Development of upper limb proprioceptive accuracy in children and adolescents.
This study was designed to determine differences in the proprioceptively guided movements of children (8-10 years) and adolescents (16-18 years). Participants were blindfolded and asked to actively match passively determined target positions of the elbow joint under three matching conditions. Overall, children were less accurate than adolescents in all matching tasks and utilized different kinematic strategies for making the matching movements. Specifically, children made larger absolute errors and utilized matching movements which, compared to adolescents, were of shorter duration and less irregular in terms of their velocity profiles. An assessment of limb asymmetry was also performed revealing a non-dominant arm matching advantage but only for children and only in the task requiring interhemispheric transfer of a memory-based model of limb position. The proprioceptive differences observed in this study are likely the result of experience-driven refinement in the utilization of somatosensory feedback throughout childhood and into adolescence.


Assessment of sustainable agricultural development based on the water-energy-food nexus framework in the middle and upper reaches of the Yellow River, China.
Water, energy and food are inextricably linked in agricultural system. Social and environmental issues arising from socio-economic development pose new challenges for sustainable agricultural development. Achieving sustainable agriculture from the perspective of water, energy and food resource conservation is of critical importance to the national strategy for high-quality development of the Yellow River Basin in China. In this study, the mass productivity and economic productivity of water and energy in agricultural system were considered, and an integrated assessment index system for agricultural system based on the Water-Energy-Food Nexus (WEFN) was proposed in three dimensions: reliability, coordination and resilience. Based on these indicators, the agricultural water-energy-food nexus index (AWEFNI) and integrated risk index (IRI) were performed to assess the current status of agricultural development in the middle and upper reaches of the Yellow River. Results indicate that the AWEFNI in the middle and upper reaches of the Yellow River is increasing year by year, and the level of sustainable agricultural development is improving, but the overall level is lower. The AWEFNI values vary widely among provinces. The reliability of single subsystem in the study area accounts for more than 1/3 of the AWEFNI, with poor water endowment, rich food and energy resource endowments, the coordination of the AWEFN is weakening. The resilience of the third subsystem is gradually declining. The contradiction in water and energy supply and demand in Ningxia is the most prominent among the five provinces, and the level of AWEFN development is the lowest, so the regulation policies should be implemented as soon as possible to promote the synergistic development of AWEFN around the region.


Current perspectives on the role of CD8+ T cells in systemic sclerosis.
Despite long-standing recognition of the importance of T cells in systemic sclerosis (SSc; scleroderma), the role of CD8+ T cells in disease pathogenesis has not been well studied. Our work has shown that over-production of the pro-fibrotic cytokine IL-13 by peripheral blood effector/memory CD8+ T cells is critical for predisposing patients to more severe forms of cutaneous fibrosis. Moreover, IL-13-producing CD8+ T cells induce a pro-fibrotic phenotype in normal and SSc dermal fibroblasts, and exhibit a strong cytotoxic activity ex vivo. We also found that CD8+ T cells are predominantly abundant in the skin lesions of patients in the early stages of diffuse cutaneous (dc)SSc compare to late-stage disease patients. Isolation of CD8+ T cells from the lesional skin of early active dcSSc patients, established that they are skin-resident, express cytolytic molecules and co-express extremely high levels of IL-13 and IFNγ. Other recent studies corroborate these findings and together strongly suggest that CD8+ T cells contribute to SSc pathogenesis through the production of high levels of cytokines with pro-inflammatory and pro-fibrotic function as well as by exhibiting a cytotoxic activity.


Physiological and histopathological alterations in Capoeta baliki and Squalius pursakensis after caused by some environmental pollutants.
The present study was aimed to apply physiological and histological biomarkers of pelagic and benthic fish species as biomonitoring of environmental pollutants. Capoeta baliki and Squalius pursakensis were caught from 5 stations in Kirmir Stream (Turkey). After measuring the total length and weight for condition factor analysis, liver, gill, brain, and kidney tissues of fish were taken for histopathological analysis. Dorsal muscles of fish tissues were analyzed for polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs). The mean condition factor of C. baliki and S. pursakensis were 1.14 and 0.97, respectively. It was indicated that the first one was in good condition than the latter one. According to histopathological observations, the alterations in the tissues may be associated with the environmental pollutants' exposure. The total concentration of PAHs of dorsal muscle of C. baliki and S. pursakensis found ranged from 0.915 to 108.421 µg/kg and 0.601 to 675.248 µg/kg, respectively. The highest total concentrations of OCPs were found as 44.16 µg/kg for C. baliki and as 562.12 µg/kg for S. pursakensis. The PCB 28 (10.83 µg/kg), PCB 52 (10.92 µg/kg), PCB 138 (226.24 µg/kg), and the total concentrations of PBDEs were found as 151.74 µg/kg in only S. pursakensis. The result of the concentrations of the investigated pollutants was generally found higher in S. pursakensis which is a higher trophic level than C. baliki. Histopathological alterations were detected as hyperemia in liver, gill, and brain; as hydrophobic degeneration in liver; hyperplasia in gill; and tubular degeneration in kidney tissues of both species. The obtained result of the study shows that the environmental pollutants may affect the physiological and histological status of fish.


