Regulation of the erythroid transcription factor NF-E2 by cyclic adenosine monophosphate-dependent protein kinase.
Activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (A-kinase) promotes hemoglobin synthesis in several erythropoietin-dependent cell lines, whereas A-kinase-deficient murine erythroleukemia (MEL) cells show impaired hemoglobin production; A-kinase may regulate the erythroid transcription factor NF-E2 by directly phosphorylating its p45 subunit or by changing p45 interactions with other proteins. We have mapped the major A-kinase phosphorylation site of p45 to Ser(169); Ala substitution for Ser(169) resulted in a protein that was no longer phosphorylated by A-kinase in vitro or in vivo. The mutant protein formed NF-E2 complexes that bound to DNA with the same affinity as wild-type p45 and functioned normally to restore beta-globin gene expression in a p45-deficient MEL cell line. Transactivation properties of the (Ser (169)--> Ala) mutant p45 were also indistinguishable from wild-type p45 when Gal4-p45 fusion constructs were tested with a Gal4-dependent reporter gene. Transactivation of the reporter by both mutant and wild-type p45 was significantly enhanced when A-kinase was activated by membrane-permeable cAMP analogs or when cells were cotransfected with the catalytic subunit of A-kinase. Stimulation of p45 transactivation by A-kinase required only the N-terminal transactivation domain of p45, suggesting that A-kinase regulates the interaction of p45 with downstream effectors.


Loss of Neuroligin3 specifically downregulates retinal GABAAα2 receptors without abolishing direction selectivity.
The postsynaptic adhesion proteins Neuroligins (NLs) are essential for proper synapse function, and their alterations are associated with a variety of neurodevelopmental disorders. It is increasingly clear that each NL isoform occupies specific subsets of synapses and is able to regulate the function of discrete networks. Studies of NL2 and NL4 in the retina in particular have contributed towards uncovering their role in inhibitory synapse function. In this study we show that NL3 is also predominantly expressed at inhibitory postsynapses in the retinal inner plexiform layer (IPL), where it colocalizes with both GABAA- and glycinergic receptor clusters in a 3:2 ratio. In the NL3 deletion-mutant (knockout or KO) mouse, we uncovered a dramatic reduction of the number of GABAAα2-subunit containing GABAA receptor clusters at the IPL. Retinal activity was thereafter assessed in KO and wild-type (WT) littermates by multi-electrode-array recordings of the output cells of retina, the retinal ganglion cells (RGCs). RGCs in the NL3 KO showed reduced spontaneous activity and an altered response to white noise stimulation. Moreover, upon application of light flashes, the proportion of cells firing at light offset (OFF RGCs) was significantly lower in the NL3 KO compared to WT littermates, whereas the relative number of cells firing at light onset (ON RGCs) increased. Interestingly, although GABAAα2-bearing receptors have been related to direction-selective circuits of the retina, features of direction selective-retinal ganglion cells recorded remained unperturbed in the NL3 KO. Together our data underscore the importance of NL3 for the integrity of specific GABAAergic retinal circuits and identifies NL3 as an important regulator of retinal activity.


Biology of killer yeasts.
Killer yeasts secrete proteinaceous killer toxins lethal to susceptible yeast strains. These toxins have no activity against microorganisms other than yeasts, and the killer strains are insensitive to their own toxins. Killer toxins differ between species or strains, showing diverse characteristics in terms of structural genes, molecular size, mature structure and immunity. The mechanisms of recognizing and killing sensitive cells differ for each toxin. Killer yeasts and their toxins have many potential applications in environmental, medical and industrial biotechnology. They are also suitable to study the mechanisms of protein processing and secretion, and toxin interaction with sensitive cells. This review focuses on the biological diversity of the killer toxins described up to now and their potential biotechnological applications.


Identifying Novel Gene Variants in Coronary Artery Disease and Shared Genes With Several Cardiovascular Risk Factors.
Coronary artery disease (CAD) is a critical determinant of morbidity and mortality. Previous studies have identified several cardiovascular disease risk factors, which may partly arise from a shared genetic basis with CAD, and thus be useful for discovery of CAD genes. We aimed to improve discovery of CAD genes and inform the pathogenic relationship between CAD and several cardiovascular disease risk factors using a shared polygenic signal-informed statistical framework. Using genome-wide association studies summary statistics and shared polygenic pleiotropy-informed conditional and conjunctional false discovery rate methodology, we systematically investigated genetic overlap between CAD and 8 traits related to cardiovascular disease risk factors: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. We found significant enrichment of single-nucleotide polymorphisms associated with CAD as a function of their association with low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. Applying the conditional false discovery rate method to the enriched phenotypes, we identified 67 novel loci associated with CAD (overall conditional false discovery rate <0.01). Furthermore, we identified 53 loci with significant effects in both CAD and at least 1 of low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, systolic blood pressure, and type 1 diabetes mellitus. The observed polygenic overlap between CAD and cardiometabolic risk factors indicates a pathogenic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to CAD.


Hydrogen control of ferromagnetism in a dilute magnetic semiconductor.
We show that upon exposure to a remote dc hydrogen plasma, the magnetic and electronic properties of the dilute magnetic semiconductor Ga1-xMnxAs change qualitatively. While the as-grown Ga1-xMnxAs thin films are ferromagnetic at temperatures T less, similar 70 K, the samples are found to be paramagnetic after the hydrogenation, with a Brillouin-type magnetization curve even at T=2 K. Comparing magnetization and electronic transport measurements, we conclude that the density of free holes p is significantly reduced by the plasma process, while the density of Mn magnetic moments does not change.


Adverse Childhood Experiences and Quality of Life: A Mediating Role of Physical Activity.
Examine whether barriers to physical activity (PA) and PA level serve as serial mediators to the relationship between adverse childhood experiences (ACEs) and perceived quality of physical health. Design: Cross-sectional. Setting: A public university in Southeast United States. Seventy-five participants (18- 49 years). Measures: Self-report measures related to ACEs, barriers to PA, amount of PA, and perceived quality of physical health. Serial mediation analysis. Barriers to PA was a first-order mediator, and PA level was a second-order mediator between ACEs and perceived quality of physical health. Barriers to PA and PA levels serially mediated the relationship between ACEs and perceived quality of physical health (c = -1.01, SE = .251, P = .0002, 95% CI [-1.50, -.499]). The direct effect of ACEs on perceived quality of physical health was nonsignificant when mediators were controlled (c' = -.383, SE = .252, P = .133, 95% CI [-.886, .120]). Higher ACE scores were associated with more barriers to PA, lower PA levels, and in turn, lower perceived quality of physical health. The current study highlights specific pathways that contribute to the relationship between ACEs and perceived quality of physical health. Albeit limited by the sample size, preliminary data support prioritization of interventions that reduce barriers to PA when trying to increase PA in populations that are prone to early adversity.


EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part I. General Aspects (Short Version).
This is the first part of the Guidelines on Interventional Ultrasound of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and covers all general aspects of ultrasound-guided procedures (short version; the long version is published online).


Migration-prone glioma cells show curcumin resistance associated with enhanced expression of miR-21 and invasion/anti-apoptosis-related proteins.
In study, the expression patterns and functional differences between an original glioma cell population (U251 and U87) and sublines (U251-P10, U87-P10) that were selected to be migration-prone were investigated. The expressions levels of VEGF and intracellular adhesion molecule-1 (ICAM-1) were increased in the migration-prone sublines as well as in samples from patients with high-grade glioma when compared to those with low-grade glioma. In addition, cells of the migration-prone sublines showed increased expression of the oncogenic microRNA. miR-21, which was also associated with more advanced clinical pathological stages in the patient tissue specimens. Treatment of U251 cells with an miR-21 mimic dramatically enhanced the migratory activity and expression of anti-apoptotic proteins. Furthermore, treatment with curcumin decreased the miR-21 level and anti-apoptotic protein expression, and increased the expression of pro-apoptosis proteins and microtubule-associated protein light chain 3-II (LC3-II) in U251 cells. The migration-prone sublines showed decreased induction of cell death markers in response to curcumin treatment. Finally, U251-P10 cells showed resistance against curcumin treatment. These results suggest that miR-21 is associated with regulation of the migratory ability and survival in human glioma cells. These findings suggest novel mechanisms of malignancy and new potential combinatorial strategies for the management of malignant glioma.


[Radiative Properties of Cirrus Clouds Based on Hexagonal and Spherical Ice Crystals Models].
Single scattering properties for spherical and hexagonal ice crystal models with different size parameters and wavelengths were employed to calculate satellite observed radiation and downward flux in ground surface using RSTAR radiative transfer model. Results indicated that simulated satellite observed radiation and ground surface downward radiant flux from different shapes of ice crystal models were different. The difference in the spectral radiation fluxes between 0. 4 and 1. 0 µm was largest, and particle shapes affected the downward radiant flux significantly. It was verified that the proper selection of the effective ice crystal model is not only important for retrieval of the microphysical and optical parameters of the cirrus cloud, but also important for obtaining the radiant flux on the earth's surface correctly. These results are important for retrieving cloud microphysical parameters and simulation of the ground surface downward radiant flux.


Clinical application of a direct placement mercury-free alloy.
This article provides information about a recently introduced, mercury-free restorative alloy. This direct placement alloy uses gallium rather than mercury to mix the alloy particles. The material has recently been approved for use in the United States. Although its handling and physical properties are similar in most ways to amalgam, there are a few differences that require careful attention to assure success for the restoration. This article discusses these handling characteristics, the procedures for placement, and offers specific directions and recommendations to avoid potential problems with its use. Information on recent clinical research is included in the article.


