Clinical pharmacology of SQ 10,996, a potential antidepressive agent.
Single oral doses of SQ 10,996 ranging from 500 to 1000 mg (0.34 to 15.3 mg/kg), given once daily for 3 consecutive days to groups of healthy volunteers, were well tolerated. One of three subjects given 1250 mg (17.1 mg/kg) and two of three subjects given 1500 mg (15.6 and 21.4 mg/kg) became drowsy on the second and third days; this symptom disappeared within 24 hrs after cessation of dosage. A short-term, multiple-dose tolerance study was carried out with a formulation of SQ 10,996, the bioavailability of which was comparable to that of the formulation used earlier in the ascending-dose tolerance study. When 200-mg doses were administered every 12, 8, or 6 hrs over a 6-day period, mean steady-state serum concentrations of approximately 4, 7, and 8 mug/ml were attained within 48 hrs; unexpectedly, no subject showed any sign of drowsiness. The half-life for SQ 10,996 in serum, estimated from concentrations in serum after the last dose, was approximately 13 hrs, significantly shorter than the half-life found previously after the administration of single 10-mg doses. These clinical pharmacology studies in healthy volunteers have shown SQ 10,996 to be biologically available and well tolerated. Future studies will test its antidepressive potential in patients.


Determination of best particle tracking velocimetry method for two-dimensional dusty plasmas.
A practical procedure of determining the best choice of particle tracking velocimetry (PTV) methods for the analysis of two-dimensional (2D) dusty plasmas is provided. Using the measured particle positions with errors, the algorithm of PTV introduces further systematic errors while calculating particle velocities. To better quantify the errors, computer simulations of 2D Yukawa liquids are performed so that the true particle positions and velocities are precisely known. Synthetic data are achieved by varying the time interval between frames and adding the uncertainty with the different magnitude to the particle position data. Various PTV methods are used to calculate the velocity data from the achieved synthetic data, and the obtained velocity data from these PTV methods are compared with the true velocity data using two diagnostics to determine the best PTV method for various conditions. The results of various PTV methods with the simulation data are further confirmed by the demonstration using the 2D dusty plasma experimental data. This practical procedure is also applicable to determine the best PTV method for dusty plasmas in different conditions, such as those in Tokamaks, and for other physical systems, including colloids, granular materials, and fluid mechanics.


CT in penetrating craniocervical injury by wooden foreign bodies: reminder of a pitfall.
The authors report three cases of penetrating craniocervical injury by wooden foreign bodies, which were initially hypodense on CT and thought to be air. When these structures were scrutinized with higher window settings, they had a higher attenuation and a unique striated internal architecture which the authors propose may be specific to wood.


Changes in the producer payments scheme for milk.
The volume of milk for manufacture has more than doubled since 1970 and now exceeds that taken by the liquid market. To match producer payments more closely to market realities the MMB will, from April 1984, replace the fat and solids-non-fat compositional quality payment scheme with one based on fat, protein and lactose. In the last 10 years the seasonal trough of production has moved from December to August/September. In an attempt to slow this trend and also provide a disincentive to additional supplies at peak, the MMB is altering its seasonal price adjustments. Milk prices will be increased in August and September and decreased in May and June. The changes in themselves will not affect the total sum of money available to producers, hence most of them will see little difference to their annual income. The exception will be those producers supplying milk of either especially low or high protein and, to a lesser extent, fat content. The change in seasonal adjustments will however cause a noticeable disruption in the cash flow to all producers. The price changes are not likely to produce an immediate management response but should encourage producers to consider critically their existing feeding, breeding and calving policies.


Susceptibility of the Most Popular Soybean Cultivars in South-East Europe to Macrophomina phaseolina (Tassi) Goid.
Oxidative stress in soybean seedlings and the length of the soybean stem lesions infected with the fungus Macrophomina phaseolina (Tassi) Goid were evaluated to determine the most tolerant soybean cultivar to this pathogen. The level of superoxide anion radical (O2•-) production, the activity of the antioxidant enzyme superoxide-dismutase (SOD), and the intensity of lipid peroxidation (LP) were measured in four soybean cultivars: Favorit, Atlas, Victoria, and Rubin. Results showed that O2•- radical production and SOD activity were the most elevated in the cv. Favorit inoculated with M. phaseolina, while the level of lipid peroxidation intensity was the lowest compared to the control. This indicates that the soybean cv. Favorit has managed to prevent infection with M. phaseolina. Furthermore, higher O2•- radical production and lower SOD enzyme activity were measured in cv. Victoria, with enhanced lipid peroxidation. This means that the cv. Victoria was infected with M. phaseolina, and was the most sensitive. None of the tested oxidative stress parameters showed a significant difference in the cvs. Atlas and Rubin compared to the control. Furthermore, the highest lesion length was measured in the cv. Victoria, followed by cv. Favorit, while the lowest lesion length was measured in the cv. Atlas followed by the cv. Rubin; and thus, the cv. Atlas followed by the cv. Rubin, were the most tolerant soybean cultivars to this pathogen.


GM-CSF enhances sensitivity of leukemic clonogenic cells to long-term low dose cytosine arabinoside with sparing of the normal clonogenic cells.
Leukemic clonogenic cells (CFU-L) and normal myeloid progenitor cells (CFU-GM) were exposed to Ara-C in the presence of crude CSF obtained from placentas (HPCM) or recombinant human GM-CSF for varying periods. The cytotoxicity of Ara-C to CFU-L increased considerably when the exposure time to Ara-C in the presence of HPCM was extended from 20 hours to 10 days. The ID50 of the CFU-L was 1.5 +/- 2.2 x 10(-8) M Ara-C compared to 5.5 +/- 2.9 x 10(-8) M Ara-C for the CFU-GM after an exposure to Ara-C for 10 days (p less than 0.05). Replacement of crude CSF from placenta conditioned medium by rh GM-CSF resulted in identical observations. Interesting was the observation that secondary leukemic colony forming cells were more or at least equally sensitive to Ara-C in the presence of GM-CSF when compared to the primary leukemic clonogenic cells. This contrasted the secondary normal CFU-GM, which were less sensitive to Ara-C than the primary CFU-GM. This indicates that GM-CSF induces leukemic clonogenic cells with selfrenewal capacity into proliferation, and in doing so, it may enhance the cytotoxicity of a cell cycle specific drug like Ara-C with sparing of the normal clonogenic cells.


Folic acid supplementation rescues bladder injury in fetal rats with myelomeningocele.
Bladder dysfunction has been linked to the progression of renal failure in children with neurogenic bladder (NB) dysfunction. The purpose of this study was to determine whether bladder injuries in fetal rats with myelomeningocele (MMC) may be treated with folic acid. Pregnant Sprague-Dawley rats were randomly divided into three groups. On the 10th day of gestation, pregnant rats were intragastrically injected with all-trans retinoic acid (ATRA) (60 mg/kg) to induce MMC fetal rats. The same amount of olive oil was put into the control group to create normal fetal rats. The rats in the rescue group were given folic acid (40 mg/kg) by gavage 0.5 and 12 hr after ATRA therapy. Bladders were obtained via cesarean section on embryonic day E20.5 and examined for MMC. The histology of the fetuses was examined using hematoxylin and eosin staining, and immunohistochemistry (IHC) was utilized to determine the expression of α-smooth muscle actin (α-SMA) and neuron-specific nuclear-binding protein (NeuN). Furthermore, the levels of neuromuscular development-related and apoptotic proteins were determined by western blotting. The incidence of MMC in the model group was 60.6% (20/33) while it was much lower in the rescue group (21.4%). In comparison to the model group, the weight and crown-rump length of the fetal rats in the rescue group were significantly improved. IHC revealed that there was no significant difference in the expression of α-SMA and NeuN between the control and ATRA groups, while the expression levels decreased significantly in the MMC group. Western blot analysis showed that there was no significant difference between the model and ATRA groups, but the expression of the α-SMA protein and the β3-tubulin was much lower in the MMC group than in the control group. After the administration of folic acid, the α-SMA and β3-tubulin proteins considerably increased in the folic acid-rescued MMC group and folic acid-rescued ATRA group. Meanwhile, in the control group, the expression of cleaved caspase-3 in the bladder tissue was significantly higher, and the expression of poly (ADP-ribose) polymerase (PARP) protein was significantly lower compared to the control group. Folic acid therapy reduced cleaved caspase-3 expression while increasing PARP expression in comparison to the MMC group. NB in MMC fetal rats is associated with the reduction of bladder nerve and smooth muscle-related protein synthesis. However, folic acid therapy can help improve these functional deficiencies. Folic acid also exhibits strong anti-apoptotic properties against NB in MMC fetal rats.


One-pot solvothermal synthesis of graphene wrapped rice-like ferrous carbonate nanoparticles as anode materials for high energy lithium-ion batteries.
Well dispersed rice-like FeCO3 nanoparticles were produced and combined with reduced graphene oxide (RGO) via a one-pot solvothermal route. SEM characterization shows that rice-like FeCO3 nanoparticles are homogeneously anchored on the surface of the graphene nanosheets; the addition of RGO is helpful to form a uniform morphology and reduce the particle size of FeCO3 to nano-grade. As anode materials for lithium-ion batteries, the FeCO3/RGO nanocomposites exhibit significantly improved lithium storage properties with a large reversible capacity of 1345 mA h g(-1) for the first cycle and a capacity retention of 1224 mA h g(-1) after 50 cycles with a good rate capability compared with pure FeCO3 particles. The superior electrochemical performance of the FeCO3/RGO nanocomposite electrode compared to the pure FeCO3 electrode can be attributed to the well dispersed RGO which enhances the electronic conductivity and accommodates the volume change during the conversion reactions. Our study shows that the FeCO3/RGO nanocomposite could be a suitable candidate for high capacity lithium-ion batteries.


