aggressive and more coordinated with their mates in both movement and vocalizations. Finally, M. a. moretoni songs are more complex than M. a. lorentzi, but song complexity does not vary between sexes in either population. These results suggest that correlated phenotypic shifts in coloration and tail morphology in females as well as song complexity and aggression in both sexes may have occurred in response to changes in the intensity of social selection pressures. This highlights increased competitive pressures in both sexes can facilitate the evolution of complex multimodal signals.


Construction and optimization of a family of genetically encoded metabolite sensors by semirational protein engineering.
A family of genetically-encoded metabolite sensors has been constructed using bacterial periplasmic binding proteins (PBPs) linearly fused to protein fluorophores. The ligand-induced conformational change in a PBP allosterically regulates the relative distance and orientation of a fluorescence resonance energy transfer (FRET)-compatible protein pair. Ligand binding is transduced into a macroscopic FRET observable, providing a reagent for in vitro and in vivo ligand-measurement and visualization. Sensors with a higher FRET signal change are required to expand the dynamic range and allow visualization of subtle analyte changes under high noise conditions. Various observations suggest that factors other than inter-fluorophore separation contribute to FRET transfer efficiency and the resulting ligand-dependent spectral changes. Empirical and rational protein engineering leads to enhanced allosteric linkage between ligand binding and chromophore rearrangement; modifications predicted to decrease chromophore rotational averaging enhance the signal change, emphasizing the importance of the rotational freedom parameter kappa2 to FRET efficiency. Tighter allosteric linkage of the PBP and the fluorophores by linker truncation or by insertion of chromophores into the binding protein at rationally designed sites gave rise to sensors with improved signal change. High-response sensors were obtained with fluorescent proteins attached to the same binding PBP lobe, suggesting that indirect allosteric regulation during the hinge-bending motion is sufficient to give rise to a FRET response. The optimization of sensors for glucose and glutamate, ligands of great clinical interest, provides a general framework for the manipulation of ligand-dependent allosteric signal transduction mechanisms.


Is there a dose-response relation of dietary glycemic load to risk of type 2 diabetes? Meta-analysis of prospective cohort studies.
Although much is known about the association between dietary glycemic load (GL) and type 2 diabetes (T2D), prospective cohort studies have not consistently shown a positive dose-response relation. We performed a comprehensive examination of evidence on the dose response that links GL to T2D and sources of heterogeneity among all prospective cohort studies on healthy adults available in the literature. We conducted a systematic review of all prospective cohort studies and meta-analyses to quantify the GL-T2D relation both without and with adjustment for covariates. Among 24 prospective cohort studies identified by August 2012, the GL ranged from ∼60 to ∼280 g per daily intake of 2000 kcal (8.4 MJ). In a fully adjusted meta-analysis model, the GL was positively associated with RR of T2D of 1.45 (95% CI: 1.31, 1.61) for a 100-g increment in GL (P < 0.001; n = 24 studies; 7.5 million person-years of follow-up). Sex (P = 0.03), dietary instrument validity (P < 0.001), and ethnicity (European American compared with other; P = 0.04) together explained 97% of the heterogeneity among studies. After adjustment for heterogeneities, we used both funnel and trim-and-fill analyses to identify a negligible publication bias. Multiple influence, cumulative, and forecast analyses indicated that the GL-T2D relation tended to have reached stability and to have been underestimated. The relation was apparent at all doses of GL investigated, although it was statistically significant only at >95 g GL/2000 kcal. After we accounted for several sources of heterogeneity, findings from prospective cohort studies that related the GL to T2D appear robust and consistently indicate strong and significantly lower T2D risk in persons who consume lower-GL diets. This review was registered at http://www.crd.york.ac.uk/PROSPERO as CRD42011001810.


Clinical management of the congenitally missing maxillary lateral incisor and mandibular second premolar: a clinical perspective.
The decision to close maintain, or open space at the agenesis sites of the maxillary lateral incisor and mandibular second premolar is generally based on several factors, including the class of malocclusion, skeletal pattern (divergence), esthetics, function, and periodontics. Replacement of congenitally missing maxillary lateral incisors, the second most commonly missing teeth, can involve (1) canine replacement, (2) tooth-supported restoration, and (3) implants. This paper contrary to the opinion of other authors, favors replacement of the congenitally missing lateral incisors in one of several ways, versus orthodontic space closure.


Investigating the Function of Content and Argumentation Items in a Science Test: A Multidimensional Approach.
The latest national science framework has formally stated the need for developing assessments that test both students' content knowledge and scientific practices. In response to this call, a science assessment that consists of (a) content items that measure students' understanding of a grade eight physics topic and (b) argumentation items that measure students' argumentation competency has been developed. This paper investigated the function of these content and argumentation items with a multidimensional measurement framework from two perspectives. First, we performed a dimensionality analysis to investigate whether the relationship between the content and argumentation items conformed to test deign. Second, we conducted a differential item functioning analysis in the multidimensional framework to examine if any content or argumentation item unfairly favored students with an advanced level of English literacy. Methods and findings of this study could inform future research on the validation of assessments measuring higher-order and complex abilities.