Cardiovascular Risk Associated with Methotrexate versus Retinoids in Patients with Psoriasis: A Nationwide Taiwanese Cohort Study.
Psoriasis is an inflammatory disease associated with cardiovascular disease. Methotrexate (MTX) is a first-line systemic anti-psoriatic agent that may also protect against cardiovascular disease. We examined the cardiovascular risks among patients with psoriasis who were receiving MTX or the comparator, retinoids. We analysed data from the Taiwanese National Health Insurance database. The primary outcome was a composite of hospitalisation for ischaemic heart disease, ischaemic stroke and all-cause mortality (composite cardiovascular outcome). Propensity score-weighted analyses were used to evaluate patients who were followed from therapy initiation to the earliest instance of outcome occurrence, insurance disenrollment, death or study termination. We identified 13,777 patients who received MTX and 6020 patients who received retinoids from 2000 to 2012. Compared to retinoids, MTX was associated with lower crude incidences of cardiovascular outcomes, hospitalisation for ischaemic heart disease, ischaemic stroke and all-cause mortality. In intention-to-treat analyses, MTX was associated with lower risks of composite cardiovascular outcomes (adjusted hazard ratio [HR]: 0.84, 95% confidence interval [CI]: 0.76-0.94), ischaemic heart disease (HR: 0.87, 95% CI: 0.71-1.06), ischaemic stroke (HR: 1.06, 95% CI: 0.89-1.27) and all-cause mortality (HR: 0.75, 95% CI: 0.66-0.85). Similar results were found in as-treated analyses. In this nationwide cohort of patients with psoriasis, compared to retinoids, MTX was associated with a modestly lower risk of cardiovascular events.


Application of Dall-Miles cable grip system for transtrochanteric osteotomy.
We have applied the Dall-Miles cable grip system for fixation in 15 cases of a transtrochanteric valgus osteotomy for osteoarthritis. After three phases of modification, we could achieve stable fixation for the three fragments of the greater trochanter, proximal and distal femur using only one set of this system and could prevent migration and over-traction of the abductor muscles by this way.


Patients' Experience of Winter Depression and Light Room Treatment.
Background. There is a need for more knowledge on the effects of light room treatment in patients with seasonal affective disorder and to explore patients' subjective experience of the disease and the treatment. Methods. This was a descriptive and explorative study applying qualitative content analysis. A purposeful sample of 18 psychiatric outpatients with a major depressive disorder with a seasonal pattern and a pretreatment score ≥12 on the 9-item Montgomery-Åsberg Depression self-rating scale was included (10 women and 8 men, aged 24-65 years). All patients had completed light room treatment (≥7/10 consecutive weekdays). Data was collected two weeks after treatment using a semistructured interview guide. Results. Patients described a clear seasonal pattern and a profound struggle to adapt to seasonal changes during the winter, including deterioration in sleep, daily rhythms, energy level, mood, activity, and cognitive functioning. Everyday life was affected with reduced work capacity, social withdrawal, and disturbed relations with family and friends. The light room treatment resulted in a radical and rapid improvement in all the major symptoms with only mild and transient side effects. Discussion. The results indicate that light room treatment is essential for some patients' ability to cope with seasonal affective disorder.


Potential of Fourier transform infrared spectroscopy (FT-IR) to differentiate environmental Aspergillus fungi species A. niger, A. ochraceus, and A. westerdijkiae using two different methodologies.
We assessed the ability of Fourier transform infrared spectroscopy (FT-IR) to differentiate three important and morphologically similar Aspergillus species: A. ochraceus and A. westerdijkiae, and A. niger. Fungi were processed by two methods, powdered mycelia and conidiospore-saline solution, and then recorded in a spectrometer. Second derivatives with nine points of smoothing were applied as spectra data pretreatment. Partial least squares regression was used for the species comparison models and a prediction test was used to evaluate the models. The powdered-mycelia methodology correctly identified 100% of the prediction test set to discriminate A. niger from A. ochraceus and A. westerdijkiae; in addition, it had a 86.6% success rate in discriminating A. ochraceus and A. westerdijkiae. This is the first time a study assessed the ability of FT-IR to differentiate A. niger, A. ochraceus, and A. westerdijkiae, and we believe this technique is very promising for classifying and distinguish fungi isolates.


Medicinal Plants as a Natural Greener Biocontrol Approach to "The Grain Destructor" Maize Weevil (Sitophilus zeamais) Motschulsky.
According to the United Nations (UN), the global population may skyrocket to 9.8 billion people in 2050 and 11.2 billion in 2100, placing an overwhelming burden on food security as the world will have to meet this growing demand. Maize is the largest staple grain crop produced in developing countries. The maize weevil, Sitophilus zeamais, is one of the most destructive post-harvest pests of stored cereals and grains. The maize weevil contributes up to 40% of total food-grain losses during storage, mainly in developing countries. Current synthetic pesticides are ineffective, and, moreover, they raise serious environmental safety concerns as well as consumer health hazards. Drawing from past oversights and current environmental realities and projections, the global population has been switching to green living by developing sustainable strategies. In our context, these new greener strategies include the utilization of medicinal plants to control maize weevil infestation, which unlocks unlimited innovative possibilities, and, thus, improves the yield, quality, and safety of maize. Medicinal plants are less toxic, easily biodegradable, and capable of protecting grain from pests. This paper systematically outlines the literature on host plants as well as the feeding and associated diseases of the maize weevil. In light of this, we cement medicinal plants as excellent candidates in the pursuit of greener, sustainable, more potent, and cost-effective pesticides.


Endogenous endophthalmitis: a 10-year review of culture-positive cases in northern China.
The aim of this study was to report the clinical features and treatment outcomes in a series of patients with endogenous endophthalmitis treated over a 10-year period in a single hospital in northern China. The authors conducted a retrospective chart review of 19 patients (23 eyes) treated for culture-proven endogenous endophthalmitis at the First Hospital of China Medical University between 1998 and 2007. Patients were followed up for a mean of 15.9 months (range: 0.5-41 months). The main systemic predisposing risk factors were diabetes mellitus (52.6%), immunosuppressive therapy (36.8%), and malignancies (31.6%). Fungal isolates were present in 14 eyes (60.9%), gram-positive isolates in 8 eyes (34.8%), and gram-negative isolates in 1 eye (4.3%). All patients received intravenous antibiotics or antifungal agents, and other treatments included injection of intravitreal medication in 7 eyes (30.4%) and pars plana vitrectomy with injection of intravitreal medication in 14 eyes (60.9%). Final visual outcomes were obtainable for 21 eyes (one patient died 15 days after diagnosis). Ten (47.6%) of these 21 eyes achieved a visual acuity of 20/400 or better, and 11 (52.4%) achieved a visual acuity worse than 20/400, including 5 that were eviscerated. The median visual acuity was counting fingers (range: 20/25 to no light perception). Eyes with endophthalmitis caused by Candida species tended to have better visual outcomes than did eyes with bacterial and Aspergillus causes. Similar to the findings of previous studies, this study showed that fungi, especially Candida species, were the most common causative organisms of endogenous endophthalmitis. Endogenous endophthalmitis is generally associated with poor visual acuity outcomes, particularly when caused by more virulent species of fungi, such as Aspergillus.


Quantification of superantigen induced IFN-gamma production by computerised image analysis--inhibition of cytokine production and blast transformation by pooled human IgG.
A quantitative image analysis technique was developed to assess the cytokine content of immunocytochemically stained cytokine producing cells. Peripheral blood mononuclear cells were stimulated to induce cytokine production with the superantigen streptococcal pyrogenic exotoxin-A. We have developed a method based on indirect immunocytochemistry which identifies IFN-gamma producing cells by a characteristic morphology generated by the accumulation of IFN-gamma in the Golgi organelle. An image analysis technique permitted discrimination between these producer cells and IFN-gamma binding target cells, which showed a different appearance, with staining restricted to the cell surface membrane. A semi-automated routine programme allowed the signal from a video camera to be processed by computerised image analysis methodology. This enabled us to measure the number of cytokine producing cells, the cytokine staining intensity in individual cells and the cell size expressed in actual cell area. The incidence of IFN-gamma producing cells determined by image analysis measurement was compared to results obtained using manual microscopy. Cell size was assessed by the image analysis system as well as by flow cytometry. Administration of pooled human IgG for intravenous use (IVIg) to the superantigen stimulated cells significantly down-regulated IFN-gamma production, both in terms of the numbers of producer cells and in terms of cytokine staining intensity in individual cells. In addition blast transformation of cells was substantially reduced. These effects, mediated by IVIg, were also evident following delayed IVIg administration 24 h after the initial cell stimulation.


Macroscopic and microscopic characterization of a uriniferous perirenal pseudocyst in a Domestic Short Hair cat.
The macroscopic and microscopic features of a uriniferous perirenal pseudocyst in a castrated male 12-year-old American Domestic Short Hair cat are characterized. The development in humans and animals of a perirenal pseudocyst due to the accumulation of urine, lymph, or blood is discussed. In the presented case, microscopic evidence suggests that the pseudocyst developed following formation of a split in the kidney capsule. Emphasis is placed on the development of uriniferous pseudocysts and three proposed criteria for their development: trauma, abnormal openings that allow extravasation of urine, or urethral obstruction.


Removal of boron from aqueous solution using magnetic carbon nanotube improved with tartaric acid.
Boron removal capacity of multi-walled carbon nanotubes (MWCNTs) modified with tartaric acid was investigated in this study. Modification of MWCNTs with tartaric acid was confirmed by Boehm surface chemistry method and fourier transform infra-red (FT-IR) spectroscopy. Experiments were performed to determine the adsorption isotherm and adsorption thermodynamic parameters of boron adsorption on tartaric acid modified MWCNTs (TA-MWCNTs). The effect of variables including initial pH, dosage of adsorbent, contact time and temperature was investigated. Analysis of data showed that adsorption equilibrium could be better described by Freundlich isotherm and the maximum adsorption capacities obtained at the pH of 6.0 was 1.97 mg/g. The estimated thermodynamic values of free energy (ΔG°), entropy (ΔS°) and enthalpy (ΔH°) indicated a spontaneous and an endothermic process. Furthermore, the TA-MWCNTs was magnetized for separation of boron-contaminated adsorbent from aqueous solution by applying magnetic field. The results showed that magnetic TA-MWCNTs particles were separated effectively after adsorption from contaminated water.


