G Quadruplex in Plants: A Ubiquitous Regulatory Element and Its Biological Relevance.
G quadruplexes (G4) are higher-order DNA and RNA secondary structures formed by G-rich sequences that are built around tetrads of hydrogen-bonded guanine bases. Potential G4 quadruplex sequences have been identified in G-rich eukaryotic non-telomeric and telomeric genomic regions. Upon function, G4 formation is known to involve in chromatin remodeling, gene regulation and has been associated with genomic instability, genetic diseases and cancer progression. The natural role and biological validation of G4 structures is starting to be explored, and is of particular interest for the therapeutic interventions for human diseases. However, the existence and physiological role of G4 DNA and G4 RNA in plants species have not been much investigated yet and therefore, is of great interest for the development of improved crop varieties for sustainable agriculture. In this context, several recent studies suggests that these highly diverse G4 structures in plants can be employed to regulate expression of genes involved in several pathophysiological conditions including stress response to biotic and abiotic stresses as well as DNA damage. In the current review, we summarize the recent findings regarding the emerging functional significance of G4 structures in plants and discuss their potential value in the development of improved crop varieties.


Physicochemical and bioactive constituents, microbial counts, and color components of spray-dried Syzygium cumini L. pulp powder stored in different packaging materials under two controlled environmental conditions.
Currently, the demand for functional food items that impart health benefits has been rising. Blackberry (Syzygium cumini L.) fruit has high anthocyanin content and other functional attributes. However, this seasonal fruit is highly perishable, and a large proportion of it goes unharvested and wasted worldwide. Spray drying of the fruit pulp can impart improved shelf life, ensuring long-term availability for consumers to exploit its health benefits. The storage quality varies according to the type of packaging material and the storage environment. Therefore, in this study, the shelf life span of the spray-dried Syzygium cumini L. pulp powder (SSCPP) was investigated during 6 months of storage under three types of packaging materials (i.e., polystyrene, metalized polyester, and 4-ply laminates) in a low-temperature environmental (LTE) and at ambient environmental conditions. The physicochemical stability of bioactive principles (TPC and TAC), microbial counts, and color components were analyzed at 0, 2, 4, and 6 months of storage. There was a significant gradual loss of dispersibility and solubility with an increase in flowability, bulk density, and wettability during the entire storage period for all three packaging materials. The TSS, pH, TPC, TAC, and microbial counts decreased in the SSCPP both at ambient and LTE conditions during the study. Among all the packaging materials, the 4-ply laminate was found to be the most appropriate and safe for storage of spray-dried SCPP at LTE conditions.


Journey from Jumping Genes to Gene Therapy.
Gene therapy for cancer is a still evolving approach that resulted from a long history of studies into genetic modification of organisms. The fascination with manipulating gene products has spanned hundreds if not thousands of years, beginning with observations of the hereditary nature of traits in plants and culminating to date in the alteration of genetic makeup in humans via modern technology. From early discoveries noting the potential for natural mobility of genetic material to the culmination of clinical trials in a variety of disease, gene transfer has had an eventful and sometimes tumultuous course. Within the present review is a brief history of the biology of gene transfer, how it came to be applied to genetic diseases, and its early applications to cancer therapies. Some of the different types of methods used to modify cells, the theories behind the approaches, and some of the limitations encountered along the way are reviewed.


A Pressure Plate-Based Method for the Automatic Assessment of Foot Strike Patterns During Running.
The foot strike pattern (FSP, description of how the foot touches the ground at impact) is recognized to be a predictor of both performance and injury risk. The objective of the current investigation was to validate an original foot strike pattern assessment technique based on the numerical analysis of foot pressure distribution. We analyzed the strike patterns during running of 145 healthy men and women (85 male, 60 female). The participants ran on a treadmill with integrated pressure plate at three different speeds: preferred (shod and barefoot 2.8 ± 0.4 m/s), faster (shod 3.5 ± 0.6 m/s) and slower (shod 2.3 ± 0.3 m/s). A custom-designed algorithm allowed the automatic footprint recognition and FSP evaluation. Incomplete footprints were simultaneously identified and corrected from the software itself. The widely used technique of analyzing high-speed video recordings was checked for its reliability and has been used to validate the numerical technique. The automatic numerical approach showed a good conformity with the reference video-based technique (ICC = 0.93, p < 0.01). The great improvement in data throughput and the increased completeness of results allow the use of this software as a powerful feedback tool in a simple experimental setup.


Alterations in VEGF expression induced by antidepressant drugs in female rats under chronic social stress.
Vascular endothelial growth factor (VEGF) is thought to serve a role in neurogenesis and the stress response. Although a definite link between the action of antidepressants and VEGF has not been identified, it is assumed that VEGF, as a neurotrophic factor, serves an important role in the effects of antidepressant treatment. To examine this, the present study subjected adult female rats to four weeks of social instability stress and measured the effect of antidepressant treatment on the expression of VEGF. Firstly, endocrine markers of stress and body weight were measured in parallel with behavioral tests prior to and following subjection to stress. Then, the effect of 28-day daily treatment with desipramine (DMI; 10 mg/kg), fluoxetine (5 mg/kg) or tianeptine (10 mg/kg) on the number of copies of VEGF mRNA in the amygdala, hippocampus and hypothalamus, and on serum VEGF protein levels, of rats subjected to chronic stress was determined. In addition, the weight of the adrenal glands was measured following subjection to stress. Exposure to chronic stress was found to increase the rats' sucrose preference, and diminish their tendency for general exploration and time spent in the open. The relative adrenal weights of the stressed rats were significantly increased compared with the control. Plasma concentrations of corticosterone and adrenocorticotropic hormone were not significantly augmented. In addition, the present study identified that stress elevated VEGF mRNA expression in all studied neural structures. Furthermore, the results identified that the stress-induced increase in VEGF mRNA expression in the amygdala and hypothalamus was attenuated by long-term administration of DMI. Conversely, a decrease in serum VEGF concentration was observed in stressed rats, which was not reversed by treatment with antidepressants. In conclusion, the current study suggests that under conditions of stress, VEGF serves a role in the mechanism of action of DMI, through modulating activity of the norepinephrine system.


Conformational evaluation of HIV-1 trimeric envelope glycoproteins using a cell-based ELISA assay.
HIV-1 envelope glycoproteins (Env) mediate viral entry into target cells and are essential to the infectious cycle. Understanding how those glycoproteins are able to fuel the fusion process through their conformational changes could lead to the design of better, more effective immunogens for vaccine strategies. Here we describe a cell-based ELISA assay that allows studying the recognition of trimeric HIV-1 Env by monoclonal antibodies. Following expression of HIV-1 trimeric Env at the surface of transfected cells, conformation specific anti-Env antibodies are incubated with the cells. A horseradish peroxidase-conjugated secondary antibody and a simple chemiluminescence reaction are then used to detect bound antibodies. This system is highly flexible and can detect Env conformational changes induced by soluble CD4 or cellular proteins. It requires minimal amount of material and no highly-specialized equipment or know-how. Thus, this technique can be established for medium to high throughput screening of antigens and antibodies, such as newly-isolated antibodies.


Loss of hippocampal neurogenesis, increased novelty-induced activity, decreased home cage activity, and impaired reversal learning one year after irradiation of the young mouse brain.
Radiotherapy is a major cause of long-term complications in survivors of pediatric brain tumors. These complications include intellectual and memory impairments as well as perturbed growth and puberty. We investigated the long-term effects of a single 8 Gy irradiation dose to the brains of 14-day-old mice. Behavior was assessed one year after irradiation using IntelliCage and open field, followed by immunohistochemical investigation of proliferation and neurogenesis in the dentate gyrus of the hippocampus. We found a 61% reduction in proliferation and survival (BrdU incorporation 4 weeks prior to sacrifice), 99% decrease in neurogenesis (number of doublecortin-positive cells) and gliosis (12% higher astrocyte density) one year following irradiation. Irradiated animals displayed increased activity in a novel environment but decreased activity in their home cage. Place learning in the IntelliCage was unaffected by irradiation but reversal learning was impaired. Irradiated animals persevered in visiting previously correct corners to a higher extent compared to control animals. Hence, despite the virtual absence of neurogenesis in these old mice, spatial learning could take place. Reversal learning however, where a previous memory was replaced with a new one, was partly impaired. This model is useful to study the so called late effects of radiotherapy to the young brain and to evaluate possible interventions.


Pure non-gestational choriocarcinoma of ovary a case report with autopsy findings.
Primary choriocarcinoma of the ovary (PCO) is rare. This can be gestational (GCO) or non-gestational (NGCO) in origin. It is difficult to differentiate between CGO and NGCO. Non-gestational choriocarcinoma carries a bad prognosis than GCO. We present a case of NGCO who had pulmonary metastasis.


Hematemesis as Initial Presentation in a 10-Week-Old Infant with Eosinophilic Gastroenteritis.
Eosinophilic gastroenteritis is a rare condition characterized by eosinophilic inflammation in the gastrointestinal tract resulting in a variety of gastrointestinal symptoms. There is currently a dearth of information on this topic in the pediatric literature, as very few cases have been reported. In this report, we present a case of eosinophilic gastroenteritis in a 10-week-old patient with initial presenting symptom of hematemesis. To our knowledge, this is the youngest case reported in the literature and is unique in its initial presentation.


[Value of fractional nitric oxide concentration in exhaled breath in assessing level of asthma control in children].
To investigate the value of fractional nitric oxide concentration in exhaled breath (FeNO) in assessing the level of asthma control in children. A total of 226 asthmatic children were divided into controlled asthma (n= 86), partially controlled asthma (n=63), and uncontrolled asthma groups (n=77). Ninety healthy children were enrolled as controls. FeNO was measured for both asthmatic and healthy children using the Swedish-designed NIOX system. The control group had an FeNO of 14±6 ppb, the controlled asthma group had an FeNO of 29±26 ppb, the partially controlled asthma group had an FeNO of 32±30 ppb, and the uncontrolled asthma group had an FeNO of 40±32 ppb. The three asthma groups showed significantly higher FeNO than the control group (P<0.05). The uncontrolled asthma group showed significantly higher FeNO than the controlled asthma group (P<0.05), but there were no significant differences in FeNO between the partially controlled and uncontrolled asthma groups and between the partially controlled and controlled asthma groups (P>0.05). Asthmatic children have significantly higher FeNO than healthy children, and FeNO is correlated with the level of asthma control.