Clinical outcome measures in juvenile idiopathic arthritis.
Juvenile idiopathic arthritis (JIA), as a chronic condition, is associated with significant disease- and treatment-related morbidity, thus impacting children's quality of life. In order to optimize JIA management, the paediatric rheumatologist has begun to regularly use measurements of disease activity developed, validated and endorsed by international paediatric rheumatology professional societies in an effort to monitor the disease course over time and assess the efficacy of therapeutic interventions in JIA patients.A literature review was performed to describe the main outcome measures currently used in JIA patients to determine disease activity status.The Juvenile Disease Activity Score (JADAS), in its different versions (classic JADAS, JADAS-CRP and cJADAS) and the validated definitions of disease activity and response to treatment represent an important tool for the assessment of clinically relevant changes in disease activity, leading more and more to a treat-to-target strategy, based on a tight and thorough control of the patient condition. Moreover, in recent years, increasing attention on the incorporation of patient-reported or parent-reported outcomes (PRCOs), when measuring the health state of patients with paediatric rheumatic diseases has emerged.We think that the care of JIA patients cannot be possible without taking into account clinical outcome measures and, in this regard, further work is required.


Radiopacity evaluation of new root canal filling materials by digitalization of images.
The aim of this study was to evaluate the radiopacity of five root canal filling materials (AH Plus, Intrafill, Roeko Seal, Epiphany, and EndoRez). Following the International Organization of Standardization 6876/2001, five circular specimens (10 x 1 mm) were made from each material. After the material set, radiographs were made using occlusal film and a graduated aluminum step-wedge varying in thickness from 2 to 16 mm. The dental X-ray unit (GE1000) was set at 50 Kvp, 10 mA, 18 pulses/second, and distance of 33.5 cm. The radiographs were digitized, and the radiopacity was compared with the aluminum step-wedge, using WIXWIN-2000 software (Gendex). Data (mm Al) were analyzed using ANOVA and Tukey tests. AH Plus and Epiphany were the most radiopaque materials (9.8 and 8.8 mm Al, respectively), followed by EndoRez (7.2 mm Al). Roeko Seal and Intrafill presented the lowest radiopacity values (5.7 and 6.1 mm Al, respectively). Although the materials evaluated demonstrated different radiopacities, all had values above the minimum recommended by the International Organization of Standardization.


Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients.
The 5'-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients. Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg(-1) min(-1)) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64 +/- 2 years; BMI 28 +/- 1 kg/m(2)). Plasma glucose rate of appearance (R (a)) was reduced following AICAR administration, while plasma glucose rate of disappearance (R (d)) was similar in the AICAR and control test. Consequently, blood glucose disposal (R (d) expressed as a percentage of R (a)) was increased following AICAR infusion (p < 0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p < 0.001). Plasma NEFA R (a) and R (d) were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p < 0.001). The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.


Impact of a postdischarge smoking cessation intervention for smokers admitted to an inpatient psychiatric facility: a randomized controlled trial.
Persons with a mental disorder smoke at higher rates and suffer disproportionate tobacco-related burden compared with the general population. The aim of this study was to determine if a smoking cessation intervention initiated during a psychiatric hospitalization and continued postdischarge was effective in reducing smoking behaviors among persons with a mental disorder. A randomized controlled trial was conducted at an Australian inpatient psychiatric facility. Participants were 205 patient smokers allocated to a treatment as usual control (n = 101) or a smoking cessation intervention (n = 104) incorporating psychosocial and pharmacological support for 4 months postdischarge. Follow-up assessments were conducted at 1 week, 2, 4, and 6 months postdischarge and included abstinence from cigarettes, quit attempts, daily cigarette consumption, and nicotine dependence. Rates of continuous and 7-day point prevalence abstinence did not differ between treatment conditions at the 6-month follow-up; however, point prevalence abstinence was significantly higher for intervention (11.5%) compared with control (2%) participants at 4 months (OR = 6.46, p = .01). Participants in the intervention condition reported significantly more quit attempts (F[1, 202.5] = 15.23, p = .0001), lower daily cigarette consumption (F[4, 586] = 6.5, p < .001), and lower levels of nicotine dependence (F[3, 406] = 8.5, p < .0001) compared with controls at all follow-up assessments. Postdischarge cessation support was effective in encouraging quit attempts and reducing cigarette consumption up to 6 months postdischarge. Additional support strategies are required to facilitate longer-term cessation benefits for smokers with a mental disorder.