Assessing unmet needs in patients with cancer: An investigation of differential item functioning of the Needs Evaluation Questionnaire across gender, age and phase of the disease.
The main aim of this study was to provide evidence of the broad employability of the NEQ with patients of different gender and age with cancer in different phases of the disease and care process, using an Item Response Theory (IRT) approach and investigating Differential Item Functioning (DIF). The NEQ was completed by 762 patients visiting, consecutively, outpatient clinics or admitted to oncology wards. Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. The properties of the questionnaire were analyzed by applying IRT to test how well each item of the scale concurs in measuring unmet needs, how reliable the whole scale is, and whether the scale was metrically invariant across gender, age, and phase of the disease. Results showed that the NEQ performed well in measuring unmet needs and measurement equivalence of the scale across gender, age, and phase of the disease was verified. The current study supports the utility and broad employability of the NEQ, thus providing empirical evidence that it is psychometrically sound and metrically equivalent across different groups of cancer patients. As such, the scale could be an effective tool when planning psychosocial interventions to improve the care process and patients' quality of life.


Flow-directed PCA for monitoring networks.
Measurements recorded over monitoring networks often possess spatial and temporal correlation inducing redundancies in the information provided. For river water quality monitoring in particular, flow-connected sites may likely provide similar information. This paper proposes a novel approach to principal components analysis to investigate reducing dimensionality for spatiotemporal flow-connected network data in order to identify common spatiotemporal patterns. The method is illustrated using monthly observations of total oxidized nitrogen for the Trent catchment area in England. Common patterns are revealed that are hidden when the river network structure and temporal correlation are not accounted for. Such patterns provide valuable information for the design of future sampling strategies.


Selfprotective smart orthopedic implants.
In this review, we discuss current advances leading to an exciting change in implant design for orthopedic surgery. The initial biomaterial approaches in implant design are being replaced by cellular-molecular interactions and nanoscale chemistry. New designs address implant complications, particularly loosening and infection. For infection, local delivery systems are an important first step in the process. Selfprotective 'smart' devices are an example of the next generation of orthopedic implants. If proven to be effective, antibiotics or other active molecules that are tethered to the implant surface through a permanent covalent bond and tethering of antibiotics or other biofactors are likely to transform the practice of orthopedic surgery and other medical specialties. This new technology has the potential to eliminate periprosthetic infection, a major and growing problem in orthopedic practice.


Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated subjects with type 2 diabetes.
The objective of this study was to assess the effect of mealtime amylin replacement with pramlintide on long-term glycemic and weight control in subjects with type 2 diabetes. This 52-week, randomized, placebo-controlled, multicenter, double-blind, dose-ranging study in 538 insulin-treated subjects with type 2 diabetes compared the efficacy and safety of 30-, 75-, or 150-microg doses of pramlintide, a synthetic analogue of the beta-cell hormone amylin, to placebo when injected subcutaneously three times daily (TID) with major meals. Pramlintide therapy led to a mean reduction in HbA1c of 0.9% and 1.0% from baseline to week 13 in the 75- and 150-microg dose groups, which was significant compared to placebo (p = 0.0004 and p = 0.0002, respectively). In the 150-microg dose group, there was a mean reduction in HbA1c of 0.6% from baseline to week 52 (p = 0.0068 compared to placebo). The greater reduction in HbA1c with pramlintide was achieved without increases in insulin use or severe hypoglycemia, and was accompanied by a significant (p < 0.05) reduction in body weight in all dose groups compared to placebo. Three times the proportion of subjects in the 150-microg pramlintide group compared to the placebo group achieved a concomitant reduction in both HbA1c and body weight from baseline to week 52 (48% versus 16%). The most common adverse event reported with pramlintide treatment was nausea, which was mild to moderate and dissipated early in treatment. The results from this study support the safety and efficacy of pramlintide administered three times a day with major meals, in conjunction with insulin therapy, for improving long-term glycemic and weight control in subjects with type 2 diabetes.


Plantar Static Pressure Distribution in Normal Feet Using Cotton Socks with Different Structures.
The major goal of investigating plantar pressure in patients with pain or those at risk for skin injury is to reduce pressure under prominent metatarsal heads, especially the first and second metatarsals. In research, the insole is used to reduce plantar pressure by increasing the contact area in the midfoot region, which, in turn, induces an uncomfortable feeling near the arch during walking. It is deduced that sock structure can redistribute plantar pressure distribution. Seven sock types with seven structures (plain, single cross tuck, mock rib inlay, cross miss, mock rib, double cross tuck, and double cross miss) for the sole area were produced. A plantar pressure measurement device was used to measure plantar static pressure in ten participants. The barefoot plantar pressure distribution was compared with the plantar pressure distribution with socks. In the seven sock samples, the mean plantar pressure of the cross miss and mock rib structures at high plantar pressure zones (toe and first through fourth metatarsal bone regions) were decreased, and, as a result, the pressure shifted to relatively low pressure zones (fifth metatarsal bone and midfoot regions). These results indicate that wearing socks with cross miss and mock rib structures will reduce mean plantar pressure values compared with the barefoot condition in high plantar pressure zones. In general, the results suggest that mean plantar pressure is redistributed from high to low plantar pressure zones.


Bullous dermatosis of hemodialysis.
Five patients with chronic renal failure who were undergoing maintenance hemodialysis developed a self-limited bullous dermatosis restricted to light exposed areas, primarily involving the dorsa of the hands. Porphyrin levels and phototesting were normal, but histologic sections of the bullae showed thickening of venule walls, hypogranulated mast cells, and perivenular deposition of immunoglobulins. This combination of features has not previously been described and may reflect a pathologic process unique to chronic hemodialysis.


Effect of underground working on vitamin D levels and bone mineral densities in coal miners: a controlled study.
The aim of this study was to determine the effect of underground working on 25-hydroxyvitamin D (25-OHD) levels and bone mineral density (BMD) values in coal miners. Fifty coal miners working underground and 50 surface workers as controls, matched for age and body mass index, from Zonguldak, Turkey, were recruited to the study. Levels of 25-OHD, biochemical bone markers, and lumbar spine and femur BMD values were measured in all study participants. Lumbar spine and femur BMD values were significantly higher in underground workers compared with surface workers, but there was no significant difference in 25-OHD levels between the two groups. Duration of underground working, age, 25-OHD levels, cigarette consumption and dietary calcium intake were not correlated with BMD values. Underground physical working does not seem to be a significant risk factor for low 25-OHD levels or low BMD values.


What Each Clinical Anatomist Has to Know about Left Renal Vein Entrapment Syndrome (Nutcracker Syndrome): A Review of the Most Important Findings.
Nutcracker syndrome (NCS) is the most common term for compression of the left renal vein between the superior mesenteric artery and the abdominal aorta. The development of NCS is associated with the formation of the left renal vein (LRV) from the aortic collar during the sixth to eighth week of gestation and abnormal angulation of the superior mesenteric artery from the aorta. Collateralization of venous circulation is the most significant effect of NCS. It includes mainly the left gonadal vein and the communicating lumbar vein. Undiagnosed NCS may affect retroperitoneal surgery and other radiological and vascular procedures. The clinical symptoms of NCS may generally be described as renal presentation when symptoms like haematuria, left flank pain, and proteinuria occur, but urologic presentation is also possible. Radiological methods of confirming NCS include Doppler ultrasonography as a primary test, retrograde venography, which can measure the renocaval pressure gradient, computed tomography angiography, which is faster and less traumatic, intravascular ultrasound, and magnetic resonance angiography. Treatment can be conservative or surgical, depending on the severity of symptoms and degree of LRV occlusion. Nutcracker syndrome is worth considering especially in differential diagnosis of haematuria of unknown origin.


Addressing ethical issues in everyday practice.
In primary-care practice, just as in critical care, ethical dilemmas challenge pediatricians to make choices in the best interests of their patients. Parents are important to the growth and development of children and have broad responsibility for making virtually all decisions regarding nutrition, clothing, housing, education, religion, and medical care. Society's deference to parental choice promotes the value of family integrity, ensures the availability of an identifiable decision maker, and acknowledges the legitimate role parents play in shaping their child's development. However, pediatricians have obligations to assess and advocate for the best interests of their patients. This requires that physicians reach out to their patients and take the time to listen to children and to involve them in their own care. The proper role of a child in planning care depends less on chronologic age than on developmental and personal capacity. Even young children have a keen awareness of their own clinical situations and options and should be involved as best as is possible in decision making. All decision making for children should be collaborative among patients, parents, and professionals. A situation including an involved child, an informed parent, and a caring and compassionate caregiver working collaboratively is most likely to result in optimal decisions for pediatric patients. Bartholome concluded in 1995 that pediatricians should respect children for the persons they are in the process of becoming by being willing to assist them to participate to the extent of their capacity in making decisions about their health. Combining that view with fostering respect for the strongly held beliefs and values of parents is the direction pediatricians should travel to make decisions in the best interests of children.


Roux-en-Y diversion for intractable reflux after esophagectomy.
Reflux esophagitis is a significant problem after esophagectomy and gastric reconstruction. When mixed reflux damages the esophageal remnant or results in aspiration problems, appropriate medical management is in order. If medical management fails, a surgical option is available. This study reports results of a Roux-en-Y diversion in postesophagectomy patients affected by debilitating reflux complications. Between 1990 and 2006, 4 of 223 esophagectomy patients required surgical correction for mucosal damage to their esophageal remnant or repeat aspirations. Patient, clinical, operative, histopathologic, and postoperative data were collected. Two of 3 patients with a substernal reconstruction underwent antrectomy with a 60-cm Roux-en-Y diversion. One patient with significant reflux disease and aspiration episodes also had a gastrobronchial fistula. The gastric interposition was defunctionalized, and a staged reconstruction with antrectomy and a Roux-en-Y diversion was completed. One patient with a prevertebral reconstruction had a Roux-en-Y diversion without antrectomy. There was no mortality and minimal morbidity. Two patients are asymptomatic and 2 are improved. Endoscopic assessment documented normal mucosa in the esophageal remnant for 2 of the 4 patients postoperatively; in 2 others, metaplastic columnar mucosa persisted. Active inflammation regressed in all 4 patients. Complete duodenal diversion with a 60-cm Roux-en-Y gastrojejunostomy is an effective operation to correct debilitating reflux complications after esophagectomy. Reflux symptoms are corrected and the mucosa is allowed to heal. The surgical approach is influenced by the position of the gastric transplant. Protection of the vascular supply to the gastric tube is the challenge of the operation.