Shared Responsibility for Type 1 Diabetes Care Is Associated With Glycemic Variability and Risk of Glycemic Excursions in Youth.
We examined how parent and youth responsibility for type 1 diabetes (T1D) care is related to adherence and glycemic outcomes, namely, glycemic variability and risk of glycemic excursions. One hundred thirty-five parent-youth dyads (10-16 years old; diagnosed with T1D for at least 6 months) participated in this study. Percent responsibility of T1D care attributed to the youth, parent, or shared was measured using the Diabetes Family Responsibility Questionnaire. We collected youth's hemoglobin A1c (HbA1c) and glucometer downloads to examine relationships between responsibility and HbA1c, frequency of blood glucose monitoring (self-monitoring blood glucose, SMBG), risk of glycemic excursions, and actual glycemic variability using bivariate correlations and path analysis. Participants reported shared responsibility for almost half of T1D self-care tasks. Bivariate correlations showed shared responsibility was associated with less variability, whereas parent responsibility was associated with greater glycemic variability and risk for glycemic excursions. Youth responsibility was associated with lower frequency of SMBG. The path analyses confirmed our correlational findings (ps<.05) and better characterized interactions with age for youth-reported responsibility. Our results support the hypothesis that shared T1D responsibility is associated with better diabetes outcomes in youth.


Oxidants produced by methylglyoxal-modified collagen trigger ER stress and apoptosis in skin fibroblasts.
Methylglyoxal (MG), a highly reactive dicarbonyl, interacts with proteins to form advanced glycation end products (AGEs). AGEs include a variety of compounds which were shown to have damaging potential and to accumulate in the course of different conditions such as diabetes mellitus and aging. After confirming collagen as a main target for MG modifications in vivo within the extracellular matrix, we show here that MG-collagen disrupts fibroblast redox homeostasis and induces endoplasmic reticulum (ER) stress and apoptosis. In particular, MG-collagen-induced apoptosis is associated with the activation of the PERK-eIF2α pathway and caspase-12. MG-collagen contributes to altered redox homeostasis by directly generating hydrogen peroxide and oxygen-derived free radicals. The induction of ER stress in human fibroblasts was confirmed using collagen extracts isolated from old mice in which MG-derived AGEs were enriched. In conclusion, MG-derived AGEs represent one factor contributing to diminished fibroblast function during aging.


Role of infant vocal development in candidacy for and efficacy of cochlear implantation.
Previous research has documented the importance of audition in the development of typical infant vocalization. Of particular interest is the development of canonical babbling, which is related to mastery of the timing elements of speech. Children with severe to profound hearing loss who use hearing aids have demonstrated both delayed and deviant canonical babbling. The vocal development of 12 children has been followed as they have been considered for cochlear implantation. Nine of these children have undergone implantation, and 5 of these children have been followed for more than 1 year after implantation. On average, canonical babbling emerged at 6.5 months after implantation. The time frame in which some children developed words was accelerated in terms of length of auditory experience as compared with normal-hearing peers. Mature oral-motor development is likely the primary contributing factor in this time course. One child who received a cochlear implant began to babble with hearing aids. It is not known whether normal canonical babbling is sufficient evidence on which to base candidacy decisions; however, our data suggest that children who produce canonical babbling maintain and build upon those skills after implantation.


Sunitinib-Induced Acute Interstitial Nephritis in a Thrombocytopenic Renal Cell Cancer Patient.
Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is currently the standard of care for patients with metastatic renal cell carcinoma. Renal adverse events associated with sunitinib include proteinuria, renal insufficiency secondary to focal segmental glomerulosclerosis (FSGS), and thrombotic microangiopathy. We describe the second reported instance of biopsy-proven sunitinib-induced acute interstitial nephritis (AIN), in a challenging case complicated by thrombocytopenia. The case illustrates the importance of early diagnosis and intervention in ensuring long-term recovery from renal complications. Four other cases of AIN reported along with inhibition of the vascular endothelial growth factor (VEGF) by either TKI (sunitinib and sorafenib) or antibodies (bevacizumab) suggest a possible class effect. Given our experience, we recommend monitoring renal function with VEGF inhibition, and in the case of renal failure in the setting of an unclear diagnosis, we recommend prompt biopsy.


Modulation of thymic endocrine function by thyroid and steroid hormones.
The thymic epithelium is responsible for the secretion of thymic hormones that intervene in some steps of intra- and extra-thymic T cell differentiation. In the present paper, we studied the in vivo and in vitro influences of thyroid and steroid hormones on the secretion of thymulin, one of the chemically-defined thymic hormones. Triodothyronine injected in young mice or applied into supernatants of cultured thymic epithelial cells resulted in an increase of thymulin synthesis and secretion, respectively evaluated by the analyses of thymulin containing cells and thymulin levels. The influence of steroids was investigated in vivo by steroid depletion (adrenalectomy and/or castration) and in vitro by the addition of various steroids and/or their specific antagonists to cultured thymic epithelial cells. Surgical ablation of adrenals and/or gonads induced a transient depletion of circulating thymulin and, by feedback mechanism, an increase in the numbers of thymulin containing cells. From the in vitro data we could conclude that the various steroid hormones (that exhibited a stimulatory effect) can act directly on the thymic epithelium, probably via specific receptors. The bulk of data above described represents a strong evidence for the physiological involvement of the neuroendocrine network, on the hormonal function of the thymic epithelium.


Adsorption and freezing of diblock copolymers on stripe-patterned surfaces: a scaling analysis.
We present the results of scaling analysis of diblock copolymers adsorbed on stripe-patterned surfaces of various widths. Our previous studies [K. Sumithra and E. Straube, J. Chem. Phys. 125, 154701 (2006)] show that the adsorption of diblock copolymer on patterned surfaces yields two peaks in the specific heat capacity, thereby indicating two transition. In the current study, we characterize these two transitions. The scaling of the adsorption energy data proves that the first peak in the heat capacity curve is, in fact, associated with the adsorption transition. We found that for this transition the classical scaling laws are obeyed and that the critical crossover exponent is unaltered with respect to the case of homogeneous polymers. However, we found a change in the scaling exponent in the case of parallel component of the radius of gyration. It is evident from the scaling analysis of the parallel component of the radius of gyration that the chain is stretched along the direction of the stripes. The scaling plot shows, for (square root <Rg parallel2>)/Nnu, an exponent of approximately 0.55 which is much different from that expected of a self-avoiding chain (nud=2-nu)/phi which is 0.25. The observed value is closer to an exponent of (nud=1-nu)/phi=0.69, for a completely stretched chain in one dimension. The perpendicular component of the radius of gyration <Rg perpendicular2> shows deviation from the power law and the slope is steeper than the expected value of -2. We have also defined an order parameter to characterize the second transition and have found that it corresponds to a freezing transition where there are only a few dominant conformations. The perpendicular component of the radius of gyration also supports this information.


Purification, characterization and gene cloning of thermostable O-acetyl-L-homoserine sulfhydrylase forming gamma-cyano-alpha-aminobutyric acid.
A thermophilic and cyanide ion-tolerant bacterium, Bacillus stearothermophilus CN3 isolated from a hot spring in Japan, was found to produce thermostable gamma-cyano-alpha-aminobutyric acid synthase. The enzyme was purified and characterized. The purified enzyme has a molecular mass of approximately 180 kDa and consists of four identical subunits. It was stable in the pH range of 6.0 to 10.5 and up to 60 degrees C. The enzyme catalyzed the gamma-replacement reaction of O-acetyl-L-homo-serine with cyanide ions. The gene encoding the gamma-cyano-alpha-aminobutyric acid synthase was isolated from B. stearothermophilus CN3. Sequence homology analysis revealed that the gamma-cyano-alpha-aminobutyric acid synthase from the bacterium is O-acetyl-L-homoserine sulfhydrylase. A recombinant plasmid, constructed by ligation of the cloned gene and an expression vector, was introduced into Escherichia coli JM109. The transformed E. coli cells overexpressed gamma-cyano-alpha-aminobutyric acid synthase. The heat stable gamma-cyano-alpha-aminobutyric acid synthase can be applied to the synthesis of [5-11C]L-glutamic acid used as a tracer for positron emission tomography.


Effects of chronic treatment with ramipril, a new ACE blocking agent, on presynaptic sympathetic nervous system of SHR.
Acute administration of captopril has been reported to decrease noradrenaline (NA) release from the sympathetic nerves. In this study the chronic effects of ramipril on the sympathetic nervous system of male spontaneously hypertensive rats (SHR) have been investigated and compared to those of captopril and enalapril. As parameters for catecholamine biosynthesis and storage, the activity of tyrosine hydroxylase and the catecholamine content of the hearts and the adrenal medulla were measured by HPLC in treated and control SHR. To assess sympathetic outflow plasma NA and adrenaline (A) levels were determined during preganglionic stimulation (PS) of the spinal cord. Under none of these drugs could differences be observed between the treated and control animals, neither in the biosynthesis and storage of catecholamines in the heart and adrenal medulla nor in the sympathetic outflow. However, the dose response curves of blood pressure vs PS were significantly shifted to the right when ACE-inhibitors were administered, most strongly by ramipril. In view of the unaltered presynaptic sympathetic function long term treatment with ACE-inhibitors is suggested to increase bradykinin and angiotensin I. Bradykinin and angiotensin I are capable of releasing NA and A from the adrenal medulla, like angiotensin II.


The Family System and Depressive Symptoms during the College Years: Triangulation, Parental Differential Treatment, and Sibling Warmth as Predictors.
Guided by Bowen theory, we investigated the relationships between parent-child triangulation, parental differential treatment (PDT), sibling warmth, and individual depressive symptoms in a sample of 77 sibling dyads, aged 18-25 years, recruited through undergraduate classes at a U.S. public University. Results of the actor-partner interdependence models suggested that being triangulated into parental conflict was positively related to both siblings' perception of PDT; however, as one sibling felt triangulated, the other perceived reduced levels of PDT. For both siblings, the perception of higher levels of PDT was related to decreased sibling warmth and higher sibling warmth was associated with fewer depressive symptoms. The implications of these findings for research and the treatment of depression in the college-aged population are discussed.


