PAC Bayesian Performance Guarantees for Deep (Stochastic) Networks in Medical Imaging.
Application of deep neural networks to medical imaging tasks has in some sense become commonplace. Still, a "thorn in the side" of the deep learning movement is the argument that deep networks are prone to overfitting and are thus unable to generalize well when datasets are small (as is common in medical imaging tasks). One way to bolster confidence is to provide mathematical guarantees, or bounds, on network performance after training which explicitly quantify the possibility of overfitting. In this work, we explore recent advances using the PAC-Bayesian framework to provide bounds on generalization error for large (stochastic) networks. While previous efforts focus on classification in larger natural image datasets (e.g., MNIST and CIFAR-10), we apply these techniques to both classification and segmentation in a smaller medical imagining dataset: the ISIC 2018 challenge set. We observe the resultant bounds are competitive compared to a simpler baseline, while also being more explainable and alleviating the need for holdout sets.


Low temperature geothermal systems in carbonate-evaporitic rocks: Mineral equilibria assumptions and geothermometrical calculations. Insights from the Arnedillo thermal waters (Spain).
Geothermometrical calculations in low-medium temperature geothermal systems hosted in carbonate-evaporitic rocks are complicated because 1) some of the classical chemical geothermometers are, usually, inadequate (since they were developed for higher temperature systems with different mineral-water equilibria at depth) and 2) the chemical geothermometers calibrated for these systems (based on the Ca and Mg or SO4 and F contents) are not free of problems either. The case study of the Arnedillo thermal system, a carbonate-evaporitic system of low temperature, will be used to deal with these problems through the combination of several geothermometrical techniques (chemical and isotopic geothermometers and geochemical modelling). The reservoir temperature of the Arnedillo geothermal system has been established to be in the range of 87±13°C being the waters in equilibrium with respect to calcite, dolomite, anhydrite, quartz, albite, K-feldspar and other aluminosilicates. Anhydrite and quartz equilibria are highly reliable to stablish the reservoir temperature. Additionally, the anhydrite equilibrium explains the coherent results obtained with the δ18O anhydrite - water geothermometer. The equilibrium with respect to feldspars and other aluminosilicates is unusual in carbonate-evaporitic systems and it is probably related to the presence of detrital material in the aquifer. The identification of the expected equilibria with calcite and dolomite presents an interesting problem associated to dolomite. Variable order degrees of dolomite can be found in natural systems and this fact affects the associated equilibrium temperature in the geothermometrical modelling and also the results from the Ca-Mg geothermometer. To avoid this uncertainty, the order degree of the dolomite present in the Arnedillo reservoir has been determined and the results indicate 18.4% of ordered dolomite and 81.6% of disordered dolomite. Overall, the results suggest that this multi-technique approach is very useful to solve some of the problems associated to the study of carbonate-evaporitic geothermal systems.


Fertility tracking tool for visually impaired and non-visually impaired women: A qualitative study.
A natural family planning device, Fertility Tracking Tool (FTT), was developed to serve as a visual and tactile guide in monitoring the fertile and infertile days of the menstrual cycle. However, there is lack of preferences about the tool among visually impaired and non-visually impaired women. Therefore, understanding their viewpoints will provide additional input for the final design of the product. This study aimed to explore the opinions of potential users of FTT in terms of acceptability, price sensitivity, buying intention, product placement, branding, and packaging. The study employed a qualitative research design with data gathered from focus group discussions. Eleven FGD sessions were conducted participated by one group of visually impaired and ten groups of non-visually impaired women from Iligan City, Philippines, selected through purposive sampling technique. Semi-structured FGD guide was utilized, and the sessions were audio-recorded. The data were analyzed through thematic analysis. The themes that emerged in the study were "adaptable" with three sub-themes (easy to use, safe to use, and aesthetic), "cost-effective", "marketable", "accessibility convenience", "remarkable brand", and "complementary packaging". The study shows that the FTT is acceptable to both visually impaired and non-visually impaired women because it is user-friendly, has no side effects, and has a unique design. The accounts implying less price sensitivity, buying intention, accessibility preferences, notable branding, and auxiliary packaging are indications of the business potential of FTT. This study made a novel contribution to the nursing practice as the FTT is a newly invented device for natural family planning. The strong support from the government is necessary for FTT commercialization or even free distribution to the qualified users, not only in the research locale but extending the nationwide. The extensive FTT use may increase the natural contraceptive utilization in the Philippines, resulting in improved women's health and population control. The FTT utilization can also be adapted across the globe to result in a better impact.


External calcium dependence of the uterine contraction induced by prostaglandins E2 and F2 alpha and its antagonism with natural progestins.
Prostaglandins (PGs) E2 and F2 alpha are strong inducers of uterine contraction by promoting a Ca2+ increase into the cell through specific receptors coupled with the calcium channels. On the contrary, progesterone and 5 beta-reduced progestins promote smooth muscle relaxation by blocking the ion calcium influx. Thus, this study was designed to emphasize the importance of external calcium in the PGs-induced rat uterus contraction. Likewise, also studied was the antagonism and the interaction between PGs and progestins (progesterone and its 5 alpha and 5 beta-reduced derivatives) in the myometrium. Results showed that uterine contraction induced by PGs depends on external calcium, since verapamil or extracellular calcium depletion abolished the PGs effect. Regarding the PGs-progestins antagonism, it was observed that pregnanedione, pregnanolone and epipregnanolone were quite effective for counteracting of PGs-induced contraction. However, progesterone was effective in a middle range, whereas 5 alpha-reduced progestins (allopregnanedione and allopregnanolone) were almost ineffective. It has been concluded that the participation of PGs and progestins in the modulation of uterine contraction might be achieved through the control of calcium influx by opening (PGs) or blocking (progestins) receptor-operated calcium channels.


Hierarchical longitudinal models of relationships in social networks.
Motivated by the need to understand the dynamics of relationship formation and dissolution over time in real-world social networks we develop a new longitudinal model for transitions in the relationship status of pairs of individuals ("dyads"). We first specify a model for the relationship status of a single dyad and then extend it to account for important inter-dyad dependencies (e.g., transitivity - "a friend of a friend is a friend") and heterogeneity. Model parameters are estimated using Bayesian analysis implemented via Markov chain Monte Carlo. We use the model to perform novel analyses of two diverse longitudinal friendship networks: an excerpt of the Teenage Friends and Lifestyle Study (a moderately sized network) and the Framingham Heart Study (FHS) (a large network).


Ethyl pyruvate enhances spontaneous remyelination by targeting microglia phagocytosis.
Ethyl pyruvate (EP), a simple derivative of the endogenous energy substrate pyruvate, provides strong anti-inflammatory and anti-oxidative properties. but its role in remyelination has not been explored. In this study, EP efficiently improved the behavioural performance and histological demyelination in cuprizone (CPZ)-induced mouse model. In terms of action, EP treatment enhanced microglia migration, increased the phagocytosis of myelin debris by BV2 microglia and primary microglia, induced cell proliferation and subsequent cell death. At the same time, EP induced microglia to exhibit M2 phenotype, representing decreased iNOS/TNF-α and increased Arg-1/IL-10. In addition, EP decreased microglia enrichment in myelin sheath, and declined TLR4/p-NF-kb/p65 and IL-1β and IL-6, inhibiting microglia-mediated neuroinflammation. As a result, EP treatment promoted the generation of oligodendrocyte progenitor cells (OPCs) and the differentiation from maturation to mature oligodendrocytes, which may be related to the up-regulation of Sox2. Given these data, we provided the proof-of-experiment that EP should be beneficial in multiple sclerosis or demyelinating lesions. However, further studies on the possibility to use EP as therapeutic application are warranted.


The impact of nuts on diabetes and diabetes risk.
Nuts have many nutritional benefits: they are high in monounsaturated and polyunsaturated fats, fiber, vitamin, minerals, and phytonutrients. Population studies indicate that individuals who regularly consume nuts have reduced risk for cardiovascular disease and diabetes. In clinical trials, nuts appear to have a neutral effect on glucose and insulin, and a beneficial effect on lipid profile. Thus, nuts can be a healthy dietary component for individuals with diabetes or those at risk for diabetes, providing overall caloric intake is regulated to maintain a healthy body weight.


Chronic Microaspiration and Frailty: A Geriatric Smoking Gun?
Chronic microaspiration and diffuse aspiration bronchiolitis may account for some otherwise unexplained frailty in nursing home patients.


P9 in median nerve SEPs is a junctional potential generated by the change of the volume conductor size between trunk and neck.
We aimed to investigate the origin of P9 in median SEPs by applying the junctional potential theory. We studied the distribution over the body surface with contralateral shoulder reference in 4 normal subjects. A stationary potential field P9/tN9 (=truncal N9) was recorded: P9 over head and neck (the smaller part), tN9 over trunk (the larger part), the boundary being located between trunk and neck. This polarity agreed with that expected from simulation studies. P9 is a junctional potential generated by the change of the volume conductor size between trunk and neck.


[Comparative study of the efficacy of the DBVCy protocol (daunoblastin, bleomycin, vincristine, cytostasan) and the ABVD protocol in advanced Hodgkin's lymphoma. A prospective inter-clinic study within the framework of the Hauptforschungsrichtung Geschwulsterkrankungen].
In MOPP-resistant patients with Hodgkin-lymphoma stage III B and IV the well known ABVD-protocol was compared with the DBVCy-protocol (daunorubicin, bleomycin, vincristine, cytostasan) in a randomized prospective trial. 73 patients were evaluable, 35 received ABVD, 38 DBVCy. 4 out of 35 (11%) in the ABVD-group and 9 out of 38(24%) in the DBVCy-group reached complete remission. The median duration of the remission for DBVCy was 4,5 months, for ABVD 3,4 months (no significance). Median survivals (61 months in DBVCy and 37 months in ABVD) did not show significant differences; but the DBVCy-scheme seems to be better tolerabel. With the given evaluation can not be proved a difference between the two groups, but it is not likely, that one of the regimen is very much better or very much worse as the other.


Modeling and analysis for the transmission dynamics of cotton leaf curl virus using fractional order derivatives.
In this study, we examine the Atangana Baleanu Caputo fractional order for the transmission dynamics of the Cotton Leaf Curl Virus disease. The model took into account both cotton plants and vector populations. The existence and uniqueness, positivity and boundedness of the solution to the model, as well as other fundamental concepts, were examined. Additionally, the Ulam-Hyres condition stability of the suggested model was demonstrated using functional techniques. Using the Adams-Bashforth method, the numerical solution for our suggested model was computed. The numerical result shows that the disease spreads more slowly as the fractional order decreases from 1.00 to 0.72.