Fourier Transform-Ion Mobility-Orbitrap Mass Spectrometer: A Next-Generation Instrument for Native Mass Spectrometry.
A new instrument configuration for native ion mobility-mass spectrometry (IM-MS) is described. Macromolecule ions are generated by using a static ESI source coupled to an RF ion funnel, and these ions are then mobility and mass analyzed using a periodic focusing drift tube IM analyzer and an Orbitrap mass spectrometer. The instrument design retains the capabilities for first-principles determination of rotationally averaged ion-neutral collision cross sections and high-resolution measurements in both mobility and mass analysis modes for intact protein complexes. Operation in the IM mode utilizes FT-IMS modes (originally described by Knorr ( Knorr , F. J. Anal. Chem . 1985 , 57 ( 2 ), 402 - 406 )), which provides a means to overcome the inherent duty cycle mismatch for drift tube (DT)-IM and Orbitrap mass analysis. The performance of the native ESI-FT-DT-IM-Orbitrap MS instrument was evaluated using the protein complexes Gln K (MW 44 kDa) and streptavidin (MW 53 kDa) bound to small molecules (ADP and biotin, respectively) and transthyretin (MW 56 kDa) bound to thyroxine and zinc.


[Functional state of serotoninergic system on a background of different pharmacokinetic of Midazolam].
A comprehensive investigation of the high-performance liquid chromatographic separation of Midazolam and his ozidized metabolits, their bases and other low-molecular-weight UV-absorbing compounds that might be found in serum is reported. The drug was administrated (2,0mg/kg) to 40 white mouses and the blood samples were collecetd for further analysis followind 30, 60, 90, 120 and 180 min. after the injection. The serotoninergic systems has been analyzed. Quantitative data were calculated by inner standart method. Oxidazed forms of Midazolam were qualitatively and quantitatively identified. Our data proved the ability of Midazolam to adsorb on the albumin and globulin fraction of plasma. Metabolism of serotonin and triptopchan is closely dependent on the concentration of psychotropic drug. Concentration of aminoacids (triptophan, tirosyn) in the blood is synshronized with the course of pharmacokinetic of the psychotropic preparation and functional state of serotoninergic system. Alterations may be due, on the one hand, to exhaustion of the stores, and on the other hand, to deterioration of the monoamines' synthesis process. The investigation of pharmacokinetics of invariable form of Midazolam and its oxidized metabolits is very important for practical medicine. Effective action of pshychotropic drugs is impossible without extensive knowlege of their phramacokinetics and pharmacodynamics. They are concerned with the need to dermine concentration in body fluids.


Gender difference in kidney electrolyte transport. I. Role of AT1a receptor in thiazide-sensitive Na+-Cl- cotransporter activity and expression in male and female mice.
We studied gender differences in Na+-Cl- cotransporter (NCC) activity and expression in wild-type (WT) and AT1a receptor knockout (KO) mice. In renal clearance experiments, urine volume (UV), glomerular filtration rate, absolute Na+ (ENa) and K+ (EK), and fractional Na+ (FENa) and K+ excretion were measured and compared at peak changes after bolus intravenous injection of hydrochlorothiazide (HCTZ; 30 mg/kg). In WT, females responded more strongly than males to HCTZ, with larger fractional increases of UV (7.8- vs. 3.4-fold), ENa (11.7- vs. 5.7-fold), FENa (7.9- vs. 4.9-fold), and EK (2.8- vs. 1.4-fold). In contrast, there were no gender differences in the responses to the diuretic in KO mice; HCTZ produced greater effects on male KO than on WT but similar effects on females. In WT, total (tNCC) and phosphorylated (pNCC) NCC protein expressions were 1.8- and 4.6-fold higher in females compared with males (P < 0.05), consistent with the larger response to HCTZ. In KO mice, tNCC and pNCC increased significantly in males to levels not different from those in females. There were no gender differences in the expression of the Na+/H+ exchanger (NHE3) in WT; NHE3 protein decreased to similar extents in male and female KO animals, suggesting AT1a-mediated NHE3 expression in proximal tubules. The resulting increase in delivery of NaCl to the distal nephron may underlie increased NCC expression and activity in mice lacking the AT1a receptor.


Pentraxin 3 promotes cardiac differentiation of mouse embryonic stem cells through JNK signaling pathway.
Cardiovascular disease is a leading cause of death worldwide, requiring the development of new therapeutic strategies including stem cell therapy. Pentraxins (PTXs) are a superfamily of proteins highly involved in different myocardial disorders, and thus this study aimed to identify the modulation of long pentraxin 3 (PTX3) in the differentiation of mouse embryonic stem cells (mESCs) toward cardiomyocytes. Cell toxicity of PTX3 was detected by MTT and LDH assays in mESCs. Embryoid bodies (EBs) were differentiated using hanging drop method, and the beating was observed under microscope. Expressional levels of early cardiac progenitor marker genes were assessed by qRT-PCR. Expression of marker proteins in early myocardial development and the activation of JNK signaling pathway was evaluated by Western blot. PTX3 treatment at 50 ng/mL significantly promoted the expression of cardiac-specific marker genes including Nkx2.5, Mef2c, Tbx5, dHand, and αMHC, and increased the expression of cardiac maturity indicative markers including connexin 43 and troponin C1. PTX3 enhanced the phosphorylation of JNK across the incubation duration, whereas the activation of p38 remained the same as control group. Co-treatment of JNK signaling pathway inhibitor SP600125 impaired the PTX3-promoted transcription of Nkx2.5, Mef2c, Tbx5, dHand, and αMHC. This study revealed the promotion of PTX3 in the differentiation of mESCs into cardiomyocytes and the underlying mechanism.


Polyps at the site of ureterosigmoidostomy.
Anatomoclinical findings in 6 patients under long-term control of ureterosigmoidostomy, performed 5 to 26 years previously for nonneoplastic bladder pathology, are reported. Four histologically confirmed polyps are described and histopathogenetic theories are discussed. The authors suggest that these polyps arise from the ureter via glandular metaplasia due to external contact surgically created in urinary diversion.


Adolescents' online communication and well-being: Findings from the 2018 health behavior in school-aged children (HBSC) study.
Digital transformation has influenced all areas of adolescents' lives, including the ways adolescents maintain friendships. Interpersonal communication is one of the most common activities while online. Online communication may provide adolescents with opportunities to expand their social contacts, but these encounters can be risky, especially when the communication is with unknown people on the internet. This study examined the associations between different forms of online communication behavior and well-being. Data were collected from Finnish adolescents as part of the Health Behavior in School-Aged Children (HBSC) study in 2018. The participants were 3,140 Finnish adolescents aged 11-15 years. Descriptive analyses were used to examine the frequency of different forms of online communication behaviors. The associations between online communications and individual factors were analyzed using the X2 test and 95% confidence intervals. Structural equation modeling (SEM) was used to analyze the extent to which adolescents' online communication behavior explained the variance in adolescents' well-being indicators. Overall, 60% of the adolescents reported communicating intensively with close friends, with higher rates of intensive communication reported by girls, higher age groups, and the high health literacy group. 22% of adolescents reported intensive communication with friends they got to know through the internet (online friends), while intensive online communication with unknown people was reported by 13% of adolescents. Overall, around one-fourth of adolescents preferred sharing personal matters online rather than in face-to-face encounters, and 10% of adolescents reported using the internet daily to get to know new people, and to look for like-minded company. The SEM analysis showed that keeping online contact with offline friends was linked to a positive outcome in all the measured well-being indicators; however, intensive communication with people contacted only online (online friends and unknown people) was negatively associated with well-being indicators (lower self-rated health, lower life satisfaction, higher loneliness, and problematic social media use). Both positive and negative associations were observed between online communication and well-being, depending on the target and content of the communication. The results indicate that online communication has benefits for adolescents who have more offline social life. Overall, one should ensure that the impact of interventions is proportionately greater for adolescents at the bottom end of the health gradient.


[The correlation between toe- and ankle pressure, clinical symptoms and angiography in patients with leg ischemia].
The severity of leg ischemia is usually evaluated by measuring ankle pressure. This is a simple measurement but can be misleading in patients with severe sclerosis in ankle arteries in which case toe pressure is believed to be more reliable. The purpose of this study was to compare toe pressure with ankle pressure, clinical symptoms and angiography and thus evaluate the usefulness of toe pressure in the assessment of leg ischemia. In total of 58 legs from 30 patients that came to Landspítali University Hospital because of leg ischemia we measured toe- and ankle pressure and assessed the clinical stage of leg ischemia. All patients also had an angiography of their leg arteries. There was a correlation between pressure measurements and the clinical stage of leg ischemia and also between pressure measurements and results from angiography of leg arteries. There was not a significant difference between the correlation for toe- and ankle pressure respectively. In two cases it was impossible to measure ankle pressure but in both cases it was possible to measure toe pressure. Toe- and ankle pressure measurements are equally useful in the evaluation of leg ischemia. Ankle pressure is a more simple measurement than toe pressure but can be impossible to perform when the ankle arteries are very sclerotic. When that is the case toe pressure can often be measured instead.


Ethnic disparities in diabetic complications in an insured population.
Higher rates of microvascular complications have been reported for minorities. Disparate access to quality health care is a common explanation for ethnic disparities in diabetic complication rates in the US population. Examining an ethnically diverse population with uniform health care coverage may be useful. To assess ethnic disparities in the incidence of diabetic complications within a nonprofit prepaid health care organization. Longitudinal observational study conducted January 1, 1995, through December 31, 1998, at Kaiser Permanente Medical Care Program in northern California. A total of 62 432 diabetic patients, including Asians (12%), blacks (14%), Latinos (10%), and whites (64%). Incident myocardial infarction (MI), stroke, congestive heart failure (CHF), and nontraumatic lower extremity amputation (LEA), defined by primary hospitalization discharge diagnosis, procedures, or underlying cause of death; and end-stage renal disease (ESRD), defined as renal insufficiency requiring renal replacement therapy or transplantation for survival or by underlying cause of death. Patterns of ethnic differences were not consistent across complications and frequently persisted despite adjustment for a wide range of demographic, socioeconomic, behavioral, and clinical factors. Adjusted hazard ratios (relative to that of whites) were 0.56, 0.68, and 0.68 for blacks, Asians, and Latinos, respectively (P<.001), for MI; 0.76 and 0.72 for Asians and Latinos, respectively (P<.01), for stroke; 0.70 and 0.61 for Asians and Latinos, respectively (P<.01), for CHF; 0.40 for Asians (P<.001) for LEA; and 2.03, 1.85, and 1.46 for blacks, Asians, and Latinos, respectively (P<.01), for ESRD. There were no statistically significant black-white differences for stroke, CHF, or LEA and no Latino-white differences for LEA. This study confirms previous reports of elevated incidence of ESRD among ethnic minorities, despite uniform medical care coverage, and provides new evidence that rates of other complications are similar or lower relative to those of whites. The persistence of ethnic disparities after adjustment suggests a possible genetic origin, the contribution of unmeasured environmental factors, or a combination of these factors.