Stem/Progenitor Cells and Related Therapy in Bronchopulmonary Dysplasia.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly seen in preterm infants, and is triggered by infection, mechanical ventilation, and oxygen toxicity. Among other problems, lifelong limitations in lung function and impaired psychomotor development may result. Despite major advances in understanding the disease pathologies, successful interventions are still limited to only a few drug therapies with a restricted therapeutic benefit, and which sometimes have significant side effects. As a more promising therapeutic option, mesenchymal stem cells (MSCs) have been in focus for several years due to their anti-inflammatory effects and their secretion of growth and development promoting factors. Preclinical studies provide evidence in that MSCs have the potential to contribute to the repair of lung injuries. This review provides an overview of MSCs, and other stem/progenitor cells present in the lung, their identifying characteristics, and their differentiation potential, including cytokine/growth factor involvement. Furthermore, animal studies and clinical trials using stem cells or their secretome are reviewed. To bring MSC-based therapeutic options further to clinical use, standardized protocols are needed, and upcoming side effects must be critically evaluated. To fill these gaps of knowledge, the MSCs' behavior and the effects of their secretome have to be examined in more (pre-) clinical studies, from which only few have been designed to date.


Severe ileus and urinary retention in a patient with tuberculous meningitis.
An acute ileus and/or urinary retention are recognized as emergent complications requiring appropriate depressurizing treatments. Meningitis should be suspected as a cause of these autonomic disturbances.


GENETICS OF PRECALLING PERIOD IN THE ORIENTAL ARMYWORM, MYTHIMNA SEPARATA (WALKER) (LEPIDOPTERA: NOCTUIDAE), AND IMPLICATIONS FOR MIGRATION.
Migration in insects usually occurs prereproductively so the precalling period, between emergence and the first release of pheromone, determines the number of nights over which females of migrants such as Mythimna separata can express their migratory potential. Precalling periods (PCP's) ranged from 3 to 21 nights in F1 females from insects collected in the field in eastern China. As technical problems precluded the use of a sib-analysis design, the genetic basis of this variation was investigated by analysis of the correlation between daughters' and mother's PCP's and by selection in isofemale lines followed by reciprocal crosses. The results of these analyses indicated that PCP is strongly influenced by genes located on the X chromosome, inherited from the male parent in Lepidoptera. Genetic regulation of migratory potential, of which PCP is a crucial component, can be expected to evolve in tropical species such as Mythimna separata, whose larval habitats are associated with unpredictable tropical rainfall. This species has no preimaginal diapause but makes regular seasonal incursions every spring and early summer to high temperate latitudes at which it cannot overwinter. Where migrants are carried by winds, as occurs in these migrations, the predominantly poleward winds at this time of year must create a genetic cline across latitude, in which migratory potential of the summer populations founded by the migrants increases with increasing latitude. We suggest that X-linkage of genes influencing PCP may reduce the genetic load associated with this polymorphism by reducing the frequencies of inappropriate PCP genotypes in these summer populations. Thus, in autumn when winds are predominantly northerly, fewer individuals at any latitude will lack the capability to make the return journey southward. Some support for this model is provided by the observed distributions of PCP's of F1 females from moths collected in the field in central and northern eastern China. If X-linkage of genes influencing PCP contributes to the stability of these migratory cycles, it can be expected in other species with similar migratory strategies.


Fractal behavior of functionalized fullerene aggregates. I. Aggregation of two-handed tetraaminofullerene with DNA.
In tris-buffered saline (TBS) with a trace of dimethylformamide (DMF), the homoaggregation process of a functionalized fullerene, the two-handed tetraaminofullerene (TH), and the heteroaggregation process (complex formation) of TH with DNA (pGL3-control plasmid) were studied dynamically by using a combination of static and dynamic laser light scattering measurements. Fractal behavior was investigated in the aggregation process of both TH homoaggregates and TH-DNA heteroaggregates. The stability of aggregates in solution depends on the molar concentration ratio R(M), defined as the molar ratio of moles of TH to moles of the DNA base pair. Higher R(M) values resulted in lower aggregate stability. The transition of the fractal dimension (Df) in TH homoaggregation by rapidly mixing 3.78 microM TH with an equal volume of the blank buffer was found to vary from a value of 1.46 to 2.02. Dynamic light scattering results revealed that, in the aggregation process, the change in the size distribution of aggregates with time could be related to a Df transition. In the Df transition region, the size distribution of homoaggregates displayed a drastic change from a single-mode distribution to a bimodal distribution, which clearly suggested a restructuring process with the formation of large aggregates. When the aggregation process finally reached equilibrium, Df = 2.02, the size of the homoaggregates had a single mode but a broad distribution. However, TH-DNA heteroaggregation showed a Df transition from 1.58 to 1.7, but over a shorter time range of less than 5 min. Then, the Df value fluctuated in the range of 1.7 and finally reached an equilibrium value of Df approximately 1.78, which was independent of molar concentration. There are two main action forces involved in the heteroaggregation process: van der Waals forces and attractive electrostatic forces, with the latter one being stronger and faster than that of the former. Therefore, a two-step action could occur in the heteroaggregation process. In the beginning of mixing, the attractive electrostatic forces dictated the aggregation process, and then van der Waals forces also got involved in the entire aggregation process. By using an initial concentration of 3.78 microM each and R(M) = 1, TH-DNA heteroaggregates showed more stable solution behavior than the homoaggregates. The lower Df value of the heteroaggregates could be related to a looser compact structure. Results from scanning electron microscopy (SEM) also disclosed the different textures between TH homoaggregates and TH-DNA heteroaggregates; the former had a more dense packing than the latter one.


[Analysis of coverage of the tobacco issue in Mexican print media].
Estimate the frequency and manner in which mass media represent tobacco and tobacco control policies. 660 stories published in six Mexican newspapers during 2007 were content analyzed. The majority of the news stories were published in the last quarter of the year, due to discussion of pending local and federal legislation. The vast majority of the stories were in favor of tobacco control policies (49%) or neutral (41%). The most frequently occurring themes in the stories were: legislation (36%), tobacco smoke (28%), economy (24%), and packaging (17%). Actors mentioned were: governmental institutions (24%), legislators (21%), tobacco industry (18%), and national and international non-governmental organizations (7 and 8%, respectively). Advocacy efforts should take advantage of mass media, which appears generally neutral or in favor of tobacco control policies in Mexico.


[The role of different E3 ubiquitin ligases in regulation of the P53 tumor suppressor protein].
Ubiquitin-dependent proteasomal degradation is one of the major pathways of non-lysosomal protein degradation in the cell. The ubiquitination process involves several enzymatic reactions and includes the following enzymes: E1--activating, E2--conjugating, and the third--E3--ligating enzymes. E3 ligases determine the specificity of ubiquitination reaction, i. e. what target protein will be subjected to the covalent modification by ubiquitins. The p53b tumor suppressor protein is one of the most intensively studied over the past several decades. Regulation of its activity is a complex and multi-level process that involves many factors. Ubiquitination is one of the major post-translational modifications of p53, and plays a fundamental role in the control of p53 function, its amount, activity and subcellular localization. This review is focused on p53-specific E3 ubiquitin ligases that are potential targets for cancer therapy using small molecule inhibitors.


Comparison of two strategies for short dialysis using 1m2 and 2m2 surface area dialysers.
Two matched groups of patients were dialysed either thrice weekly on a double re-used Gambro (2m2) for four and a half hours per dialysis (Group A) or thrice weekly five hours per dialysis on a single non re-used Gambro (1m2) (Group B). There was no significant differences in measured parameters of nitrogen retention between the groups, nor did the mean motor nerve conduction velocity alter significantly in any patient. Both groups preferred short dialysis. No manifestations of inadequate dialysis appeared up to 18 months even in bilateral nephrectomised patients of whom there were 2 in each group. Group B experienced significantly fewer hypovolaemic symptoms during dialysis and the single system in thus preferred. The mean dialysis index in Group A was 1.0 and 0.9 in Group B. These results suggest that a dialysis index of 1.0 overestimates dialysis needs.


Ab initio calculation of valley splitting in monolayer δ-doped phosphorus in silicon.
: The differences in energy between electronic bands due to valley splitting are of paramount importance in interpreting transport spectroscopy experiments on state-of-the-art quantum devices defined by scanning tunnelling microscope lithography. Using vasp, we develop a plane-wave density functional theory description of systems which is size limited due to computational tractability. Nonetheless, we provide valuable data for the benchmarking of empirical modelling techniques more capable of extending this discussion to confined disordered systems or actual devices. We then develop a less resource-intensive alternative via localised basis functions in siesta, retaining the physics of the plane-wave description, and extend this model beyond the capability of plane-wave methods to determine the ab initio valley splitting of well-isolated δ-layers. In obtaining an agreement between plane-wave and localised methods, we show that valley splitting has been overestimated in previous ab initio calculations by more than 50%.


Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1; Pten mutant mice.
In this report, we have investigated the relationship between androgen levels and prostate tumorigenesis in Nkx3.1; Pten mutant mice, a genetically engineered mouse model of human prostate cancer. By experimentally manipulating serum levels of testosterone in these mice for an extended period (i.e., 7 months), we have found that prolonged exposure of Nkx3.1; Pten mutant mice to androgen levels that are 10-fold lower than normal (the "Low-T" group) resulted in a marked acceleration of prostate tumorigenesis compared with those exposed to androgen levels within the reference range (the "Normal-T" group). We found that prostate tumors from the Low-T mutant mice share a similar gene expression profile as androgen-independent prostate tumors from these mutant mice, which includes the deregulated expression of several genes that are up-regulated in human hormone-refractory prostate cancer, such as Vav3 and Runx1. We propose that exposure to reduced androgens may promote prostate tumorigenesis by selecting for molecular events that promote more aggressive, hormone-refractory tumors.


Factors affecting the development of spontaneous recurrence of methamphetamine psychosis.
The process triggering spontaneous recurrences of methamphetamine (MAP) psychosis (i.e. flashbacks) was studied in 41 flashbackers, along with 84 non-flashbackers with a history of MAP psychosis. Plasma monoamine metabolite levels were assayed in 25 of the 41 flashbackers, 16 of the 84 non-flashbackers, 9 subjects with persistent MAP psychosis and 28 control subjects. All flashbackers had experienced threatening events or frightening paranoid-hallucinatory states during previous MAP use. The dominant factor triggering flashbacks was a mild fear of other people. Plasma norepinephrine levels were elevated during flashbacks. The results suggest that a mild fear of other people may have elicited memories of MAP psychosis associated with threatening experiences through increased sensitivity to psychosocial stressors. As a result the flashbacks occurred, including an increase in peripheral noradrenergic activity.