Criterion-related validity of the Marital Disaffection Scale as a measure of marital estrangement.
The Marital Disaffection Scale was administered, along with measures of positive feelings towards spouse, problem-drinking behavior of spouse, workaholic behavior of spouse, and marital status, to 323 female members of the American Counseling Association. Scores on the Marital Disaffection Scale showed significant inverse correlations (r = -.94) with positive feelings towards spouse and (rpb = -.63) with marital status. Scores on the Marital Disaffection Scale showed significant positive relationships (r = .36) with spouse's problem drinking behavior and (r = .48) with workaholic behavior of spouse. The results support the use of the Marital Disaffection Scale as a measure of emotional estrangement in marriage.


Effectiveness of different adhesive primers on the bond strength between an indirect composite resin and a base metal alloy.
There is a need for achieving reliable chemical bond strength between veneering composites resins and casting alloys through the use of simplified procedures. The purpose of this study was to examine the shear bond strength of an indirect composite resin to a Ni-Cr alloy, using 4 primers and 2 airborne-particle-abrasion procedures. Fifty-six Ni-Cr (Heraenium NA) discs, 10 mm in diameter and 1.5 mm in height, were fabricated. Twenty-four discs were airborne-particle abraded with 50-microm Al2O3 particles, while another 24 were airborne-particle abraded with 250-microm Al2O3 particles. The following primers were applied on 6 discs of each airborne-particle-abrasion treatment group: Solidex Metal Photo Primer (MPP50, MPP250), Metal Primer II (MPII50, MPII250), SR Link (SRL50, SRL250), and Tender Bond (TB50, TB250). The Rocatec system was used on another 6 discs, airborne-particle abraded according to the manufacturer's recommendations, which served as the control group (R). Two more discs were airborne-particle abraded with 50-microm and 250-microm Al2O3 particles, respectively, to determine the Al content on their surfaces, without any bonding procedure. The indirect composite resin used was Sinfony. Specimens were thermally cycled (5 degrees C and 55 degrees C, 30-second dwell time, 5000 cycles) and tested in shear mode in a universal testing machine. The failure mode was determined with an optical microscope, and selected specimens were subjected to energy dispersive spectroscopy (EDS). Mean bond strength values were analyzed using 2-way ANOVA followed by Tukey's multiple comparison tests (alpha=.05) and compared to the control group using 1-way ANOVA followed by Tukey's multiple comparison tests (alpha=.05). The groups abraded with 50-microm particles exhibited significantly higher bond strength compared to the groups abraded with 250-microm particles. Group MPII50 exhibited the highest mean value (17.4 +/-2 MPa). Groups MPP50, MPP250, and TB50, TB250 showed adhesive failures and significantly lower bond strength compared to group R. Groups MPII50, MPII250, and SRL50, SRL250 showed combination failures and no significant difference compared with group R. EDS revealed interfacial rather than adhesive failures. Airborne-particle abrasion with 50-microm Al2O3 particles may result in improved bond strength, independent of the primer used. The bond strength of Metal Primer II and SR Link specimens was comparable to that of specimens treated with Rocatec.


Chemical development of intracellular protein heterodimerizers.
Cell activation initiated by receptor ligands or oncogenes triggers complex and convoluted intracellular signaling. Techniques initiating signals at defined starting points and cellular locations are attractive to elucidate the output of selected pathways. Here, we present the development and validation of a protein heterodimerization system based on small molecules cross-linking fusion proteins derived from HaloTags and SNAP-tags. Chemical dimerizers of HaloTag and SNAP-tag (HaXS) show excellent selectivity and have been optimized for intracellular reactivity. HaXS force protein-protein interactions and can translocate proteins to various cellular compartments. Due to the covalent nature of the HaloTag-HaXS-SNAP-tag complex, intracellular dimerization can be easily monitored. First applications include protein targeting to cytoskeleton, to the plasma membrane, to lysosomes, the initiation of the PI3K/mTOR pathway, and multiplexed protein complex formation in combination with the rapamycin dimerization system.


Alopecia and Iron Deficiency: An Interventional Pilot Study in Primary Care to Improve the Request of Ferritin.
The aim was to study the demographic and laboratory pattern of primary care patients with alopecia undergoing laboratory testing, more specifically, the request of hemoglobin and ferritin and values showing anemia and iron deficiency, and to evaluate the effects of an intervention involving automatic ferritin registration and measurement when not requested. Retrospective and prospective observational cross-sectional studies were conducted, as well as an intervention to automatically register and measure ferritin when not requested by the general practitioner. There were 343 and 1032 primary care laboratory requests prompted by alopecia in the retrospective and prospective studies. Hemoglobin was requested in almost every patient and ferritin in 88%. 5% of the cohort had anemia, and 25% had iron deficiency. The intervention registered and measured that 123 ferritin and 24 iron deficiencies were detected in patients with alopecia, all women, at a cost of 10.6€. Primary care patients with alopecia and laboratory tests request were mainly young female. Our intervention added ferritin when not requested, detecting iron deficiency in 27.9% of women, potentially avoiding the adverse effects of iron deficiency on hair loss.


Economic Effect of Confiscation of Cattle Viscera Infected with Cystic Echinococcosis, Huancayo Province, Peru.
We report cystic echinococcosis (CE) prevalence in Huancayo Province, Peru, and the associated economic effect of bovine organ condemnation. CE prevalence during the 16-month study period was 42.8% and caused $14,595 in economic losses. CE threatens food security in the region by reducing farmers' income and viscera supply in markets.


Organization and evolutionary relatedness of OR37 olfactory receptor genes in mouse and human.
We report a comprehensive comparative analysis of human and mouse olfactory receptor (OR) genes encoding OR37 subtypes to determine the repertoire, chromosomal organization, and relatedness of these genes. Two OR37 clusters were found in both mouse (chromosome 4) and human (chromosome 9); with five genes in cluster I and three (mouse) and seven genes (human) in cluster II. The pronounced diversity of noncoding sequence regions in both genomic loci indicates a long-term coexistence of the two clusters and the genes within the clusters. In contrast, the coding regions, particularly of genes in cluster I, showed remarkably high sequence identity, a feature quite unique for OR genes. The conservation of only the coding sequences indicates that OR37 may be under negative selection pressure and suggests that the OR37 receptor family may be tuned to recognize distinct sets of signaling molecules. A comparison of mouse and human OR37 gene clusters revealed that genes in cluster I are highly related within each species whereas genes in cluster II are highly related across species. These data reflect a unique and complex evolutionary history of the OR37 family.


Polymorph control: past, present and future.
The appearance and disappearance of polymorphs is no longer a mysterious and inexplicable process. Although methods for polymorph control are still imperfect, there is a large armoury of methods that can be used to tackle this important and challenging problem. We survey the methods and their successes over the last few years.


A trichromatic test for spheric and astigmatic refraction.
An improved chromatic rotatable refraction test for simultaneous spheric and astigmatic refraction is described. Its new features are interposition of a bright yellow stripe between the conventional red and green fields and a pair of parallel test lines, which traverse vertically all colored fields. Thereby astigmatic errors become easily visible.


The IkappaB protein Bcl-3 negatively regulates transcription of the IL-10 gene in macrophages.
NF-kappaB/Rel transcription factors, implicated in inflammatory and immune responses against pathogens, are regulated by IkappaB proteins. The physiological and molecular function of the IkappaB family member Bcl-3 is understood only poorly. In this study, the role of Bcl-3 in an innate immune response was examined by gene targeting. We demonstrate that Bcl-3(-/-) mice are highly susceptible to Listeria monocytogenes infection. This correlates with diminished production of IL-12 p70 and IFN-gamma in vivo, which is mainly due to elevated synthesis of IL-10. Isolated peritoneal macrophages from Bcl-3(-/-) mice also produce elevated amounts of IL-10, which inhibit IL-12 p70 synthesis in an autocrine fashion. Thus, these data establish Bcl-3 as an inhibitor of IL-10 expression in macrophages. Furthermore, we show that Bcl-3 is not implicated in IL-10 mRNA stabilization but regulates the initiation of IL-10 transcription. Taken together, our results show that an essential function of Bcl-3 during an innate immune response against bacteria is to inhibit transcription of the IL-10 gene in macrophages.


Isolation of an antibacterial component from roasted coffee.
A coffee beverage obtained from instant dark coffee that had been previously shown to possess high antibacterial activity, was acidified (pH 2) and extracted with ethyl acetate. After alkalinization (pH 12) the aqueous phase was re-extracted with the organic solvent. The acidic and basic extracts were evaporated to dryness and the aqueous phase freeze-dried. Residues were dissolved in sterile water and assayed for antibacterial activity against two reference bacteria (Staphylococcus aureus ATCC 25923 and Streptococcus mutans 9102). The acidic extract was found to be highly active and was separated by gel permeation chromatography (GPC) into five fractions. Fractions GPC4 and GPC5 were found to possess antibacterial activity: most of the activity was evident in fraction GPC5. These fractions were separated by RP-HPLC using a gradient elution with methanol water as mobile phase. Both GPC fractions gave an active subfraction with methanol-water (70:30, v/v). The experimental conditions used to separate the antibacterial compound that originates during the roasting process, indicate that it possesses low molecular mass (probably no more than 200 Da), weak acidic properties and an lambda(max) at 205 nm. The very small amount of this compound isolated from roasted coffee, indicates that it may be a very strong antibacterial agent.


Pancreatic duct obstruction triggers acute necrotizing pancreatitis in the opossum.
The common channel theory suggests that bile reflux, through a common biliopancreatic channel, triggers acute pancreatitis. In the present study, this controversial issue was evaluated using an experimental model of hemorrhagic necrotizing pancreatitis. American opossums underwent ligation of the pancreatic duct alone, bile and pancreatic duct separately, or common biliopancreatic duct; the severity of pancreatitis was evaluated at selected times after ligation. Animals in all three experimental groups developed hemorrhagic necrotizing pancreatitis; the severity of pancreatitis was similar in each group, although only those subjected to common biliopancreatic duct ligation experienced bile reflux. Bile reflux into the pancreatic duct, via a common biliopancreatic channel, is not necessary for the development of pancreatitis and does not worsen the severity of pancreatitis associated with pancreatic duct obstruction in this model.