COVID-19 and Moral Distress: A Pediatric Critical Care Survey.
Moral distress adversely affects the delivery of high-quality patient care and places health care professionals at risk for burnout, moral injury, and the loss of professional integrity. To investigate whether pediatric critical care professionals are experiencing moral distress during the COVID-19 pandemic and, if so, for what reasons. An exploratory survey of pediatric critical care professionals was conducted via the Pediatric Acute Lung Injury and Sepsis Investigators Network from April to May 2020. The survey was derived from a framework integrating contemporary literature on moral distress, moral resilience, and expert consensus. Integration of descriptive statistics for quantitative data and thematic analysis for qualitative data yielded mixed insights. Overall, 85.8% of survey respondents reported moral distress. Nurses reported higher degrees of moral distress than other professional groups. Inducers of moral distress were related to challenges to professional integrity and lack of organizational support. Five themes were identified: (1) psychological safety, (2) expectations of leadership, (3) connectedness through a moral community, (4) professional identity challenges, and (5) professional versus social responsibility. Most respondents were confident in their ability to reason through ethical dilemmas (76.0%) and think clearly when confronting an ethical challenge even when pressured (78.9%). During the COVID-19 pandemic, pediatric critical care professionals are experiencing moral distress due to various factors that challenge their professional integrity. Despite these challenges, they also exhibit attributes of moral resilience. Organizations have opportunities to cultivate a psychologically safe and healthy work environment to mitigate anticipatory, present, and lingering moral distress.


Postnatal maturation of the direct corticospinal projections in the macaque monkey.
Postnatal changes in the topography of the multiple corticospinal projections in the macaque monkey were followed using retrogradely transported fluorescent tracers, and related to the monkey's acquisition of manual dexterity; both behavioral and anatomical maturation were completed by about 8 postnatal months. Cortical origins of the corticospinal projections were examined by constructing planar projection maps of the distributions of labeled corticospinal neuron somas; these somas were found only in lamina V. At birth elaborate somatotopically organized corticospinal projections from primary motor cortex (area 4), the mesial supplementary motor area and cingulate areas 23 and 24, area 12, dorsolateral area 6a beta, the dorsolateral and ventral area 6a alpha (area F4), parietal areas 2/5, 7b and the peri-insular cortex (including area SII), were clearly defined, with axons extending to all spinal cord segments. While this pattern of regional projections broadly resembled that of the mature macaque, there were, however, substantial maturational changes during the 8 months after birth. These included (1) a halving of the area of cerebral cortex from which the contralateral corticospinal projection originated and (2) a threefold reduction in the number of labeled corticospinal neurons projecting to all segments of the cord. Collateral elimination rather than neuronal cell death was the likely mechanism for this reduction in the population and areal extent of corticospinal neurons in the maturing macaque. The surviving corticospinal axon terminals also developed substantially during the postnatal period. At birth some terminals had invaded the intermediate zone in each spinal segment, but few had penetrated the dorsal and ventral horns. By 6 postnatal months, however, many corticospinal neurons were retrogradely labeled following the injection of fluorescent labels into each of these spinal zones in cervical and lumbar spinal segments. These data demonstrate a considerable postnatal reduction in corticospinal neurons projecting to the contralateral spinal cord, and imply that many of the axons that are eliminated never synapse on spinal neurons. It is suggested that during the middle fetal period the axons of many of the cortical neurons in lamina V that in the mature monkey will terminate on particular neuron populations in the thalamus, brainstem, or spinal cord, traverse a common pathway down through the internal capsule into the spinal cord, passing close to these successive targets, and possibly forming collaterals at these levels. In the postnatal period each such neuron establishes a stable, effective synaptic input to only one or a few of these subcortical target populations, and the remaining collateral branches regress. The postnatal maturation of corticospinal neurons, examined in this study, is compatible with such a model.


Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy).
Trichohepatoenteric syndrome (THES) is an autosomal-recessive disorder characterized by life-threatening diarrhea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation, and cardiac defects. We attempted to characterize the phenotype and elucidate the molecular basis of THES. Twelve patients with classic THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250,000 single nucleotide polymorphism arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analyzed. The effect of mutations on protein production and/or localization in hepatocytes and intestinal epithelial cells from affected patients was characterized by immunohistochemistry. Previously unrecognized platelet abnormalities (reduced platelet alpha-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system, and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3-5q21.2. Sequencing of candidate genes showed mutations in TTC37, which encodes the uncharacterized tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (sodium hydrogen exchanger 2, sodium hydrogen exchanger 3, aquaporin 7, sodium iodide symporter, and hydrogen potassium adenosine triphosphatase [ATPase]) showed reduced expression or mislocalization in all THES patients with different profiles for each. In contrast the basolateral localization of Na/K ATPase was not altered. THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect, which may be owing to abnormal stability and/or intracellular localization of TTC37 target proteins.