The Effect of Nanoparticle Composition on the Surface-Enhanced Raman Scattering Performance of Plasmonic DNA Origami Nanoantennas.
A versatile generation of plasmonic nanoparticle dimers for surface-enhanced Raman scattering (SERS) is presented by combining a DNA origami nanofork and spherical and nonspherical Au or Ag nanoparticles. Combining different nanoparticle species with a DNA origami nanofork to form DNA origami nanoantennas (DONAs), the plasmonic nanoparticle dimers can be optimized for a specific excitation wavelength in SERS. The preparation of such nanoparticle dimers is robust enough to enable the characterization of SERS intensities and SERS enhancement factors of dye-modified DONAs on a single dimer level by measuring in total several thousands of dimers from five different dimer designs, each functionalized with three different Raman reporter molecules and measured at four different excitation wavelengths. Based on these data, SERS enhancement factor (EF) distributions have been determined for each dimer design and excitation wavelengths. The structures and measurement conditions with the highest EFs are suitable for single-molecule SERS (SM-SERS), which is realized by placing single dye molecules into hot spots. We demonstrate that the probability of placing single molecules in a strongly enhancing hot spot for SM-SERS can be increased by using anisotropic nanoparticles with several sharp edges, such as nanoflowers. Combining a Ag nanoparticle with a Au particle in one dimer structure allows for a broadband excitation covering almost the whole visible range. The most versatile plasmonic dimer structure for SERS combines a spherical Ag nanoparticle with a Au nanoflower. Employing the discontinuous Galerkin time domain method, we numerically investigate the bare, symmetric dimers with respect to spectral and near-field properties, showing that, indeed, the nanoflowers induce multiple hot spots located at the edges which surpass the intensity of the spherical dimers, indicating the possibility for SM-SERS. The presented DONA structures and SERS data provide a robust basis for applying such designs as versatile SERS tags and as substrates for SM-SERS measurements.


Complete Replacement of Nitrite With a Lactobacillus fermentum on the Quality and Safety of Chinese Fermented Sausages.
This study investigated the positive effects of complete replacement of nitrite with a Lactobacillus fermentum on the quality and safety of Chinese fermented sausages, and evaluated the risk of this strain. The effects of the strain on pH, color, nitrite, thiobarbituric acid reactive substances (TBARS), total volatile basenitrogen (TVB-N), metmyoglobin (Met-Mb), biological amines, free amino acid content, and sensory index have been studied. The results revealed that the strain reduced the pH of the sausages, which reduced the risk of food-borne pathogens, and accelerated the acidification and gelation process. The inoculation of the strain produced pink color similar to 50 mg/kg nitrite, significantly reducing the residual risk of nitrite in the sausages. In addition, the strain effectively improved quality and nutrition of the sausages through preventing fat oxidation, protein decomposition, and myoglobin oxidation and increasing free amino acid content. The harmful biogenic amines species of the treated sample were reduced, although the tyramine contents were higher than the control, and the contents of the two groups were all far below the specified limit (800 mg/kg). The sensory analysis showed that the strain enhanced the taste, flavor, sourness, and overall acceptability of the sample sausages. Therefore, replacing nitrite completely with the strain L. fermentum could be a potential strategy to produce healthier and safer acceptable sausages through decreasing the risk of nitrite and improving nutrition and quality of the sausages.


The middle ear mass: a rare but important diagnosis.
The authors report a rare case of primary intracranial meningioma presenting as a middle ear mass with conductive hearing loss. The authors aim to highlight the importance of diagnosing a middle ear mass, which although rare, may have a substantial impact on ongoing patient management. A discussion of other middle ear pathologies is made in order to demonstrate the subtle differences in presentation.


[Freud, the biography, his autobiography and his biographers].
Freud has a dual attitude to the biographical genre. When he places himself in the position of psychoanalyst-biographer of others, he is enthusiastic, speaking of ground to be conquered for psychoanalysis, and his works, as well as his correspondence, show that he continued to devote himself to investigations which resulted in interpretations of a number of personalities, the most detailed of which dealt with Leonardo de Vinci, Goethe, Dostoyevsky, President Wilson, and Moses. On the other hand, even though during the first years of the discovery of psychoanalysis he allowed himself, in a more or less veiled manner, confidences of an autobiographical nature, Freud remained very secretive about himself. He limited himself to making public only the routine information found on his university resume or the details of his life directly related to the discovery and the development of psychoanalysis. Hidden behind die Sache, the Cause, the man always vigorously defended himself against those who, braving the periodical destruction to which he subjected his archives, claimed to apply to him this "investigative drive" whose heuristic richness he otherwise celebrated. It is by means of fantasies of identification to the work, present in every biographical attempt, that we attempt to address here the contradictions of this dual attitude.


[Bone metastasis of malignant solid tumors in childhood].
A total of 452 cases of childhood malignant solid tumors were treated over the last twenty years at the National Children's Hospital. These included 175 cases of neuroblastoma, 64 cases of Wilms' tumor, 65 cases of malignant lymphoma, 45 cases of soft tissue sarcoma, 31 cases of hepatoma, 20 cases of malignant teratoma, 17 cases of testicular tumor, 7 cases of ovarian tumor and 28 cases of other forms of malignant solid tumor. Bone metastasis was observed in 62 of 175 cases of neuroblastoma, 3 of 64 cases of Wilms' tumor, one of 65 cases of malignant lymphoma, 4 of 45 cases of soft tissue sarcoma, one case of pulmonary blastoma and one case of osteogenic sarcoma, giving a total occurrence of bone metastasis in 72 of the 452 cases. The main sites of bone metastasis in neuroblastoma were the skull (61.4%), femur (56.8%), orbit (27.3%) and spine (22.7%). The average values of serum calcium and alkaline phosphatase activity showed no significant difference. The patients with bone metastasis were treated with a combination of radiation therapy and intensive chemotherapy, resulting in temporary improvement. The survival of patients with stage IV neuroblastoma with bone metastasis was worse than that of similar patients without bone metastasis.


Non-invasive prenatal diagnosis of beta-thalassemia by semiconductor sequencing: a feasibility study in the sardinian population.
β-Thalassemia is the most common autosomal recessive single-gene disorder in Sardinia, where approximately 10.3% of the population is a carrier. Prenatal diagnosis is carried out at 12 weeks of gestation via villocentesis and is commonly aimed at ascertaining the presence or absence of the HBB variant c.118C>T, which is the most common in Sardinia. In this study, we describe for the first time the application of semiconductor sequencing to the non-invasive prenatal diagnosis of β-thalassemia in 37 couples at risk for this variant. In particular, by using a haplotyping-based approach with a hidden Markov model (HMM) and a dedicated pipeline, the two parental haplotypes most likely inherited by the foetus could be established in 30 out of 37 cffDNA samples. Specifically, the paternally inherited haplotype was correctly determined in all 30 of the samples, while the maternal haplotype was incorrectly predicted in six of the 30 genotyped samples. The lack of informative SNPs hampered the inference of both parental haplotypes in the remaining seven samples. As shown in previous studies, we have confirmed that the haplotyping-based approach represents a valuable resource, as it improves the detection of both parental haplotypes inherited by the foetus. In general, our results are encouraging, as we have proven that NIPD is also feasible in couples who are at risk for a monogenic disorder and share the same variant.


Molecular characterization of sialophorin (CD43), the lymphocyte surface sialoglycoprotein defective in Wiskott-Aldrich syndrome.
Sialophorin (CD43) of leukocytes and platelets is a surface sialoglycoprotein that is phenotypically defective on lymphocytes of patients with the X chromosome-linked immunodeficiency Wiskott-Aldrich syndrome. Previous studies with monoclonal antibodies indicate that sialophorin is a component of a T-lymphocyte activation pathway. Here we describe the cDNA cloning and derived amino acid sequence of human sialophorin. The sequence predicts an integral membrane polypeptide with an N-terminal hydrophobic signal region followed by a mucin-like 235-residue extracellular region with a uniform distribution of 46 serine, 47 threonine, and 24 proline residues. This is followed by a 23-residue transmembrane region and a 123-residue C-terminal intracellular region. These latter regions have been highly conserved during evolution; the intracellular region contains a number of potential phosphorylation sites that might mediate transduction of activation signals. The chromosomal location of the sialophorin gene was determined and the implications of this assignment for the pathogenesis of the Wiskott-Aldrich syndrome are discussed.


LncRNA-MIAT activates hepatic stellate cells via regulating Hippo pathway and epithelial-to-mesenchymal transition.
Long non-coding RNA-myocardial infarction-associated transcript (lncRNA-MIAT) has been reported to play an important role in the development of multiple cancers. However, the biological roles of MIAT in liver fibrosis are still unknown. In this study, the expression of MIAT is up-regulated during liver fibrosis. Silencing MIAT leads to the suppression of hepatic stellate cell (HSC) proliferation and collagen expression. Double immunofluorescence analysis additionally demonstrates that MIAT inhibition leads to the suppression of type I collagen and α-SMA in vitro. In vivo, MIAT knockdown contributes to the inhibition of fibrosis progression and collagen accumulation. MIAT is confirmed as a target of miR-3085-5p, and the co-location of MIAT and miR-3085-5p is found in HSC cytoplasm. Interestingly, there is a negative correlation between MIAT expression and miR-3085-5p level in cirrhotic patients as well as activated HSCs. In addition, the effects of MIAT inhibition on HSC inactivation are blocked down by miR-3085-5p inhibitor. YAP is a target of miR-3085-5p. Reduced YAP caused by loss of MIAT is reversed by miR-3085-5p inhibitor. Notably, YAP knockdown results in the suppression of MIAT-mediated epithelial-to-mesenchymal transition (EMT) process. In conclusion, we demonstrate that MIAT enhances the activation of HSCs, at least in part, via miR-3085-5p/YAP/EMT signaling pathway.