Assessment of hydrophobic-ion paired insulin incorporated SMEDDS for the treatment of diabetes mellitus.
To overcome the low oral bioavailability of insulin, we hypothesized that the insulin-hydrophobic ion pairing (HIP) complex incorporated self-microemulsifying drug delivery system (SMEDDS) would be beneficial. In the present study, an oral insulin delivery system was developed and estimated using the HIP technique and SMEDDS. Further insulin-HIP complexes were characterized using various spectroscopical techniques. Additionally, insulin-HIP complexes were subjected to analysis of complexes' conformational stability in the real physiological solution using computational approaches. On the other hand, in vitro, and in vivo studies were carried out to investigate the permeability and hypoglycemic effect. Subsequently, in an in vitro non-everted gut sac study, the apparent permeability coefficient (Papp) was approximately 8-fold higher in the colon than in the jejunum, and the HIP-incorporated SMEDDS showed an approximately 3-fold higher Papp value than the insulin solution. The hypoglycemic effect after in situ colon instillation, the HIP complex between insulin and sodium docusate-incorporated SMEDDS showed a pharmacological availability of 2.52 ± 0.33 % compared to the subcutaneously administered insulin solution. Thus, based on these outcomes, it can be concluded that the selection of appropriate counterions is important in developing HIP-incorporated SMEDDS, wherein this system shows promise as a tool for oral peptide delivery systems.


Correction to: Real-World Clinical Practice Use of 8-Week Glecaprevir/Pibrentasvir in Treatment-Naïve Patients with Compensated Cirrhosis.
In the original article, there is an error in Fig. 1.


Characterizing the settleability of grit particles.
Grit chambers are installed at the headworks of a water resource recovery facility (WRRF) to reduce the impact of grit particles to the equipment and processes downstream. This settling process should thus be designed and operated in an efficient way. Despite the importance of knowing settling characteristics for design and operation of grit chambers, previous grit definitions have been based only on particle size characteristics, and not on settling velocities. Thus, this study presents an evaluation of the performance of two promising settling velocity characterization methods, ViCAs and elutriation, to characterize wastewater particles in view of the design and the optimization of the efficiency of the grit removal unit. PRACTITIONER POINTS: Settling characteristics are the governing parameter for grit chamber design. Since grit particles are vastly heterogeneous, it is preferred to measure these characteristics directly rather than to estimate them from particle size (and assumptions of density, form factor, …). More detailed settling information about grit particles can improve grit chamber design and estimation of removal performance. Adapted ViCAs and elutriation methods for faster settling particles allow studying the particle settling characteristics in a grit chamber. These methods are simple, fast, and cheap and only require small wastewater samples. A relationship was found between the influent TSS concentration and the location of the PSVD curve, with higher TSS concentrations corresponding to higher settling velocities. It was demonstrated that the dynamics of the wastewater characteristics under dry, wet, and snowmelt weather conditions influence grit settling characteristics.


Factors affecting motivation during the first six weeks of treatment.
Since the new conceptualization of motivation as a product of interpersonal exchanges, clinicians and researchers have shown a growing interest in understanding the process of and identifying factors increasing motivation for treatment. Elaborated from the self-determination theory, a motivational model was tested among 140 participants (recruited in a public outpatient readaptation center for substance-related disorders) who persevered in treatment for at least 6 weeks. The results support the usefulness of the self-determination theory in the field of motivation for treatment of substance-related disorders, and suggest some recommendations to enhance motivation: therapists must pay attention to the progression toward goal attainment and foster the perception of competence of their clients; treatment centers should offer a context that supports autonomy and that involves significant others.


Triazolothiadiazine derivative positively modulates CXCR4 signaling and improves diabetic wound healing.
Development of specific therapies that target and accelerate diabetic wound repair is an urgent need to alleviate pain and suffering and the huge socioeconomic burden of this debilitating disease. C-X-C Motif Chemokine Ligand 12 (CXCL12) also know an stromal cell-derived factor 1α (SDF-1α) is a chemokine that binds the CXC chemokine receptor type 4 (CXCR4) and activates downstream signaling resulting in recruitment of hematopoietic cells to locations of tissue injury and promotes tissue repair. In diabetes, low expression of CXCL12 correlates with impaired wound healing. Activation of CXCR4 receptor signaling with agonists or positive allosteric modulators (PAMs) provides a potential for small molecule therapeutic discovery and development. We recently reported high throughput screening and identification of the CXCR4 partial agonist UCUF-728, characterization of in vitro activity and reduced wound closure time in diabetic mice at 100 μM as a proof-of-concept study. We report here, the discovery of a second chemical scaffold demonstrating increased agonist potency and represented by thiadiazine derivative, UCUF-965. UCUF-965 is a potent partial agonist of β-arrestin recruitment in CXCR4 receptor overexpressing cell line. Furthermore, UCUF-965 potentiates the CXCL12 maximal response in cAMP signaling pathway, activates CXCL12 stimulated migration in lymphoblast cells and modulates the levels of specific microRNA involved in the complex wound repair process, specifically in mouse fibroblasts. Our results indicate that UCUF-965 acts as a PAM agonist of the CXCR4 receptor. Furthermore, UCUF-965 enhanced angiogenesis markers and reduced wound healing time by 36% at 10.0 μM in diabetic mice models compared to untreated control.


Comparative analysis of the boundary layer filtering of odor signals in the amblypygid (whip spider) species Paraphrynus laevifrons and Phrynus marginemaculatus.
Amblypygids use a pair of modified walking legs (antenniform) as chemosensory and mechanosensory appendages. At the tip of these legs are covered in chemosensory sensilla, which the animals use to sample odor stimuli in their environment by moving the antenniform leg through the air. We designed a set of experiments to measure the filtering effect that aerodynamic boundary layers have on the temporal and spatial structure of chemical stimuli. In addition, two different species of amblypygids (Paraphrynus laevifrons and Phrynus marginemaculatus) that live in two distinct habitats were used for a comparative analysis. Pulses of a tracer molecule were quantified at different distances and flow velocities using an electrochemical detection system. Temporal attributes of the chemical pulses were extracted and were statistically compared across velocities, distances from the appendage, and the two species. Overall, the boundary layer significantly decreased the concentration and increased the duration of pulses for both species. This filtering effect was more pronounced for P. marginemaculatus than P. laevifrons, as the chemical signal was lower in concentration and longer in duration at any distance from the antenniform leg. It is speculated that the difference in boundary layer filtering, as a function of appendage morphology, is tuned to the different types of odor plumes in these animals' native habitats.


Effects of soluble dietary fibers on the viscosity property and digestion kinetics of corn starch digesta.
Four soluble dietary fibers (SDFs) were fortified with corn starch (CS) at different concentrations to match the same viscosity equivalents. The mixtures were subjected to a simulated digestion procedure to study the effects of SDFs on viscosity properties and digestion kinetics of CS. Results showed that SDFs increased the hydration property and decreased the water mobility of digesta. During digestion process, SDFs increased the apparent viscosity of digesta to some extent, and showed significant difference to delay the decay of digesta viscosity (kv). The amylolysis inhibitory ability was similar when each SDF was present at the same viscosity equivalent, however, significant differences were found on the digestion rate constant of k2. Linear correlations between kv and k2 were established for 1 and 2 equivalent groups. These results demonstrated that SDFs could delay the digestion process as chemistry differences, which related to their ability on delaying the change of digesta viscosity.


Innovation in nursing health care practice: expansion of access in primary health care.
analyze the reorganization of the health care practice of nurses as an innovative strategy for expansion of access in primary care. qualitative and quantitative study, which interviewed 32 management and care nurses and collected documentary data from public reports of production of nursing consultations from 2010 to 2014, in a municipality in southern Brazil. Data processing for textual analysis was performed by IRAMUTEQ software; for simple descriptive statistical analysis, the program Excel 2013 was used. in the innovative care practice class, associated with awareness of change, related to implementation of the FHS, its challenges and advantages, the following subclasses were identified: reorganization of schedules, nursing consultation, physical restructuring of BHUs, and shared consultation. the need to expand access to and valorization of care practice encourages the development of innovative strategies. The protagonism of care needs to be discussed in the various spaces so that each professional carry out the respective role with competence and efficacy. analisar a reorganização da prática assistencial do enfermeiro como estratégia inovadora para ampliação do acesso na atenção primária. estudo qualiquantitativo, tendo sido entrevistados 32 enfermeiros gerenciais e assistenciais e coletados dados documentais de relatórios públicos de produção de consultas dos enfermeiros de 2010 a 2014, num município sul-brasileiro. O processamento dos dados para análise textual foi realizado pelo software IRAMUTEQ; para análise estatística descritiva simples, o programa Excel 2013. na classe prática assistencial inovadora, associada à sensibilização para a mudança, relacionada à implantação da ESF, seus desafios e fortalezas, foram identificadas as subclasses: reorganização das agendas, consulta do enfermeiro, reestruturação física das UBS e consulta compartilhada. a necessidade de ampliar o acesso e valorização da prática assistencial incentiva o desenvolvimento de estratégias inovadoras. O protagonismo do cuidado precisa ser discutido nos diversos espaços a fim de que cada profissional desempenhe seu papel com competência e resolutividade.


Effects of oestradiol-17 beta on the synthesis of RNA, proteins and lipids in the pyloric caeca of the female starfish Asterias rubens.
1. The effects of oestradiol-17 beta on processes of synthesis in the pyloric caeca of female Asterias rubens were studied. 2. In vitro treatment with 2.5 X 10(-7) M oestradiol-17 beta resulted in significantly higher RNA levels. 3. In vivo treatment with oestradiol-17 beta resulted in higher lipid levels in the pyloric caeca, but RNA levels, protein levels and the incorporation of 6-[14C]orotic acid, L-leucine-[14C] and sodium 1-[14C] acetate into RNA, proteins and lipids, respectively were not affected, neither were the indices of the gonads and pyloric caeca.


Urodynamic findings in Parkinson's disease.
Neurological evaluation was performed in 24 men and 5 women with Parkinson's disease who had persistent bladder symptoms. Detrusor hyperreflexia was found in 26 (90 per cent) of the patients. Sporadic involuntary electromyography activity of the external sphincter during involuntary detrusor contractions was encountered in 61 per cent but in none did this cause obstruction. Coordinated striated sphincter relaxation during voluntary detrusor contraction was found in 13 patients (45 per cent). Among 22 men who were in the prostatic disease age group only 4 (18 per cent) had definite prostatic obstruction. Moreover, none of 8 men with persistent symptoms after prostatectomy had evidence of bladder outlet obstruction.