Endosulfan splenic pathology and amelioration by vitamin C in New Zealand rabbit.
Endosulfan, a chlorinated hydrocarbon insecticide/acaricide, is a member of a cyclodiene sub-group of poisons to a wide variety of insects and mites. It is also toxic to humans and animals, but there is limited knowledge about endosulfan-related splenic and overall immunotoxicity. The aim of this study was to review pathological findings of endosulfan toxicity in the spleen and to examine potential protective effects of the anti-oxidant Vitamin C (Vit C). Here, after 6-week exposures, the spleens of New Zealand White rabbits were examined grossly and histopathologically and tissue caspase-3 activity was assessed immunohistochemically. Rabbits in four groups were used: Group END were given by oral gavage a sub-lethal dose of endosulfan (1 mg/kg) in corn oil daily for 6 weeks; Group END + C received the same dose of endosulfan daily and Vit C (20 mg/kg) every other day by gavage during this period; Group Vit C received oral corn oil daily and 20 mg/kg Vit C every other day; and Group OIL received corn oil daily for 6 weeks. Analyses of the tissues collected 1 week after the final dosing revealed lymphocyte depletion and necrosis in spleens of the hosts that received the pesticide (END only and END + C); hemorrhage and slight neutrophilic infiltration was also noted. Caspase-3 immunoreactivity was marked in lymphocytes in all spleens of rabbits in both END groups. Overall, these toxicities were mitigated by Vit C co-treatment; in END + C hosts, markedly decreased depletion of lymphocytes, inflammation and caspase-3 immunoreactivity were observed. However, even with mitigation, the level of toxicity present was still greater than any seen in the spleens of hosts that received OIL or Vit C alone. These results revealed endosulfan could cause toxicity in the rabbit spleen, characterized by depletion of lymphocytes, inflammation, necrosis and hemorrhage, and that this toxicity could begin to be mitigated by Vit C co-treatment.


Experimental induction of lung damage in the f344 rat upon exposure to citral, retinoic Acid (atra), ovalbumin and mold spores.
The experimental impact of retinoic acid (All Trans Retinoic Acid; ATRA), citrals, ovalbumin and mold spores in the development of lung pathology and tissue remodeling are not well established in the literature. As well, the role of these agents in lung pathology was not ascertained under an in vivo setting. Therefore, it is hypothesized that citrals, ATRA, ovalbumin and mold-spore exposure will sensitize lung tissues and will lead to the development of lung tissue pathology in these animals. The study used an IACUC approved between-subject in vivo randomized split plot factorial design (F344 rat model; N=30). Mold spores were applied to animals by intra-tracheal route whereas vehicle, ovalbumin, C1, C2 and ATRA were administered by intra-peritoneal route. Rat weight data and blood were collected on Days 1 and 21. All animals were sacrificed on day 21 and lung tissues were processed for histopathology. Evidence from weights and blood (ANOVA and Duncan) as well as histopatholgical analysis supported the findings that exposure of these animals to C1, C2, ATRA, ovalbumin and mold spores showed different levels of lung tissue damage representing environmental exposure to these agents. This promising study showed variable lung tissue responses to the administration of ATRA, ovalbumin, citrals, and mold spores in the development of various levels of lung tissue pathologies.


Asymmetric Lithium Extraction and Insertion in High Voltage Spinel at Fast Rate.
Spinel-structured ordered-LiNi0.5Mn1.5O4 (o-LNMO) has experienced a resurgence of interest in the context of reducing scarce elements such as cobalt from the lithium-ion batteries. O-LNMO undergoes two two-phase reactions at slow rates. However, it is not known if such phenomenon also applies at fast rates. Herein, we investigate the rate-dependent phase transition behavior of o-LNMO through in operando time-resolved X-ray diffraction. The results indicate that a narrow region of the solid solution reaction exists for charge and discharge at both slow and fast rates. The overall phase transition is highly asymmetric at fast rates. During fast charge, it is a particle-by-particle mechanism resulting from an asynchronized reaction among the particles. During fast discharge, it is likely a core-shell mechanism involving transition from Li0+xNi0.5Mn1.5O4 to Li1+xNi0.5Mn1.5O4 in the outer layer of particles. The Li0.5Ni0.5Mn1.5O4 phase is suppressed during fast discharge and appears only through Li redistribution upon relaxation.


Use of liquid chromatography/tandem mass spectrometry to detect distinctive indicators of in situ RDX transformation in contaminated groundwater.
An important element of monitored natural attenuation is the detection in groundwater of distinctive products of pollutant degradation or transformation. In this study, three distinctive products of the explosive RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) were detected in contaminated groundwater from the Iowa Army Ammunition Plant; the products were MNX (hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine), DNX (hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine), and TNX (hexahydro-1,3,5-trinitroso-1,3,5-triazine). These compounds are powerful indicators of RDX transformation for several reasons: (a) they have unique chemical features that reveal their origin as RDX daughter products, (b) they have no known commercial, industrial, or natural sources, and (c) they are well documented as anaerobic RDX metabolites in laboratory studies. The products were analyzed by LC/MS/MS (liquid chromatography/mass spectrometry/mass spectrometry) with selected reaction monitoring and internal standard quantification using [ring-U-15N]RDX. Validation tests showed the novel LC/MS/MS method to be of favorable sensitivity (detection limits ca. 0.1 microg/L), accuracy, and precision. The products, which were detected in all groundwater samples with RDX concentrations of > ca. 1 microg/L (25 out of 55 samples analyzed), were present at concentrations ranging from near the detection limit to 430 microg/L. MNX was the typically the most abundant of the three nitroso-substituted products; concentrations of the products seldom exceeded 4 mol % of the RDX concentration, although they ranged as high as 26 mol % (TNX). Geographic and temporal distributions of RDX, MNX, DNX, and TNX were assessed. A degradation product resulting from RDX ring cleavage, methylenedinitramine, was not detected by LC/MS/MS in any sample (detection limit ca. 0.6-4 microg/L). This extensive field characterization of MNX, DNX, and TNX distributions in groundwater by a highly selective analytical method (LC/MS/MS) is significant because very little is known about the occurrence of intrinsic RDX transformation in contaminated aquifers.


Angular on-line tube current modulation in multidetector CT examinations of children and adults: the influence of different scanning parameters on dose reduction.
The purpose of this study was to assess the potential of angular on-line tube current modulation on dose reduction in pediatric and adult patients undergoing multidetector computed tomography (MDCT) examinations. Five physical anthropomorphic phantoms that simulate the average individual as neonate, 1-year-old, 5-year-old, 10-year-old, and adult were employed in the current study. Phantoms were scanned with the use of on-line tube current modulation (TCM). Percent dose reduction (%DR) factors achieved by applying TCM, were determined for standard protocols used for head and neck, shoulder, thorax, thorax and abdomen, abdomen, abdomen and pelvis, pelvis, and whole body examinations. A preliminary study on the application of TCM in MDCT examinations of adult patients was performed to validate the results obtained in anthropomorphic phantoms. Dose reduction was estimated as the percentage difference of the modulated milliamperes for each scan and the preset milliamperes prescribed by the scan protocol. The dose reduction in children was found to be much lower than the corresponding reduction achieved for adults. For helical scans the %DR factors, ranged between 1.6% and 7.4% for the neonate, 2.9% and 8.7% for the 1-year old, 2% and 6% for the 5-year-old, 5% and 10.9% for the 10-year-old, and 10.4% and 20.7% for the adult individual. For sequential scans the corresponding %DR factors ranged between 1.3% and 6.7%, 4.5% and 11%, 4.2% and 6.6%, 6.4% and 12.3%, and 8.9% and 23.3%, respectively. Broader beam collimations are associated with decreased %DR factors, when other scanning parameters are held constant. TCM did not impair image noise. In adult patients, the %DR values were found to be in good agreement with the corresponding results obtained in the anthropomorphic adult phantom. In conclusion, on-line TCM may be considered as a valuable tool for reducing dose in routine CT examinations of pediatric and adult patients. However, the dose reduction achieved with TCM in neonates and young children was found to be lower than that obtained for adults. Therefore, on-line TCM should work as an additional means to reduce dose and should not replace other conventional means of reducing dose, especially in neonates and young children.


Simultaneous measurement of hormone release and secretagogue binding by individual pituitary cells.
The quantitative relationship between receptor binding and hormone secretion at the single-cell level was investigated in the present study by combining a reverse hemolytic plaque assay for measurement of luteinizing hormone (LH) secretion from individual pituitary cells with an autoradiographic assay of 125I-labeled gonadotropin-releasing hormone (GnRH) agonist binding to the same cells. In the plaque assay, LH secretion induces complement-mediated lysis of the LH-antibody-coated erythrocytes around the gonadotropes, resulting in areas of lysis (plaques). LH release from individual gonadotropes was quantified by comparing radioimmunoassayable LH release to hemolytic area in similarly treated cohort groups of cells; plaque area was linearly related to the amount of LH secreted. Receptor autoradiography was performed using 125I-labeled GnRH-A (a superagonist analog of GnRH) both as the ligand and as the stimulant for LH release in the plaque assay; the developed silver grains appearing over cells in the center of plaques were measured microscopically. The grains appeared to represent specific and high-affinity receptors for GnRH because no pituitary cells other than gonadotropes bound the labeled ligand and grain development was progressively inhibited by coincubation with increasing doses of unlabeled GnRH-A. Despite high correlations between mean grain number and mean plaque area in dose-response curves, the correlation coefficients for these parameters were low (range 0.02-0.38) in the individual cells comprising these groups. We conclude that GnRH receptor number for any individual gonadotrope is a weak determinant of the amount of LH it can secrete; nevertheless, full occupancy of all its GnRH receptors is required for any gonadotrope to reach its full LH-secretory capacity. Apparently the levels of other factors comprising the steps along the secretory pathway determine the secretory capacity of an individual cell.