Recombinant lactoferrin (Lf) of Vechur cow, the critical breed of Bos indicus and the Lf gene variants.
Vechur cow, categorized as a critically maintained breed by the FAO, is a unique breed of Bos indicus due to its extremely small size, less fodder intake, adaptability, easy domestication and traditional medicinal property of the milk. Lactoferrin (Lf) is an iron-binding glycoprotein that is found predominantly in the milk of mammals. The full coding region of Lf gene of Vechur cow was cloned, sequenced and expressed in a prokaryotic system. Antibacterial activity of the recombinant Lf showed suppression of bacterial growth. To the best of our knowledge this is the first time that the full coding region of Lf gene of B. indicus Vechur breed is sequenced, successfully expressed in a prokaryotic system and characterized. Comparative analysis of Lf gene sequence of five Vechur cows with B. taurus revealed 15 SNPs in the exon region associated with 11 amino acid substitutions. The amino acid arginine was noticed as a pronounced substitution and the tertiary structure analysis of the BLfV protein confirmed the positions of arginine in the β sheet region, random coil and helix region 1. Based on the recent reports on the nutritional therapies of arginine supplementation for wound healing and for cardiovascular diseases, the higher level of arginine in the lactoferrin protein of Vechur cow milk provides enormous scope for further therapeutic studies.


A correlation between bone (B), insertion torque (IT), and implant stability (S): BITS score.
Although criteria for assessing bone quality have been reported, an overall score that correlates bone quality with the primary stability and secondary stability of implants is not yet available. The purpose of this article was to propose a scoring index that will establish a correlation among the bone density values from computed tomography, maximum insertion torque values, and resonance frequency analysis in different phases of implant treatment. In this study, 60 implant sites were evaluated to assess bone density (Hounsfield units), insertion torque values (Ncm), and primary stability and secondary stability (implant stability quotient values obtained by using resonance frequency analysis). On the basis of computed tomography data, the bone was classified as D1 to D4. The insertion torque was noted and classified into 2 groups, A and B. The implant stability quotient values obtained from resonance frequency analysis depicting primary stability and secondary stability were classified into 5 groups. The primary score noted was a result of the values obtained for the 3 parameters at the time of implant placement. The secondary score was obtained by considering the values of the bone density and resonance frequency analysis recorded at different time intervals. Bone densities of D2, D3, and D4 were noted, dividing the bone type into 3 groups. The maximum torque noted in the study was 40 Ncm. The difference between various insertion torque values and bone types was found to be statistically nonsignificant. Higher mean implant stability quotient values were obtained for primary and secondary stability for the D2 bone than for D3 and D4 bone. When analyzed according to the time of insertion, the mean values increased at second stage surgery in all bone types. The difference in mean values among all bone types was found to be statistically significant (P<.001). A comparison of primary and secondary implant stability quotient values in all bone types did not find any statistical significance (P=.780). A score was recorded at the time of implant placement and at the time of second stage surgery, and the prosthetic treatment was planned accordingly. The score highlights the importance of considering the association of bone quality, insertion torque values, and stability as denoted by implant stability quotient throughout treatment. Based on the variation in the score noted at recall visits, alterations in the treatment plan can be made with respect to the healing period and prosthetic design.


Explant culture: A relevant tool for the study of telocytes.
Telocytes are cells present in the stroma of various tissues including the prostate. The detection of telocytes is still very much dependent on obtaining ultrastructural data that show the presence of telopodes, which are cytoplasmic projections that alternate between dilated regions, the podoms, and thin segments, the podomers. These structures are the distinctive characteristics of the telocytes. Thus, in vitro assays are important for the study of telocytes, which are more easily identified in culture, which also enables the experimental manipulation of these cells. The isolation of telocytes per se does not allow the analysis of the behavior of these cells in relation to other cell types in a given organ. In this sense, in the prostate, explants could be a useful tool for the study of telocytes. The present study obtained prostatic explants and evaluated the influence of recombinant proteins, scattering factor (SCF) and stromal-derived factor 1 (SDF-1), which could impact on the migration of CD34-positive cells. Telocytes migrate out of explants and SDF-1 stimulates the proliferation and formation of telocyte networks in vitro. Telocytes are not smooth muscle cell progenitors in the prostate; on the contrary, they are CD90- and CD44-negative cells and, hence, have limited progenitor capacity. The present study demonstrated that explants are useful tools to elucidate the nature of telocytes and their functions.