Segmented flow and curtain flow chromatography: overcoming the wall effect and heterogeneous bed structures.
The variation in mobile phase velocity as a function of the column radius has been shown to be a major limitation in the efficiency of HPLC columns. One contributing factor to the variability in the flow velocity stems from the heterogeneity in the radial packing density, leading to what has been described as the 'wall-effect'. The wall-effect generates parabolic-type elution profiles, which dilutes the sample and creates tailing bands. In this communication a new column technology is discussed that has been designed to overcome the wall effect, minimising the limitations associated with packing heterogeneity. This technology has been referred to as active flow technology and consists of two types of column designs, parallel segmented flow and curtain flow. In both these column designs sample that elutes through the column in the radial central region of the bed is separated from the flow that elutes along the wall region. Hence, the sample that elutes through the most efficiently packed region of the bed is collected to the detector. As a consequence more theoretical plates are obtained, and sensitivity is increased since the sample is not diluted by the diffuse tail. Sensitivity is enhanced further in the curtain flow design. The benefits of these new columns are discussed.


Maturation of mismatch negativity in typically developing infants and preschool children.
1) To determine whether an adult-like mismatch negativity (MMN) can be reliably elicited in typically developing awake infants and preschool children, and if so 2) to examine whether maturational changes exist in MMN latencyand amplitude. Two experiments were designed to elicit MMN using an "oddball" paradigm. In Experiment 1, a 1000-Hz tone served as the standard stimulus and a 1200-Hz tone as the deviant. In Experiment 2, a 1000-Hz standard stimulus and a 2000-Hz deviant were presented. Infants' ages ranged from 2 to 47 and 3 to 44 mo in Experiments 1 and 2, respectively. In Experiment 1, a negativity was not elicited in the majority of the infants and preschoolers tested. In Experiment 2, a negativity was reliably elicited in the infants and preschoolers across all ages. A significant negative correlation was observed between age and latency, but not for age and amplitude for this negativity. This negativity was found to decrease at a rate of 1 msec/mo. Infants younger than 12 mo of age showed a significantly larger positivity to the deviant than to the standard between 150-300 and 200-300 msec in Experiments 1 and 2, respectively. The discriminative processes indexed by MMN in response to frequency changes areimmature in infants and preschool children. Although there is convincing evidence that the negativity elicited in Experiment 2 is an immature MMN, the possibility that it may be an "obligatory effect" indexing recovery from refractoriness cannot be ruled out at this time. The results from these experiments suggest that the MMN component haslimited use as a clinical tool at this time for infants and young children.


A novel method to determine residual detergent in biological samples post endotoxin reduction treatment and evaluation of strategies for subsequent detergent removal.
Endotoxin removal using detergent washes and extractions are well-established, efficient, and cost-effective methods; however, removing residual detergent post treatment has been shown to be a challenge. In this communication, we show a simple and fast method for determining the detergent concentration in a protein solution post treatment and highlight strategies for detergent removal to achieve levels below the critical micelle concentration (CMC), the minimum concentration at which detergent micelles form.


Stress proteins as biomarkers of oxidative stress: effects of antioxidant supplements.
The potential benefits to health of the supply of antioxidants, either through dietary intake or as supplements, is equivocal. There is a need to develop biomarkers that may act as monitors of cellular defense as influenced by antioxidant status. Thirty-two individuals participated in the project and 19 received supplements for 5 weeks in the form of a capsule containing a defined mixture of antioxidants. No change was noted in levels of superoxide dismutase and glutathione peroxidase following antioxidant supplementation. On the other hand, increase in total antioxidant status and decrease in malondialdehyde, protein carbonyl formation, and erythrocyte hemolysis were noted. In lymphocytes isolated from individuals receiving antioxidant supplements and subjected to a heat shock in the presence of the free radical generator 2, 2'-azobis-(2-amidinopropane)-dihydrochloride, enhanced synthesis of heat shock proteins hsp 105, hsp 90, hsp 70, and hsp 40 by contrast with decreased synthesis of heme oxygenase HO-1 (hsp 32) were noted. We conclude that antioxidant status modulates the synthesis of stress proteins.


Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue.
Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3's expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.


Effects of acipimox on serum lipids, lipoproteins and lipolytic enzymes in hypertriglyceridemia.
Two separate studies were carried out with acipimox, a new antilipolytic agent with long-lasting activity. First, in a randomized, double-blind, cross-over study a dose of 750 mg/day of acipimox versus placebo was employed for 60 days in 11 patients with type IV hyperlipoproteinemia. Mean plasma triglyceride levels were reduced after acipimox compared to placebo (434 +/- 60 vs 777 +/- 224 mg/dl, P less than 0.01). Serum total cholesterol fell also significantly after acipimox compared to placebo. No significant alteration was observed in the HDL2/HDL3 ratio or in the concentration or composition of the HDL subfractions. Six patients with severe hypertriglyceridemia (2 type IV and 4 type V) and low lipoprotein lipase (LPL) activity took part in a second, open study, lasting for 9 months. Acipimox was given at a dose of 750 mg/day for the first 6 months and 1200 mg/day for the last period. The response of serum total and VLDL triglycerides was inconsistent. HDL cholesterol was significantly raised (+33.3%) after 9 months of treatment due to changes of HDL2 and HDL3 cholesterol, phospholipid and protein concentrations. LPL activity was markedly reduced in adipose tissue at 9 months. No significant changes occurred in postheparin plasma LPL activity. In contrast, hepatic lipase activity showed a reduction of about 25% from 6 months of treatment onwards.


Hierarchically self-assembled homochiral helical microtoroids.
Fabricating microscale helical structures from small molecules remains challenging due to the disfavoured torsion energy of twisted architectures and elusory chirality control at different hierarchical levels of assemblies. Here we report a combined solution-interface-directed assembly strategy for the formation of hierarchically self-assembled helical microtoroids with micrometre-scale lengths. A drop-evaporation assembly protocol on a solid substrate from pre-assembled intermediate colloids of enantiomeric binaphthalene bisurea compounds leads to microtoroids with preferred helicity, which depends on the molecular chirality of the starting enantiomers. Collective variable-temperature spectroscopic analyses, electron microscopy characterizations and theoretical simulations reveal a mechanism that simultaneously induces aggregation and cyclization to impart a favourable handedness to the final microtoroidal structures. We then use monodispersed luminescent helical toroids as chiral light-harvesting antenna and show excellent Förster resonance energy transfer ability to a co-hosted chiral acceptor dye, leading to unique circularly polarized luminescence. Our results shed light on the potential of the combined solution-interface-directed self-assembly approach in directing hierarchical chirality control and may advance the prospect of chiral superstructures at a higher length scale.


Furosemide binding to human albumin and plasma of nephrotic children.
The extent and nature of furosemide (F) binding to human albumin (HA) and to the plasma of 6 children with nephrotic syndrome were studied by equilibrium dialysis at 37 degrees C and pH 7.4 with 14C-F. At a total concentration of 3.4 mug/ml (therapeutic range), the unbound fraction of F to 4 gm per 100 ml HA was 2.79 plus or minus 0.35. The degree of binding was relatively constant from 1.8 to 36 mug/ml of F concentration. The percentage of unbound F doubled when total concentration of the drug was increased more than 130 times (1.8 to 245 mug/ml). F has two classes of binding sites (n1 = 1.42, k1 = 5.07 times 10-4 M-minus 1; n2 = 3.4, k2 = 1.58 times 10-4 M-minus 1); interaction with HA involves hydrophobic, ionic, and hydrogen forces. Acetylsalicylic acid (ASA), acetazolamide, diazoxide, phenylbutazone, sulfisoxazole (S), and tolbutamide (T) decreased F binding. Combinations of ASA, S, and T exerted a strong additive displacing effect. The binding of the F metabolite (4-chloro-5-sulfamoylanthranilic acid, CSA) was studied at 1.3 and 2.6 mug/ml. The unbound fraction was 5 times that of F. CSA did not influence F binding. Studies with plasma of 7 healthy adults showed that albumin is the only plasma protein responsible for F binding. The plasma albumin concentration range of the children with nephrotic syndrome was 0.6 to 2.1 gm per 100 ml. There was some correlation between albumin concentration and binding of F (2.8 to 9.6% unbound); this corresponded with findings with HA. Albumin concentrations lower than 2 gm per 100 ml seemed to influence the extent of the unbound fraction of F considerably.


Visual consciousness: dissociating the neural correlates of perceptual transitions from sustained perception with fMRI.
To investigate the possible dichotomy between the neurophysiological bases of perceptual transitions versus sustaining a particular percept over time, an fMRI study was conducted with subjects viewing fragmented pictures. Unlike most other perceptually unstable stimuli, fragmented pictures give rise to only one perceptual transition and a continuous period of sustained perception. Earlier research is inconclusive on the subject of which anatomical regions should be attributed to what temporal aspect of perception, and the aim of the present study was to shed more light on the subject. In this study occipitotemporal and fronto-parietal regions were found to be activated for both aspects. However, regions in the medial-temporal lobe were activated specifically for transitions, whereas medial and dorsolateral prefrontal regions were activated specifically for sustained perception. These results provide further support for the theory that the initial creation of perceptual awareness and upholding perceptual awareness over time are separate processes involving different brain regions.


Impact of 'mild' asthma on health outcomes: findings of a systematic search of the literature.
The present bibliographic review shows that patients considered to have mild asthma often suffer impairment in quality of life (QoL) and use considerable scheduled and unscheduled health care resources. I found that asthma investigators used no consistent classification scheme for asthma severity, and the level of agreement amongst specialists when categorizing patients with asthma was low. Asthma severity has been classified using a wide range of parameters including medication use, asthma symptoms, lung function, hospitalizations and incidence of exacerbations. Most studies showed a general association between asthma severity and health-related quality of life (HRQoL) such that patients with severe disease suffered greater impairment. However, few patients with mild asthma enjoyed unimpaired HRQoL. Indeed depression and impaired HRQoL were reported as frequently in patients with mild asthma as in those with more severe disease. Although in general severe patients used the most health care resources, even patients with mild asthma used considerable health care resources including emergency room care and hospitalizations. In summary, the term 'mild' when applied to asthma is potentially misleading given the impaired HRQoL and avoidable health care utilization prevalent amongst such patients. The application of disease severity classification in clinical asthma management has not been validated. It may now be appropriate to examine these classifications more critically in order to determine if they have clinical or research usefulness. By contrast, the strategy of treating to achieve disease control has been validated and offers the advantage of simplicity in its application.