Purification and characterization of S1 mutants of alpha-lytic protease having altered catalytic properties.
A procedure is described for purifying alpha-lytic protease and its mutants from culture supernatants of recombinant Escherichia coli. The method affords substantial amounts (approx. 80 mg) of homogeneous enzyme. We compared the cleavage preferences of wild-type alpha-lytic protease and of mutants containing the substitutions Ala190 ("parent"), Ala190/Val192/His213/Met218 (mutant 1), Ala190/His213/Leu218 (mutant 9), and Ala190/Thr213/Leu218 (mutant 55), and for each enzyme we found broad agreement between the results obtained with synthetic ester and amide substrates. Kinetic constants were determined for the purified enzymes using selected tetrapeptide p-nitroanilide substrates. Mutant 55 had broad specificity and high activity. In terms of kcat/Km it cleaved at Met and Phe residues two to three times as effectively as the Ala190 enzyme and cleaved at Ala 7 times more effectively than the wild-type protease. The Ala190/His213 enzymes showed a preference for cleavage at His and Met residues. Not only were their kcat values for cleavage at His increased (in relation to the Ala190 enzyme) by an order of magnitude, but they also exhibited large decreases in kcat/Km for cleavage at other residues; for example, the value for cleavage at Phe was 400- to 600-fold lower. Mutant 9 cleaved a recombinant IGF-II fusion protein at a unique His residue and also at a nearby Asn residue.


Selective alterations of insulin actions by glucagon in isolated rat epididymal adipocytes.
Previously we demonstrated that glucagon inhibits high affinity insulin binding without influence on low affinity binding in rat adipocytes in vitro. In this study we investigated the effects of glucagon on insulin actions in adipocytes in vitro. Glucagon modified neither glucose oxidation nor lipogenesis stimulated by insulin. The antilipolytic action of insulin was decreased by preincubation of the cells with glucagon. Glucose transport enhanced by insulin was diminished by preincubation of the cells with glucagon. The decrease in antilipolysis was a lowering of the maximal response to insulin, whereas the decrease in glucose transport was a lowering of the sensitivity to insulin. These results suggested that glucagon does not necessarily inhibit all of the insulin actions, and that the mechanism of insulin stimulation of glucose transport, which is supposed to be mediated by glucagon-sensitive insulin receptor, is different from those of insulin-induced antilipolysis, glucose oxidation, and lipogenesis.


Connexin43 enhances glioma invasion by a mechanism involving the carboxy terminus.
Gliomas are particularly difficult to cure owing largely to their invasive nature. The neoplastic changes of astrocytes which give rise to these tumors frequently include a reduction of connexin43 (Cx43), the most abundant connexin isoform expressed in astrocytes. Cx43 is a subunit of gap junctions (GJ), intercellular channels which directly link the cytosol of adjacent cells and allow the regulated passage of ions and small molecules. To examine the role of Cx43 in glioma motility, we identified two variant C6 cell lines which endogenously express high (C6-H) or low (C6-L) levels of Cx43. In wound healing and transwell assays, C6-H cells were more motile than C6-L cells. To deduce whether Cx43 mediated these differences, assays were conducted on C6-H cells retrovirally transduced with Cx43 shRNA. Coincident with the stable knockdown of endogenous Cx43, a decrease in motility and invasion was observed. Gap junctional intercellular communication was also decreased, however motility assays conducted in the presence of GJ inhibitors did not reveal significant differences in cell motility. C6 cells transfected with full length or C-terminal truncated Cx43 (Cx43DeltaCT) were subjected to the aforementioned motility assays to expose alternate mechanisms of Cx43-mediated motility. Cells expressing full length Cx43 exhibited increased motility while cells expressing Cx43DeltaCT did not. This report, the first in which RNAi has been employed to reduce Cx43 expression in gliomas, indicates that the downregulation of Cx43 decreases motility of C6 cells. Furthermore, it is the first report to suggest that the Cx43 CT plays an important role in glioma motility.


Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics.
This study evaluated the dose-related ethanol-like subjective effects of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine hydrochloride in recently detoxified alcoholics. Twenty male inpatients meeting DSM-III-R criteria for alcohol dependence and who had not consumed alcohol for 10 to 27 days prior to the study completed 3 test days that involved the intravenous infusion of ketamine hydrochloride (0.1 mg/kg or 0.5 mg/kg) or saline solution under randomized double-blind conditions. Ethanol-like subjective effects were assessed using the Sensation Scale; the Biphasic Alcohol Effects Scale; visual analog scales to measure "high" and degree of similarity to ethanol, cocaine, and marijuana; a scale assessing the number of standard alcohol drinks producing similar subjective effects; and visual analog scales measuring ethanol craving. Ketamine produced dose-related ethanol-like effects on each scale measuring its similarity to ethanol. Its effects were more similar to the sedative or descending limb effects of ethanol than to the stimulant or ascending limb effects. Ketamine effects also were more like ethanol than marijuana or cocaine. Ethanol-like effects were more prominent at the higher ketamine dose, a dose rated as similar to greater levels of ethanol intoxication. However, ketamine did not increase craving for ethanol. The production of ethanol-like subjective effects by ketamine supports the potential clinical importance of NMDA receptor antagonism among the mechanisms underlying the subjective effects of ethanol in humans.


Modified and Dysfunctional Lipoproteins in Atherosclerosis: Effectors or Biomarkers?
Atherosclerotic diseases are the leading cause of mortality in industrialized countries. Correspondingly, studying the pathogenesis of atherosclerosis and developing new methods for its diagnostic and treatment remain in the focus of current medicine and health care. This review aims to discuss the mechanistic role of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in atherogenesis. In particular, the generally accepted hypothesis about the key role of oxidized LDL in atherogenesis is questioned, and an alternative concept of multiple modification of LDL is presented. The fundamental question discussed in this review is whether LDL and HDL are effectors or biomarkers, or both. This is important for understanding whether lipoproteins are a therapeutic target or just diagnostic indicators.


Unplanned extubation in a paediatric intensive care unit: impact of a quality improvement programme.
Unplanned tracheal extubation is an important quality issue in current medical practice as it is a common occurrence in paediatric intensive care units. We have assessed the effectiveness of a continuous quality improvement programme in reducing the incidence of unplanned extubation over a 5-year period. After a 2-year baseline period, we developed action plans to address the issues identified. Following implementation of the programme, the overall incidence of unplanned extubation decreased from 2.9 unplanned extubations per 100 intubated patient days in the first year to 0.6 in the last year (p = 0.0001). This reduction was the result of a decrease in unplanned extubation in children younger than 2 years of age. Although mortality was similar to that of children who did not experience an unplanned extubation, those with an unplanned extubation had a significantly longer duration of mechanical ventilation, longer stay in the intensive care unit, and longer hospital stay. We found that the implementation of a continuous quality improvement programme is effective in reducing the overall incidence of unplanned extubations.


Current clinical spectrum of neurosyphilis in immunocompetent patients.
Neurosyphilis (NS) is nowadays a less frequent disease. Its incidence and clinical spectrum have changed over time. To estimate the incidence of NS and describe the clinical spectrum of NS in immunocompetent patients in the last decade. Demographic and clinical features, cerebrospinal fluid (CSF) changes, neuroimaging findings and outcome were retrospectively analyzed. Forty-three patients met NS criteria. The yearly incidence was 0.2- 2.1 cases per 100,000 inhabitants. The mean age was 48.1 years, males being more frequently involved. The most frequent clinical patterns were meningovascular (30.2%), meningeal (25.6%) and general paresis (25.6%). Compared to prepenicillin series, we observed a decrease in late forms, mainly tabes dorsalis. CSF titers studied by the Venereal Disease Research Laboratory were higher in early NS. Neuroimaging findings were nonspecific. Outcome was better for early forms. Compared to the preantibiotic era, a lower frequency of late NS was observed, similar to that reported in other modern series which include patients with HIV infection. Therefore, this trend seems to be due to the impact of antibiotics rather than to HIV infection.


Contemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders.
Great efforts in clinical and basic research have shown progress in understanding the neurobiological mechanisms of neurodevelopmental disorders, such as autism, schizophrenia, and attention-deficit hyperactive disorders. Literature on this field have suggested that these disorders are affected by the complex interaction of genetic, biological, psychosocial and environmental risk factors. However, this complexity of interplaying risk factors during neurodevelopment has prevented a complete understanding of the causes of those neuropsychiatric symptoms. Recently, with advances in modern high-resolution neuroscience methods, the neural circuitry analysis approach has provided new solutions for understanding the causal relationship between dysfunction of a neural circuit and behavioral alteration in neurodevelopmental disorders. In this review we will discuss recent progress in developing novel optogenetic and chemogenetic strategies to investigate neurodevelopmental disorders.


Different environmental variables predict body and brain size evolution in Homo.
Increasing body and brain size constitutes a key macro-evolutionary pattern in the hominin lineage, yet the mechanisms behind these changes remain debated. Hypothesized drivers include environmental, demographic, social, dietary, and technological factors. Here we test the influence of environmental factors on the evolution of body and brain size in the genus Homo over the last one million years using a large fossil dataset combined with global paleoclimatic reconstructions and formalized hypotheses tested in a quantitative statistical framework. We identify temperature as a major predictor of body size variation within Homo, in accordance with Bergmann's rule. In contrast, net primary productivity of environments and long-term variability in precipitation correlate with brain size but explain low amounts of the observed variation. These associations are likely due to an indirect environmental influence on cognitive abilities and extinction probabilities. Most environmental factors that we test do not correspond with body and brain size evolution, pointing towards complex scenarios which underlie the evolution of key biological characteristics in later Homo.


Computational study of solution behavior of magainin 2 monomers.
Antimicrobial peptides (AMPs) play crucial role as mediators of the primary host defense against microbial invasion. They are considered a promising alternative to antibiotics for multidrug resistant bacterial strains. For complete understanding of the antimicrobial defense mechanism, a detailed knowledge of the dynamics of peptide-membrane interactions, including atomistic studies on AMPs geometry and both peptide and membrane structural changes during the whole process is a prerequisite. We aim at clarifying the conformation dynamics of small linear AMPs in solution as a first step of in silico protocol for establishing a correspondence between certain amino-acid sequence motifs, secondary-structure elements, conformational dynamics in solution and the intensity and mode of interaction with the bacterial membrane. To this end, we use molecular dynamics simulations augmented by well-tempered metadynamics to study the free-energy landscape of two AMPs with close primary structure and different antibacterial activity - the native magainin 2 (MG2) and an analog (MG2m, with substitutions F5Y and F16W) in aqueous solution. We observe that upon solvation, the initial α-helical structures change differently. The native form remains structured, with three shorter α-helical motifs, connected by random coils, while the synthetic analog tends predominantly to a disordered conformation. Our results indicate the importance of the side-chains at positions 5 and 16 for maintaining the solvated peptide conformation. They also provide a modeling background for recent experimental observations, relating the higher α-helical content in solution (peptide pre-folding) in the case of small linear AMPs to a lower antibacterial activity.