Differences between otolith- and semicircular canal-activated neural circuitry in the vestibular system.
In the last two decades, we have focused on establishing a reliable technique for focal stimulation of vestibular receptors to evaluate neural connectivity. Here, we summarize the vestibular-related neuronal circuits for the vestibulo-ocular reflex, vestibulocollic reflex, and vestibulospinal reflex arcs. The focal stimulating technique also uncovered some hidden neural mechanisms. In the otolith system, we identified two hidden neural mechanisms that enhance otolith receptor sensitivity. The first is commissural inhibition, which boosts sensitivity by incorporating inputs from bilateral otolith receptors, the existence of which was in contradiction to the classical understanding of the otolith system but was observed in the utricular system. The second mechanism, cross-striolar inhibition, intensifies the sensitivity of inputs from both sides of receptive cells across the striola in a single otolith sensor. This was an entirely novel finding and is typically observed in the saccular system. We discuss the possible functional meaning of commissural and cross-striolar inhibition. Finally, our focal stimulating technique was applied to elucidate the different constructions of axonal projections from each vestibular receptor to the spinal cord. We also discuss the possible function of the unique neural connectivity observed in each vestibular receptor system.


The histone H2B Arg95 residue efficiently recruits the transcription factor Spt16 to mediate Ste5 expression of the pheromone response pathway.
In yeast Saccharomyces cerevisiae, the immunosuppressant rapamycin inhibits the TORC1 kinase causing rapid alteration in gene expression and leading to G1 arrest. We recently reported the isolation and characterization from the histone mutant collection of a histone H2B R95A mutant that displays resistance to rapamycin. This mutant is defective in the expression of several genes belonging to the pheromone response pathway including STE5 encoding a scaffold protein that promotes the activation of downstream MAP kinases. Cells lacking Ste5 cannot arrest the cell cycle in response to rapamycin and as a consequence exhibit similar resistance to rapamycin as the H2B R95A mutant. Herein, we show that the H2B R95A mutation weakens the association of H2B with Spt16 a component of the FACT complex (FAcilitates Chromatin Transcription), and an essential factor that interacts with the histone H2A-H2B dimer to promote transcription and preserve chromatin integrity. From a collection of spt16 mutants, spt16 E857K and spt16-11 showed striking sensitivity to rapamycin as compared to the parent strain. spt16 E857K and spt16-11 expressed distinct forms of Ste5, while a suppressor mutation H2B A84D of the spt16-11 mutant prevents the expression of Ste5 and confers marked resistance to rapamycin. We interpret these findings to suggest that the Arg95 residue of histone H2B is required to recruit Spt16 to maintain the expression of STE5, which performs a role to arrest cells in the G1 phase in response to rapamycin.


Response of dust particle pollution and construction of a leaf dust deposition prediction model based on leaf reflection spectrum characteristics.
Urban plants can improve several environmental pollution problems in cities, especially dust prevention, noise reduction, purification of the atmosphere, etc. To explore the influence of dust deposition on the spectral characteristics of the leaf, a foliar dust deposition prediction model based on high-spectrum data was established. Taking Euonymus japonicus L., the common greening tree species in Beijing, as the research object, high (T1), medium (T2), and low (T3) dust pollution gradients were set and hyperspectral data were collected. Results showed that: (1) in the dust-contaminated environment with different concentrations, the trend of the reflectance curve of the leaves of Euonymus japonicus L. was generally consistent. The spectral reflectance of the leaf surface was positively correlated with the amount of leaf dust. (2) There were five obvious reflection peaks and five main absorption valleys with the same positions and ranges in the 350-2500 nm range. (3) The spectral reflectance of leaf flour dust particles of Euonymus japonicus L. was significantly different before and after dusting, and its size was generally clean leaves > dust-depositing leaves. The sensitive range of its spectral response was 695-1400 nm. (4) The overall trend of the first derivative spectrum was basically the same. The red edge slope and the blue edge slope appeared as T3 > T2 > T1, the red edge position and the blue edge position appeared as T1 < T2 < T3. The red edge position of the leaf surface after dust deposition had an obvious "blueshift", and the moving distance increases with the increase of dust retention on leaf surface. (5) The leaf water index (y = - 1.18x2 + 0.5424x + 0.9917, R2 = 0.8030, RMSE = 0.187) had the highest accuracy in the regression model of leaf surface dust deposition using spectral parameters. The test showed that the R2 reached 0.9019, which indicated that the model has a good fitting effect. This prediction model can effectively estimate the dust deposition of the leaf surface of Euonymus japonicus L.