Development and properties of functional yoghurt enriched with postbiotic produced by yoghurt cultures using cheese whey and skim milk.
This study aimed to examine the effects of supplementation of postbiotics derived from Streptococcus thermophilus (ST) and Lactobacillus delbrueckii subsp. bulgaricus (LB) in cheese whey (CW) and skim milk (SM) on antioxidant activity, viability of yoghurt starters, and quality parameters of low-fat yoghurt during 22 days of storage. The LB-CW (L delbrueckii ssp. bulgaricus postbiotic-containing cheese whey) sample exhibited the highest antioxidant activity, with 18.71% inhibition (p > 0.05). This sample also showed the highest water holding capacity (77.93%; p < 0.05) and a trend toward receiving the most favorable sensory attributes (p > 0.05) compared to the other samples. The LB-CW and LB-SM yoghurt samples exhibited significantly higher body and texture scores compared to the ST-SM-fortified yoghurt (p < 0.05). However, there was no significant difference in the overall acceptability of the LB-SM and ST-SM yoghurt samples across both starters (p > 0.05). Such findings highlight the potential of postbiotics as functional ingredients to enhance the nutritional and sensory aspects of yoghurt, further contributing to its appeal as a health-promoting product.


Quantitative assay of human T-cell leukemia/lymphoma virus transformation.
The in vitro transformation of normal T-lymphocytes by human T-cell leukemia/lymphoma virus (HTLV-I) is possible utilizing cocultivation techniques. We now report on a quantitative assay for HTLV-I transformation. Transformed cell lines were produced by cocultivation of either preactivated (phytohemagglutinin and T-cell growth factor) or nonactivated peripheral blood mononuclear cells with an equal number of lethally irradiated HTLV-I-positive donor cells (MT-2). After 14 days in liquid culture, transformed cells were plated in a 2-layer soft agarose system with or without T-cell growth factor (TCGF). Colony formation among 50 normal controls was observed at varying efficiencies with a mean number of 179 colonies (range, 6-599) in the presence of TCGF (up to a 2-log difference). The day 14 T-cell cultures demonstrated relatively low colony-forming efficiencies (less than or equal to 0.1%) and enhanced colony formation in the presence of TCGF. Day 14 after cocultivation was chosen for this assay based on a dose-response relationship between colony formation and the virus-positive donor cell inoculum and the known kinetics of colony growth of normal activated T-cells. An analysis of individual colonies indicated that they were of target cell origin and HTLV-I positive. Recombinant beta-interferon in increasing concentrations caused a decrease in colony formation as measured in this assay. Long-term cell cultures (2-18 months) showed higher colony-forming efficiencies (up to 1.0%) which were not enhanced by TCGF. The ability to quantitatively evaluate transformation via colony counts will provide an opportunity to study differences in transforming efficiencies attributable to varying target cells, donor cells, or blocking factors such as interferons, drugs, or anti-HTLV-I antibodies.


Cloning and sequencing of the chromosomal DNA and cDNA encoding the mitochondrial citrate synthase of Aspergillus niger WU-2223L.
The complementary DNA (cDNA) and chromosomal DNA encoding the citrate synthase (EC 126.96.36.199) gene (cit1) of Aspergillus niger WU-2223L, a citric acid-producing strain, were cloned. Synthetic oligonucleotide primers were designed according to the amino acid sequences of already known eukaryotic citrate synthases and the codon bias of A. niger genes. The 920-bp DNA fragment was amplified by polymerase chain reaction with these primers using chromosomal DNA of WU-2223L as a template, and was employed to screen a cDNA library of A. niger. One full-length cDNA clone was isolated and sequenced, within which an ORF of 1425 by encoding a protein of 475 as with a molecular weight of 52,153 Da was found. Its N-terminal region contains a typical mitochondrial-targeting motif. The predicted as sequence was 82, 68, and 65% homologous with the mitochondrial citrate synthases of Neurospora crassa, Saccharomyces cerevisiae, and pig, respectively, but it showed lower homology to bacterial citrate synthases. The full-length cDNA clone was used to screen a chromosomal library of A. niger WU-2223L, and a 7.5 kb-SalI fragment containing the corresponding chromosomal gene was isolated. Comparison of the chromosomal and cDNA sequences revealed that the cit1 gene is interrupted by six introns. In the chromosomal DNA, upstream of the coding region, a CT-rich region, but not the TATAAA or CAAT motifs, was found. Escherichia coli MOB150, a citrate synthase-deficient mutant showing a glutamate-requiring phenotype, was transformed with the plasmid pKAC-35S, which is the expression vector pKK223-3 containing the cDNA fragment encoding a putative mature protein of A. niger citrate synthase. The transformant harboring pKAC-35S showed citrate synthase activity and a glutamate-nonrequiring phenotype.


Rice and cold stress: methods for its evaluation and summary of cold tolerance-related quantitative trait loci.
Cold stress adversely affects rice (Oryza sativa L.) growth and productivity, and has so far determined its geographical distribution. Dissecting cold stress-mediated physiological changes and understanding their genetic causes will facilitate the breeding of rice for cold tolerance. Here, we review recent progress in research on cold stress-mediated physiological traits and metabolites, and indicate their roles in the cold-response network and cold-tolerance evaluation. We also discuss criteria for evaluating cold tolerance and evaluate the scope and shortcomings of each application. Moreover, we summarize research on quantitative trait loci (QTL) related to cold stress at the germination, seedling, and reproductive stages that should provide useful information to accelerate progress in breeding cold-tolerant rice.


The power-proportion method for intracranial volume correction in volumetric imaging analysis.
In volumetric brain imaging analysis, volumes of brain structures are typically assumed to be proportional or linearly related to intracranial volume (ICV). However, evidence abounds that many brain structures have power law relationships with ICV. To take this relationship into account in volumetric imaging analysis, we propose a power law based method-the power-proportion method-for ICV correction. The performance of the new method is demonstrated using data from the PREDICT-HD study.


Long-term follow-up in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention.
Long-term follow-up after primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI) beyond 5 years is poorly described. There are no risk-stratification systems available for routine use. This retrospective, academic, two-centre analysis included consecutive patients who presented with acute STEMI between March 2008 and December 2019. In total, 5263 patients underwent pPCI; all patients were included in the analysis only once. Baseline characteristics were gathered from prospective local registries and based on initial hospitalization. The study enrolled 5263 patients who had been treated with pPCI; it found that cardiovascular mortality was the most frequent cause of death (65.0%) on long-term follow-up to 12 years. Myocardial infarction associated mortality was 27.2%. Cardiovascular mortality was dominant, including in the landmark analysis beyond 1 year. Multivariate analysis identified significant predictors for long-term cardiovascular mortality: age, history of diabetes mellitus, history of renal insufficiency, history of heart failure, Killip class, and successful pPCI at presentation. A predictive model was built to evaluate the risk of cardiovascular death with a high discrimination value (C-statistic = 0.84). Cardiovascular diseases remain the leading cause of long-term mortality after pPCI in the Central European population. Our novel predictive model provides risk stratification; it could identify patients who would experience the greatest benefit from aggressive secondary prevention measures.


Study on the inclusion complexes of bromazepam with beta- and beta-hydroxypropyl-cyclodextrins.
Solubility enhancement of the water insoluble bromazepam was studied during the formation of its inclusion complexes with beta-cyclodextrin (beta-CD) and beta-hydroxypropyl-cyclodextrin (beta-HP-CD). The phase solubility technique established by Higuchi and Connors and UV-spectrophotometric methods (zero- and second-order derivative approaches) were used to measure the changes introduced in this chemical system. The amount of time, which was necessary to reach equilibrium between inclusion complexes and their free components, was estimated and found equal to 24 h. The study was carried out at (i) pH 7.0 and 25 degrees C and (ii) pH 7.4 and 37 degrees C. The solubility of bromazepam increased linearly as a function of concentration for both beta-and beta-hydroxypropyl-cyclodextrins. Thus, the phase solubility diagrams were classified as of A(L) type in all cases. Under the above-mentioned conditions, the formation constants of the inclusion complexes were calculated and their stoichiometry was evaluated, found in the range of 69-85 M(-1) and 1:1, respectively.


Embryonic cuticle establishment: the great (apoplastic) divide.
The plant cuticle, a dynamic interface between plants and their environment, is formed by the secretion of hydrophobic lipids and waxes into the outer wall of aerial epidermal cells. Cuticle formation is such a ubiquitous feature of epidermal cells, and is of such fundamental importance for plant survival, that identifying and understanding specific developmental roles for this structure has been a major challenge for plant scientists. In recent work, we have tried to understand the functional relationships between a signaling feedback loop required for epidermal cell specification in developing plant embryos, and a seed specific signaling cascade, involving components localized both in the embryo and in the embryo surrounding endosperm, and necessary for embryo cuticle function. Analysis of the strongly synergistic genetic relationships between these 2 independent pathways, combined with mathematical simulations of the behavior of the signaling feedback loop, have allowed us to propose an important, and hitherto unsuspected, role for the embryonic cuticle as an apoplastic diffusion barrier, necessary for preventing the excessive diffusion of developmentally important signaling molecules away from developing embryo into surrounding tissues.


Microstructural evolution and corrosion behavior of a laser surface modified cast Co-Cr-Mo-C alloy.
A Co-Cr-Mo-C biomedical alloy was processed by investment casting, and its surface was modified using pulsed laser melting. The modified surface underwent rapid solidification, and the exhibited microstructure as well as its corrosion properties were investigated. It was found that the laser surface modified (LSM) Co-Cr-Mo-C alloy possesses enhanced corrosion resistance when compared with the same alloy in the as-cast condition. Microstructural determinations indicated that the LSM Co-Cr-Mo-C alloy exhibited a lack significant solute segregation and a predominantly cellular morphology as a result of the development of a cellular solid-liquid front. The cellular morphology was characterized by a fine distribution of nano-scale M23 C6 carbides at the intercellular regions. Moreover, the austenite (γ) to athermal ε-martensite transformation was totally suppressed in the cellular solidified regions. In contrast, the as-cast alloy develops a coarse dendritic microstructure with coarse carbides in the interdendritic regions. Solute segregation is also present, as well as athermal ε-martensite (13 pct). It was found that the corrosion resistance of the LSM alloy in the Ringer solution exhibits improved corrosion potential and a reduced corrosion current density (-281 mV and 0.032 μA/cm2 , respectively),when compared with the same alloy in the investment as-cast condition (-356 mV and 0.150 μA/cm2 ).