Etiologic research: needed revisions of concepts and principles.
Even though etiologic research has been the central concern in academic epidemiology, its concepts have remained confused or malformed, starting from that of etiology itself; and the same applies to its principles, starting from the notion that the principal variants of an etiologic study are the 'cohort' study and the 'case-control' study. This article suggests revisions of some central concepts pertaining to the object (and objective) of an etiologic study, and it posits an updated conception of the essence--singular--the study itself. This is supplemented by some novel, yet merely orientational, propositions in respect to quality-assurance in etiologic research.


Multispectral co-occurrence with three random variables in dynamic contrast enhanced magnetic resonance imaging of breast cancer.
Presented is a new computer-aided multispectral image processing method which is used in three spatial dimensions and one spectral dimension where the dynamic, contrast enhanced magnetic resonance parameter maps derived from voxel-wise model-fitting represent the spectral dimension. The method is based on co-occurrence analysis using a 3-D window of observation which introduces an automated identification of suspicious lesions. The co-occurrence analysis defines 21 different statistical features, a subset of which were input to a neural network classifier where the assessments of the voxel-wise majority of a group of radiologist readings were used as the gold standard. The voxel-wise true positive fraction (TPF) and false positive fraction (FPF) results of the computer classifier were statistically indistinguishable from the TPF and FPF results of the readers using a one sample paired t-test. In order to observe the generality of the method, two different groups of studies were used with widely different image acquisition specifications.


Risk factors for anastomotic leakage after laparoscopic intracorporeal colorectal anastomosis with a double stapling technique.
Laparoscopic rectal transection carries the risk of anastomotic leakage because of its technical difficulty and long staple line with an inadequate cutting angle. Our objective was to investigate the risk factors affecting anastomotic leakage after laparoscopic intracorporeal colorectal anastomosis with a double stapling technique. Between November 2006 and September 2008, 270 consecutive patients underwent laparoscopic sigmoidectomy and anterior resection with double stapling technique for distal sigmoid and rectal cancer. Data were collected prospectively. Univariate and multivariate analyses were performed to determine risk factors for anastomotic leakage. Additionally, we evaluated the relationship between the number of stapler firings and clinical parameters. Anastomotic leakage was noted in 17 (6.3%) of 270 patients. In univariate analyses, tumor location (p = 0.021), operation time (p = 0.025), number of stapler firings (p = 0.040), and diameter of the circular stapler (p = 0.022) were significant risk factors for anastomotic leakage. Multivariate analyses showed that middle or lower rectal cancer was an independent factor affecting anastomotic leakage (p = 0.013). The number of stapler firings increased significantly in men (p = 0.023), in patients with a tumor at a lower level (p = 0.034), and in those with longer operation times (p < 0.001). A reduction in the number of linear stapler firings is necessary to avoid anastomotic leakage after laparoscopic colorectal anastomosis with a double stapling technique. We recommend that a diverting ileostomy is mandatory in patients with middle and lower rectal cancer where multiple linear staplers were used.


Developmental Potential of Abnormally Fertilized Oocytes and the Associated Clinical Outcomes.
This study aims to investigate the embryo development potential of extending the culture of abnormally fertilized zygotes with no pronuclear (0PN), monopronuclear (1PN), and poor-quality day 3 embryos and to determine the associated clinical outcomes. This is a retrospective study performed between January 2014 and May 2018 at Jinhua People's Hospital. The normal developed embryos and the abnormal 0PN, 1PN, and poor-quality day 3 embryos were cultured to day 5 or 6 for embryo transfer. Clinical outcomes resulting from abnormal embryos and normally developed embryos were compared. A total of 6466 embryos (1542 0PN, 852 1PN, and 4072 poor-quality day 3 embryos) from 831 treatment cycles were cultured to the blastocyst stage. The total blastulation rate was 17.3% (1121/6466) with 18.2% in 0PN, 26.1% in 1PN, and 15.2% in poor-quality day 3 embryos. The rate for good-quality blastocyst formation was 9.5% (616/6466) with 11.2% in 0PN group, 14.8% in 1PN group, and 7.8% in poor-quality day 3 embryos, respectively. Blastulation rates of 0PN and 1PN derived from intracytoplasmic sperm injection (ICSI) were significantly lower compared with the in vitro fertilization group. A total of 243 cycles were transferred with blastocysts originating from abnormal embryos, resulting in 109 (44.9%) clinical pregnancies and 19 (17.4%) miscarriages; in the control group, a total of 350 cycles resulted in 214 (61.1%) clinical pregnancies and 18 (8.4%) miscarriages. The live birth rate was significantly lower in the abnormal embryo group than that in the control group. Collectively, conventional in vitro fertilization derived 0PN and 1PN zygotes, not ICSI, together with day 3 embryos with poor quality, that were able to reach the blastocyst stage and produce a fair pregnancy rate and live birth rate.