The effect of thyrocalcitonin therapy and phosphate deprivation on tumoral calcinosis.
Six siblings were screened for clinical and biochemical evidence of tumoral calcinosis. The 3 brothers showed all the characteristic manifestations of this entity. Two of them were treated for an initial period of 6 months with large doses of thyrocalcitonin, with virtually no response. After a 9-month equilibration period they were treated by phosphate depletion, and at the end of 6 months they were re-investigated. There was no appreciable objective or radiological difference in the extent of the masses. It was concluded that, in these 2 patients, surgical excision of the tumours was the only feasible form of therapy.


Packing spheres tightly: influence of mechanical stability on close-packed sphere structures.
Many experiments and simulations of packings of monodisperse hard spheres report a dominance of the face-centered cubic structure in the hexagonally close-packed limit, even though it has no significant energetic or entropic gain over other close-packed configurations. Combining simulations and experiments, we demonstrate that a simple mechanical instability which occurs during the packing process may play an important role in selecting the face-centered cubic structure over other close-packed alternatives. Our argument is supported by detailed quantitative analyses of key configurations in sphere packings and highlights the importance of the packing dynamics. The proposed mechanism is elementary and should therefore play a role in a wide range of sphere systems.


Behavioral profile assessment in offspring of Swiss mice treated during pregnancy and lactation with caffeine.
The association between caffeine consumption and various psychiatric manifestations has long been observed. The objective was to assess the behavioral profile in offspring of Swiss mice treated during pregnancy and lactation with caffeine. For this purpose, two groups (n = 6 each and BW ~ 35 g) of female mice were treated during pregnancy and lactation by: tap water and caffeine solution at a concentration of 0.3 mg/mL through oral route. The offspring obtained, by completing 70 days of life, was underwent a behavioral battery test. Statistical analysis was performed by student t test and the different significance adopted was p < 0.05. According to our results, it was not found any significant differences in tail suspension and forced swimming tests. In anxiety related responses however, the mice of caffeine group had greater number of fecal pellets (178 %, p = 0.001) in the open field test, higher number of attempts (51 %, p = 0.03) in light-dark box and decreased percentage of entries in open arms (41 %, p = 0.01) in elevated plus maze test. Moreover, in the marble burying test, there was a significant decrease in the number of buried marbles compared with controls (110 %, p = 0,002). In the meantime, in the von Frey test, it was observed an exacerbation of mechanical allodynia both in basal conditions and after the carrageenan administration (p < 0.001). Furthermore, caffeine treatment during pregnancy and lactation causes long-term behavioral changes in the mice offspring that manifest later in life.


Inhibition of interleukin-2 production by myricetin in mouse EL-4 T cells.
Myricetin is a naturally occurring flavonoid that is commonly found in tea, berries, fruits, vegetables, and medicinal herbs. This study examined the effects of myricetin on the production of interlukin-2 (IL-2), a potent T cell growth factor. Treatment with myricetin significantly inhibited the secretion of the IL-2 protein from mouse EL-4 T cells activated with phorbol 12-myristate 13-acetate (PMA) plus ionomycin (Io) in a dose-dependent manner. Flow cytometric analysis showed that myricetin suppressed the intracellular production of the IL-2 protein. Furthermore, the effects of myricetin on mRNA expression were analyzed by reverse transcription-polymerase chain reaction and it showed that myricetin reduced the expression of IL-2 mRNA induced by PMA plus Io. This suggests that myricetin has potential immunosuppressive effects by inhibiting the production of IL-2.