Does self-ligating brackets type influence the hysteresis, activation and deactivation forces of superelastic NiTi archwires?
To compare hysteresis, activation and deactivation forces produced by first-order deformation of Contour 0.014-in NiTi wire (Aditek, Brazil) in four brands of self-ligating brackets: Damon MX, Easy Clip, Smart Clip and In-Ovation. Activation and deactivation forces were measured in an Instron universal tensile machine at 3 mm/minute speed to a total displacement of 4 mm. Tests were repeated eight times for each bracket/wire combination. Statistical analysis comprised ANOVA and Tukey's multiple comparisons test. Using a 4-mm deformation, mean activation forces increased in the following order: Damon = 222 gf, Easy Clip = 228 gf, In-Ovation = 240 gf and Smart Clip = 306 gf. The same order was observed for mean hysteresis values, i.e., 128 gf, 140 gf, 150 gf and 206 gf, respectively. The respective values of deactivation forces for the Damon, Easy Clip, In-Ovation and Smart Clip brackets were 94 gf, 88 gf, 90 gf and 100 gf. Brackets with higher activation forces were accompanied by higher hysteresis values, which resulted in clinically similar deactivation forces, regardless of the type of self-ligating brackets used.


Altered deoxyribonuclease activity in cancer cells and its role in non toxic adjuvant cancer therapy with mixed vitamins C and K3.
The alterations of deoxyribonuclease DNase activity in cancer cells were the basis of the utilization of mixed vitamins C and K3 in a nontoxic, adjuvant cancer therapy. In order to localize exactly the altered activities of DNase in cancer cells, histochemical methods were utilized. The deficiency of alkaline and acid DNase activity appeared to be characteristic for non-necrotic cells of malignant human and animal tumors. This enzymatic deficiency appeared in experimental carcinogenesis before the phenotypic signs of malignancy. Tumor promoters directly reduced the activity of both DNases. The incidence of spontaneous malignant human and animal tumors appeared to be inversely proportional to the intensity of the activity of both DNases in normal cells and tissues from which these tumors were derived. The fact that alkaline and acid DNase activity was reactivated during the spontaneous and therapeutically induced necrosis of cancer cells suggests that this enzymatic deficiency of DNase activity in cancer cells was due to the action of specific inhibitors of DNases. Characteristic variations of serum alkaline DNase activity in positive responders to therapy, examined in more than 800 cancer-bearing patients, may be the basis for the development of a useful test for therapeutic prognosis and for monitoring of cancer bearing patients. Acid DNase was selectively reactivated in malignant tumor cells by vitamin C (sodium ascorbate), whereas alkaline DNase was reactivated by vitamin K3. Joint vitamin C and K3 administration produced in vitro and in vivo tumor growth inhibition, potentiation and sensitization of chemo- and/or radiotherapy and a decrease in the number of metastases in animals with experimental tumors. Joint vitamin C and K3 administration may be considered as a possible new, non-toxic, adjuvant cancer therapy, which can be easily introduced into the classic protocols of clinical cancer therapy without any supplementary risk for patients.


Comparative in vitro activities of GSK2251052, a novel boron-containing leucyl-tRNA synthetase inhibitor, against 916 anaerobic organisms.
We studied the comparative in vitro activity of GSK2251052, a novel boron leucyl-tRNA synthetase inhibitor, against 916 clinical anaerobic isolates using CLSI methods. The GSK MIC50/MIC90 for all isolates tested were 2 and 4 μg/ml, and the MIC90s against 302 Bacteroides fragilis and Bacteroides thetaiotaomicron strains were 4 and 8 μg/ml, respectively. All Clostridium perfringens strains had GSK2251052 MICs of >32 μg/ml. There was no relationship between increased MICs for any other antibiotics and that of GSK2251052.


Where are the rest of us? Improving representation of minority faculty in academic medicine.
Low numbers of underrepresented minority faculty members in academic medicine (black, Hispanic, Asian/Pacific Islander, Native American/Alaskan) continue to be a concern for medical schools because there is higher attrition and talent loss among this group. Although much has been written on this topic, there has not been a systematic review of the indexed literature published. We searched MEDLINE, Web of Knowledge, ProQuest, and Google Scholar for articles relating to minority faculty and identified relevant articles. We then graded the evidence using the Strength of Recommendation Taxonomy. The same criteria were applied to extract evidence-based observations of challenges faced by minority faculty and provide recommendations. Of the 548 studies identified and reviewed, 15 met inclusion criteria for this literature review. Of the 15, 9 were cross-sectional studies and 6 were analyses of existing Association of American Medical Colleges workforce data. The cross-sectional studies documented perceived bias in the recruitment of faculty, quantified the lack of minority mentors, and revealed that black and Hispanic faculty members are more prevalent in states with higher minority populations. Studies using the Association of American Medical College workforce data also documented evidence of promotion bias, the lack of diversity in academic plastic surgery, and the lack of minority researchers funded by the National Cancer Institute. This systematic review provides evidence that racism, promotion disparities, funding disparities, lack of mentorship, and diversity pressures exist and affect minority faculty in academic medicine. Based on these observed challenges, this review also provides specific recommendations that could improve representation of minority faculty members in academic medicine. These recommendations include implementing proven pipeline programs to increase the number of minority medical students, a systemwide adoption of proven culture change initiatives, reexamination of assignments to ensure equitable time distribution, and a reduction of medical school debt.


Age-related changes in the association of resting-state fMRI signal variability and global functional connectivity in non-demented healthy people.
Research suggests that the aging relates to variability of resting-state fMRI (rs-fMRI) signal and the functional connectivity. However, the association between the spatial and temporal activity of resting-state fMRI signal was less documented. We recruited 477 healthy Han Chinese participants, who were separated into young, middle and old groups to investigate the relationship between the variability and global functional connectivity (gFC) in different age ranges using standard deviation (SD) of time series and gFC, respectively. Our analysis revealed the changing patterns during healthy aging: 1) 17 brain regions(Olfactory_L, Orbital_L etc.) were identified to have significant association of age with both SD and gFC respectively by linear regression analysis; 2) Two typical associations could be observed between SD and gFC: positive and negative correlations; 3) The variation ratio of SD to gFC was changing with age at the voxel level by using unsupervised clustering method. It is the first time to combine voxel-wise variability and gFC together for the study of age-related changes with rs-fMRI signal. This study may provide a new clue for understanding the synchronization of human brain based on SD and gFC due to the effect of aging.


Refinements using free-tissue transfer for complex cranial base reconstruction.
Resection of skull base tumors may sometimes result in massive extirpation defects that are not amenable to local tissue closure. Closure of large basicranial defects can be performed with either a myocutaneous, a deepithelialized myocutaneous, or a simple muscle free flap designed from the ample rectus abdominis vascular territory. This free-tissue donor site has abundant and reliable well-vascularized tissue that can easily be customized to seal these tenuous areas. The rectus abdominis muscle and its vascularized territory were used in 18 of 19 consecutive patients at our center to close basicranial ablation defects. Of these, 6 were rectus abdominis muscle flaps, 5 were myocutaneous rectus abdominis flaps, and 7 were deepithelialized rectus abdominis muscle flaps. All free flaps survived. The intracranial space was sealed successfully in all but one patient. This patient underwent reconstruction with a muscle free flap and had a postoperative cerebrospinal fluid leak. This complication could have been avoided by using a deepithelialized myocutaneous flap to obliterate the central dead space with the vascularized subcutaneous fat. Two patients experienced minor wound infections, and one had a subdural abscess that was fully contained by a free flap placed over the duraplasty. One patient had a donor-site hernia. There was no incidence of meningitis. Knowledge of the anatomy of the vascular territory of the deep inferior epigastric vessels can be used judiciously to secure three-dimensional reconstruction of the skull base. The donor site supplies ample tissue for reconstruction and allows individual tailoring for obliteration of geometrically complex extirpation defects in and around the cranial base without the need to reposition the patient.


Left ventricular basal inferior pseudoaneurysm and left atrial dissection after myocardial infarction: Case report.
Left atrial dissection is a rare entity, mostly occurring after mitral valve surgery, with only a few cases described after myocardial infarction. The authors report a case of a 60-year-old man who presented with an inferior myocardial infarction, complicated with pseudoaneurysm of basal segment of left ventricular inferior wall, which expanded through the mitral ring to left atria, causing left atrial free wall dissection. The left ventriculo-atrial communication through the pseudoaneurysm caused major para-mitral regurgitation and the development of acute heart failure. Good clinical outcome was achieved with stabilization of acute heart failure with high-dose diuretic therapy and delayed cardiac surgery with closure of left ventriculo-atrial communication.


Modulation of cellular cholesterol and its effect on cornified envelope formation in cultured human epidermal keratinocytes.
When cultured human epidermal keratinocytes (NHK) reach confluence they start to differentiate and an increase in the total cellular cholesterol content is observed. This increase parallels the appearance of a characteristic feature of terminal keratinocyte differentiation, the spontaneous formation of cornified envelopes (CE). Synthesis of CE is catalyzed by the plasma membrane-associated transglutaminase (TGm). Supplementation of the medium with inhibitors of cholesterologenesis suppressed increase in cholesterol levels and CE formation but did not interfere with TGm expression or TGm activity. Modulation of the plasma membrane cholesterol-phospholipid ratio of confluent NHK cultures using either pure phospholipid liposomes or liposomes enriched in cholesterol strongly affected spontaneous CE formation. Pure phospholipid liposomes completely inhibited CE formation, whereas cholesterol-enriched liposomes ensured envelope formation, even in the presence of inhibitors of cholesterol synthesis. From these results we conclude that in differentiating NHK an increase in the cellular cholesterol level is part of the differentiation program and is essential for the spontaneous CE formation.


The structure of the synaptonemal complexes in meiocytes of European domestic goose (Anser anser).
The synaptonemal complex (SC) is a protein structure which binds two homologues during prophase of the first meiotic division and assures the correct course of genetic recombination. The demonstration and identification of SCs in European domestic goose Anser anser was the aim of the current research. Standard techniques of SC identification do not allow for an analysis of their molecular structure. In meiotic cells of one-day-old nestlings and 17-week-old geese the haploid number of bivalents, darkly stained kinetochores and subtelomeric regions may be evidence for the presence of SCs. Experimental chromosome staining with the DAPI fluorochrome permitted the observation of the characteristic ladder-like structure of SCs and the course of synapsis formation within homologues from early leptotene to their degradation in late pachytene. The detailed molecular structure of synaptonemal complexes can be analysed with an electron or scanning microscope only. Because the bivalent is a direct result of the complex's presence, in the literature the presence of bivalents is equivalent to the term "synaptonemal complex". However, the bivalent and the SC are two different structures.