How do sinking phytoplankton species manage to persist?
Phytoplankton require light for photosynthesis. Yet, most phytoplankton species are heavier than water and therefore sink. How can these sinking species persist? Somehow, the answer should lie in the turbulent motion that redisperses sinking phytoplankton over the vertical water column. Here, we show, using a reaction-advection-diffusion equation of light-limited phytoplankton, that there is a turbulence window sustaining sinking phytoplankton species in deep waters. If turbulent diffusion is too high, phytoplankton are mixed to great depths, and the depth-averaged light conditions are too low to allow net positive population growth. Conversely, if turbulent diffusion is too low, sinking phytoplankton populations end up at the ocean floor and succumb in the dark. At intermediate levels of turbulent diffusion, however, phytoplankton populations can outgrow both mixing rates and sinking rates. In this way, the reproducing population as a whole can maintain a position in the well-lit zone near the top of the water column, even if all individuals within the population have a tendency to sink. This theory unites earlier classic results by Sverdrup and Riley as well as our own recent findings and provides a new conceptual framework for the understanding of phytoplankton dynamics under the influence of mixing processes.


Functional genomic analysis of a commercial wine strain of Saccharomyces cerevisiae under differing nitrogen conditions.
DNA microarray analysis was used to profile gene expression in a commercial isolate of Saccharomyces cerevisiae grown in a synthetic grape juice medium under conditions mimicking a natural environment for yeast: High-sugar and variable nitrogen conditions. The high nitrogen condition displayed elevated levels of expression of genes involved in biosynthesis of macromolecular precursors across the time course as compared to low-nitrogen. In contrast, expression of genes involved in translation and oxidative carbon metabolism were increased in the low-nitrogen condition, suggesting that respiration is more nitrogen-conserving than fermentation. Several genes under glucose repression control were induced in low-nitrogen in spite of very high (17%) external glucose concentrations, but there was no general relief of glucose repression. Expression of many stress response genes was elevated in stationary phase. Some of these genes were expressed regardless of the nitrogen concentration while others were found at higher levels only under high nitrogen conditions. A few genes, FSP2, RGS2, AQY1, YFL030W, were expressed more strongly with nitrogen limitation as compared to other conditions.


Aberrant expression and methylation status of putatively imprinted genes in placenta of cloned piglets.
Unlike embryos derived from fertilization, most cloned embryos die during postimplantation development, and those that survive to term are frequently defective. Many of the observed defects involve placenta. Abnormal placentation has been described in several cloned species. Imprinted genes are important regulators of placenta growth, and may be subjected to faulty reprogramming during somatic cell nuclear transfer. We aimed to determine the expression levels and methylation patterns of imprinted genes in placentas of live cloned piglets and dead ones. Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that the expression of all four imprinted genes (IGF2, H19, PEG3, and GRB10) was significantly reduced in placentas of dead clones compared with placentas of live cloned piglets and controls (p < 0.05). In contrast, both live and dead cloned piglets exhibited steady-state mRNA levels for these genes within the control range (p > 0.05). Transcript levels for these genes in live clones rarely differed from those of controls in both piglets and placentas. Examination of the methylation status of DMR2 of IGF2 and CTCF3 of H19 genes revealed that both genes exhibited significant high methylation levels in placentas of dead clones compared with placentas of live clones and controls. In contrast, both genes showed a normal differential methylation pattern in live cloned piglets and their placentas compared with controls. Importantly, dead cloned piglets also showed a normal pattern. Our results suggest that abnormal expression of imprinted genes in placenta may contribute to the development failure in pig somatic cell nuclear transfer (SCNT), which may be caused by abnormal methylation patterns in differentially methylated regions (DMRs) of imprinted genes as a result of incomplete reprogramming during SCNT.