Fibroblast growth factor 23 does not directly influence skeletal muscle cell proliferation and differentiation or ex vivo muscle contractility.
Skeletal muscle dysfunction accompanies the clinical disorders of chronic kidney disease (CKD) and hereditary hypophosphatemic rickets. In both disorders, fibroblast growth factor 23 (FGF23), a bone-derived hormone regulating phosphate and vitamin D metabolism, becomes chronically elevated. FGF23 has been shown to play a direct role in cardiac muscle dysfunction; however, it is unknown whether FGF23 signaling can also directly induce skeletal muscle dysfunction. We found expression of potential FGF23 receptors ( Fgfr1-4) and α-Klotho in muscles of two animal models (CD-1 and Cy/+ rat, a naturally occurring rat model of chronic kidney disease-mineral bone disorder) as well as C2C12 myoblasts and myotubes. C2C12 proliferation, myogenic gene expression, oxidative stress marker 8-OHdG, intracellular Ca2+ ([Ca2+]i), and ex vivo contractility of extensor digitorum longus (EDL) or soleus muscles were assessed after treatment with various amounts of FGF23. FGF23 (2-100 ng/ml) did not alter C2C12 proliferation, expression of myogenic genes, or oxidative stress after 24- to 72-h treatment. Acute or prolonged FGF23 treatment up to 6 days did not alter C2C12 [Ca2+]i handling, nor did acute treatment with FGF23 (9-100 ng/ml) affect EDL and soleus muscle contractility. In conclusion, although skeletal muscles express the receptors involved in FGF23-mediated signaling, in vitro FGF23 treatments failed to directly alter skeletal muscle development or function under the conditions tested. We hypothesize that other endogenous substances may be required to act in concert with FGF23 or apart from FGF23 to promote muscle dysfunction in hereditary hypophosphatemic rickets and CKD.


Variability in Trauma Case Volume in Orthopedic Surgery Residents.
Orthopedic trauma surgery is a critical component of resident education. Surgical case logs obtained from the Accreditation Council of Graduate Medical Students from 2009 to 2013 for orthopedic surgery residents were examined for variability between the 90th and 10th percentiles in regards to the volume of cases performed. There was an upward trend in the mean number of cases performed by senior residents from 484.4 in 2009 to 534.5 in 2013, representing a 10.3% increase. There was a statistically significant increase in the number of cases performed for humerus/elbow, forearm/wrist, and pelvis/hip during this period (P<0.05). Although the difference between the 10th and 90th percentile case volumes narrowed over the study period, the difference between these groups remained significant in 2013 (P=0.02). In 2013, all categories of trauma cases had a greater than 2.2-fold difference between the 10th and 90th percentile of residents for numbers of trauma cases performed. Although case volume is not the sole determinant of residency education and competency, evidence suggests that case volume plays a crucial role in surgeon confidence and efficiency in performing surgery. Further studies are needed to better understand the effect of this variability seen among residents performing orthopedic trauma surgery.


A Review on Biopolymer-Based Biodegradable Film for Food Packaging: Trends over the Last Decade and Future Research.
In recent years, much attention has been paid to the use of biopolymers as food packaging materials due to their important characteristics and properties. These include non-toxicity, ease of availability, biocompatibility, and biodegradability, indicating their potential as an alternative to conventional plastic packaging that has long been under environmental scrutiny. Given the current focus on sustainable development, it is imperative to develop studies on biopolymers as eco-friendly and sustainable food packaging materials. Therefore, the aim of this review is to explore trends and characteristics of biopolymer-based biodegradable films for food packaging, analyze the contribution of various journals and cooperation between countries, highlight the most influential authors and articles, and provide an overview of the social, environmental, and economic aspects of biodegradable films for food packaging. To achieve this goal, a bibliometric analysis and systematic review based on the PRISMA method were conducted. Relevant articles were carefully selected from the Scopus database. A bibliometric analysis was also conducted to discuss holistically, comprehensively, and objectively biodegradable films for food packaging. An increasing interest was found in this study, especially in the last 3 years with Brazil and China leading the number of papers on biodegradable films for food packaging, which were responsible for 20.4% and 12.5% of the published papers, respectively. The results of the keyword analysis based on the period revealed that the addition of bioactive compounds into packaging films is very promising because it can increase the quality and safety of packaged food. These results reveal that biodegradable films demonstrate a positive and promising trend as food packaging materials that are environmentally friendly and promote sustainability.


Estimation of nuclear volume as an indicator of maturation of glial precursor cells in the developing rat spinal cord: a stereological approach.
Studies on nuclear volume have shown that it is an indication of the state of differentiation of cells. This study provides evidence indicating increasing nuclear volume during cell maturation. Using unbiased stereological techniques, nuclear volume of both proliferating and non-proliferating glial cells was analysed in the developing spinal cord. Proliferating glial precursor cells were identified using a 5-bromo-2'-deoxyuridine (BrdU) incorporation assay. The nuclear volume of BrdU-labelled cells and unlabelled cells was determined in both periventricular regions and the white matter of the cord at different embryonic ages. In the periventricular region BrdU-labelled nuclei were smaller than unlabelled nuclei at all ages examined. These labelled cells represent dividing undifferentiated progenitors. The unlabelled neighbouring cells with larger nuclei represent a more differentiated population. In the white matter BrdU-labelled nuclei were of similar volume to the unlabelled nuclei. Both of these groups represent glial precursor cells that have migrated from deeper regions and are at similar stages of differentiation, perhaps with different proliferative potential. These findings indicate that the nuclear volume of early glial cells increases as these cells migrate and differentiate.


Genomic and metagenomic insights into the microbial community of a thermal spring.
Water springs provide important ecosystem services including drinking water supply, recreation, and balneotherapy, but their microbial communities remain largely unknown. In this study, we characterized the spring water microbiome of Comano Terme (Italy) at four sampling points of the thermal spa, including natural (spring and well) and human-built (storage tank, bathtubs) environments. We integrated large-scale culturing and metagenomic approaches, with the aim of comprehensively determining the spring water taxonomic composition and functional potential. The groundwater feeding the spring hosted the most atypical microbiome, including many taxa known to be recalcitrant to cultivation. The core microbiome included the orders Sphingomonadales, Rhizobiales, and Caulobacterales, and the families Bradyrhizobiaceae and Moraxellaceae. A comparative genomic analysis of 72 isolates and 30 metagenome-assembled genomes (MAGs) revealed that most isolates and MAGs belonged to new species or higher taxonomic ranks widely distributed in the microbial tree of life. Average nucleotide identity (ANI) values calculated for each isolated or assembled genome showed that 10 genomes belonged to known bacterial species (> 95% ANI), 36 genomes (including 1 MAG) had ANI values ranging 85-92.5% and could be assigned as undescribed species belonging to known genera, while the remaining 55 genomes had lower ANI values (< 85%). A number of functional features were significantly over- or underrepresented in genomes derived from the four sampling sites. Functional specialization was found between sites, with for example methanogenesis being unique to groundwater whereas methanotrophy was found in all samples. Current knowledge on aquatic microbiomes is essentially based on surface or human-associated environments. We started uncovering the spring water microbiome, highlighting an unexpected diversity that should be further investigated. This study confirms that groundwater environments host highly adapted, stable microbial communities composed of many unknown taxa, even among the culturable fraction.


[Impact of the ''Enhanced Recovery After Surgery'' program in knee arthroplasty at the institutional level].
total knee arthroplasty has gained popularity over decreasing pain, restoring mobility and improving patients' quality of life. At the institutional level, there is no multidisciplinary model in the treatment of our patients, and in our environment, physical rehabilitation starts late, making it difficult for patients to reincorporate and attain adequate pain control. a controlled, randomized, prospective and longitudinal study was conducted, 55 patients underwent total knee arthroplasty, assigned to two study groups: the ERAS (enhanced recovery after surgery) group (n = 27) and the usual group (n = 28). Inclusion criteria were patients with Kellgren-Lawrence classification grade 4 gonarthrosis, age between 30-70 years and follow-up for six months. Descriptive statistics were performed using medians and interquartile range, while inferential statistics were performed using the Kruskal-Wallis test. the results obtained at six months showed no statistically significant differences in age (p = 0.327) and gender (p = 0.588). The results obtained in the scales of VAS, WOMAC and IKDC showed statistically significant difference (p = 0.000). The rapid recovery group with a 120° flexion median and the usual group with 90° flexion, both groups with 0° extension. the enhanced recovery after surgery pathway in joint replacement procedures showed good results on pain, function, mobility and complications compared to patients undergoing usual management.