The Biomedical Engineering Labor Market in Greece: A Survey Investigating Job Outlook, Satisfaction and Placement.
In this study, we have evaluated the real-world conditions, the job outlook and the job satisfaction in the Biomedical Engineering (BME) sector in Greece on the basis of the experience of about 12% of the graduates of the BME Department of the University of West Attica, Greece. An anonymous online questionnaire, implemented on the Microsoft Forms platform using multiple choice questions, short text answers and Likert-based scales, became publicly available to the graduates of the BME department. About 12% of the department's graduates responded to the survey. Results show that the time to first employment is very fast for both men and women. About 51.4% of men and 69.4% of women find their first job employment in the BME sector even before their graduation. The internship is considered important for first job placement by more than 50.6% of participants. BME jobs are perceived as most interesting (73.6%), in a good environment (71.9%), with satisfactory career prospects (45.9%), with satisfactory monthly net salary (44.2%) and satisfactory working hours (52.8%). Men are mostly employed in Service (40.5%), whereas women are mostly employed in Sales (33.3%). Most graduates with BSc degree are employed in Service (39.1%) and Sales (21.8%), most graduates with MSc degree are employed in Service (34.6%) and Hospitals/Health care centers (21.2%), and most graduates with PhD degree are employed in Academia and R&D (62.5%). Most well-paid participants (>1500 euros net salary) were PhD holders (71.5%), followed by MSc holders (25%) and BSc holders (16.2%). Maximum monthly salaries were found for those with more than 10 years of experience. In terms of BME sector, most well-paid participants (>1500 euros monthly net salary) are those working with R&D (86.7%), Sales (86.7%) and Management (60%). There is a high demand for biomedical engineers in the labor market in Greece, despite the continuing economic recession that the country is suffering from the past 12 years.


Force field parameters for rotation around chi torsion axis in nucleic acids.
To raise the accuracy of the force field for nucleic acids, several parameters were elaborated, focusing on the rotation around chi torsion axis. The reliability of molecular dynamics (MD) simulation was significantly increased by improving the torsion parameters at C8--N9--C1'--X (X = H1', C2', O4') in A, G and those at C6--N1--C1'--X in C, T, and U. In this work, we constructed small models representing the chemical structure of A, G, C, T, and U, and estimated energy profile for chi-axis rotation by executing numerous quantum mechanical (QM) calculations. The parameters were derived by discrete Fourier transformation of the calculated QM data. A comparison in energy profile between molecular mechanical (MM) calculation and QM one shows that our presently derived parameters well reproduce the energy surface of QM calculation for all the above torsion terms. Furthermore, our parameters show a good performance in MD simulations of some nucleic acids. Hence, the present refinement of parameters will enable us to perform more accurate simulations for various types of nucleic acids.


Comparison of 50- and 100-g L -tryptophan depletion and loading formulations for altering 5-HT synthesis: pharmacokinetics, side effects, and mood states.
Differences in 5-hydroxytryptamine (5-HT) function have been the subject of extensive research in psychiatric studies. Many studies have manipulated L -tryptophan (Trp) levels to temporarily decrease (depletion) or increase (loading) 5-HT synthesis. While most researchers have used a 100-g formulation, there has been ongoing interest in using smaller-sized formulations. This study examined the time course of multiple plasma indicators of brain 5-HT synthesis after a 50-g depletion and loading as a comparison to the corresponding 100-g formulations that are typically used. Plasma was collected from 112 healthy adults at seven hourly intervals after consumption of either a 50- or 100-g depletion or loading. Self-ratings of mood and somatic symptoms were completed before and after Trp manipulations. The primary findings were that (1) the 50- and 100-g formulations produced the expected changes in plasma indicators after both depletion (-89% and -96%, respectively) and loading (+570% and +372%, respectively); (2) the 100-g depletion showed more robust effects at the 4, 5, and 6 h measurements than the 50-g depletion; (3) there was significant attrition after both the 100-g depletion and loading, but not after either of the 50-g formulations; and (4) both the 50- and 100-g depletions produced increases in negative self-ratings of mood and somatic symptoms, while loading significantly increased negative ratings after the 100 g only. There are important considerations when choosing among formulation sizes for use in Trp manipulation studies, and the complete 7-h time-course data set of the typical plasma Trp measures presented here may help researchers decide which methodology best suits their needs.


Propagation of adenovirus types 40 and 41 in the PLC/PRF/5 primary liver carcinoma cell line.
The sensitivity of cell cultures to adenovirus types 40 and 41 (Ad40/41) was compared by means of cell culture infectious dose (ID50) assays using monolayer cultures in microtitre plates. The PLC/PRF/5 cell line derived from a primary human hepatocellular carcinoma was 100 times more sensitive to a laboratory strain of Ad41, and 10 times more sensitive to a laboratory strain of Ad40 and two Ad41 stool isolates, than Graham 293 and Chang conjunctival cells commonly used for the propagation of these viruses. In microtitre plate titration assays PLC/PRF/5 cells retained an optimal condition for longer and displayed cytopathogenic effects earlier and more clearly than the other cell lines. In contrast to previously used cells, PLC/PRF/5 cells also proved successful for the quantitation of Ad41, but not Ad40, by conventional plaque assays. The reason for the exceptional susceptibility of PLC/PRF/5 cells has not been elucidated, but the findings open attractive new doors for research on Ad40/41.


In Staphylococcus aureus the regulation of pyruvate kinase activity by serine/threonine protein kinase favors biofilm formation.
Staphylococcus aureus, a natural inhabitant of nasopharyngeal tract, survives mainly as biofilms. Previously we have observed that S. aureus ATCC 12600 grown under anaerobic conditions exhibited high rate of biofilm formation and L-lactate dehydrogenase activity. Thus, the concentration of pyruvate plays a critical role in S. aureus, which is primarily catalyzed by pyruvate kinase (PK). Analyses of the PK gene sequence (JN645815) revealed presence of PknB site in PK gene indicating that phosphorylation may be influencing the functioning of PK. To establish this hypothesis the pure enzymes of S. aureus ATCC 12600 were obtained by expressing these genes in PK 1 and PV 1 (JN695616) clones and passing the cytosolic fractions through nickel metal chelate column. The molecular weights of pure recombinant PK and PknB are 63 and 73 kDa, respectively. The enzyme kinetics of pure PK showed K M of 0.69 ± 0.02 µM, while the K M of PknB for stpks (stpks = NLCNIPCSALLSSDITASVNCAK) substrate was 0.720 ± 0.08 mM and 0.380 ± 0.07 mM for autophosphorylation. The phosphorylated PK exhibited 40 % reduced activity (PK = 0.2 ± 0.015 μM NADH/min/ml to P-PK = 0.12 ± 0.01 μM NADH/min/ml). Elevated synthesis of pyruvate kinase was observed in S. aureus ATCC 12600 grown in anaerobic conditions suggesting that the formed pyruvate is more utilized in the synthesis phase, supporting increased rate of biofilm formation.


31P-NMR spectroscopy and ultrastructural studies on nephrotoxicity of cyclosporine A.
NMR-spectroscopy and electron microscopy were applied in order to find out whether nephrotoxic effects of cyclosporine A in combination with ischaemia on rat kidney are of significance for the energy metabolism of the organ. CSA was administered in daily doses of 15 mg/kg rat over 20 days. Use was made of the particular advantage of 31P-NMR-spectroscopy to follow up the dynamics of high-energy phosphate concentrations in the same tissue. Ultrastructural changes were observed in the region of the proximal tubule. Some mitochondria showed degenerative changes, others increased density of cristae. The total number of mitochondria was increased. This observation together with the coexistence of vacuolarly degenerated mitochondria and mitochondria with increased activity after CSA treatment is interpreted as expression of a compensatory mechanism that keeps constant the totality of high-energy phosphates despite damage to some mitochondria.


Hepatitis B virus-X protein recruits histone deacetylase 1 to repress insulin-like growth factor binding protein 3 transcription.
Hepatitis B virus (HBV), a major causative agent of hepatocelluar carcinoma (HCC), encodes an oncogenic X-protein (HBx) which has been known as a transcriptional transactivator on multiple viral and celluar promoters. In the report, we verified that HBx transcriptionally repress insulin-like growth factor binding protein-3 (IGFBP-3) by promoting HBx/histone deacetylase 1 (HDAC1) complex formation. HBx recruited HDAC1 forms complex with Sp1 in a p53-independent manner) and deacetylates Sp1 which resulted in the diminished binding of Sp1 on targeted DNA during transcriptional repression. Deacetylation of Sp1 by HBx recruited HDAC1 likely to be a part of the mechanism that controls HBx induced IGFBP-3 repression and the modification of chromatin structure.


Ferritin as a cytosol iron transport intermediate in human reticulocytes.
The major iron-bearing cytosol components of human reticulocytes identified after incubation with 59 Fe-125I-transferrin have been studied further. Component C previously found to behave consistently as an intermediate in the iron transport pathway to haem is shown to consist entirely of ferritin. After a short pulse of labelled transferrin incubation, chase experiments showed a fall of ferritin label with time and a corresponding increase in haemoglobin-iron incorporation. There was no loss of ferritin to the culture medium. Restriction of iron uptake by reticulocytes using both p-hydroxymercuribenzoate inhibition of uptake and incubation with progressively lower saturations of iron-transferrin gave linearly related incorporation of 59Fe into ferritin and haemoglobin at all levels of iron uptake, thus negating the concept of ferritin as an 'overspill' form of reticulocyte iron. The results suggest that cytosol ferritin is an obligatory intermediate in reticulocyte iron transport.


Palladium-catalyzed Ullmann-type reductive homocoupling of iodoaryl glycosides.
A catalytic synthesis of novel biaryl-linked divalent glycosides was achieved using an electroreductive palladium-catalyzed iodoaryl-iodoaryl coupling reaction. This new method was optimized for the synthesis of divalent biaryl-linked mannopyranosides that was subsequently generalized toward several carbohydrate substrates with yields up to 96%.