Histochemical localization of acetylcholinesterase in the lateral eye and brain of Limulus polyphemus: might acetylcholine be a neurotransmitter for lateral inhibition in the lateral eye?
The distribution of acetylcholinesterase (AChE) in the lateral eye and brain of the horseshoe crab was investigated with histochemical means using standard controls to eliminate butyrylcholinesterase and nonspecific staining. Intense staining was observed in the neural plexus of the lateral compound eye, in the lateral optic nerve, and in various neuropils of the brain. Nerve fibers with moderate to weak staining were widespread in the brain. No somata were stained in either the lateral eye or the brain. The distribution of acetylcholinesterase in the supraesophageal ganglia and nerves of the giant barnacle was also investigated for comparison. Although both the median optic nerve of the barnacle and the lateral optic nerve of the horseshoe crab appear to contain the fibers of histaminergic neurons, only the lateral optic nerve of the horseshoe crab shows AChE staining. Other parts of the barnacle nervous system, however, showed intense AChE staining. These results along with the histochemical controls eliminate the possibility that some molecule found in histaminergic neurons accounted for the AChE staining but support the possibility that acetylcholine might be involved as a neurotransmitter in lateral inhibition in the horseshoe crab retina. Two reasonable neurotransmitter candidates for lateral inhibition, histamine and acetylcholine, must now be investigated.


The contextual effect of trust on perceived support: Evidence from Roma and non-Roma in East-Central Europe.
In recent years, trust has been conceptualized as an important source of social capital, setting off cross-disciplinary research on both the benefits and predictors of trust at the individual and contextual level. In this paper, we turn to the individual outcomes of living in a trustful context, and explore the relationship between trust, itself one of the main components of social capital, and social support, seen as one of the most important effects of social capital. In particular, we ask how social capital-and the relationship between trust and social support-functions in the context of unequal societies. We model perceived support as an outcome across three levels, from no support to proximate to distal support, and using a cross-national study of Roma and non-Roma across 12 European countries, we track the relationship between trust and support across both mainstream and marginalized populations. Our findings suggest that living in contexts with more trust has protective effects particularly for members of marginalized groups: the Roma are more likely to have distal support in contexts with higher trust. We conclude that contextual trust helps to broaden the circle of support beyond family and friends; thus, trust can indeed be a synthetic force that binds individuals together in broadened structures of support.


Improvement of diabetic wound healing by topical application of Vicenin-2 hydrocolloid film on Sprague Dawley rats.
Impaired wound healing is a debilitating complication of diabetes that leads to significant morbidity, particularly foot ulcers. The risk of developing diabetic foot ulcers for diabetic patients is 15% over their lifetime and approximately 85% of limb amputations is caused by non-healing ulcers. Unhealed, gangrenous wounds destroy the structural integrity of the skin, which acts as a protective barrier that prevents the invasion of external noxious agents into the body. Vicenin-2 (VCN-2) has been reported to contain prospective anti-oxidant and anti-inflammatory properties that enhance cell proliferation and migration. Sodium Alginate (SA) is a natural polysaccharide that possesses gel forming properties and has biodegradable and biocompatible characteristics. Therefore, the objective of this study is to evaluate the effect of SA wound dressings containing VCN-2 on diabetic wounds. Wounds were inflicted in type-1 diabetic-streptozotocin (STZ) induced male Sprague Dawley rats. Subsequently, relevant groups were topically treated with the indicated concentrations (12.5, 25 and 50 μM) of VCN-2 hydrocolloid film over the study duration (14 days). The control group was treated with vehicle dressing (blank or allantoin). Wounded tissues and blood serum were collected on 0, 7 and 14 days prior to sacrifice. Appropriate wound assessments such as histological tests, nitric oxide assays, enzyme-linked immunosorbent assays (ELISA) and immunoblotting assays were conducted to confirm wound healing efficacy in the in vivo model. One-way Analysis of Variance (ANOVA) was used for statistical analysis. Results showed that hydrocolloid film was recapitulated with VCN-2 enhanced diabetic wound healing in a dose-dependent manner. VCN-2 reduced pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), mediators (iNOS and COX-2), and nitric oxide (NO) via the NF-κB pathway. Data suggests that the VCN-2 film facilitated healing in hyperglycemic conditions by releasing growth factors such as (VEGF and TGF-β) to enhance cell proliferation, migration, and wound contraction via the VEGF and TGF-β mechanism pathways. This study's findings suggest that VCN-2 may possess wound healing potential since topical treatment with VCN-2 hydrocolloid films effectively enhanced wound healing in hyperglycemic conditions.


Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function.
Diabetes is a multifactorial disorder characterized by loss or dysfunction of pancreatic β-cells. β-cells are heterogeneous, exhibiting different glucose sensing, insulin secretion and gene expression. They communicate with other endocrine cell types via paracrine signals and between β-cells via gap junctions. Here, we identify the importance of signaling between β-cells via the extracellular signal WNT4. We show heterogeneity in Wnt4 expression, most strikingly in the postnatal maturation period, Wnt4-positive cells, being more mature while Wnt4-negative cells are more proliferative. Knock-out in adult β-cells shows that WNT4 controls the activation of calcium signaling in response to a glucose challenge, as well as metabolic pathways converging to lower ATP/ADP ratios, thereby reducing insulin secretion. These results reveal that paracrine signaling between β-cells is important in addition to gap junctions in controling insulin secretion. Together with previous reports of WNT4 up-regulation in obesity our observations suggest an adaptive insulin response coordinating β-cells.


Egyptian experience in increasing utilization of reperfusion therapies in acute ischemic stroke.
Background The rate of alteplase (tPA) thrombolysis utilization in acute stroke in Egypt is <1%. We report on the causes of this low rate of reperfusion therapies and take corrective action to improve it. Methods Two prospective observational studies were conducted at Ain Shams University hospitals. The first included 269 acute stroke patients admitted to the hospital over a six-month period. Obstacles to reperfusion therapy were identified, and based on the results, a corrective action plan was implemented including making alteplase(tPA) available, training, and establishing a standardized local protocol for reperfusion therapy. A second study was then conducted that included 284 acute ischemic stroke patients over another six-month period. Results In the first study, 53/269 patients (19.7%) arrived at hospital within 4.5 h and were eligible for reperfusion therapy. Of those, seven (13.2%) received alteplase(tPA), representing 2.6% of the total ischemic stroke patients admitted. The main causes for not giving thrombolytic therapy was unavailability of alteplase(tPA) (56.5%), wrong treatment decision (17.4%), missed window while performing brain imaging (15%), and unavailability of intermediate care bed (10.9%). The second study showed that out of 284 cases admitted with acute ischemic stroke, 37 were eligible for thrombolysis and 35 received alteplase(tPA) (94.3%), representing 12.3% of the total ischemic stroke admissions. Conclusion A comprehensive action plan that centers around making the drug available and training resulted in a significant improvement of reperfusion therapy utilization in Egypt.


The structure of the external rectus eye muscles of the carpet shark Cephaloscyllium isabella.
The external rectus muscles of the carpet shark Cephaloscyllium isabella contain two types of muscle fibre. A core of large white fibres which have regular myofibrils with extensive sarcoplasmic reticulum, triads located at the Z disc and a pronounced H band and M line. Mitochondria are frequent but tend to be smaller and less abundant than mitochondria of the smaller red fibre type. The red fibres which surround the central region are rich in mitochondria, have little sarcoplasmic reticulum and triads which are infrequent and dispersed. Sarcomere banding of red fibres is characterised by a faint H band and M line while the Z disc is thick in comparison with that found on the white muscle fibre sarcomere.


Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotine per se.
The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available. In animal studies, limited evidence suggests an association between long-term nicotine exposure and a lack of a complete carcinogenic effect. Conclusive studies using current bioassay guidelines, however, are missing. In studies using chemical/physical carcinogens or transgenic models, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a modulating (stimulating) effect on carcinogenesis. This is primarily due to the large number of conflicting studies. In contrast, a majority of studies provides sufficient evidence for an association between nicotine exposure and enhanced carcinogenesis of cancer cells inoculated in mice. This modulating effect was especially prominent in immunocompromized mice. Overall, taking the human and animal studies into consideration, there appears to be inadequate evidence to conclude that nicotine per se does or does not cause or modulate carcinogenesis in humans. This conclusion is in agreement with the recent US Surgeon General's 2014 report on the health consequences of nicotine exposure.


[The ecological and epidemiological aspects of the spread of Vibrio parahaemolyticus in a freshwater region].
For the first time Vibrio parahaemolyticus have been isolated in this country in a freshwater region both from patients with the diarrheal syndrome and from environmental objects. In the region of the lower course of the Volga morbidity in acute enteric infections (AEI) caused by these vibrios may reach 9.1% of all AEI cases in some years. The formation of an ecological niche suitable for the circulation of these bacteria has taken place in the Volga delta. All these facts indicate that freshwater reservoirs and their hydrobios present potential epidemic danger and, therefore, the possibility of sporadic AEI morbidity and outbreaks of infections caused by V.parahaemolyticus exists in freshwater regions with natural and climatic conditions similar to those of the region of the lower course of the Volga.


Sodium, K, Ca, Mg, Fe, Cu, and Zn concentrations in molluscs from the Magellan Strait (Chile): their contribution to dietary intake.
The concentrations of the essential metals Na, K, Ca, Mg, Fe, Cu, and Zn were determined in 126 specimens of molluscs belonging to five different species: Mytilus chilensis, n=47; Nacella deaurata, n=65; Aulacomya ater, n=4; Fissurella picta, n=4; Acanthina monodon, n=6, collected from the coastline of the Magellan Strait. Significant differences were obtained among the mean metal concentrations in the mollusc species considered. The contribution to the dietary daily intake of these metals for the consumption of one serving of these molluscs was high, especially the contribution to the Fe intake for the consumption of N. deaurata. Some significant differences were observed among the mean concentrations for the studied metals according to the zone of sampling. The influence of the zone of sampling on the mean concentration of metals in N. deaurata was higher than in M. chilensis. The application of lineal discriminant analysis (LDA) made it possible to differentiate statistically between specimens according to the mollusc species. Within the each mollusc species, the LDA helped to identify specimens according to the zone of sampling and weight/length ratio.