Interleukin-1 receptor antagonist expression is inversely associated with outcomes of hepatitis B-related acute-on-chronic liver failure.
Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring anti-inflammatory antagonist of the proinflammatory cytokine IL-1, a critical factor in many inflammatory diseases. The aim of the present study was to investigate the role of IL-1ra in hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Serum cytokine concentrations were measured using a Q-Plex array in 31 patients with HB-ACLF, 28 patients with acute hepatitis B (AHB), 31 patients with chronic hepatitis B (CHB) and 15 healthy control patients (HCs). Additionally, peripheral blood mononuclear cells (PBMCs) from patients with HB-ACLF were incubated with PBS or lipopolysaccharide and/or different concentrations of recombinant human IL-1ra (rhIL-1ra) in vitro. Cytokines in the supernatant were measured using a Q-Plex array. The median serum IL-1ra level in patients with HB-ACLF was 186.46 (350.22) pg/ml, which was significantly higher than all other groups (AHB, P=0.012; CHB, P<0.001; HCs, P<0.001). However, the ratio of IL-1ra/IL-1β was significantly lower in the HB-ACLF group compared with the AHB group (P=0.048). Median serum IL-1ra levels in patients with AHB were also significantly increased compared with those in the CHB (P<0.001) and HC (P<0.001) groups. Patients who succumbed to mortality within 3 months of the study were found to have significantly lower IL-1ra concentrations (P=0.02) and IL-1ra/IL-1β ratios (P=0.007) compared with surviving patients with HB-ACLF. Furthermore, serum IL-1ra concentrations were negatively associated with the Model for End-stage Liver Disease score (r=-0.870; P<0.001). Cytokine secretion by PBMCs in vitro was significantly inhibited in a dose-dependent manner by rhIL-1ra (125-500 ng/ml; all P<0.05). These results suggest that IL-1ra is associated with the development of liver inflammation, which is reduced in patients with HB-ACLF and inversely associated with disease severity.


Successful treatment of primary sclerosing cholangitis with a steroid and a probiotic.
Primary sclerosing cholangitis (PSC) is a serious disease that not only affects quality of life but can also have a significant effect on patient survival. The treatment for PSC is primarily supportive with the aim of controlling cholestatic symptoms and preventing complications. Ursodeoxycholic acid may induce biochemical improvements in affected patients; however, long-term pediatric studies to determine its possible benefits in young patients are lacking. Thus, the treatment of pediatric PSC remains a significant clinical challenge. We describe a patient with PSC and undetermined colitis who was treated with a combination of a steroid, salazosulfapyridine, and a probiotic. This treatment provided benefits both for PSC and the undetermined colitis. These findings suggest that bacterial flora and gut inflammation are closely associated with the pathogenesis of inflammatory bowel disease-related PSC. Suppression of bowel inflammation and maintenance of bacterial homeostasis may be important for treating PSC.


Building a better particle: Leveraging physicochemical understanding of amorphous solid dispersions and a hierarchical particle approach for improved delivery at high drug loadings.
Amorphous solid dispersions are a promising option for managing compounds with poor aqueous solubility. However, for compounds with high melting points, thermal stability limitations, or poor solubility in volatile solvents, conventional routes of hot melt extrusion or spray drying may not be viable. Co-precipitated amorphous dispersions (cPAD) can provide a solution. For the material studied in this paper, the cPAD material that was seemingly identical to spray dried material in terms of being single phase amorphous (as measured by DSC and XRD ) but showed slower dissolution behavior. It was identified that physical properties of the cPAD material could be improved to enhance wettability and improve dissolution performance. This was achieved by incorporating the cPAD material into a matrix of water soluble excipients generated via evaporative isolation routes. Importantly, this approach appears to offer another route to further increase the drug load in final dosage units and is significant as increased drug loading generally results in slower or incomplete release. Results showed successful proof of concept via in vitro biorelevant dissolution and confirmatory canine pharmacokinetic studies yielding comparable exposure for capsules comprised of conventional spray dried material as well as capsules with elevated drug load comprised of cPAD hierarchical particles.


New Insight of Water-Splitting Photocatalyst: H2O2-Resistance Poisoning and Photothermal Deactivation in Sub-micrometer CoO Octahedrons.
Hydrogen production by photocatalytic overall water-splitting represents an ideal pathway for clean energy harvesting, for which developing high-efficiency catalysts has been the central scientific topic. Nanosized CoO with high solar-to-hydrogen efficiency (5%) is one of the most promising catalyst candidates. However, poor understanding of this photocatalyst leaves the key issue of rapid deactivation unclear and severely hinders its wide application. Here, we report a sub-micrometer CoO octahedron photocatalyst with high overall-water-splitting activity and outstanding ability of H2O2-resistance poisoning. We show that the deactivation of CoO catalyst originates from the unintended thermoinduced oxidation of CoO during photocatalysis, with coexistence of oxygen and water. We then demonstrate that introduction of graphene, as a heat conductor, largely enhanced the photocatalytic activity and stability of the CoO. Our work not only provides a new insight of CoO for photocatalytic water splitting but also demonstrates a new concept for photocatalyst design.


A point mutation in the regulatory light chain reduces the step size of skeletal muscle myosin.
Current evidence favors the theory that, when the globular motor domain of myosin attaches to actin, the light chain binding domain or "lever arm" rotates, and thereby generates movement of actin filaments. Myosin is uniquely designed for such a role in that a long alpha-helix (approximately 9 nm) extending from the C terminus of the catalytic core is stabilized by two calmodulin-like molecules, the regulatory light chain (RLC) and the essential light chain (ELC). Here, we introduce a single-point mutation into the skeletal myosin RLC, which results in a large (approximately 50%) reduction in actin filament velocity (V(actin)) without any loss in actin-activated MgATPase activity. Single-molecule analysis of myosin by optical trapping showed a comparable 2-fold reduction in unitary displacement or step size (d), without a significant change in the duration of the strongly attached state (tau(on)) after the power stroke. Assuming that V(actin) approximately d/tau(on), we can account for the change in velocity primarily by a change in the step size of the lever arm without incurring any change in the kinetic properties of the mutant myosin. These results suggest that a principal role for the many light chain isoforms in the myosin II class may be to modulate the flexural rigidity of the light chain binding domain to maximize tension development and movement during muscle contraction.


Confocal fluorescence microscopy for rapid evaluation of invasive tumor cellularity of inflammatory breast carcinoma core needle biopsies.
Tissue sampling is a problematic issue for inflammatory breast carcinoma, and immediate evaluation following core needle biopsy is needed to evaluate specimen adequacy. We sought to determine if confocal fluorescence microscopy provides sufficient resolution to evaluate specimen adequacy by comparing invasive tumor cellularity estimated from standard histologic images to invasive tumor cellularity estimated from confocal images of breast core needle biopsy specimens. Grayscale confocal fluorescence images of breast core needle biopsy specimens were acquired following proflavine application. A breast-dedicated pathologist evaluated invasive tumor cellularity in histologic images with hematoxylin and eosin staining and in grayscale and false-colored confocal images of cores. Agreement between cellularity estimates was quantified using a kappa coefficient. 23 cores from 23 patients with suspected inflammatory breast carcinoma were imaged. Confocal images were acquired in an average of less than 2 min per core. Invasive tumor cellularity estimated from histologic and grayscale confocal images showed moderate agreement by kappa coefficient: κ = 0.48 ± 0.09 (p < 0.001). Grayscale confocal images require less than 2 min for acquisition and allow for evaluation of invasive tumor cellularity in breast core needle biopsy specimens with moderate agreement to histologic images. We show that confocal fluorescence microscopy can be performed immediately following specimen acquisition and could indicate the need for additional biopsies at the initial visit.


Immunomodulatory activity of Asparagus racemosus on systemic Th1/Th2 immunity: implications for immunoadjuvant potential.
Roots of Asparagus racemosus Willd (Shatavari in vernacular) are widely used in Ayurveda as Rasayana for immunostimulation, galactogogue as also in treatment of conditions like ulcers and cancer. Various studies have indicated immunomodulatory properties of Shatavari root extracts and formulations. To study the effect of standardized Asparagus racemosus root aqueous extract (ARE) on systemic Th1/Th2 immunity of SRBC sensitized animals. We used HPTLC to quantify steroidal saponins (Shatavarin IV, Immunoside) and flow cytometry to study effects of ARE on Th1/Th2 immunity. SRBC specific antibody titres and DTH responses were also monitored as markers of Th2 and Th1 responses, respectively. We also studied lymphocyte proliferation. Cyclosporin, cyclophosphamide and levamisole were used as controls. Treatment with ARE (100mg/(kg b.w.p.o.)) resulted in significant increase of CD3(+) and CD4/CD8(+) percentages suggesting its effect on T cell activation. ARE treated animals showed significant up-regulation of Th1 (IL-2, IFN-g) and Th2 (IL-4) cytokines suggesting its mixed Th1/Th2 adjuvant activity. Consistent to this, ARE also showed higher antibody titres and DTH responses. ARE, in combination with LPS, Con A or SRBC, produced a significant proliferation suggesting effect on activated lymphocytes. The study suggests mixed Th1/Th2 activity of ARE supports its immunoadjuvant potential.


A Machine Learning Approach to Personalize Computerized Cognitive Training Interventions.
Executive functions are a class of cognitive processes critical for purposeful goal-directed behavior. Cognitive training is the adequate stimulation of executive functions and has been extensively studied and applied for more than 20 years. However, there is still a lack of solid consensus in the scientific community about its potential to elicit consistent improvements in untrained domains. Individual differences are considered one of the most important factors of inconsistent reports on cognitive training benefits, as differences in cognitive functioning are both genetic and context-dependent, and might be affected by age and socioeconomic status. We here present a proof of concept based on the hypothesis that baseline individual differences among subjects would provide valuable information to predict the individual effectiveness of a cognitive training intervention. With a dataset from an investigation in which 73 6-year-olds trained their executive functions using an online software with a fixed protocol, freely available at www.matemarote.org.ar, we trained a support vector classifier that successfully predicted (average accuracy = 0.67, AUC = 0.707) whether a child would improve, or not, after the cognitive stimulation, using baseline individual differences as features. We also performed a permutation feature importance analysis that suggested that all features contribute equally to the model's performance. In the long term, this results might allow us to design better training strategies for those players who are less likely to benefit from the current training protocols in order to maximize the stimulation for each child.