Ankylosing spondylitis disease activity and serum vitamin D levels: A systematic review and meta-analysis.
To prove that serum vitamin D (VD) levels are strongly associated with ankylosing spondylitis (AS) disease activity, the association between serum VD levels and key monitoring indicators of AS disease activity has been analyzed, such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Studies published in PubMed, Cochrane Library, EMBASE, and China National Knowledge Infrastructure by August 30, 2022 were searched, and 6 studies finally met the selection criteria. Serum 25-hydroxyvitamin D (25(OH)D), ESR, CRP levels, and correlation coefficients between serum VD and BASDAI, ESR, CRP in AS, and control in these studies were extracted for the meta-analysis. When compared to controls, patients with AS had considerably lower blood 25(OH)D levels (MD = -7.53 ng/mL, 95% CI, -9.78 to -5.28, P < .001) and significantly higher ESR and CRP levels (ESR: MD = 11.75 mm/h, 95% CI, 4.20 to 19.31, P = .002; CRP: MD = 15.36 mg/L, 95% CI, 4.95 to 25.77, P = .004). Additionally, a negative correlation was discovered between serum VD levels and BASDAI, ESR, and CRP (Fisher' Z = -0.34, -0.38, -0.35, respectively). The findings of our meta-analysis demonstrated a negative correlation between serum VD levels and the main monitoring indices of disease activity in patients with AS and verified that the differences in the continent and ethnicity may be one of the major contributors to this finding.


High serum tryptophan concentration in pollinosis patients is associated with unresponsiveness to pollen extract therapy.
The immunologic background of allergic asthma and rhinitis includes a preponderance of Th2-type immunity. In parallel, Th1-type immune response is suppressed by Th2-type cytokines. As a consequence, biochemical pathways triggered by Th1-type cytokine interferon-gamma, such as tryptophan degradation by indoleamine 2,3-dioxygenase and neopterin production, might be altered. We examined whether they are related to the outcome of hyposensitization therapy in atopic patients. In serum specimens of 44 atopic patients (18 women, 26 men) before any specific immunotherapy, tryptophan and kynurenine concentrations were measured by HPLC, and the kynurenine to tryptophan ratio (kyn/trp) was calculated. Neopterin concentrations were measured by ELISA. Results were compared with concentrations in 38 serum specimens from healthy blood donors and with the outcome of specific subcutaneous immunotherapy in atopics: on clinical grounds, 27 patients were classified as responders, and 17 patients as non-responders. Serum tryptophan concentrations were higher in atopics (84.3 +/- 24.4 microM) than in blood donors (57.9 +/- 7.46 microM; p < 0.001), kynurenine and kyn/trp were not different between the 2 groups. All of the neopterin concentrations measured in patients were <8.7 nM, the upper limit of the normal. Non-responders to subcutaneous immunotherapy had significantly higher tryptophan concentrations (95.7 +/- 27.0 microM) than responders (77.1 +/- 19.9 microM; p = 0.01). No other marker concentrations differed between the groups. The measurement of serum tryptophan may present an option to predict the outcome of pollen extract therapy. Higher tryptophan levels may result from lower indoleamine 2,3-dioxygenase activity in atopics. However, this possible relationship needs to be confirmed in further studies.


Transcapillary escape rate and relative metabolic clearance of glycated and non-glycated albumin in type 1 (insulin-dependent) diabetes mellitus.
The transcapillary escape rate and relative plasma disappearance of glycated and non-glycated albumin were measured in 25 male Type 1 (insulin-dependent) diabetic patients using a double tracer technique. The patients were divided into three groups on the basis of their urinary albumin excretion: group 1, normal albumin excretion (less than 30 mg/24 h) (n = 8); group 2, microalbuminuria (30-300 mg/24 h) (n = 9); and group 3, clinical nephropathy (greater than 300 mg/24 h) (n = 8). Six male age-matched non-diabetic persons served as control subjects. The transcapillary escape rate of glycated albumin was similar in group 1 and control subjects (4.7 +/- 2.1 versus 5.1 +/- 1.7%), but significantly increased in group 2 (7.0 +/- 1.7%, p less than 0.05) and in group 3 (7.9 +/- 3.1%, p less than 0.05). The transcapillary escape rate of glycated albumin was slightly lower than that of non-glycated albumin in all groups, but significant only in normal control subjects. No difference in the catabolic rate of glycated and non-glycated albumin was found. We conclude that the in vivo effects of glycation on the clearance and transcapillary passage of albumin are small and not likely to play any significant role in the development of late diabetic microvascular complications.


Early microglial response in experimental thiamine deficiency: an immunohistochemical analysis.
Early glial changes have consistently been reported in experimental thiamine deficiency (TD) (Tellez and Terry, Am. J. Pathol. 52:777-794, 1968.) and in Wernicke Encephalopathy in humans (Victor et al., F.A. Davis Co., Philadelphia, 1989.). However, the precise nature of these changes and their relationship to the phenomenon of selective neuronal cell loss in TD has not been elucidated. In the present studies, antibodies against GFAP and ED1 were used to evaluate astrocytic and microglial/macrophagic changes respectively in adjacent sections of the brains of thiamine-deficient rats at various stages (n = 6 per stage) during the progression of encephalopathy. Additionally, the integrity of the blood-brain barrier at the same stages was assessed using IgG immunohistochemistry. Counts of immuno-positive cells revealed significant increases of ED1-immunostaining in the inferior olive, medial geniculate nucleus, and medial thalamic nuclei on day 8 of the treatment paradigm, prior to any evidence of increased IgG immunostaining or significant neuronal cell loss. ED1 immunostaining increased over time, resulting in intense staining by the loss of righting reflex stage (day 13-15). Focal increases of IgG-immunoreactivity in inferior olive, medial dorsal thalamus, and medial geniculate nucleus were observed on day 10, followed by increased GFAP-immunostaining consistent with reactive gliosis. Early microglial activation leading to the release of cytotoxic substances including reactive oxygen species, glutamate and cytokines appears to be the initial cellular response to TD and could be responsible for the focal neuronal loss characteristic of this disorder.


Conjunctival structural and functional reconstruction using acellular bovine pericardium graft (Normal GEN®) in rabbits.
To evaluate the effectiveness of acellular bovine pericardium grafts (Normal GEN®) used as scaffolds for conjunctival reconstruction. The acellular bovine pericardium graft and the amnion graft were implanted into the bulbar conjunctival defects of adult rabbits. Conjunctival samples of implanted materials and blank defect controls were observed at day 3, 7, 14, 21, 28, and 56 postoperatively. Histological examination was observed at day 14, 28, and 56 of surgery, including hematoxylin-eosin staining, periodic acid-Schiff staining, and Masson's trichrome staining, while immunofluorescent microscopy was observed at 14 days and 28 days after surgery. Results were compared among the Normal GEN®, amnion, and blank defect controls. All three groups showed complete conjunctival reconstruction. Wounds that were not grafted closed by formation of conjunctival scar characterized by a linear array of densely packed collagen fibers in Tenon's capsule. Subepithelial tissue in the grafted groups comprised a loosely organized network of randomly oriented collagen that resembled that of the normal bulbar conjunctiva. However, there was a dense layer of aligned collagen between the conjunctival Tenon's capsule and the sclera in the NormalGEN® group, about 250 μm in thickness. Implantation of the NormalGEN® graft promoted the formation of conjunctiva as a kind of scaffold both in structure and in function. It had more advantageous mechanical properties than the amnion, strong and elastic, during the period of conjunctival reconstruction.


Identifying potential patients with diabetes-related dementia: a descriptive approach using routinely collected data.
Diabetes-related dementia (DRD) is a new dementia subtype associated with type 2 diabetes mellitus, first described in 2013. This study investigated data from a local New Zealand memory service to identify patients that met the criteria for DRD. Using routinely collected data from 2013-2021, we selected a sample of people with dementia, diabetes, and no CT evidence of Alzheimer's disease (AD), vascular dementia, or frontotemporal dementia. We compared their socio-demographic, clinical, and cognitive characteristics with a sample of patients with diabetes and Alzheimer's disease. Forty (16%) of 249 patients with diabetes and dementia had "normal" CT scans (DRD subgroup), and 38 (15%) had AD (AD subgroup). Compared to NZ Europeans, disproportionally more Māori and Pacific Islanders (70.2%) were in the DRD subgroup. In the Pacific subgroup (n=31), the DRD subgroup had higher memory subscores than the AD subgroup (p=0.047), and the Kaplan-Meier plot suggested poorer survival (p=0.13). Māori patients with diabetes and dementia were more likely to meet all four criteria for DRD. We have replicated the findings of the 2013 DRD research and have demonstrated a higher risk for the DRD subtype of dementia among the Māori and Pacific Islander patients in our sample.


TCF-1+ PD-1+ CD8+T cells are associated with the response to PD-1 blockade in non-small cell lung cancer patients.
To determine whether TCF-1+PD-1+CD8+T cells are associated with the response to PD-1 blockade in non-small cell lung cancer (NSCLC) patients. We investigated the expression of TCF-1+PD-1+CD8+T cells and elucidated their predictive role in NSCLC patients. Pretreatment specimens from 20 advanced NSCLC patients who underwent PD-1 immunotherapy or combined with chemotherapy were analyzed. The frequencies of TCF-1+ cells in PD-1+CD8+T cells were determined in these biospecimens using multi-label immunofluorescence staining and multi-spectral acquisition technology. The clinical roles of TCF-1+PD-1+CD8+T cells were assessed via analyzing our cases and human NSCLC data collected from public databases. A high frequency of TCF-1+PD-1+CD8+T cells was identified in responders compared with non-responders (p = 0.0024), and the patients with high expression of this cell subset had durable clinical benefit of anti-PD-1 therapy. There were no significant association between the expression of TCF-1+PD-1+CD8+T cells and patients' age, smoking history, pathologic type, and genetic status. In univariate analysis by the Cox hazard model, high frequency of TCF-1+ PD-1+ CD8+T cells was significantly correlated with patients' benefit of PD-1 blockade (p = 0.024). Our study indicated that TCF-1+PD-1+CD8+T cells are associated with the response to PD-1 blockade, and may be a predictor of anti-PD-1 therapy.


The skin-lightening effects of artocarpin on UVB-induced pigmentation.
This study was conducted to evaluate the effects of the prenylated flavonol artocarpin from the heartwood of Artocarpus incisus on ultraviolet (UV)-induced hyperpigmentation of guinea pig skin. An efficient lightening effect was observed following topical application of artocarpin to UV-stimulated hyperpigmented dorsal skins of brownish guinea pigs.