Hepatic DR5 induces apoptosis and limits adenovirus gene therapy product expression in the liver.
A major limitation of adenovirus (Ad) gene therapy product expression in the liver is subsequent elimination of the hepatocytes expressing the gene therapy product. This elimination is caused by both necrosis and apoptosis related to the innate and cell-mediated immune response to the Ad. Apoptosis of hepatocytes can be induced by the innate immune response by signaling through death domain receptors on hepatocytes including the tumor necrosis factor alpha (TNF-alpha) receptor (TNFR), Fas, and death domain receptors DR4 and DR5. We have previously shown that blocking signaling through TNFR enhances and prolongs gene therapy product expression in the liver. In the present study, we constructed an Ad that produces a soluble DR5-Fc (AdsDR5), which is capable of neutralizing TNF-related apoptosis-inducing ligand (TRAIL). AdsDR5 prevents TRAIL-mediated apoptosis of CD3-activated T cells and decreases hepatocyte apoptosis after AdCMVLacZ administration and enhances the level and duration of lacZ transgene expression in the liver. In addition to blocking TRAIL and directly inhibiting apoptosis, AdsDR5 decreases production of gamma interferon (IFN-gamma) and TNF-alpha and decreases NK cell activation, all of which limit Ad-mediated transgene expression in the liver. These results indicate that (i) AdsDR5 produces a DR5-Fc capable of neutralizing TRAIL, (ii) AdsDR5 can reduce activation of NK cells and reduce induction of IFN-gamma and TNF-alpha after Ad administration, and (iii) administration of AdsDR5 can enhance Ad gene therapy in the liver.


The Immune Response to the fVIII Gene Therapy in Preclinical Models.
Neutralizing antibodies to factor VIII (fVIII), referred to as "inhibitors," remain the most challenging complication post-fVIII replacement therapy. Preclinical development of novel fVIII products involves studies incorporating hemophilia A (HA) and wild-type animal models. Though immunogenicity is a critical aspect of preclinical pharmacology studies, gene therapy studies tend to focus on fVIII expression levels without major consideration for immunogenicity. Therefore, little clarity exists on whether preclinical testing can be predictive of clinical immunogenicity risk. Despite this, but perhaps due to the potential for transformative benefits, clinical gene therapy trials have progressed rapidly. In more than two decades, no inhibitors have been observed. However, all trials are conducted in previously treated patients without a history of inhibitors. The current review thus focuses on our understanding of preclinical immunogenicity for HA gene therapy candidates and the potential indication for inhibitor treatment, with a focus on product- and platform-specific determinants, including fVIII transgene sequence composition and tissue/vector biodistribution. Currently, the two leading clinical gene therapy vectors are adeno-associated viral (AAV) and lentiviral (LV) vectors. For HA applications, AAV vectors are liver-tropic and employ synthetic, high-expressing, liver-specific promoters. Factors including vector serotype and biodistribution, transcriptional regulatory elements, transgene sequence, dosing, liver immunoprivilege, and host immune status may contribute to tipping the scale between immunogenicity and tolerance. Many of these factors can also be important in delivery of LV-fVIII gene therapy, especially when delivered intravenously for liver-directed fVIII expression. However, ex vivo LV-fVIII targeting and transplantation of hematopoietic stem and progenitor cells (HSPC) has been demonstrated to achieve durable and curative fVIII production without inhibitor development in preclinical models. A critical variable appears to be pre-transplantation conditioning regimens that suppress and/or ablate T cells. Additionally, we and others have demonstrated the potential of LV-fVIII HSPC and liver-directed AAV-fVIII gene therapy to eradicate pre-existing inhibitors in murine and canine models of HA, respectively. Future preclinical studies will be essential to elucidate immune mechanism(s) at play in the context of gene therapy for HA, as well as strategies for preventing adverse immune responses and promoting immune tolerance even in the setting of pre-existing inhibitors.


Effects of Epley procedure on BPPV patients: a systematic review of randomized controlled trails.
The purpose of the study is to assess the effects of the Epley maneuver on patients with BPPV. International libraries such as MEDLINE, Cochrane, Web of Science, and PubMed, among others, were used to evaluate evidence on the effectiveness of Epley's procedure on BPPV published between January 2000 and December 2022. For accessing the articles, several search phrases, such as "Epley Maneuver", "BPPV", "Vertigo", "Vestibular Rehabilitation", and "Physical Therapy" were utilized. A total of 69 papers were retrieved and assessed for inclusion and exclusion criteria based on the article title, abstract, and inclusion and exclusion criteria. Following that, the quality of the chosen studies was assessed using the PEDro scale. Only seven studies fulfilled the eligibility criterion and were evaluated out of a potential 69 records found. A total of 413 BPPV-screened individuals were examined. The findings of the studies chosen for review revealed that Epley's technique had a considerable, significantly positive influence on the alleviation of symptoms for BPPV patients, including nystagmus, dizziness, and quality of life. The patients described feeling better after performing the Epley maneuver for a prolonged time. The research ended with data confirming the benefit of the Epley maneuver in relieving symptoms in BPPV patients.


Ventilatory function of factory workers exposed to tea dust.
A cross-sectional study was conducted in order to determine the prevalence of respiratory symptoms and the effect on ventilatory capacity in workers exposed to tea dust for at least five years during the sifting process of tea manufacture compared to a control group of field workers who were not exposed to tea dust previously. Fifty-three subjects each in the study and control groups were matched for age, sex, ethnic group and height. Prevalence of chronic respiratory symptoms was obtained by questionnaire. Spirometric measurements included forced vital capacity (FVC), forced expiratory volume in the first second (FEV1.0) and forced mid-expiratory flow rate (FEF 25-75%). The study group had a chest radiograph. The odds ratio for any chronic respiratory symptom was 11.6 (95% confidence interval [CI] = 3.7-39.4) in the study group. Mean values for the spirometric tests were lower in the study group; the differences in FEV 1.0 and FEF 25-75% were significant. Tuberculosis was not found in the study group, while one subject (2.4%) had radiological evidence of bronchiectasis. It may therefore be concluded that chronic tea dust exposure causes increased prevalence of respiratory symptoms and a significant degree of small airways obstruction.


Comparison of Phytochemical Composition and Untargeted Metabolomic Analysis of an Extract from Cnidoscolus aconitifolius (Mill.) I. I. Johnst and Porophyllum ruderale (Jacq.) Cass. and Biological Cytotoxic and Antiproliferative Activity In Vitro.
Cnidoscolus aconitifolius (CA) and Porophyllum ruderale (PR) are representative edible plants that are a traditional food source in Mexico. This research aimed to analyze the phytochemical composition and untargeted metabolomics analysis of CA and PR and evaluate their antiproliferative effect in vitro. The phytochemical composition (UPLC-DAD-QToF/MS-ESI) identified up to 38 polyphenols and selected organic acids that were clustered by the untargeted metabolomics in functional activities linked to indolizidines, pyridines, and organic acids. Compared with PR, CA displayed a higher reduction in the metabolic activity of human SW480 colon adenocarcinoma cells (LC50: 10.65 mg/mL), and both extracts increased the total apoptotic cells and arrested cell cycle at G0/G1 phase. PR increased mRNA Apc gene expression, whereas both extracts reduced mRNA Kras expression. Rutin/epigallocatechin gallate displayed the highest affinity to APC and K-RAS proteins in silico. Further research is needed to experiment on other cell lines. Results suggested that CA and PR are polyphenol-rich plant sources exhibiting antiproliferative effects in vitro.


Recent Advances in the Development of Noble Metal NPs for Cancer Therapy.
With the development of nanotechnology, noble metal nanoparticles are widely used in the treatment of cancer due to their unique optical properties, excellent biocompatibility, surface effects, and small size effects. In recent years, researchers have designed and synthesized a large number of nanomedicines that can be used for cancer treatment based on the morphology, physical and chemical properties, mechanism of action, and toxicological studies of noble metal nanoparticles. Furthermore, the integration of diagnosis and treatment, hyperthermia, cytotoxicity research, and drug delivery system based on the study of noble metal nanoparticles can be used as effective means for cancer treatment. This article focuses on the analysis of noble metal nanoparticles that are widely used in the treatment of cancer, such as gold nanoparticles, silver nanoparticles, platinum nanoparticles, and palladium nanoparticles. The various methods and mechanisms of action of noble metal nanoparticles in the treatment of cancer are objectively summarized in detail. Based on the research on the therapeutic safety and toxicity of noble metal nanoparticles, the development prospect of noble metal nanoparticles in the future clinical application is prospected.


Visualized simulative surgery in preoperative planning for proximal femoral varus osteotomy of DDH.
To assess the preoperative planning of visualized simulative surgery (VSS) and clinical outcomes based on computer-aided design (CAD) and 3D reconstruction for proximal femoral varus osteotomy of DDH. A total of 31 consecutive patients (23 females and 8 males) with DDH who underwent proximal femoral varus osteotomy were retrospectively reviewed between June 2014 and July 2018. Patients were divided into conventional group (n = 15) and VSS group (n = 16) according to different surgical methods. In VSS group, 16 consecutive patients who underwent proximal femoral varus osteotomy were evaluated preoperatively with the aid of VSS. The VSS steps included morphological evaluation of DDH, simulated reconstruction of proximal femoral varus osteotomy, and the implantation of locking compression pediatric hip plate (LCP-PHP). Meanwhile, the osteotomy degrees, surgery time, and radiation exposure were compared between the two groups. The average follow-up time was 33.5 months (range, 24 to 46 months). The varus angle for proximal femoral varus osteotomy was 24.2 ± 1.1° in VSS group and 25.1 ± 1.0° in conventional group (P = 0.4974). The surgery time was 31.0 ± 4.5 mins in VSS group and 48.2 ± 7.3 mins in conventional group, while radiography was 5.0 ± 1.5 times in VSS group and 8.3 ± 2.4 times in conventional group. There was a statistical significance in surgery time and radiography (P < 0.0001) when compared with the conventional group. The VSS can greatly decrease surgery time and radiation exposure for proximal femoral varus osteotomy, which could also be a tool to train young doctors to improve surgical skills and academic communication.