Sensitivity to input variability of the Adjuvant! Online breast cancer prognostic model.
Adjuvant! Online (www.adjuvantonline.org) is a software model that predicts the benefit of adjuvant therapy for women with early-stage breast cancer. The model has been validated, is widely consulted, and has been shown to influence patient choices in the clinical setting. Adjuvant! requires the clinician to input patient age, tumor size, grade, hormone receptor status, number of positive lymph nodes, and comorbidity level. Because comorbidity is strongly and independently associated with survival, this study tested the hypothesis that Adjuvant! predictions would be sensitive to comorbidity inputs. Investigators used single-variable deterministic sensitivity analysis to evaluate the effect of varying each input of the model independently for three representative case examples based on National Comprehensive Cancer Network guidelines (NCCN). The main outcome of interest was 10-year mortality prediction. The analyses show that Adjuvant!'s 10-year mortality predictions are most sensitive to patients' comorbidity levels and the extent of nodal involvement for the cases, particularly among older women. Comorbidity was the most influential input except in younger women, aged 40 years. The Adjuvant! model is sensitive to patient comorbidity, and impact on the model outputs are significant enough that they are likely to affect physician recommendations and patients' treatment choices. For example, incorrect assessments of comorbidities could lead physicians to overtreat or undertreat a patient who is in a gray zone relative to the NCCN guidelines. These results point to the importance of accurately assessing comorbidities in patients with breast cancer when using Adjuvant! and highlight the need for a standardized process of comorbidity ascertainment.


The amino-terminal non-catalytic region of Salmonella typhimurium SigD affects actin organization in yeast and mammalian cells.
The internalization of Salmonella into epithelial cells relies on the function of bacterial proteins which are injected into the cell by a specialized type III secretion system. Such bacterial effectors interfere with host cell signalling and induce local cytoskeletal rearrangements. One of such effectors is SigD/SopB, which shares homology with mammalian inositol phosphatases. We made use of the Saccharomyces cerevisiae model for elucidating new aspects of SigD function. Endogenous expression of SigD in yeast caused severe growth inhibition. Surprisingly, sigD alleles mutated in the catalytic site or even deleted for the whole C-terminal phosphatase domain still inhibited yeast growth by inducing loss of actin polarization and precluding the budding process. Accordingly, when expressed in HeLa cells, the same sigD alleles lost the ability of depleting phosphatidylinositol 4,5-bisphosphate from the plasma membrane, but still caused disappearance of actin fibres and loss of adherence. We delineate a region of 25 amino acids (residues 118-142) that is necessary for the effect of SigD on actin in HeLa cells. Our data indicate that SigD exerts a toxic effect linked to its N-terminal region and independent of its phosphatase activity.


Differential susceptibility of a rat glioma cell line and its clones to herpes simplex virus types 1 and 2.
A rat glioma cell line, C6-BU-1, showed differential susceptibility to herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), namely, all the HSV-1 strains tested so far persisted in this cell line but the HSV-2 strains did not. Two clones were derived from C6-BU-1 cells and designated C-17 and C-72. The C-72 as well as the parental C6-BU-1 cells supported the replication of HSV-1, but not that of HSV-2. In contrast, C-17 was highly resistant to both HSV-1 and HSV-2. Hydrocortisone treatment converted C-17 to being susceptible to HSV-1, but not to HSV-2. Therefore, C6-BU-1 cells consist of subpopulations heterogeneous in susceptibility to HSV-1 which may be possibly interchangeable.


Measuring functional performance in patients with COPD: a discussion of patient-reported outcome measures.
Chronic obstructive pulmonary disease (COPD) is a chronic condition and a major public health concern. Moreover, its prevalence is increasing. COPD commonly affects patient performance of daily activities that people perform in order to meet basic needs, fulfill usual roles, and maintain their health and well-being. What types of activities are affected and to what degree? How do these effects change over time? What impact, positive or negative, do various treatments have on the capacity of patients to perform activities? To address these questions, the concept of activity performance must be defined and appropriately measured. This paper presents a model of function that defines functional performance as distinct but related to physiological impairments and functional capacity. A systematic review of the literature was conducted to locate patient-reported outcome (PRO) instruments that have been used to capture functional performance in clinical studies of COPD and have been validated with patients with COPD. The content of each measure was reviewed to assess depth and breadth of coverage. The systematic review yielded nine validated PROs used to capture functional performance in clinical studies of COPD: three are generic; six were designed specifically for use in patients with COPD. Variability in content coverage occurred across the PROs, with some sacrificing depth for breadth. Few of the PROs covered the full range of content as defined in the model. Limiting selected PROs to those that have been used with patients with COPD, while relevant to this population, may preclude other PRO instruments that can measure functional performance. The relevance of another instrument would, however, need to be confirmed with patients with COPD. Selection of endpoints and instruments for clinical studies of COPD and its treatment must be driven by a clear definition of concepts of interest and the relevance of content areas to patients. Some existing instruments may provide adequate coverage of endpoints or content areas under investigation. Others clearly will not.


Characteristics of juvenile dermatomyositis in Japan.
Questionnaires were sent to 1290 hospitals in Japan asking for data on patients with juvenile dermatomyositis (JDM) diagnosed between June 1984 and May 1994. Of the 204 patients identified by these questionnaires, 102 met the criteria for JDM. JDM is categorized into three subtypes: Banker-type JDM, Brunsting-type and fulminant-type; patients with the latter exhibit markedly elevated serum levels of creatinine phosphokinase (> 10,000 U/mL) and appear to be at risk of renal failure. Cutaneous manifestations were present in 98% of patients and preceded the appearance of other symptoms. This tendency is one of the reasons for the difficulty in some cases in diagnosing the onset of JDM. Better criteria for early treatment of JDM are needed. The results of the present study suggest that itching and calcinosis are factors that indicate a poor prognosis in patients with JDM. Muscle enzyme levels do not always reflect disease activity, suggesting that methods other than measurement of muscle enzymes, such as measurement of the levels of neoprerin and von Willebrand factor antigen, as well as magnetic resonance imaging should be used to be evaluate disease severity. Patients with Brunsting-type JDM who exhibit dysphagia and antinuclear antibody positivity and patients with Banker-type JDM should be treated aggressively. Pulse therapy should be selected as the initial therapy in patients with fulminant-type JDM.


Cancer-drug associations: a complex system.
Network analysis has been performed on large-scale medical data, capturing the global topology of drugs, targets, and disease relationships. A smaller-scale network is amenable to a more detailed and focused analysis of the individual members and their interactions in a network, which can complement the global topological descriptions of a network system. Analysis of these smaller networks can help address questions, i.e., what governs the pairing of the different cancers and drugs, is it driven by molecular findings or other factors, such as death statistics. We defined global and local lethality values representing death rates relative to other cancers vs. within a cancer. We generated two cancer networks, one of cancer types that share Food and Drug Administration (FDA) approved drugs (FDA cancer network), and another of cancer types that share clinical trials of FDA approved drugs (clinical trial cancer network). Breast cancer is the only cancer type with significant weighted degree values in both cancer networks. Lung cancer is significantly connected in the FDA cancer network, whereas ovarian cancer and lymphoma are significantly connected in the clinical trial cancer network. Correlation and linear regression analyses showed that global lethality impacts the drug approval and trial numbers, whereas, local lethality impacts the amount of drug sharing in trials and approvals. However, this effect does not apply to pancreatic, liver, and esophagus cancers as the sharing of drugs for these cancers is very low. We also collected mutation target information to generate cancer type associations which were compared with the cancer type associations derived from the drug target information. The analysis showed a weak overlap between the mutation and drug target based networks. The clinical and FDA cancer networks are differentially connected, with only breast cancer significantly connected in both networks. The networks of cancer-drug associations are moderately affected by the death statistics. A strong overlap does not exist between the cancer-drug associations and the molecular information. Overall, this analysis provides a systems level view of cancer drugs and suggests that death statistics (i.e. global vs. local lethality) have a differential impact on the number of approvals, trials and drug sharing.


Cholinergic stimulation activates a non-selective cation current in canine pyloric circular muscle cells.
1. Cholinergic stimulation of circular muscle from the canine pyloric sphincter results in excitatory junction potentials and an increase in slow-wave frequency. Experiments were performed on isolated pyloric muscle cells to determine the effects of acetylcholine on membrane conductance and voltage-dependent ionic currents. 2. Acetylcholine depolarized circular muscle cells and increased membrane conductance. Under voltage clamp, these effects were associated with the development of an inward current. 3. The ACh-dependent current (IACh) reversed at about -20 mV and was about equally selective for potassium and sodium. Changes in the chloride gradient had no effect on the reversal potential of IACh. 4. The response to ACh was blocked by atropine suggesting that the response was mediated by muscarinic receptors. IACh could not be elicited in the presence of ions normally used to block potassium currents (e.g. bath-applied TEA+ and replacement of Ki+ with Csi+. 5. In some cells single-channel openings could be resolved in response to ACh. These channels had a slope conductance of 30 pS, and open probability increased with depolarization. 6. Acetylcholine had little or no effect on voltage-dependent Ca2+ currents, and increased voltage-dependent outward currents. The latter effect may have been due to increased release of Ca2+ from internal stores. 7. The non-selective cationic current elicited by ACh can explain the excitatory junction potentials in pyloric muscle cells that are generated by transmural nerve stimulation and may also explain the chronotropic effects of ACh on slow waves.


Augmented Degradation of Factors VIII and IX in the Intermittent Movement State.
The most common clinical presentation of hemophilia A and hemophilia B is bleeding in large joints and striated muscles. It is unclear why bleeding has a predilection to affect joints and muscles. As muscles and joints are involved in intermittent movement, we explored whether this phenomenon could be associated with an impact on factor VIII and IX levels. Purified proteins and a mouse model were assessed using coagulation assays, Western blot analysis and immuno-staining. Movement caused an increase in thrombin activity and a decrease in factor VIII and factor IX activity. The decrease in factor VIII activity was more significant in the presence of thrombin and during movement. Under movement condition, sodium ions appeared to enhance the activity of thrombin that resulted in decreased factor VIII activity. Unlike factor VIII, the reduction in factor IX levels in the movement condition was thrombin-independent. High factor VIII levels were found to protect factor IX from degradation and vice versa. In mice that were in movement, factor VIII and IX levels decreased in the microcirculation of the muscle tissue compared with other tissues and to the muscle tissue at rest. Movement had no effect on von Willebrand factor levels. Movement induces reduction in factor VIII and IX levels. It enables an increase in the binding of sodium ions to thrombin leading to enhanced thrombin activity and augmented degradation of factor VIII. These data suggest a potential mechanism underlying the tendency of hemophilia patients to bleed in muscles and joints.