In-vitro activity of cefpodoxime proxetil (RU 51807): a comparative disk diffusion study on isolates from geriatric patients.
997 strains isolated from clinical specimens arrived at the "Pio Albergo Trivulzio" microbiology laboratory were tested using disks of cefpodoxime, amoxicillin + clavulanic acid, cefaclor, cefuroxime, ofloxacin, cotrimoxazole, ceftriaxone and cefalexin. Gram-positive strains were tested also with erythromycin, while gram-negative bacteria were tested against aztreonam. Cefpodoxime overall activity was well above the effectiveness of the other oral cephalosporins and on the same order as ceftriaxone and ofloxacin. Cefpodoxime proved to be also more active than the combination amoxicillin-clavulanic acid.


In vitro purging of bone marrow for autologous marrow transplantation in acute myelogenous leukemia using myeloid-specific monoclonal antibodies.
Autologous bone marrow transplantation (ABMT) for acute myelogenous leukemia has gained new popularity recently due to the availability of techniques to purge the autograft of residual leukemia cells. One of the methods of purging involves the use of monoclonal antibodies (mAbs) directed to antigens expressed on the surface of leukemia cells. Several mAbs lend themselves to this use because of their high degree of reactivity with leukemia cells and their lack of reactivity with normal pluripotent hematopoietic progenitor cells. Candidate mAbs include those directed to the CD14, CD15, and CD33 molecules. This review focuses on the pre-clinical data concerning the use of mAbs to these antigens and on the results of on-going clinical trials of ABMT using mAb-mediated purging.


Two closely related, and unexpected, quinolinone derivatives: a three-dimensional hydrogen-bonded framework structure and a hydrogen-bonded molecular ribbon of R(2)(2)(18) and R(4)(4)(24) rings.
1,5-Bis(4-chlorophenyl)-3-(2-oxo-1,2-dihydroquinolin-3-yl)pentane-1,5-dione, (Ia), and 1,5-bis(2-chlorophenyl)-3-(2-oxo-1,2-dihydroquinolin-3-yl)pentane-1,5-dione, (Ib), crystallize as an 84:16 mixture, 0.84C(26)H(19)Cl(2)NO(3)·0.16C(26)H(19)Cl(2)NO(3), in the space group I4(1)/a, where the molecules of the two isomers occupy very similar sites in the unit cell. A combination of one N-H...O hydrogen bond and one C-H...O hydrogen bond links the molecules, regardless of isomeric form, into a single three-dimensional framework structure. The molecules of (9RS,10RS)-8,9-bis(4-chlorobenzyl)-10-(2-oxo-1,2-dihydroquinolin-3-yl)-5,6,9,10-tetrahydrophenanthridine, C(36)H(22)Cl(2)N(2)O(4), (II), are linked by two hydrogen bonds, one each of the N-H...O and C-H...O types, into a molecular ribbon in which centrosymmetric rings of R(2)(2)(18) and R(4)(4)(24) types alternate. The hydrogen-bonded ribbons enclose channels, which contain highly disordered solvent molecules.


Classic PCOS phenotype is not associated with deficiency of endogenous vitamin D and VDR gene polymorphisms rs731236 (TaqI), rs7975232 (ApaI), rs1544410 (BsmI), rs10735810 (FokI): a case-control study of lower Silesian women.
The role of endogenous vitamin D and vitamin D receptor (VDR) gene polymorphism in polycystic ovary syndrome (PCOS) is still controversial. The objective of this study was to investigate for the first time in women with "classic" PCOS phenotype and healthy controls the role of the serum endogenous vitamin D level and VDR gene polymorphisms in PCOS etiology. Ninety-two women with "classic" PCOS phenotype and 85 controls from lower Silesia with comparable body mass index (BMI) were studied. In all women the waist circumference, android/gynoid fat deposit, parameters of lipid and glucose metabolism, testosterone, free androgen index, sex hormone binding globulin (SHBG) and vitamin D were evaluated. Also, VDR gene polymorphisms rs731236, rs7975232, rs1544410 and rs10735810 were assessed. Serum vitamin D levels in both groups were comparable. Also high, comparable frequencies of hypovitaminosis and vitamin D deficiency in both groups were observed. Women with "classic" PCOS phenotype had statistically significantly higher values of all measured parameters, except serum SHBG and high-density lipoprotein (HDL)-cholesterol, which were lower. The frequency of VDR genotype polymorphism was also comparable in both groups. For the first time, we show that endogenous vitamin D deficiency and VDR polymorphisms are not associated with homogeneous "classic" PCOS phenotype.


Computational methods to analyze and predict the binding mode of inhibitors targeting both human and mushroom tyrosinase.
Tyrosinase, a copper-containing enzyme critical in melanin biosynthesis, is a key drug target for hyperpigmentation and melanoma in humans. Testing the inhibitory effects of compounds using tyrosinase from Agaricus bisporus (AbTYR) has been a common practice to identify potential therapeutics from synthetic and natural sources. However, structural diversity among human tyrosinase (hTYR) and AbTYR presents a challenge in developing drugs that are therapeutically effective. In this study, we combined retrospective and computational analyses with experimental data to provide insights into the development of new inhibitors targeting both hTYR and AbTYR. We observed contrasting effects of Thiamidol™ and our 4-(4-hydroxyphenyl)piperazin-1-yl-derivative (6) on both enzymes; based on this finding, we aimed to investigate their binding modes in hTYR and AbTYR to identify residues that significantly improve affinity. All the information led to the discovery of compound [4-(4-hydroxyphenyl)piperazin-1-yl](2-methoxyphenyl)methanone (MehT-3, 7), which showed comparable activity on AbTYR (IC50 = 3.52 μM) and hTYR (IC50 = 5.4 μM). Based on these achievements we propose the exploitation of our computational results to provide relevant structural information for the development of newer dual-targeting molecules, which could be preliminarily tested on AbTYR as a rapid and inexpensive screening procedure before being tested on hTYR.


[Lacan's view on the question of psychoanalytic training].
In his criticism of psychoanalytic institutions in 1956 Lacan was not truly an innovator: Bernfeld and Balint before him had already conducted a severe critical analysis of the training given to analysts within the I.P.A. Lacan's role as an innovator lies elsewhere: in his search for a solution to the questions raised by his predecessors, a solution that is intrinsically linked to his theorisation of the subject of the unconscious.


The potential health and revenue effects of a tax on sugar sweetened beverages in Zambia.
The global burden of non-communicable diseases (NCDs) has been rising. A key risk factor for NCDs is obesity, which has been partly linked to consumption of sugar sweetened beverages (SSBs). A tax on SSBs is an attractive control measure to curb the rising trend in NCDs, as it has the potential to reduce consumption of SSBs. However, studies on the potential effects of SSB taxes have been concentrated in high-income countries with limited studies in low-income and middle-income countries. Using data from the 2015 Zambia Living Conditions Monitoring Survey (LCMS) data, the 2017 Zambia NCD STEPS Survey, and key parameters from the literature, we simulated the effect of a 25% SSB tax in Zambia on energy intake and the corresponding change in body mass index (BMI), obesity prevalence, deaths averted, life years gained and revenues generated using a mathematical model developed using Microsoft Excel. We conducted Monte Carlo simulations to construct 95% confidence bands and sensitivity analyses to account for uncertainties in key parameters. We found that a 25% SSB would avert 2526 deaths, though these results were not statistically significant overall. However, when broken down by gender, the tax was found to significantly avert 1133 deaths in women (95% CI 353 to 1970). The tax was found to potentially generate an additional US$5.46 million (95% CI 4.66 to 6.14) in revenue annually. We conclude that an SSB tax in Zambia has the potential to significantly decrease the amount of disability-adjusted life years lost to lifestyle-related diseases in women, highlighting important health equity outcomes. Women have higher baseline BMI and therefore are at higher risk for NCDs. In addition, an SSB tax will provide government with additional revenue which if earmarked for health could contribute to healthcare financing in Zambia.


Lipid microdomains: structural correlations, fluctuations, and formation mechanisms.
Compositional lipid microdomains ("lipid rafts") in mammalian plasma membranes are believed to facilitate many important cellular processes. While several physically distinct scenarios predicting the presence of finite-sized microdomains in vivo have been proposed in the past, direct experimental verification or falsification of model predictions has remained elusive. Herein, we demonstrate that the combination of the spatial correlation and temporal fluctuation spectra of the lipid domains can be employed to unambiguously differentiate between the existing theoretical scenarios. Furthermore, the differentiation of the raft formation mechanisms using this methodology can be achieved by collecting data at physiologically relevant conditions without the need to tune control parameters.


[Acute experimental pyelonephritis. Treatment with tobramycin. Influence of the rhythm of administration on efficacy and renal tolerability].
Acute experimental pyelonephritis was produced in rabbits by injecting E. coli (tobramycin MIC 1 mg/l) into the left kidney and temporarily obstructing the ureter. Animals were given 10 mg/kg tobramycin intramuscularly 48 h after surgery and subsequently every day for 7, 10 or 15 days, either in a single daily dose or in three divided doses at 8 h intervals. Animals were killed 24 h after the last injection. Comparison of results shows that kidneys were sterilized by a single daily dose but not by three divided daily doses. In rabbits given the single daily dose regimen, kidneys recovered a normal macroscopical and histological aspect, serum anti-E. coli antibodies rose more slowly and less significantly, serum creatinine increased less, and renal enzymatic activities were restored (alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase). These findings suggest better efficacy and renal tolerance of the single daily dose regimen as compared to the three daily divided dose regimen in the treatment of acute experimental pyelonephritis.