"Induced-fit" mechanism for catecholamine binding to the beta2-adrenergic receptor.
We engineered single and multiple mutations of serines 203, 204, and 207 in the fifth transmembrane domain of the beta(2)-adrenergic receptor, a region known to interact with hydroxyl groups of the catechol ring. Using such mutants, we measured the binding affinities of a panel of six catecholamine agonists differing only in the presence of substituents in the ethanolamine tail of the molecule. Although all ligands shared an intact catechol ring, they exhibited different losses of binding energy in response to the mutations. For all mutations, we found a clear relationship between the loss of binding caused by receptor mutation and that caused by the ligand modification. This indicates that the catechol ring and the ethanolamine tail synergistically influence their respective interactions when binding to the receptor. To verify this idea by a formal thermodynamic test, we used a double-mutant cycle analysis. We compared the effects of each receptor mutation with those induced by the modifications of the ligand's tail. Because such changes disrupt interactions occurring at different receptor domains, they should produce cumulative losses. In contrast, we found positive cooperativity between such effects. This means that the binding of each side of the catecholamine can enhance the binding of the other, through an effect that is probably propagated via a conformational change. We suggest that the agonist-binding pocket is not rigid but is dynamically formed as the ligand builds an increasing number of contacts with the receptor.


Development of chipscale InGaN RGB displays using strain-relaxed nanosphere-defined nanopillars.
Chip-scale red, green and blue (RGB) light emission on an InGaN/GaN multi-quantum well wafer adopting a top-down fabrication approach is demonstrated in this study, facilitated by shadow-masked nanosphere lithography for precise site-controlled nano-patterning. Exploiting the strain relaxation mechanism by fabricating arrays of nanosphere-defined nanopillars of two different dimensions utilizing a sequential shadow-masked nanosphere coating approach into the blue and green light-emitting pixel regions on a red-light emitting InGaN/GaN wafer, RGB light emission from a monolithic chip is demonstrated. The micro-sized RGB light-emitting pixels emit at 645 nm-680 nm, 510 nm-521 nm and 475 nm-498 nm respectively, achieving a maximum color gamut of 60% NTSC and 72% sRGB. Dimensional fluctuations of the nanopillars of 73% and 71% for the green and blue light-emitting pixels, respectively, are estimated from scanning electron microscope images of the fabricated device, corresponding to fluctuations in spectral blue-shifts of 5.4 nm and 21.2 nm as estimated by strain-coupledk·pSchrödinger calculations, consistent with observations from micro-photoluminescence (μ-PL) mapping which shows deviations of emission wavelengths for the RGB light-emitting pixels to be 8.9 nm, 14.9 nm and 23.7 nm, respectively. The RGB pixels are also configured in a matrix-addressable configuration to form an RGB microdisplay, demonstrating the feasibility of the approach towards chip-scale color displays.


Antimicrobial susceptibility patterns of Campylobacter jejuni strains isolated from hospitalized children in Athens, Greece.
The antimicrobial susceptibility of 129 Campylobacter jejuni strains, isolated from hospitalized children with gastroenteritis, to five antimicrobials, including nalidixic acid, ciprofloxacin, erythromycin, ampicillin and co-amoxiclav, was determined. Isolates belonged to two time periods: group A contained strains isolated in 1987-1988; and group B 1998-2000. Antimicrobial susceptibility patterns differed significantly between the two groups with respect to quinolones, with an increase in the percentage of resistant strains in group B (30.6% versus 0% in group A), whereas erythromycin, ampicillin and co-amoxiclav were effective drugs in both groups.


[Case report: collecting (Bellini) duct carcinoma during the follow-up for bladder cancer].
A 78-year-old man had undergone transurethral resection of bladder tumor (TUR-Bt) 6 times since he was diagnosed as having bladder cancer. Past histology was urothelial carcinoma, pTa, G1-G2. During the follow-up, recurrent bladder cancer was found. Enhanced computed tomography and drip infusion pyelography revealed pelvic cancer with tumor embolus in the inferior vena cava. Therefore, TUR-Bt and total ureteronephrectomy with removal of the thrombus from the vena cava was performed. The histopathological diagnosis was urothelial carcinoma of the bladder and Bellini duct carcinoma of the kidney, but in immunohistostaining surgical specimen of both bladder and kidney showed some similarities. This disease is rare. Several reports indicate an association between Bellini and urothelial carcinoma. We describe the case of the Bellini duct carcinoma of the kidney during the follow-up for bladder cancer with possibility of the association between Bellini and urothelial carcinoma.


Assessment of portal vein patency: comparison of arterial portography and ultrasound scanning.
The accuracy of ultrasound assessment of portal vein patency has been defined by comparing it with the results of arterial portography in 115 cases. The accuracy of arterial portography was confirmed in 21 cases where orthotopic liver transplantation was performed and used as a 'bench-mark' against which to assess the ultrasound findings. Ultrasound correctly assessed portal vein patency in 87.5% of patients. It was more accurate in assessing patency (90%) than occlusion (68%). Ultrasound correctly assessed portal vein patency in 90% of cases of cirrhosis and hepatic malignancy. Difficulties occurred in children with biliary atresia particularly following the Kasai operation (37.5% accuracy). In the absence of previous surgery to the portal vein or biliary system, ultrasound is comparable to arterial portography and can be used as the sole means of assessment.


The potential role of abnormal angiotensin-converting enzyme 2 expression correlated with immune infiltration after SARS-CoV-2 infection in the prognosis of breast cancer.
The potential role of abnormal ACE2 expression after SARS-CoV-2 infection in the prognosis of breast cancer is still ambiguous. In this study, we analyzed ACE2 changes in breast cancer and studied the correlation between ACE2 and the prognosis and further analyzed the relationship between immune infiltration and the prognosis of different breast cancer subtypes. Finally, we inferred the prognosis of breast cancer patients after SARS-CoV-2 infection. We found that ACE2 expression decreased significantly in breast cancer, except for basal-like subtype. Decreased ACE2 expression level was correlated with abnormal immune infiltration and poorer prognosis of luminal B breast cancer (RFS: HR 0.76, 95%CI=0.63-0.92, p=0.005; DMFS: HR 0.70, 95%CI=0.49-1.00, p=0.046). The expression of ACE2 was strongly positively correlated with the immune infiltration level of CD8+ T cell (r=0.184, p<0.001), CD4+ T cell (r=0.104, p=0.02) and neutrophils (r=0.101, p=0.02). ACE2 expression level in the luminal subtype was positively correlated with CD8A and CD8B markers in CD8+ T cells, and CEACAM3, S100A12 in neutrophils. In conclusion, breast tumor tissues might undergo a further decrease in the expression level of ACE2 after SARS-CoV-2 infection, which could contribute to further deterioration of immune infiltration and worsen the prognosis of luminal B breast cancer after SARS-CoV-2 infection.


Relationships between organic carbon and microbial components in a Tyrrhenian area (Isola del Giglio) affected by mucilages.
The chemical and biological properties of the water column at a Tyrrhenian site (Isola del Giglio) were studied during a 3-year period. The results highlighted the oligotrophic features of the site, characterised by quite low concentrations of organic carbon (on average DOC 102 micromol/L and POC 9 micromol/L). Relevant bacterial biomass (on average 42.1 microg C/L) and a notable activity (in terms of frequency of dividing cells, on average more than 5%) were observed. However, remarkable changes for these parameters were seasonally recorded. The cyclic occurrence, generally during the late spring-summer period, of benthic mucilage indicated that localised distrophic processes may occur. In particular, the benthic mucilage events of 2000 and 2001 were investigated, although some comparative information was available also for 1999 and 2002. The mucilage aggregates generally showed high bacterial colonisation, which have remarkable effects on the organic matter cycle both inside the aggregates and in the surrounding seawater. During the benthic mucilage development, an increase of DOC and POC concentrations was observed (up to 129 and 18 micromol/L, respectively, in June 2000 and up to 145 and 10 micromol/L, respectively, in May and June 2001) in the water column adjacent to the bottom. However, a general decrease of the trophic value of particulate matter (in terms of C/N ratio) was also observed, especially in 2000 after the disappearance of the mucilage. The available energy and organic matter during the mucilage events led to an increased presence of bacteria in the bottom waters of the Isola del Giglio, with maximum biomass values in 2001. Similarly, the replicative activity of bacteria was higher in 2001 (frequency of dividing cells about 5% vs. 3% of 2000). The lower activity of 2000, in addition to the lower trophic value of organic matter and different environmental conditions (namely lower temperature), might be involved in the persistence of mucilage in 2000 with respect to the rapid disappearance observed in 2001.


Predicting risk of endovascular device infection in patients with Staphylococcus aureus bacteremia (PREDICT-SAB).
Prompt recognition of underlying cardiovascular implantable electronic device (CIED) infection in patients presenting with Staphylococcus aureus bacteremia (SAB) is critical for optimal management of these cases. The goal of this study was to identify clinical predictors of CIED infection in patients presenting with SAB and no signs of pocket infection. All cases of SAB in CIED recipients at Mayo Clinic from 2001 to 2011 were retrospectively reviewed. We identified 131 patients with CIED who presented with SAB and had no clinical signs of device pocket infection. Forty-five (34%) of these patients had underlying CIED infection based on clinical or echocardiographic criteria. The presence of a permanent pacemaker rather than an implantable cardioverter-defibrillator (odds ratio, 3.90; 95% confidence interval, 1.65-9.23; P=0.002), >1 device-related procedure (odds ratio, 3.30; 95% confidence interval, 1.23-8.86; P=0.018), and duration of SAB ≥4 days (odds ratio, 5.54; 95% confidence interval, 3.32-13.23; P<0.001) were independently associated with an increased risk of CIED infection in a multivariable model. The area under the receiver operating characteristics curve for the multivariable model was 0.79, indicating a good discriminatory capacity to distinguish SAB patients with and without CIED infection. Among patients presenting with SAB and no signs of pocket infection, the risk of underlying CIED infection can be calculated based on the type of device, number of device-related procedures, and duration of SAB. We propose that patients without any of these high-risk features have a low risk of underlying CIED infection and may be monitored closely without immediate device extraction. Prospective studies are needed to validate this risk prediction model.