Thrombi in all four cardiac chambers in a patient with an old anteroseptal myocardial infarction and atrial flutter.
Cases with thrombi in multiple cardiac chambers are rare. We report an extremely rare case in which thrombi were formed in all four cardiac chambers at the same time. A 55-year-old man presented with biventricular failure and liver dysfunction. A 12-lead ECG and an echocardiogram revealed an old anteroseptal myocardial infarction with aneurysm formation and atrial flutter. A transesophageal echocardiogram and a CT of the chest revealed thrombi in the right and left atrial appendage, right ventricular apex and left ventricular aneurysm. Pulmonary emboli were also identified. Stasis of the blood due to ventricular dysfunction and atrial flutter was considered to be responsible. The patient died of multiorgan failure due to circulatory failure.


Non-invasive optical imaging techniques for burn-injured tissue detection for debridement surgery.
Burn debridement is a challenging technique that requires significant skill to identify regions requiring excision and appropriate excision depth. A machine learning tool is being developed in order to assist surgeons by providing a quantitative assessment of burn-injured tissue. Three noninvasive optical imaging techniques capable of distinguishing between four kinds of tissue-healthy skin, viable wound bed, deep burn, and shallow burn-during serial burn debridement in a porcine model are presented in this paper. The combination of all three techniques considerably improves the accuracy of tissue classification, from 0.42 to almost 0.77.


Association between CYP2B6 c.516G >T variant and acute leukaemia: A protocol for systematic review and meta-analysis.
Acute leukemia (AL) is a kind of malignant tumor of hematopoietic system. A number of studies have suggested that Single Nucleotide Polymorphisms are significantly associated with risk of AL. Present study performs meta-analysis to evaluate the association between CYP2B6 c.516G>T variant and AL risk. Databases including PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Wanfang were searched for literatures to September 30, 2019, both in English and Chinese. Relative risk and its 95% confidence intervals were used to assess the associations. Statistical analyses of this meta-analysis were conducted by using STATA 13.0. software. A total of 7 studies, including 1038 cases and 1648 controls, were analyzed. Our results indicated that CYP2B6 c.516G>T variant was significantly related to an increased the risk of AL under dominant model, recessive model, homozygote model, and allelic model. In addition, subgroup analyses were also performed by disease classification, country, and study design. No significant associations were obtained between CYP2B6 c.516G>T variant and the risk of AL under the recessive model in the design of hospital-based (relative risk = 0.98; 95% confidence interval: 0.95-1.01; P = 0.118). Our meta-analysis indicated that the CYP2B6 variant is significantly associated with AL risk, in which CYP2B6 c.516G>T is related to an increased risk of AL.


[Growth and Control of Catheter-related Bloodstream Infection Causing Bacteria in Nutrient Solutions].
Among healthcare-associated infections, catheter-related bloodstream infection (CRBSI) shows a high case fatality rate and is serious threat. CRBSI are a problem to be eradicated. This study was conducted to reveal the growth characteristics of the causative microorganisms of CRBSI and investigate relevant control methods. The effects of biotin on growth of Candida albicans (C. albicans) in the nutrient solutions were investigated. Upon comparing general solutions and biotin-containing solutions, C. albicans showed auxotrophy against biotin, resulting in significant proliferative potential. CRBSI is caused by biofilm formation in the catheter lumen and subsequent proliferation. The effect of biotin on the colonization of C. albicans in the catheter lumen was evaluated. Candida albicans colonization in the catheter lumen and subsequent proliferation were significantly higher than those in control solutions. To investigate methods for CRBSI control, effects on pathogenic microorganisms were examined by screening for nutrient solutions with antimicrobial activity, using a catheter-lumen contamination model. A commercially available solution (PLAS-AMINO® injection; PA) containing the highest amount of sodium bisulfite was selected. Gram-positive or negative bacteria and C. albicans were used as the causative microorganisms of CRBSI in the study. Dripping PA into each catheter-lumen contamination model demonstrated bactericidal effects against all bacteria tested and strong growth-inhibitory effects on C. albicans. By using PA for contamination inside the catheter, sterilization and suppression of bacterial growth can be expected without having to remove central venous catheters and/or central venous access devices. This review provides valuable findings for the development of novel control methods for CRBSI.


Design of the ion-optics for the MRSt neutron spectrometer at the National Ignition Facility (NIF).
A new Magnetic Recoil Spectrometer (MRSt) is designed to provide time-resolved measurements of the energy spectrum of neutrons emanating from an inertial confinement fusion implosion at the National Ignition Facility. At present, time integrated parameters are being measured using the existing magnet recoil and neutron time-of-flight spectrometers. The capability of high energy resolution of 2 keV and the extension to high time resolution of about 20 ps are expected to improve our understanding of conditions required for successful fusion experiments. The layout, ion-optics, and specifications of the MRSt will be presented.


Tuber melosporum smooth spores: an anomalous feature in the genus Tuber.
This paper adds new insights on ecology and micromorphology of Tuber melosporum, a rare species with smooth spores. Eight T. melosporum ascomata collected in a 50 y old Pinus halepensis and Quercus ilex plantation in Sardinia, Italy, represent the first recovery of this species outside Spain. In comparison to the T. melosporum holotype, Italian specimens revealed differences in the number of spores in asci and spore shape. We propose an emended description of Tuber to include species without spore ornamentation.


Inhibitors of glucose uptake stimulate the production of insulin-like growth factor-binding protein (IGFBP-1) by human fetal liver.
Cultured human fetal hepatic explants were used to study the role of hexose uptake in regulating production of the GH-independent insulin-like growth factor-binding protein (IGFBP-1). Cytochalasin B (100 microM), but not cytochalasin E, inhibited 2-deoxyglucose uptake by fetal liver explants and increased production of IGFBP-1 2-fold. Two agents which stimulate cyclic nucleotide-dependent pathways, cholera toxin and theophylline, also inhibited 2-deoxyglucose uptake in this system and both stimulated IGFBP-1 production. When added to a maximally inhibiting concentration of cytochalasin B (250 microM), hexose uptake was not further inhibited by theophylline (5 mM) or cholera toxin (10 micrograms/ml), suggesting that the three substances interact with the same hexose transport mechanism. However, the stimulatory effect of theophylline (5 mM) or cholera toxin (10 micrograms/ml) on IGFBP-1 production was additive to the effect of 250 microM cytochalasin B, suggesting that another pathway, possibly involving cyclic nucleotide accumulation, could further stimulate IGFBP-1 above the effect of blocking glucose transport. Insulin (300 nM) had no effect on hexose uptake by human fetal liver explants but inhibited IGFBP-1 production, both basally and when stimulated by cytochalasin B (100 microM) or cholera toxin (1 microgram/ml). These results are consistent with the conclusion that a cyclic nucleotide-dependent pathway, activated by blocking hexose transport and inhibited by insulin, is involved in the regulation of IGFBP-1 synthesis.


alpha-N-Acetylgalactosaminidase from squid liver: purification and characterization of two enzymes.
Squid liver contains two kinds of alpha-N-acetylgalactosaminidases, which could be separated by gel filtration on Sephadex G-200 or by SP-Sephadex ion exchange chromatography. The two alpha-N-acetylgalactosaminidases, alpha-N-acetylgalactosaminidase I and II, were purified by procedures involving extraction, ammonium sulfate precipitation, and chromatographies on SP-Sephadex, Sephadex G-100, Sephadex G-200, DEAE-Sephadex, and Sepharose 6B. Enzyme I was purified 1,100-fold and enzyme II 3,000-fold. Both enzymes appeared to be homogeneous based upon the results of disc gel electrophoresis. Enzyme I had a pH optimum of 3.0 and was heat-stable. It was inhibited by N-acetylgalactosamine and galactose. On the other hand, enzyme II had a pH optimum of 4.2 and was heat-labile. Galactose did not affect the enzyme activity. In contrast to enzyme I, which showed alpha-galactosidase activity even in the final preparation, enzyme II was practically free from alpha-galactosidase activity.


Effect of Growth Hormone Receptor Deficiency on Androgen-Associated Gene Expression of Hepatic Drug Metabolizing Enzymes and Drug Transporters in Pigs.
Growth hormone receptor (GHR)-deficient pigs were generated using the CRISPR/Cas9 system to investigate the involvement of GHR-mediated growth hormone (GH) signaling in androgen-associated gene expression of hepatic drug metabolizing enzymes (DMEs) and drug transporters. We initially confirmed that no wild-type GHR mRNA was present in GHR-/- (GHR-KO) pigs; in addition, as previously reported, those pigs exhibited decreases in body weight and serum insulin-like growth factor-1 concentration and an increase in serum GH concentration compared with the levels in GHR-/+ and GHR+/+ pigs with a wild-type GHR mRNA. The real-time RT-PCR results on the mRNA levels of hepatic DMEs and drug transporters in the GHR-KO pigs and the pigs with a wild-type GHR mRNA revealed that, among the examined hepatic DMEs, the mRNA levels of CYP1A2, CYP2A19, sulfotransferase (SULT) 1A1, and SULT2A1 were higher in GHR-KO pigs than in the pigs with a wild-type GHR mRNA, whereas the opposite trend was observed for the mRNA level of uridine 5'-diphospho-glucuronosyltransferase 1A6. No such significant differences in the mRNA levels of three hepatic drug transporters including multidrug resistance protein 1 were observed. In addition, the mRNA level of hepatic cut-like homeobox 2 (CUX2), which is expressed in an androgen-dependent manner and associated with the hepatic mRNA expression of several DMEs, was significantly decreased in GHR-KO pigs. The present findings strongly suggest that not only serum androgen but also GHR-mediated GH signaling contributes to the mRNA expression of several DMEs and CUX2, but not transporters, in the pig liver.


Search for a common neurocognitive mechanism for language and movements.
Examination of the common properties in the three Ss (i.e., speech, script, and sign languages) of human communication suggests that duality of patterning is the key feature in the development of these communication systems. This feature is in essence a sequential strategy that serves as an interface between the increasing number of messages and the limited capacity of our signal production-reception systems. It is argued that since the left hemisphere has a much finer temporal resolution than the right hemisphere, both language and movement systems might have made use of this advantage provided by the left hemisphere to fulfill the requirements of sequential strategy in their early evolution.