Morphology and ultrastructure of human T-mycoplasmas.
Four serologically distinct human T-mycoplasmas grown in liquid medium were studied in the electron microscope after ultrathin sectioning and negative staining. The morphology and ultrastructure of these strains was found to be essentially identical to that of other mycoplasmas; i.e., mainly spherical or ovoid cells were observed, but also short rod-shaped cells and filamentous, partly branched forms were noted. The cells were found to be enveloped by a triple-layered membrane, on the outer surface of which an electron-dense layer consisting of radiating hairlike structures was consistently present. In addition to ribosomes, now and then arranged in a regular geometric pattern, the ultrathin sections reveal vacuole-like structures in the interior of the cells.


Active sunscreen ingredients in Australia.
UV radiation exposure is the major contributor to photocarcinogenesis and photoageing. Reducing UV radiation exposure can be achieved by using adequate sunscreen preparations. The use of sunscreen can significantly reduce the incidence of squamous cell carcinoma, actinic keratoses and invasive melanoma. In the Australian market over 900 sunscreen products are available, each with their own brand, formulation and ingredients. It can be difficult for dermatologists and consumers to determine which are the most effective and appropriate products to use. We discuss the specific active ingredients found in sunscreen formulations available in Australia, their mode of protection, photostability, solubility, and side-effects and the methods used by the Therapeutic Goods Administration to determine the ratings and efficacy of each sunscreen.


The history of the angiogenic switch concept.
Spontaneously arising tumor cells are not usually angiogenic at first. The phenotypic switch to angiogenesis is usually accomplished by a substet that induces new capillaries that then converge toward the tumor. The switch clearly involves more than simple upregulation of angiogenic activity and is thought to be the result of a net balance of positive and negative regulators. Tumor growth is although to require disruption of this balance and hence this switch must turned on for cancer progression. Progenitor endothelial cells, the crosstalk between angiogenic factors and their receptors and the interaction between vasculogenesis and lymphangiogenesis are all factors that may contribute to the switch. Its promotion is also the outcome of genetic instability resulting in the emergence of tumor cell lines. This review describes the history of the angiogenic switch illustrated in the literature and with particular reference to the three transgenic mouse models, namely RIP1-TAG2, keratin-14 (K14) (human papilloma virus) HPV16 and papilloma virus, used for stage-specific assessment of the effects of antiangiogenic and antitumorigenic agents.


Label-free imaging of lipid depositions in C. elegans using third-harmonic generation microscopy.
Elucidation of the molecular mechanisms regulating lipid storage and metabolism is essential for mitigating excess adiposity and obesity, which has been associated with increased prevalence of severe pathological conditions such as cardiovascular disorders and type II diabetes, worldwide. However, imaging fatty acid distribution and dynamics in vivo, at the cellular or organismal level is challenging. We developed a label-free method for visualizing lipid depositions in vivo, based on third harmonic generation (THG) microscopy. THG imaging requires a single pulsed-laser light source, alleviating the technical challenges of implementing coherent anti-Stokes Raman scattering spectroscopy (CARS) to detect fat stores in living cells. We demonstrate that THG can be used to efficiently and reliably visualize lipid droplets in Caenorhabditis elegans. Thus, THG microscopy offers a versatile alternative to fluorescence and dye-based approaches for lipid biology research.


Necrosis of abdominoplasty and other secondary flaps after TRAM flap breast reconstruction.
The risks of abdominoplasty flap necrosis, umbilical necrosis, and mastectomy flap edge necrosis were compared in a series of 227 patients who had undergone transverse rectus abdominis myocutaneous (TRAM) flap breast reconstructions. Abdominoplasty flap necrosis was more common in patients who smoked or previously had smoked (27.5 percent) than in nonsmokers (5.9 percent). It also was more common in patients who had had conventional TRAM flaps (16.5 percent) than in those with free TRAM flaps (7.8 percent). Similarly, umbilical necrosis was more common in smokers (27.5 percent) than in nonsmokers (11.8 percent). Current smokers had higher risks than ex-smokers, who in turn had higher risks than patients who had never smoked. Obesity appeared to have only a minor influence on abdominal flap and umbilical necrosis. Mastectomy flap edge necrosis, which had little or no impact on the final outcome, was more common after free TRAM flaps than after conventional TRAM flaps.


Relationship Between Gastrointestinal Symptoms in Autism Spectrum Disorder and Parent Stress, Anxiety, Depression, Quality of Life and Social Support.
Gastrointestinal (GI) symptoms are a common comorbidity in children and adolescents with autism spectrum disorder (ASD). Little is known about the impact that GI symptoms have on parental well-being. Parents of 409 children and adolescents with ASD completed the GI Symptoms Inventory, Parenting Stress Index-Short Form, World Health Organization Quality of Life Abbreviated Version, Hospital Anxiety and Depression Scale, and the Multidimensional Scale of Perceived Social Support. High levels of stress were demonstrated by parents with 40.1% receiving clinically significant scores. A relationship was found between parental stress and GI symptoms. Parental anxiety and depression were found at high levels but were not more common in parents of individuals with GI symptoms than those without. Lower levels of quality of life were found in parents of individuals with GI symptoms compared to parents of individuals without GI symptoms. Parents of children with GI symptoms were less satisfied with their personal and social relationships with others. Parents of children with GI symptoms had lower scores on a measure of perceived social support than parents of children and adolescents without GI symptoms. GI symptoms are stressful for parents and future research is needed to determine how to alleviate this stress and to improve the quality of life of parents of individuals with ASD.


Tregs integrate native and CAR-mediated costimulatory signals for control of allograft rejection.
Tregs expressing chimeric antigen receptors (CAR-Tregs) are a promising tool to promote transplant tolerance. The relationship between CAR structure and Treg function was studied in xenogeneic, immunodeficient mice, revealing advantages of CD28-encoding CARs. However, these models could underrepresent interactions between CAR-Tregs, antigen-presenting cells (APCs), and donor-specific Abs. We generated Tregs expressing HLA-A2-specific CARs with different costimulatory domains and compared their function in vitro and in vivo using an immunocompetent model of transplantation. In vitro, the CD28-encoding CAR had superior antigen-specific suppression, proliferation, and cytokine production. In contrast, in vivo, Tregs expressing CARs encoding CD28, ICOS, programmed cell death 1, and GITR, but not 4-1BB or OX40, all extended skin allograft survival. To reconcile in vitro and in vivo data, we analyzed effects of a CAR encoding CD3ζ but no costimulatory domain. These data revealed that exogenous costimulation from APCs can compensate for the lack of a CAR-encoded CD28 domain. Thus, Tregs expressing a CAR with or without CD28 are functionally equivalent in vivo, mediating similar extension of skin allograft survival and controlling the generation of anti-HLA-A2 alloantibodies. This study reveals a dimension of CAR-Treg biology and has important implications for the design of CARs for clinical use in Tregs.


Cetirizine: more than an antihistamine?
Cetirizine, a metabolite of hydroxyzine, is an antihistamine with as distinguishing features: 1) exquisite anti-H1 specificity: cetirizine appears unique in being devoid of action on receptors other than the H1 receptor; 2) potency: at unit dose it is the most potent antihistamine in the skin and the lung; 3) absence of metabolism. These three characteristics suggest that cetirizine be considered the choice H1 antagonist for experiments on the immediate allergic reaction. Cetirizine additionally in vitro inhibits the migration of eosinophils, and in vivo, in the skin, the infiltration by eosinophils that is characteristic for the late phase allergic reaction. Other antihistamines are less active or inactive with respect to this property. According to several lines of evidence, the effect of cetirizine on eosinophils is unlikely to be due to H1 antagonism, but is more likely a novel property of the compound.


Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine.
Amorphous solid dispersions are used as a strategy to improve the bioavailability of poorly water-soluble compounds. When formulating with a polymer, it is important not only for the polymer to stabilize against crystallization in the solid state, but also to improve the dissolution profile through inhibiting crystallization from the supersaturated solution generated by dissolution of the amorphous material. In this study, the dissolution profiles of solid dispersions of felodipine formulated with poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) were compared. In addition, concentration versus time profiles were evaluated for the supersaturated solutions of felodipine in the presence and absence of the polymers. HPMCAS was found to maintain the highest level of supersaturation for the greatest length of time for both the dissolution and solution crystallization experiments, whereas PVP was found to be the least effective crystallization inhibitor. All polymers appeared to reduce the crystal growth rates of felodipine at an equivalent supersaturation and this mechanism most likely contributes to the enhanced solution concentration values observed during dissolution of the amorphous solid dispersions.


Developing models for the prediction of hospital healthcare waste generation rate.
An increase in the number of health institutions, along with frequent use of disposable medical products, has contributed to the increase of healthcare waste generation rate. For proper handling of healthcare waste, it is crucial to predict the amount of waste generation beforehand. Predictive models can help to optimise healthcare waste management systems, set guidelines and evaluate the prevailing strategies for healthcare waste handling and disposal. However, there is no mathematical model developed for Ethiopian hospitals to predict healthcare waste generation rate. Therefore, the objective of this research was to develop models for the prediction of a healthcare waste generation rate. A longitudinal study design was used to generate long-term data on solid healthcare waste composition, generation rate and develop predictive models. The results revealed that the healthcare waste generation rate has a strong linear correlation with the number of inpatients (R(2) = 0.965), and a weak one with the number of outpatients (R(2) = 0.424). Statistical analysis was carried out to develop models for the prediction of the quantity of waste generated at each hospital (public, teaching and private). In these models, the number of inpatients and outpatients were revealed to be significant factors on the quantity of waste generated. The influence of the number of inpatients and outpatients treated varies at different hospitals. Therefore, different models were developed based on the types of hospitals.


[The status of managing the type I diabetic patient in Austria. Organization].
During the Annual Meeting of the Austrian Diabetes Association various diabetic centres presented their success and failure rates with respect to metabolic control and prevention of late complications in diabetic patients on a country-wide basis. The analysis revealed that only 30% of all type I diabetic patients are adequately controlled. Intensive education in diabetes self-management, capable of leading to optimal metabolic control in up to 50% of the instructed patients, is however available only to a small minority of the diabetic patients to date. Despite the enormous improvement which has been achieved in the management of pregnant diabetic women, intensive specialized care is often commenced far too late. In rural areas, in particular, even conventional therapy is not fully implemented and late complications are, thus, inevitable.


Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.
Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033. Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001). A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. Fonds Cancer, Belgium.