D701N mutation in the PB2 protein contributes to the pathogenicity of H5N1 avian influenza viruses but not transmissibility in guinea pigs.
H5N1 highly pathogenic avian influenza virus (HPAIV) of clade 2.3.2 has been circulating in waterfowl in Southern China since 2003. Our previous studies showed that certain H5N1 HPAIV isolates within clade 2.3.2 from Southern China had high pathogenicity in different birds. Guinea pigs have been successfully used as models to evaluate the transmissibility of AIVs and other species of influenza viruses in mammalian hosts. However, few studies have reported pathogenicity and transmissibility of H5N1 HPAIVs of this clade in guinea pigs. In this study, we selected an H5N1 HPAIV isolate, A/duck/Guangdong/357/2008, to investigate the pathogenicity and transmissibility of the virus in guinea pigs. The virus had high pathogenicity in mice; additionally, it only replicated in some tissues of the guinea pigs without production of clinical signs, but was transmissible among guinea pigs. Interestingly, virus isolates from co-caged guinea pigs had the D701N mutation in the PB2 protein. These mutant viruses showed higher pathogenicity in mice and higher replication capability in guinea pigs but did not demonstrate enhanced the transmissibility among guinea pigs. These findings indicate the transmission of the H5N1 virus between mammals could induce virus mutations, and the mutant viruses might have higher pathogenicity in mammals without higher transmissibility. Therefore, the continued evaluation of the pathogenicity and transmissibility of avian influenza virus (AIVs) in mammals is critical to the understanding of the evolutionary characteristics of AIVs and the emergence of potential pandemic strains.


Octamer-binding protein 4 affects the cell biology and phenotypic transition of lung cancer cells involving β-catenin/E-cadherin complex degradation.
Clinical studies have reported evidence for the involvement of octamer‑binding protein 4 (Oct4) in the tumorigenicity and progression of lung cancer; however, the role of Oct4 in lung cancer cell biology in vitro and its mechanism of action remain to be elucidated. Mortality among lung cancer patients is more frequently due to metastasis rather than their primary tumors. Epithelial‑mesenchymal transition (EMT) is a prominent biological event for the induction of epithelial cancer metastasis. The aim of the present study was to investigate whether Oct4 had the capacity to induce lung cancer cell metastasis via the promoting the EMT in vitro. Moreover, the effect of Oct4 on the β‑catenin/E‑cadherin complex, associated with EMT, was examined using immunofluorescence and immunoprecipitation assays as well as western blot analysis. The results demonstrated that Oct4 enhanced cell invasion and adhesion accompanied by the downregulation of epithelial marker cytokeratin, and upregulation of the mesenchymal markers vimentin and N‑cadherin. Furthermore, Oct4 induced EMT of lung cancer cells by promoting β‑catenin/E‑cadherin complex degradation and regulating nuclear localization of β‑catenin. In conclusion, the present study indicated that Oct4 affected the cell biology of lung cancer cells in vitro through promoting lung cancer cell metastasis via EMT; in addition, the results suggested that the association and degradation of the β‑catenin/E‑cadherin complex was regulated by Oct4 during the process of EMT.


Vitamin B12 deficiency optic neuropathy detected by asymptomatic screening.
Asymptomatic bilateral optic disc swelling was detected in a 19-year-old man with type 1 diabetes through routine photographic screening for retinopathy. He was found to have significant vitamin B(12) deficiency which the authors believe was the cause for the optic neuropathy. After B(12) replacement, visual function and optic disc appearances returned to normal.


Oscillatory Correlates of Visual Consciousness.
Conscious experiences are linked to activity in our brain: the neural correlates of consciousness (NCC). Empirical research on these NCCs covers a wide range of brain activity signals, measures, and methodologies. In this paper, we focus on spontaneous brain oscillations; rhythmic fluctuations of neuronal (population) activity which can be characterized by a range of parameters, such as frequency, amplitude (power), and phase. We provide an overview of oscillatory measures that appear to correlate with conscious perception. We also discuss how increasingly sophisticated techniques allow us to study the causal role of oscillatory activity in conscious perception (i.e., 'entrainment'). This review of oscillatory correlates of consciousness suggests that, for example, activity in the alpha-band (7-13 Hz) may index, or even causally support, conscious perception. But such results also showcase an increasingly acknowledged difficulty in NCC research; the challenge of separating neural activity necessary for conscious experience to arise (prerequisites) from neural activity underlying the conscious experience itself (substrates) or its results (consequences).


Dose-dependent Spasmolytic, Bronchodilator, and Hypotensive Activities of Panicum miliaceum L.
Panicum miliaceum L. is a medicinally effective plant used in indigenous system of medicine for a variety of ailments. However, there is no comprehensive study explaining its effectiveness in gastrointestinal tract, respiratory, and cardiovascular system ailments. This study was designed to validate the pharmacological basis for the folkloric use of Panicum miliaceum L. in diarrhea, asthma, and hypertension. Panicum miliaceum extract was analyzed to detect the presence of bioactive compounds by HPLC. The isolated rabbit jejunum, trachea, and aorta were used for in vitro experiments using tissue bath assembly coupled with Power Lab data acquisition system to explore their relative effects. In-vivo experiments were performed for anti-diarrheal activity. HPLC analysis revealed the presence of gallic acid, butylated hydroxytoluene, catechin, and quercetin. Concentration dependent activities were observed by relaxing K+ (low) induced contractions having spasmolytic effect with EC50 = .358 ± .052, bronchodilator (EC50 = 2.483 ± .05793), and vasorelaxant (EC50 = .383 ± .063), probably due to the ATP dependent potassium channel activation. It was confirmed through pre-exposure of glibenclamide (specific ATP-dependent K+ channel blocker) having similarities with cromakalim. Pm.Cr revealed its antidiarrheal via in vivo experiments on rats. This study indicates that Panicum miliaceum has antidiarrheal, spasmolytic, bronchodilator, and vasorelaxant activities probably due to the ATP dependent K+ channel activation.


Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia.
Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.


Determining the fate of hepatic cells by lineage tracing: facts and pitfalls.
Slow renewal of the epithelial cells by proliferation ensures homeostasis of the liver, but extensive proliferation may occur upon injury. When proliferation is impaired, transdifferentiation of mature cells or differentiation of stem cells allows production of new hepatocytes and cholangiocytes. While lineage tracings using cyclization recombinase (Cre) recombinase-mediated cell labeling represent the gold standard for defining cell fate, there are more variables than was initially realized. This led to controversies about the capacity of liver cells to switch their fate. Here, I review how cells are traced in the liver and highlight the experimental pitfalls that may cause misinterpretations and controversies.


Bone alkaline phosphatase in children with chronic renal failure.
With the introduction of a new immunoradiometric assay based on two monoclonal antibodies (Tandem-Ostase, Hybritech) the determination of bone alkaline phosphatase (BAP) to evaluate bone metabolism in chronic renal failure has become easier and more valid. Using this test we investigated BAP in a total of 90 paediatric patients, 42 (9.2+/-5.5 years) with chronic renal failure on conservative treatment, 22 (9.5+/-5.4 years) under chronic dialysis, and 26 (16.2+/-5.9 years) after renal transplantation, compared to 203 controls (10.1+/-5.7 years). The physiological age dependency found in controls including two peaks during infancy and puberty was distinctly disturbed in chronic renal failure. However, in patients BAP significantly correlated with height velocity rather reflecting the last 6 (r=0.56 P<0.001) than the last 12 months. Although BAP correlated well with total alkaline phosphatase (TAP; r=0.95 P<0.001), a significant correlation with the serum level of the intact parathyroid hormone could only be detected for BAP (r=0.45 P<0.001) but not for TAP (r=0.19 n.s.). Furthermore, BAP positively correlated with trabecular (n=40; r=0.40 P<0.05) and inversely with cortical bone density (n=19; r=-0.58 P<0.01) but no relationship was found with conventional X-ray. BAP determined by the new radioimmunoassay seems to represent an additional diagnostic tool to assess growth and bone turnover in paediatric patients with chronic renal failure that is complementary to the information provided by X-ray and total alkaline phosphatase.


[Splenic injuries: therapeutic orientation. Apropos of 46 cases].
Between 1979 and june 1983, 46 splenic trauma, with or without associated lesions, have been treated at Sainte'-Justine's Hospital. 8 children had a splenectomy, 3 had a laparotomy for other lesions without a splenectomy was done. 35 had a non operative management of splenic trauma. The ultrasound shows the splenic lesions and the blood in the peritoneal cavity. So, the "Routine Abdominal TAP" does not seem necessary in every abdominal trauma. The splenic scintigraphy is, for, now, the best exam to confirm the diagnosis and to assess the resolution of splenic lesion in 1 to 4 months. Transfusions were done in 8 of 11 operated patients and in 11 of the 35 children wo underwent a conservative management. The average stay in the hospital was 11 days in these 35 last patients. No mortality or morbidity were in relation with the conservative management in our series. The exact diagnosis of splenic trauma by ultrasound and scintigraphy allows the pediatric surgeon to choose a non operative treatment, when the child has stable vital signs. Monitoring these patients in intensive care unit is mandatory and allows a careful evaluation of the course of these splenic trauma.


Analyses of the acetate-producing pathways in Corynebacterium glutamicum under oxygen-deprived conditions.
Corynebacterium glutamicum R efficiently produces valuable chemicals from glucose under oxygen-deprived conditions. In an effort to reduce acetate as a byproduct, acetate productivity of several mutant-disrupted genes encoding possible key enzymes for acetate formation was determined. Disruption of the aceE gene that encodes the E1 enzyme of the pyruvate dehydrogenase complex resulted in almost complete elimination of acetate formation under oxygen-deprived conditions, implying that acetate synthesis under these conditions was essentially via acetyl-coenzyme A (CoA). Simultaneous disruption of pta, encoding phosphotransacetylase, and ack, encoding acetate kinase, resulted in no measurable change in acetate productivity. A mutant strain with disruptions in pta, ack and as-yet uncharacterized gene (cgR2472) exhibited 65% reduced acetate productivity compared to the parental strain, although a single disruption of cgR2472 exhibited no effect on acetate productivity. The gene cgR2472 was shown to encode a CoA-transferase (CTF) that catalyzes the formation of acetate from acetyl-CoA. These results indicate that PTA-ACK as well as CTF is involved in acetate production in C. glutamicum. This study provided basic information to reduce acetate production under oxygen-deprived conditions.