Relationship between structure of benzimidazole derivatives and selective virus inhibitory activity. Inhibition of poliovirus multiplication and cytopathic effects by 2-(alpha-hydroxybenzyl)-benzimidazole, and its 5-chloroderivative.
The virus inhibitory activity and selectivity of certain benzimidazole, benzotriazole, and naphthimidazole derivatives were determined with influenza B and polio type 2 viruses. Among the sixty-five compounds examined, several were highly active inhibitors of influenza B virus multiplication in the chorioallantoic membrane in vitro. The following compounds, listed in order of increasing inhibitory activity, were more than 100 times as active as benzimidazole: 5-(4'-toluenesulfonamido)-benzimidazole, 5-hydroxybenzotriazole-4-carboxy-alpha-naphthylamide, 4,5,6-trichlorobenzotriazole, 5-(3',4'-dichlorobenzenesulfonamido)-benzimidazole, 5-(3',4'-dichlorobenzenesulfonamido) - 1 - (3'',4'' - dichlorobenzenesulfonyl)-benzimidazole, 4-(p-chlorophenylazo)-5-hydroxybenzotriazole, and 4,5,6,7-tetrachlorobenzotriazole. However, none showed high selectivity. Of the sixty-five compounds studied with influenza virus, twenty-five were also examined with poliovirus type 2 in monkey kidney cells in vitro. Included in this group were five of the seven most active inhibitors of influenza virus, listed above. All five were more than 100 times as active in inhibiting poliovirus multiplication as the reference compound. In addition to these, two other compounds were highly active: 2-(alpha-hydroxybenzyl)-benzimidazole (HBB), and 2-(alpha-hydroxybenzyl)-5-chlorobenzimidazole, with relative inhibitory activities of 78 and 130, respectively. These two compounds, and the much less active 5,6-dichloro derivative of HBB, were the only ones which showed no, or only slight, toxic effects on cells at concentrations sufficient to cause considerable inhibition of poliovirus multiplication. Furthermore, HBB and the 5-chloro derivative were the only compounds which caused significant inhibition of the cytopathic effects of poliovirus. HBB, and its 5-chloro and 5,6-dichloro derivatives had no effect on the multiplication of influenza B virus in the chorioallantoic membrane. In addition, HBB failed to inhibit influenza B virus multiplication and cytopathic effects in monkey kidney cells. Inhibition of poliovirus-induced cell damage by HBB was characterized by the following features: the curves relating reduction in virus yield or cytopathic effects to concentration of the compound followed an approximately parallel course; somewhat higher concentrations were required to inhibit virus-induced cell damage than to reduce virus yield. HBB suppressed viral cytopathic effects for a period of time which varied directly with the concentration of compound, and inversely with the size of virus inoculum. The development of virus-induced cell damage in treated cultures on prolonged incubation was not due to inactivation of HBB. The inhibitory effect of HBB on virus-induced cell damage was reversible by removal of the compound. HBB inhibited viral cytopathic effects when given during the exponential increase phase in virus multiplication. Inhibition of virus-induced cell damage by HBB was demonstrated by photomicrographs. HBB did not inactivate the infectivity of poliovirus type 2.


Venereal herpes-like molluscum contagiosum: treatment with tretinoin.
Molluscum contagiosum spread by sexual contact may be mistaken for other venereal diseases. The occurrence of a penile lesion resembling herpes progenitalis, and successful therapy of genital mollusca with topical tretinoin (vitamin A acid) is described.


Genome-wide characterization of ovate family protein gene family associated with number of seeds per silique in Brassica napus.
Ovate family proteins (OFPs) were firstly identified in tomato as proteins controlling the pear shape of the fruit. Subsequent studies have successively proved that OFPs are a class of negative regulators of plant development, and are involved in the regulation of complex traits in different plants. However, there has been no report about the functions of OFPs in rapeseed growth to date. Here, we identified the OFPs in rapeseed at the genomic level. As a result, a total of 67 members were obtained. We then analyzed the evolution from Arabidopsis thaliana to Brassica napus, illustrated their phylogenetic and syntenic relationships, and compared the gene structure and conserved domains between different copies. We also analyzed their expression patterns in rapeseed, and found significant differences in the expression of different members and in different tissues. Additionally, we performed a GWAS for the number of seeds per silique (NSPS) in a rapeseed population consisting of 204 natural accessions, and identified a new gene BnOFP13_2 significantly associated with NSPS, which was identified as a novel function of OFPs. Haplotype analysis revealed that the accessions with haplotype 3 had a higher NSPS than other accessions, suggesting that BnOFP13_2 is associated with NSPS. Transcript profiling during the five stages of silique development demonstrated that BnOFP13_2 negatively regulates NSPS. These findings provide evidence for functional diversity of OFP gene family and important implications for oilseed rape breeding.


Cardiac fibrosis in regenerative medicine: destroy to rebuild.
The major limitations for cardiac regeneration in patients after myocardial infarction (MI) are the wide loss of cardiomyocytes and the adverse structural alterations of extracellular matrix (ECM). Cardiac fibroblast differentiation into myofibroblasts (MFB) leads to a huge deposition of ECM and to the subsequent loss of ventricular structural integrity. All these molecular events depict the fundamental features at the basis of the post-MI fibrosis and deserve in depth cellular and molecular studies to fill the gap in the clinical practice. Indeed, to date, there are no effective therapeutic approaches to limit the post-MI massive fibrosis development. In this review we describe the involvement of integrins and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)/ADAMTS-like (ADAMTSL) proteins in cardiac reparative pro-fibrotic response after MI, proposing some of them as novel potential pharmacological tools.