Streptococcus suis biofilm: regulation, drug-resistance mechanisms, and disinfection strategies.
Streptococcus suis (S. suis) is a major swine pathogen and an important zoonotic agent. Like most pathogens, the ability of S. suis to form biofilms plays a significant role in its virulence and drug resistance. A better understanding of the mechanisms involved in biofilm formation by S. suis as well as of the methods to efficiently remove and kill biofilm-embedded bacteria can be of high interest for the prevention and treatment of S. suis infections. The aim of this literature review is to update our current knowledge of S. suis biofilm formation, regulatory mechanisms, drug-resistance mechanisms, and disinfection strategies.


Mental well-being of patients from ethnic minority groups during critical care: a qualitative ethnographic study.
To investigate the state of the mental well-being of patients from ethnic minority groups and possible related risk factors for the development of mental health problems among these patients during critical medical situations in hospital. Qualitative ethnographic design. Oneintensive care unit (ICU) of a multiethnic urban hospital in Belgium. 84 ICU staff members, 10 patients from ethnic-minority groups and their visiting family members. Patients had several human basic needs for which they could not sufficiently turn to anybody, neither to their healthcare professionals, nor to their relatives nor to other patients. These needs included the need for social contact, the need to increase comfort and alleviate pain, the need to express desperation and participate in end-of-life decision making. Three interrelated risk factors for the development of mental health problems among the patients included were identified: First, healthcare professionals' mainly biomedical care approach (eg, focus on curing the patient, limited psychosocial support), second, the ICU context (eg, time pressure, uncertainty, regulatory frameworks) and third, patients' different ethnocultural background (eg, religious and phenotypical differences). The mental state of patients from ethnic minority groups during critical care is characterised by extreme emotional loneliness. It is important that staff should identify and meet patients' unique basic needs in good time with regard to their mental well-being, taking into account important threats related to their own mainly biomedical approach to care, the ICU's structural context as well as the patients' different ethnocultural background.


Molecular cloning and thermal stress-induced expression of a pi-class glutathione S-transferase (GST) in the Antarctic bivalve Laternula elliptica.
Glutathione S-transferases (GSTs) are multifunctional phase II detoxification enzymes that catalyze the attachment of electrophilic substrates to glutathione. The pi-class GST cDNA (leGSTp) was cloned from the cold-adapted Antarctic bivalve Laternula elliptica. We used degenerated primers designed based on highly conserved regions of known mollusk GSTs to amplify the corresponding L. elliptica mRNA. Full-length cDNA was obtained by rapid amplification of cDNA ends (RACE). The full sequence of the GST cDNA was 1189 bp in length, with a 5' untranslated region (UTR) of 74 bp, a 3' UTR of 485 bp, and an open reading frame of 630 bp encoding 209 amino acid residues with an estimated molecular mass of 23.9 kDa and an estimated isoelectric point of 8.3. Quantitative RT-PCR confirmed basal expression of leGSTp, which was up-regulated upon heat treatment (10 degrees C for different time periods) by a factor of 2.3 (at 24 h) and 2.7 (at 48 h) in the digestive gland and gill tissues, respectively. The recombinant leGSTp expressed in Escherichia coli was purified by affinity chromatography and characterized. The purified leGSTp exhibited high activity towards the substrates ethacrynic acid (ECA) and 1-chloro-2,4-dinitrobenzene (CDNB). The recombinant leGSTp had a maximum activity at approximately pH 8.0, and its optimum temperature was 35 degrees C.


ACTN1 rod domain mutation associated with congenital macrothrombocytopenia.
Mutations in ACTN1, the gene encoding the actin-crosslinking protein α-actinin-1, cause autosomal dominant macrothrombocytopenia. α-Actinin-1 exists as antiparallel dimers, composed of an N-terminal actin-binding domain (ABD), four spectrin-like repeats (SLRs), which form the spacer rod, and a C-terminal calmodulin-like (CaM) domain. All of the previously reported ACTN1 mutations associated with macrothrombocytopenia reside within the ABD and the CaM domain and not within the SLR domain. In this report, we describe a mutation in SLR2 of α-actinin-1 (p.Leu395Gln) associated with familial macrothrombocytopenia. A 3-year-old boy and his mother both had this mutation. They showed a mild form of thrombocytopenia without severe bleeding, accompanied by an elevated mean platelet volume. Consistent with the previous reports of mutations that reside in the ABD or the CaM domain, immunofluorescence examination revealed disorganization of the actin cytoskeleton in Gln395 mutant-transduced Chinese hamster ovary cells. Our findings suggest a novel mechanism for the pathogenesis of ACTN1-related macrothrombocytopenia that does not involve functional domain mutations.


Ultrasound follow-up of infantile hypertrophic pyloric stenosis (IHPS) during conservative therapy: ultrasound findings as criteria for diagnosis and cure.
During conservative therapy of infantile hypertrophic pyloric stenosis (IHPS) with atropine sulfate, there are many patients who do not achieve normal values of pyloric wall thickness and canal length even though they are clinically cured (vomiting has ceased); an objective criterion for cure has not yet been established. The aim of this study was to examine whether the appearance of pyloric wall stratification can be used as a criterion for cure. Twenty infants with IHPS who were treated conservatively were enrolled. Two of them ultimately required surgery. Ultrasound examinations were done serially and the pyloric wall thickness and canal length were measured. The echogenicity of the pyloric wall and the presence of wall stratification were noted. On admission, all infants satisfied the ultrasound criteria for IHPS and had a heterogeneous pyloric wall without stratification. With conservative therapy, symptoms disappeared, the pyloric wall thickness and the canal length gradually decreased, the echogenicity gradually became homogeneous and hypoechoic, and wall stratification appeared (in most cases before the pyloric wall thickness and the canal length had normalized). The absence of wall stratification suggests that cellular interstitial changes, such as edema or inflammation, are present in the pyloric wall in the acute stage. Pyloric wall stratification was absent during the acute stage, but it appeared after initiation of treatment but before the pyloric wall thickness and the canal length had normalized. The presence of pyloric wall stratification can be used as a criterion for cure; the absence of wall stratification can be added to ultrasound diagnostic criteria for IHPS.


Synthesis and evaluation of chitosan-graft-poly (2-hydroxyethyl methacrylate-co-itaconic acid) as a drug carrier for controlled release of tramadol hydrochloride.
Chitosan-graft-poly (2-hydroxyethyl methacrylate-co-itaconic acid) has been synthesized for different feed ratios of 2-hydroxyethyl methacrylate and itaconic acid and characterized by FT-IR, thermogravimetry and swelling in simulated biological fluids (SBF) and evaluated as a drug carrier with model drug, tramadol hydrochloride (TRM). Grafting decreased the thermal stability of chitosan. FT-IR spectra of tablet did not reveal any molecular level (i.e. at <10 nm scale) drug-polymer interaction. But differential scanning calorimetric studies indicated a probable drug-polymer interaction at a scale >100 nm level. The observed Korsmeyer-Peppas's power law exponents (0.19-1.21) for the in vitro release profiles of TRM in SBF and other drugs such as 5-fluorouracil (FU), paracetamol (PCM) and vanlafaxine hydrochloride (VNF) with the copolymer carriers revealed an anomalous drug release mechanism. The decreased release rates for the grafted chitosan and the enhanced release rate for the grafts with increasing itaconic acid content in the feed were more likely attributed to the enhanced drug-matrix interaction and polymer-SBF interactions, respectively. The different release profiles of FU, PCM, TRM and VNF with the copolymer matrix are attributed to the different chemical structures of drugs. The above features suggest the graft copolymer's candidature for use as a promising oral drug delivery system.


Unilateral phrenic nerve lesion in Lyme neuroborreliosis.
Among a variety of more common differential diagnoses, the aetiology of acute respiratory failure includes Lyme neuroborreliosis. We report an 87-years old huntsman with unilateral phrenic nerve palsy as a consequence of Lyme neuroborreliosis. Although Lyme neuroborreliosis is a rare cause of diaphragmatic weakness, it should be considered in the differential workup because of its potentially treatable nature.


A forensic evaluation method for DeepFake detection using DCNN-based facial similarity scores.
Detecting DeepFake videos has become a central task in modern multimedia forensics applications. This article presents a method to detect face swapped videos when the portrayed person in the video is known. We propose using a threshold classifier based on similarity scores obtained from a Deep Convolutional Neural Network (DCNN) trained for facial recognition. We compute a set of similarity scores between faces extracted from questioned videos and reference materials of the person depicted. We use the highest score to classify the questioned videos as authentic or fake, depending on the threshold chosen. We validate our method on the Celeb-DF (v2) dataset (Li et al., 2020) [13]. Using the training and testing splits specified on the dataset, we obtained an HTER of 0.020 and an AUC of 0.994, surpassing the most robust approaches against this dataset (Tran et al., 2021) [37]. Additionally, a logistic regression model was used to convert the highest score into a likelihood ratio for greater applicability in forensic analyses.


Liquid chromatographic screening of diuretics in urine.
We describe a liquid chromatographic screening procedure for the detection, in urine, of twelve of the fifteen potassium-depleting diuretics available in Australia. A 2-ml urine sample was acidified with NaH2PO4 (pH 4.1) and extracted with 4 ml ethyl acetate. The sample was cleaned up further by washing with 5 ml Na2HPO4 (pH 7.5). The ethyl acetate was then evaporated to dryness, the residue reconstituted in 100 microliters mobile phase and 5 microliter were injected onto a Merck LiChrosorb RP-18 (5 microns) column. The ultraviolet absorbance of the eluent was monitored at 271 nm for 10 min. The screen was evaluated by giving each of thirty volunteers the lowest recommended dose of one of the diuretics in the study and obtaining urine samples 4, 8 and 24 h after having taken the dose. Twelve diuretics, chlorothiazide, hydrochlorothiazide, quinethazone, chlorthalidone, methyclothiazide, clopamide, frusemide, metolazone, mefruside, bendrofluazide, cyclopenthiazide and bumetanide, were all detectable up to 24 h after a dose. We therefore conclude that the screen would be reliable for the detection of these diuretics in urine.