Microsurgical Anatomy of the Spermatic Cord and Spermatic Fascia: Distribution of Lymphatics, and Sensory and Autonomic Nerves.
An understanding of the microsurgical anatomy of the spermatic cord and spermatic fascia is important for surgeons during microsurgical varicocelectomy and denervation. We examined the distribution of the lymphatics, and the sensory and autonomic nerves of the spermatic cord. We collected spermatic cords from 11 men undergoing orchiectomy for localized testicular tumors and we biopsied a third of the spermatic fascia from 36 men undergoing microsurgical varicocelectomy. Immunohistochemical staining of the pan-neuronal marker PGP 9.5 (protein gene product 9.5), the sensory nociceptor marker CPRP (calcitonin gene-related peptide), the sympathetic marker TH (tyrosine hydroxylase), the parasympathetic marker VIP (vasoactive intestinal polypeptide) and the lymphatic marker D2-40 was performed. We counted the number of nerves and lymphatics. PGP 9.5 staining revealed dense nerve distributions in the spermatic cord and fascia. Sensory and autonomic nerve fibers were basically co-localized in the same nerve. Of the nerves 50% were identified near the vas deferens and 20% were identified in the spermatic fascia. Sensory and sympathetic nerve fibers represented most of the nerves but a few parasympathetic nerve fibers were observed. Of the lymphatics 36 per patient were identified in the spermatic cord but only a few were identified in the spermatic fascia. Sensory and sympathetic nerves accounted for the majority of the nerves. Although the functional aspects of the nerves remain undetermined, information on the distribution of nerves and lymphatics is useful when dealing with nerves and preserving lymphatics during microsurgical varicocelectomy or denervation.


Differential inhibition of thromboxane A2 and prostacyclin synthesis by low dose acetylsalicylic acid in atherosclerotic patients.
Differential inhibition of thromboxane A2 (TxA2) and prostacyclin (PGI2) biosynthesis has an antithrombotic potential, since it may change the TxA2/PGI2 formation ratio in a favourable direction. Very low doses of acetylsalicylic acid (ASA) have been demonstrated to elicit differential inhibition of TxA2 and PGI2 formation in healthy subjects; whether a similar effect can be obtained in patients with atherosclerosis is still an open question. We addressed this by analyzing the urinary excretion of the 2,3-dinor-metabolites of TxA2 (Tx-M) and PGI2 (PGI-M) in 10 patients with severe atherosclerosis during 10 consecutive days. The first three days were a basal period, under which no treatment was given. During the subsequent seven days a daily 50 mg oral dose of ASA was administered. In the basal state urinary Tx-M did not differ from that of PGI-M, the median excretion rates of the two eicosanoid metabolites being 526 (range 68-1490) and 562 (range 93-1970) pg/mg creatinine, respectively. During ASA treatment urinary Tx-M fell to a lower (p less than 0.001) level than PGI-M. Thus, during the last 5 days of ASA treatment the median excretion of Tx-M was depressed (p less than 0.001) to 148 (range 48-428) pg/mg creatinine, while that of PGI-M was decreased (p less than 0.01) to 313 (range 42-2658) pg/mg creatinine. These data indicate that a daily 50 mg dose of ASA inhibits cardiovascular formation of eicosanoids in patients with severe atherosclerosis and increased platelet TxA2 formation. Furthermore, this dose of ASA inhibits the formation of TxA2 more than that of PGI2.


Age-dependent influence of premorbid underweight status on mortality in severe burn patients: An administrative database study.
To examine the associations between premorbid nutritional status and in-hospital mortality in severe burn patients according to age in Japan. We retrospectively extracted the data of 14,345 patients aged 18-84 years admitted for burns from April 1, 2014, to March 31, 2018, using the Japanese Diagnosis Procedure Combination database. The exclusion criteria were out-of-hospital cardiac arrest, death in the emergency room, readmission, and planned admission. We collected data on age, sex, height, weight, comorbidities, burn index, and mechanical ventilation use and performed age-stratified multilevel logistic regression analyses to estimate associations between premorbid body mass index (BMI) and in-hospital mortality. We analyzed 2968 patients with a burn index ≥10, including 831 elderly aged 75-84 years. In patients aged 18-74 years, being underweight (BMI < 18.5) significantly decreased mortality (0.34 [0.15-0.77]; P = 0.010). In contrast, in patients aged 75-84 years, being underweight significantly increased mortality (2.11 [1.05-4.25]; P = 0.036). Being overweight (BMI >25) increased mortality in both age groups, but not significantly. The results suggest that pre-morbidly underweight elderly patients aged 75-84 years with severe burns have high mortality risks. Further research is needed to identify optimal care strategies for this population.