Impact of nuclear distribution element genes in the typical and atypical antipsychotics effects on nematode Caenorhabditis elegans: Putative animal model for studying the pathways correlated to schizophrenia.
The nuclear distribution element genes are conserved from fungus to humans. The nematode Caenorhabditis elegans expresses two isoforms of nuclear distribution element genes, namely nud-1 and nud-2. While nud-1 was functionally demonstrated to be the worm nudC ortholog, bioinformatic analysis revealed that the nud-2 gene encodes the worm ortholog of the mammalian NDE1 (Nuclear Distribution Element 1 or NudE) and NDEL1 (NDE-Like 1 or NudEL) genes, which share overlapping roles in brain development in mammals and also mediate the axon guidance in mammalian and C. elegans neurons. A significantly higher NDEL1 enzyme activity was shown in treatment non-resistant compared to treatment resistant SCZ patients, who essentially present response to the therapy with atypical clozapine but not with typical antipsychotics. Using C. elegans as a model, we tested the consequence of nud genes suppression in the effects of typical and atypical antipsychotics. To assess the role of nud genes and antipsychotic drugs over C. elegans behavior, we measured body bend frequency, egg laying and pharyngeal pumping, which traits are controlled by specific neurons and neurotransmitters known to be involved in SCZ, as dopamine and serotonin. Evaluation of metabolic and behavioral response to the pharmacotherapy with these antipsychotics demonstrates an important unbalance in serotonin pathway in both nud-1 and nud-2 knockout worms, with more significant effects for nud-2 knockout. The present data also show an interesting trend of mutant knockout worm strains to present a metabolic profile closer to that observed for the wild-type animals after the treatment with the typical antipsychotic haloperidol, but which was not observed for the treatment with the atypical antipsychotic clozapine. Paradoxically, behavioral assays showed more evident effects for clozapine than for haloperidol, which is in line with previous studies with rodent animal models and clinical evaluations with SCZ patients. In addition, the validity and reliability of using this experimental animal model to further explore the convergence between the dopamine/serotonin pathways and neurodevelopmental processes was demonstrated here, and the potential usefulness of this model for evaluating the metabolic consequences of treatments with antipsychotics is also suggested.


Computed tomography in intra- and suprasellar epithelial cysts (symptomatic Rathke cleft cysts).
The computed tomographic (CT) and pathologic findings in three cases of intra- and suprasellar epithelial cysts (symptomatic Rathke cleft cysts) are described. Literature review revealed that the characteristic CT finding is an intrasellar and/or suprasellar low-density mass that may or may not be enhanced. The enhancement is ringlike or capsular in nature. Whether the cyst wall is enhanced or not seems to be dependent on the histologic features. It is suggested that the enhancement may be caused by an inflammatory process, either septic or aseptic, or squamous metaplasia in the wall, which is possibly induced by degeneration or infection of the cyst contents. Without these additional pathologic processes, the Rathke cleft cyst, a simple retention cyst, may exhibit no contrast enhancement.


[Personality traits of perpetrators of various types of crimes].
This study was conducted in Nowy Wiśnicz, with prisoners sentenced for: murders, sex crimes, theft and robbery, maintenance, bullying. A Polish adaptation of PAI test, made by the author of the study, was used. The study results and its statistical analysis showed characteristic personality features of particular criminal groups can be used in rehabilitation of disturbed people, addicts, and become the basis for preparing actions reducing frequency of committing crimes.


Ca(2+)-induced down-regulation of epithelial amiloride-sensitive channels reconstituted into planar lipid bilayers.
Multichannel experiments were carried out to investigate the Ca(2+)-induced down-regulation of epithelial Na+ channels reconstituted into planar lipid bilayer membranes. Reconstitution was achieved by fusion of vesiculated apical membrane fragments to solvent-free planar lipid bilayers. We found that the presence of micromolar concentrations of Ca2+ on the side to which the vesicles were added substantially lowered the channel-mediated current. The inhibition was strongly influenced by pH. At pH 8.0, all the current was blocked by 1 mM calcium, whereas at pH 7.1 the inhibition was about 80%. The blocking kinetics was clearly voltage-dependent. The mechanism of blocking cannot be explained either in terms of interactions with a single site, or by a model in which two blocking sites are assumed.