Kinetics of human serum butyrylcholinesterase and its inhibition by a novel experimental Alzheimer therapeutic, bisnorcymserine.
An explosion in the incidence of neurodegenerative diseases, particularly Alzheimer's disease (AD), is predicted in coming decades. Hence, the need to devise and assess new treatment strategies has never been more acute. AD, although an irreversible and progressive disorder, is currently treated with palliative, symptomatic therapy: primarily with acetylcholinesterase (AChE) inhibitors to amplify remaining cholinergic activity. New agents that, additionally, affect disease progression are sorely needed. Inhibition of brain butyrylcholinesterase (BuChE) represents a new drug target for AD treatment. Therefore, hand-in-hand with the development of selective ligands to inhibit BuChE in brain, it is fundamental to optimize assay conditions for kinetic studies of human BuChE. Kinetic analysis of serum BuChE, which is structurally similar to brain enzyme, was performed at dual substrate (butyrylthiocholine iodide) concentration ranges: 3-80 microM (low) and 25-800 microM (optimal) by use of the Ellman technique. Interaction of BuChE with a novel experimental AD therapeutic, bisnorcymserine (BNC; 0.06-2.0 nM) was also studied ex vivo. The IC_{50} and other key kinetic constants were determined for human serum BuChE inhibition by BNC, which proved to be a highly potent inhibitor in comparison to its structural analogue, cymserine. BNC may, additionally, lower the amyloid plaque-associated protein, amyloid-beta peptide. In synopsis, the characterization of the kinetic parameters of BuChE and BNC, described herein, is both aiding in the design of novel agents and optimizing their translation toward clinical use.


[Hormones and bioactive substances in milk--rudiments or physiologic signals?].
Human milk and milk of lower mammals contains hormones, growth factors, as well as secondary messengers. It can be supposed that in the past this composition secured a better survival for the offspring in a certain phase of development. The question is, what role do the factors play in the physiological development today. They certainly affect the mammary gland at its own right, there is evidence about a positive effect on the intestinal mucosa of infants, even on the regulation of hormonal secretion. Hence, they represent signals sent by the maternal organism and affect the reaction of infants. Whether these effects are physiologically significant in animals and especially in humans still remains to be proved. A very rapidly progressing research promises many interesting and surprising findings in the near future. Objective evaluation of effects of milk composition on the offspring neither allows us to ignore the possibility of negative consequences in postreproductive age, since these signs are not being eliminated by natural selection during evolution.


Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial.
Sirolimus reduces acute rejection in renal transplant recipients and prevents vasculopathy in nonhuman primates and in-stent restenosis in humans. Its effects on rejection and transplant vasculopathy in human heart transplant recipients are unknown. In a randomized, open-label study, sirolimus was compared with azathioprine in combination with cyclosporine and steroids administered from the time of cardiac transplantation. We report 6-month rejection rates (primary end point), 12-month safety and efficacy data, and 6- and 24-month graft vasculopathy data in 136 cardiac allograft recipients randomly assigned (2:1) to sirolimus (n=92) or azathioprine (n=44). At 6 months, the proportion of patients with grade 3a or greater acute rejection was 32.4% for sirolimus 3 mg/d (P=0.027), 32.8% for sirolimus 5 mg/d (P=0.013), and 56.8% for azathioprine. Patient survival at 12 months was comparable among groups. Intracoronary ultrasound at 6 weeks, 6 months, and 2 years demonstrated highly significant progression of transplant vasculopathy in azathioprine-treated patients. At 6 months, a highly significant absence of progression in intimal plus medial proliferation and significant protection against luminal encroachment was evident in sirolimus-treated patients, and these effects were sustained at 2 years. Sirolimus use from the time of transplantation approximately halved the number of patients experiencing acute rejection. The measurable development of transplant vasculopathy at 6 months and 2 years in patients receiving azathioprine was not observed in patients receiving sirolimus.


Compliance With a Comprehensive Antibiotic Protocol Improves Infection Incidence in Pediatric Spine Surgery.
A multidisciplinary task force, designated Target Zero, has developed protocols for prevention of surgical site infection (SSI) for spine surgery at our institution. The purpose of this study was to evaluate how compliance with an antibiotic bundle impacts infection incidences in pediatric spine surgery. After institutional review board approval, a consecutive series of 511 patients (517 procedures) who underwent primary spine procedures from 2008 to 2012 were retrospectively reviewed to identify patients who developed SSI. Patients were followed for a minimum of 90 days postoperatively. Compliance data were collected prospectively in 511 consecutive patients and a total of 517 procedures. Three criteria were required for antibiotic bundle compliance: appropriate antibiotics completely administered within 1 hour before incision, antibiotics appropriately redosed intraoperatively for blood loss and time, and antibiotics discontinued within 24 hours postoperatively. A multivariable logistic regression analysis was used to test the association between compliance and the development of an infection. Overall antibiotic bundle compliance rate was 85%. After adjusting for risk category, estimated blood loss, and study year, the likelihood of an infection was increased in the noncompliant group compared with the compliant group (adjusted odds ratio: 3.0, 95% CI, 0.96-9.47, P=0.0587). When expressed as the number needed to treat, strict adherence to antibiotic bundle compliance prevented 1 SSI within 90 days of surgery for every 26 patients treated with the antibiotic bundle. Reasons for noncompliance included failure to infuse preoperative antibiotics 1 hour before incision (10.3%), failure to redose antibiotics intraoperatively based on time or blood loss (5.5%), and failure to discontinue antibiotics within 24 hours postoperatively (1.9%). Compliance with a comprehensive antibiotic protocol can lead to meaningful reductions in SSI incidences in pediatric spine surgery. Institutions should focus on improving compliance with prophylactic antibiotic protocols to decrease SSI in pediatric spine surgery. Level III-retrospective cohort study.


Immunophenotypic markers in renal cell carcinoma.
We studied immunophenotypic and tumor cell markers in renal cell carcinoma (RCC) to determine if there are patterns of expression which may correlate with biologic behavior and response to therapy. Fourteen RCCs from 13 patients were stained by the immunoperoxidase technique using primary antibodies to Leu 4, Leu 14, Leu 2a, Leu 3a and b, lysozyme, dendritic reticulum cell (DRC), S-100, HLA-DR, epithelial membrane antigen (EMA) and beta-2-microglobulin (B2-MG). Staining was correlated with tumor stage, nuclear grade, histologic patterns, degree of cellular infiltrate, and clinical followup. Four RCCs were stage T1, four T2, five T3, and one T4. Most tumors were clear or granular cell type, with a solid or tubular growth pattern. The number of infiltrating lymphocytes and monocytes correlated with tumor grade and stage. Tumor-infiltrating lymphocytes (TILs) were predominantly Leu 3-positive (T-helper phenotype). B-cell markers were negative. Dendritic cells were rare. HLA-DR was present on endothelial cells in 11 tumors and on tumor cells in ten. HLA-DR expression increased with tumor grade. Tumor cells expressed EMA in 12 cases; B2-MG in four cases. Two patients, stages 3 and 4, died at 2 and 6 mo. (a) T-helper cells and monocytes infiltrate RCCs. Their numbers increase with tumor grade and stage. (b) HLA-DR expression by tumor cells tends to correlate with increasing stage and grade. (c) Dendritic cells are infrequent in RCCs.


Childhood acne in a boy with XYY syndrome.
A 3-year-old boy was referred to the dermatology department with a 12-month history of facial erythema associated with a papular-pustular facial eruption consistent with childhood acne. He had been diagnosed with XYY syndrome identified during genetic analysis for cardiac anomalies at birth. XYY syndrome is an aneuploidy of the sex chromosomes which affects 1 in 1000 male births. It is often asymptomatic and identified incidentally following genetic analysis for other conditions. The syndrome can be associated with an increased risk of learning difficulties and delayed language skills. Early diagnosis could alert physicians to the possibility of subtle developmental and learning abnormalities and result in prompt management. Our case highlights the fact that the presence of childhood acne could aid in the early detection of XYY syndrome.


Mitochondrial STAT3: Powering up a potent factor.
The JAK-STAT3 signaling pathway is engaged by many cytokines and growth factor stimuli to control diverse biological processes including proliferation, angiogenesis, survival, immune modulation, and metabolism. For over two decades it has been accepted that STAT3-dependent biology is due to its potency as a transcription factor capable of regulating the expression of many hundreds of genes. However, recent evidence of non-canonical and non-genomic activities of STAT3 has emerged. The most exciting of these activities is its capacity to translocate into the mitochondria where it regulates the activity of the electron transport chain and the opening of the mitochondrial permeability transition pore. These have broad consequences including cell survival and the production of reactive oxygen species and ATP in both normal tissue and under pathological conditions. Despite these fascinating observations there are many key unanswered questions about the mechanism of STAT mitochondrial activity.


Anti-infiltration for fabrication of a suspended nanoparticle layer on porous close-packed colloidal arrays.
We develop a new method to fabricate suspended sheets of nanocrystals (NCs) on porous surfaces. The method relies on the resistance of an aqueous suspension droplet to infiltrate a porous network; hence, the method is named anti-infiltration. The process works by combining fluid dynamics of a liquid droplet during impact/absorption onto a porous surface with the convective self-assembly of NCs. The immobilization of the liquid droplet edge due to the self-assembly of NCs at the meniscus is harnessed to halt the lateral spreading of the droplet and, consequently, the capillary penetration of the liquid immediately after droplet impact. Further capillary penetration of the liquid is drastically reduced because of the competition between capillary forces and convective losses as well as the rapid occlusion of the pores as soon as a continuous NC film has formed upon evaporation of the suspension. This method holds promise for a wide variety of optoelectronic, sensing, and separation membrane applications. As an example, we demonstrate that these suspended NC layers are suitable candidates as planar defects embedded within a colloidal photonic crystal.