SPIO-enhanced magnetic resonance imaging study of placental perfusion in a rat model of intrauterine growth restriction.
To assess placental perfusion with magnetic resonance imaging (MRI) and superparamagnetic iron oxide (SPIO) in a rat model of intrauterine growth restriction (IUGR). Experimental animal study. The study complied with US National Institutes of Health recommendations for animal care. Thirty-two rats at day 16 of gestation underwent surgical ligation of the left uterine vessel to induce IUGR. Eighteen rats were examined by MRI 3 days later, after bolus injection of ferucarbotran. Signal intensities were measured in the maternal left ventricle and in the placentas of the two horns. Quantitative microcirculation parameters were calculated and compared between the placentas of the two horns. Fifty-four kinetic curves of placental perfusion were obtained in 11 rats. The mean placental blood flow was significantly lower in the ligated horns than in the normal horns (108.1 versus 159.4 ml/minute/100 ml, p = 0.0004). The mean fractional volume of the maternal vascular placental compartment did not differ significantly between the pathological (42.8%) and normal placentas (39.2%). Placental perfusion, including changes during experimental IUGR, can be measured in rats by using MRI with SPIO. These findings could have implications for human studies of placental microcirculation and for the management of disorders related to placental dysfunction.


Airway basal cell vascular endothelial growth factor-mediated cross-talk regulates endothelial cell-dependent growth support of human airway basal cells.
The human airway epithelium is a pseudostratified heterogenous layer comprised of ciliated, secretory, intermediate, and basal cells. As the stem/progenitor population of the airway epithelium, airway basal cells differentiate into ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. Transcriptome analysis of airway basal cells revealed high expression of vascular endothelial growth factor A (VEGFA), a gene not typically associated with the function of this cell type. Using cultures of primary human airway basal cells, we demonstrate that basal cells express all of the three major isoforms of VEGFA (121, 165 and 189) but lack functional expression of the classical VEGFA receptors VEGFR1 and VEGFR2. The VEGFA is actively secreted by basal cells and while it appears to have no direct autocrine function on basal cell growth and proliferation, it functions in a paracrine manner to activate MAPK signaling cascades in endothelium via VEGFR2-dependent signaling pathways. Using a cytokine- and serum-free co-culture system of primary human airway basal cells and human endothelial cells revealed that basal cell-secreted VEGFA activated endothelium to express mediators that, in turn, stimulate and support basal cell proliferation and growth. These data demonstrate novel VEGFA-mediated cross-talk between airway basal cells and endothelium, the purpose of which is to modulate endothelial activation and in turn stimulate and sustain basal cell growth.


[Colorimetric studies by means of Ehrlich's reagent of blood serum of rats with Yoshida sarcoma].
Extinctions in the sera of Yoshida-sarcoma-bearing and normal rats were determined by means of a photometric measurement after the reaction of the sera with Ehrlich's reagent. Thereby the increase of the extinctions of the tumor bearers could be confirmed, also being found in tumor patients. The difference in terms of normal animals was statistically significant. The supposed relations between the exitation of the extinctions and the level of glycoproteins could be supported by correlating calculations.


Effects of hydrofluoric acid and anodised micro and micro/nano surface implants on early osseointegration in rats.
Our aim was to evaluate the effects of hydrofluoric acid and anodised micro and micro/nano surface implants on bony ingrowth in the earliest stage of implantation in rats. Sixty cylindrical screwed titanium alloy implants with machined, micro, and hierarchical hybrid micro/nano surfaces (n=20 in each group) were inserted into the distal femurs of 30 female Sprague-Dawley rats. In vivo microcomputed tomography (micro CT) was used to assess microarchitectural changes in the bone around the implants 2 weeks after implantation. All the animals were then killed and the femurs with implants harvested for histological analysis and pull-out testing. Micro CT analysis showed that the trabecular thickness and the bone:volume ratio (bone volume:total volume) (BV:TV) increased significantly in the micro/nano group compared with the other two groups, while the trabecular separation decreased significantly in the micro/nano group compared with the machined group. The mean (SD) bone-implant contacts (%) were 38.94 (9.48), 41.67 (8.71), and 51.49 (12.49) in the machined, micro, and micro/nano groups, respectively. The maximum pull-out forces (N) were 64.95 (6.11), 71.45 (7.15), and 81.90 (13.1), respectively. Both bone-implant contacts and maximum pull-out forces were significantly higher in the micro/nano group, but there was no significant difference between the micro group and the machined group. These data indicate that the hierarchical hybrid micro/nano surface of the implant can promote osseointegration in the earliest stage of implantation, and may be a promising option for further clinical use.