Tumor-induced changes in the phenotype of blood-derived and tumor-associated T cells of early stage breast cancer patients.
Tumor-induced immune suppression has mainly been studied in patients with advanced cancer. Despite the fact that they are most likely to benefit from immunotherapy, patients with early stage cancers were under-represented in these studies. We analyzed blood and tumor-derived T cells from patients with stage 1 (n = 20), stage 2 (n = 23) or stage 3 (n = 1) breast cancer and found that, even early stage tumors induced T cell differentiation. Breast cancer patients had significantly more circulating CD8+ memory and fewer CD8+ naïve T cells than healthy controls (n = 10). Up-regulation of CD69 and PD1 on cancer patient T cells suggests previous activation, and increased expression of the chemokine receptors CCR5 and CXCR3 on CD8+ T cells indicates that their homing capacity differs from that of healthy individuals. Comparison of blood-derived and tumor-associated T cells from patients with different metastatic status and tumor grades revealed that tumor progression and aggressiveness seem to favor the expansion of memory T cells over naive T cells. We have previously shown that immunosuppression in this patient population is stronger in the tumor than in the blood. Here, we report signs of exhaustion, such as loss of CD28, on tumor-associated as compared to blood-derived CD8+ T cells, despite the fact that tumor-associated T cells are predominantly effector memory cells and express high levels of CD69. The finding that the presence of a tumor potentially induces immunosenescence early during tumorigenesis indicates that efficient immunotherapy might be difficult even in patients with early stage cancer due to T cell exhaustion and tolerance.


Current concepts in the management of breast cancer.
Current trials are aimed at determining whether less radical surgery or irradiation is equivalent to radical or modified radical mastectomy. Axillary node involvement is the most reliable indicator of prognosis. Patients with axillary node involvement and no other detectable disease should be considered for adjuvant chemotherapy. Steroid receptor analysis furnishes valuable information on prognosis and aids in treatment planning. Hormonal manipulation and/or combination chemotherapy can offer significant prolongation of life and amelioration of symptoms in many patients with advanced disease.


Enemies or weapons in hands: investigational anti-diabetic drug glibenclamide and cancer risk.
Epidemiological evidence suggests that diabetes is associated with elevated cancer risk through the actions of hyperglycemia, hyperinsulinemia and chronic inflammation. Metformin, a first-line medication for type 2 diabetes mellitus, arouses growing concerns on its anti-cancer effect. However, data regarding the effect of glibenclamide on tumor growth and cancer risk are less consistent, which may be a potential anti-cancer drug. Areas covered: In this review, we clarified probable underlying mechanisms in preclinical studies and reviewed epidemiological evidence on glibenclamide's cancer risk in clinical studies. Glibenclamide inhibited carcinogenesis through ATP-binding cassette protein super-family and ATP-sensitive potassium channels, while majority of clinical researches reported an increased or non-significant elevated cancer risk of glibenclamide users compared with metformin users. Other sulfonylureas and diarylsulfonylureas were also briefly introduced. Expert opinion: The inconsistency between the results of studies was probably ascribed to undiscovered mechanisms, confounding factors, inconsistent comparators and publication bias. Existing clinical trials were prone to be afflicted by time-related bias including immortal time bias, time-window bias, and time-lag bias. Glibenclimiade could be a promising and well-tolerated anti-neoplastic drug targeting ATP-binding cassette protein super-family and KATP channels, but its efficacy still needs to be proven in well-designed long-term randomized controlled clinical trials.


Effect of corneal lens fenestration on edema and spectacle blur.
This paper is a clinical discussion of the effects of corneal lens fenestration on visible corneal edema and spectacle blur. Most of the discussion centers about photo slit lamp material selected to illustrate some of the author's experience with the subject. Although everyone does not benefit from fenestration, photographs show several cases in which visible corneal edema is reduced. Among patient impressions, the outstanding benefit is reduction of spectacle blur.


Acetaminophen and ibuprofen in the treatment of pediatric fever: a narrative review.
A narrative review of randomized, blinded, controlled studies assessing the antipyretic effect of ibuprofen versus acetaminophen or combined or alternating treatment in children was conducted. Searches of the PubMed and Embase literature databases were conducted to identify relevant articles. Selected articles were limited to studies published in English that investigated OTC oral tablet and syrup formulations of acetaminophen and ibuprofen; there were no publication date limits. Open-label studies, nonrandomized studies, and those evaluating intravenous or suppository formulations of acetaminophen or ibuprofen were excluded. Variations in designs, endpoints, methods, and patient populations precluded our ability to conduct a formal systematic review. At physician-directed dosing (acetaminophen 15 mg/kg vs ibuprofen 10 mg/kg), no significant differences in antipyretic effects from 0‒6 h and between 0‒6, ‒12, ‒24, or ‒48 h, with single or multiple-doses, respectively, were observed. Tolerability profiles at physician dosing were similar. In 14 over-the-counter dose comparisons (acetaminophen, 10-15 mg/kg; ibuprofen, 2.5-10 mg/kg), antipyresis favored ibuprofen in 6, was similar between groups in 7, and favored acetaminophen (15 mg/kg vs ibuprofen 5 mg/kg) in 1 comparison. Both medications were well tolerated. Efficacy favored combination over individual components in 3 of 4 studies; alternating use results were mixed. All combination or alternating treatments were well tolerated. Antipyretic effects of ibuprofen and acetaminophen are similar at physician-directed doses; ibuprofen may be modestly superior at over-the-counter doses.