Preventative therapy for breast cancer: a clinical experience.
Breast Cancer incidence in the UK is estimated to rise to 71,000 per year by 2035. Preventative strategies could significantly reduce this. Preventative therapy reduces women's risk of oestrogen receptor positive breast cancer, but uptake remains low. Having established a preventative therapy clinic as part of a wider breast cancer prevention project, we explored qualitative data to inform future preventative efforts. Women aged 30 to 60 who had benign diagnoses at a symptomatic breast clinic or were under mammographic surveillance in the moderate risk family history clinic were invited to participate in the study. Those who expressed an interest and completed an initial questionnaire had their breast cancer risk calculated using the IBIS risk calculator. Those at increased risk were invited to a consultation about preventative therapy. 182 women were identified as increased risk (≥ 17% lifetime or ≥ 3% 10-year risk NICE guidelines: Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer, 20131) of whom 91 women (50%) would not have been identified by family history criteria alone. 96% attended a risk/prevention consultation and all eligible women accepted screening mammography but only 14 (8%) women requested a preventative therapy prescription during the duration of the study. Reluctance to take medication and inconvenient time of life were common reasons for declining preventative therapy. Despite this, the majority were grateful for breast cancer risk and prevention information. Women at increased risk of breast cancer accept additional screening but are reluctant to take preventative therapy. This suggests that stratified screening methods using risk calculations would have high uptake. Raising awareness of preventative therapy is important and the breast cancer community has yet to find the optimum timing and formula for discussing it and must accept women's informed preferences above artificial targets. The PIONEER study was granted Health Research Authority (HRA) ethical approval by the Westminster Ethics Committee. IRAS project ID 265619, ClinicalTrials.gov Identifier: NCT04574063. Recruitment began in September 2020 and was completed in October 2021.


The effect of maternal infection on cognitive development and hippocampus neuronal apoptosis, proliferation and differentiation in the neonatal rats.
Many epidemiological reports stated a strong association between maternal infection and development of cerebral palsy, which is a major cause of cognitive impairment. The pathophysiological mechanism of intrauterine inflammation is complex. Recently, it was demonstrated that inflammation has a modulating effect on adult neurogenesis. In this study, we discovered the effect of maternal infection to hippocampal neuronal apoptosis, proliferation and differentiation, and cognitive development in the developing brains of neonatal rats. Morris water maze test was used to assess learning and memory. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to determine neuronal apoptosis, immunostaining was conducted to assess neurogenesis, and Western blot for extracellular signal-regulated kinase (ERK), cyclic AMP responsive element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Results demonstrated that maternal infection increased neuronal apoptosis and significantly impaired spatial learning and memory ability. Maternal infection significantly increased cell proliferation, accompanied by an increased expression of ERK (P3-P7), CREB (P3-P7) and BDNF (P3). On P28, there was no significant difference of cell survival and differentiation in two groups. These results suggest that variation in ERK activity and subsequent expression of its downstream targets, including CREB and BDNF might contribute, at least partially, to modulation of inflammation related cell proliferation, survival and differentiation. Maternal infection increased hippocampal neuronal apoptosis and affected cell proliferation and differentiation in neonatal rats, which may be regarded as an etiological factor in cognitive development impairment.


Computation of unwanted sphere and cylinder in the periphery of a spectacle lens.
The author discusses practical issues relating to optometrists ordering and laboratories supplying ophthalmic lenses that meet the ANSI Z80. 1 Standard (1972) for minimizing unwanted spherical and cylindrical power in the periphery of lenses. He spells out the optical principles and formulas needed to develop a computer program that can be used by optometrists and opticians for designing lenses that meet the Z80. 1 Standard.


External ear injuries.
The unique shape of the external ear depends on the underlying cartilaginous framework. Injuries of the external ear are common. In dealing with lacerations, subperichondrial hematomas, perichondritis, burns and frostbite, particular care should be taken to maintain the cartilaginous framework and to prevent infection. In this way cosmetic deformities of the external ear can be prevented.


The trace metal levels in milk and dairy products consumed in middle Anatolia-Turkey.
In this study, aluminium (Al), lead (Pb), cadmium (Cd), selenium (Se) and arsenic (As) contents in milk and different dairy product samples were measured. Pb, Cd, As, Al and Se contents in the milk and different dairy products ranged from 0.054 mg/kg (milk powder)-1.100 mg/kg (Kaşar cheese), 0.009 mg/kg (whey powder and yogurt)-0.051 mg/kg (Tulum cheese), 0.010 mg/kg (whey powder)-0.146 mg/kg (butter), 2.848 mg/kg (ice cream)-8.778 (drained yogurt) and n.d. (ice cream, milk and whey powder, yogurt, ayran and Lor cheese)-0.434 mg/kg (Tulum cheese), respectively. The 75% of White and Kaşar cheeses, 50% of Lor and 12.5% of Tulum cheese samples contained higher Pb according to the legal limits established by the Turkish Food Codex and European Communities regulation and 12.5% of Tulum cheese sample contained Cd. It was concluded that Pb contents of milk and dairy products from this region might be highly hazardous to human.


Glucocorticoids in a Neonatal Hyperoxic Lung Injury Model: Pulmonary and Neurotoxic effects.
We aimed to compare the effect of dexamethasone (Dex), hydrocortisone (Hc), and methylprednisolone (Mpz) at equivalent doses on somatic growth, lung healing, and neurotoxicity in a hyperoxic rat model. We hypothesized that Mpz and Hc would be superior to Dex with less neurotoxicity by exerting similar therapeutic efficacy on the injured lung. Neonatal rats were randomized to control, bronchopulmonary dysplasia (BPD), Dex, Hc, and Mpz groups. All drugs were administered daily following day 15 over 7 days. Histopathological and immunohistochemical analyses of the lung and brain were performed on day 22. All types had much the same impact on lung repair. Oxidative markers in the lung were similar in the steroid groups. While nuclear factor erythroid 2-related factor and heat-shock protein 70 dropped following steroid treatment, no difference was noted in other biochemical markers in the brain between the study groups. Apoptotic activity and neuron loss in the parietal cortex and hippocampus were noted utmost in Dex, but alike in other BPD groups. Mpz does not appear to be superior to Dex or Hc in terms of pulmonary outcomes and oxidative damage in the brain, but safer than Dex regarding apoptotic neuron loss. This is the first study that compared the pulmonary efficacy and neurotoxic effects of Dex, Hc, and Mpz simultaneously in an established BPD model. This study adds to the literature on the importance of possible antioxidant and protective effects of glucocorticoid therapy in an oxidative stress-exposed brain. Mpz ended up with no more additional neuron loss or apoptosis risk by having interchangeable effects with others for the treatment of established BPD. Mpz and Hc seem safe as a rescue therapy in terms of adverse outcomes for established BPD in which lung and brain tissue is already impaired.


Nodular fascitis in the thigh followed up using ultrasonography.
A 41-year-old woman noticed a mass on the inside of her right thigh in April 2003. Ultrasound examination revealed a mass measuring 18 mm × 10 mm × 10 mm in the subcutaneous fatty tissues. Its boundary was relatively clear, with rough edges. The interior of the lesion was hyperechoic and contained an irregular hypoechoic area in its center; a color Doppler sonographic examination detected no blood flow signals. Incision biopsy examination seemed warranted. Pathologically, the specimen showed a proliferation of fibroblast-like spindle-shaped cells but no atypical cells. Immunologic staining revealed that sections were positive to vimentin; negative to CD34, CD68, α-smooth muscle actin (α-SMA), and S-100 protein; and mildly positive to HHF35. These results led to a diagnosis of nodular fascitis. Nodular fascitis is not common, and few studies have described its sonographic characteristics. We therefore used ultrasound to follow up the patient and found that the lesion was markedly smaller 3 months after the first examination, at which time it was hardly discernible as a mass. Here we compare the ultrasound and pathologic findings, and report the results of a bibliographic study.


Anatomical bases for a safe method of subclavian venipuncture. Clinical experience in 350 cases.
Based on fundamental anatomical considerations which are explained in detail we developed a safe technique for the catheterization of the subclavian v.: the point of puncture, which is situated about 25 mm below the junction between the medial and the middle thirds of the clavicle, is accurately determined with the help of a pattern described in the paper. The needle is directed towards the palpable dimple between the spinous processes of the 6th and the 7th cervical vertebrae. The only structure the cannula can reach is the medial portion of the subclavian v. into which the catheter is inserted. Therefore pneumothorax, haemothorax or other incidents do not occur. The method was tested in 350 cases and proved to be absolutely free of complications.


Permeability increase in black lipid membrane induced by compound 48/80.
When compound 48/80, a potent histamine liberator, was added in the aqueous phase facing the black lipid membrane, the conductivity of the membrane was remarkably increased. Although valinomycin displayed a distinct selectivity for K+ movement, such selection for ionic permeability was not observed in the case of compound 48/80.


Animal personalities: the advantage of diversity.
Animals do not always perform to the best of their abilities when faced with difficult choices. New findings on foraging honeybees show that co-existing strategies, where some individuals place more emphasis on accuracy and others on speed, can be advantageous to the colony in a variable environment.


Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats.
Following an oral dose of risperidone (RSP), concentrations of its major metabolite 9-hydroxyrisperidone (9-OHRSP) were high in plasma and tissues but disproportionately lower in the brain compared to RSP, indicating that 9-OHRSP may have different pharmacokinetic properties. To investigate non-compartmental pharmacokinetics of RSP and 9-OHRSP in plasma, brain and other tissues after separate administration of a single oral dose of 6 mg/kg RSP and 9-OHRSP to rats. Plasma, brain, liver, lung, kidney and spleen tissues were collected at pre-dose and at 0.5, 1, 2, 5, 6, 12, 24, 36 and 48 h post-dose, homogenized in saline and assayed for RSP and 9-OHRSP using a sensitive and specific liquid chromatography tandem mass spectrometry method. The concentration-time curve of RSP and 9-OHRSP showed that they were readily absorbed and followed a multiphase elimination pattern. The terminal elimination half-life (t(1/2) ) of RSP after the RSP dose was longest in the liver (17.6 h) and shortest in the spleen (1.2 h). The t(1/2)of 9-OHRSP after the RSP dose was shorter in plasma (3.4 h) and other tissues (approximately 8-11 h) than that for RSP but it was longer in the spleen. However, the t(1/2) of 9-OHRSP after the 9-OHRSP dose was shorter in most tissues as compared to the t(1/2) of 9-OHRSP after the RSP dose. The area under the concentration-time curve (AUC) of RSP and 9-OHRSP was 6-67 times higher in the plasma and tissues than in the brain. AUCs of 9-OHRSP in tissues after the RSP dose were 2-5 times higher than those for RSP, except in the brain, where AUCs of RSP and 9-OHRSP were similar. Pharmacokinetics of 9-OHRSP in many tissues were different after RSP and 9-OHRSP doses. The reason for disproportionate brain levels of 9-OHRSP is not clear. The overall exposure to active drug in the brain as represented by AUC was similar after the RSP and 9-OHRSP doses and the 9-OHRSP is probably an equal contributor to the pharmacological actions of RSP.