Suppression of zinc finger protein 467 alleviates osteoporosis through promoting differentiation of adipose derived stem cells to osteoblasts.
Osteoblast and adipocyte are derived from common mesenchymal progenitor cells. The bone loss of osteoporosis is associated with altered progenitor differentiation from an osteoblastic to an adipocytic lineage. In this study, a comparative analysis of gene expression profiling using cDNA microarray and realtime-PCR indicated that Zinc finger protein 467 (Zfp467) involved in adipocyte and osteoblast differentiation of cultured adipose derived stem cells (ADSCs). Our results showed that RNA interference for Zfp467 in ADSCs inhibited adipocyte formation and stimulated osteoblast commitment. The mRNA levels of osteogenic and adipogenic markers in ADSCs were regulated by si-Zfp467. Zfp467 RNAi in ADSCs could restore bone function and structure in an ovariectomized (OVX)-induced osteoporotic mouse model. Thus Zfp467 play an important role in ADSCs differentiation to adipocyte and osteoblast. This has relevance to therapeutic interventions in osteoporosis, including si-Zfp467-based therapies currently available, and may be of relevance for the use of adipose-derived stem cells for tissue engineering.


Can In Vitro-In Vivo Extrapolation Be Successful? Recognizing the Incorrect Clearance Assumptions.
For a number of years, our laboratory has been investigating the underlying reasons for the published poor in vitro-in vivo extrapolation (IVIVE) predictability of human clearance both from a theoretical and from an experimental perspective. Here, we critically examine clearance concepts and commonly employed IVIVE approaches, concluding that there is no theoretical reason that IVIVE should work, just as it does not. Our analysis, however, has identified 10 misconceptions and/or poorly understood aspects of clearance that are listed in the Conclusion section of this manuscript. Chief among these are that all published human drug clearance values are arterial clearances-clearance calculated as organ blood flow multiplied by the extraction ratio is the arterial clearance of the organ of elimination (and not the published drug clearance value)-and that the well-stirred model equation taught in all pharmacokinetic courses that relates organ blood flow, fraction unbound in blood, and intrinsic clearance has no validity. We further list 10 conclusions relating to the IVIVE process. The primary IVIVE-related conclusions are that the intrinsic clearance value determined from an in vitro incubation is an arterial intrinsic clearance, there is no theoretical basis upon which an arterial intrinsic clearance can be related to a whole-body arterial clearance to accomplish IVIVE, there are no published data demonstrating that in vitro intrinsic metabolic clearance can predict in vivo organ clearance as IVIVE assumes, and the scientific basis for the hypothesized albumin-mediated hepatic uptake phenomenon is invalid. We further propose three IVIVE process recommendations.


Retracted: Network Pharmacology and Molecular Docking-Based Investigation of Potential Targets of Astragalus membranaceus and Angelica sinensis Compound Acting on Spinal Cord Injury.
[This retracts the article DOI: 10.1155/2022/2141882.].


Induction of apoptosis in HL-60 cells by photochemically generated hydroxyl radicals.
Reactive oxygen species (ROS), especially hydroxyl radicals are postulated to mediate apoptosis of the cell. Here we demonstrate that hydroxyl radicals generated selectively by photolysis of a photo-Fenton reagent, N,N'-bis(2-hydroperoxy-2-methoxyethyl)-1,4,5,8-naphthaldiimide (NP-III), induce apoptosis in HL-60 (human promyelocytic leukemia) cells involving the activation of caspase-3.


Helmet for infant skull fixation during stereotactic neurosurgery.
A thermoplastic helmet was designed to allow the use of the Leksell stereotactic frame in infants.


Extractable nuclear antigen autoantibodies and their association with other autoantibodies and thymoma in myasthenia gravis.
The presence of autoantibodies to Extractable Nuclear Antigens (ENA) in myasthenia gravis (MG) was evaluated. These antibodies represent a subset of antinuclear antibodies (ANA), with ENA consisting of RNA and nucleoprotein. ENA autoantibodies had a prevalence of 44% in MG when tested by an


Synthesis and evaluation of molluscicidal and larvicidal activities of some novel enaminones derived from 4-hydroxyquinolinones: part IX.
A series of 10 3-(hetarylaminomethylene)quinolinediones, 12 3-(substituted aminopropenoyl)-4-hydroxyquinolinones, and 10 3-(substituted aminomethylene-5-oxo-pyrazolinyl)-4-hydroxyquinolinones were synthesized as novel enaminones derived from 3-(un)substituted 4-hydroxyquinolin-2(1H)-ones in 72-94% yields and assayed for their molluscicidal activities against Biomphalaria alexandrina and Lymnaea natalensis snails. Some of the tested enaminones presented high molluscicidal activities (LC(50)20ppm). The new compounds showed more potency against hatchability of B. alexandrina egg masses, the infection rate and prepatent period of the snails. In addition, these derivatives revealed potential larvicidal effects (100% mortality) on both miracidia and cercariae of Schistosoma mansoni at reduced exposure time. The selected active derivatives were examined against Daphnia magna and their nontoxic effect at all sublethal, lethal, and higher concentrations suggests that these compounds can play an important role as molluscicides and larvicides with environmental safe properties.


Lepidocrocite, an apatite mineral, and magnetic in teeth of chitons (Polyplacophora).
X-ray diffraction patterns show that the mature denticles of three extant chiton species are composed of the mineral lepidocrocite and an apatite mineral, probably francolite, in addition to magnetite. Each of the three minerals forms a discrete microarchitectural unit of the chiton denticles. This is the first indication that lepidocrocite is precipitated by marine organisms and an apatite mineral by chitons.


Toll-like receptors blocking restores in vitro microbicidal activity in latent tuberculosis-infected subjects.
Latent tuberculous infection (LTBI) can function as a 'reservoir' for Mycobacterium tuberculosis. Given that T-regulatory cell (Treg) numbers are augmented in LTBI, it is likely that Toll-like receptors (TLRs) may have a role in Treg function. Elucidation of the immune mechanisms associated with tuberculosis (TB) development may help to control M. tuberculosis spread.OBJECTIVE: To investigate the role of TLR2, TLR4 and TLR9 in hindered in vitro microbicidal activity and increase Treg number during LTBI. Whole blood cell cultures from individuals with LTBI and healthy controls (HCs) infected with live M. tuberculosis H37Rv strain were used to investigate the effect of TLR2, TLR4 and TLR9 on Treg number, microbicidal activity, and interferon-gamma and interleukin (IL)10 production. LTBI subjects were characterised by increased Treg number and impaired microbicidal activity when compared with HCs. Specific blockade of TLR4 and TLR9 led to a significant reduction in Treg number, a decrease in IL-10 production and substantial upregulation of microbicidal activity. M. tuberculosis infection may activate TLR4 and TLR9 pathways to suppress M. tuberculosis-specific immune responses. Here, we show that activation of TLR4 and TLR9 hinder microbicidal activity during LTBI.


Integration of multiple stimuli-sensing systems to regulate HrpS and type III secretion system in Erwinia amylovora.
The bacterial enhancer binding protein (bEBP) HrpS is essential for Erwinia amylovora virulence by activating the type III secretion system (T3SS). However, how the hrpS gene is regulated remains poorly understood in E. amylovora. In this study, 5' rapid amplification of cDNA ends and promoter deletion analyses showed that the hrpS gene contains two promoters driven by HrpX/HrpY and the Rcs phosphorelay system, respectively. Electrophoretic mobility shift and gene expression assays demonstrated that integration host factor IHF positively regulates hrpS expression through directly binding the hrpX promoter and positively regulating hrpX/hrpY expression. Moreover, hrpX expression was down-regulated in the relA/spoT ((p)ppGpp-deficient) mutant and the dksA mutant, but up-regulated when the wild-type strain was treated with serine hydroxamate, which induced (p)ppGpp-mediated stringent response. Furthermore, the csrA mutant showed significantly reduced transcripts of major hrpS activators, including the hrpX/hrpY, rcsA and rcsB genes, indicating that CsrA is required for full hrpS expression. On the other hand, the csrB mutant exhibited up-regulation of the rcsA and rcsB genes, and hrpS expression was largely diminished in the csrB/rcsB mutant, indicating that the Rcs system is mainly responsible for the increased hrpS expression in the csrB mutant. These findings suggest that E. amylovora recruits multiple stimuli-sensing systems, including HrpX/HrpY, the Rcs phosphorelay system and the Gac-Csr system, to regulate hrpS and T3SS gene expression.


Arabidopsis pab1, a mutant with reduced anthocyanins in immature seeds from banyuls, harbors a mutation in the MATE transporter FFT.
Forward genetics approaches have helped elucidate the anthocyanin biosynthetic pathway in plants. Here, we used the Arabidopsis banyuls (ban) mutant, which accumulates anthocyanins, instead of colorless proanthocyanidin precursors, in immature seeds. In contrast to standard screens for mutants lacking anthocyanins in leaves/stems, we mutagenized ban plants and screened for mutants showing differences in pigmentation of immature seeds. The pale banyuls1 (pab1) mutation caused reduced anthocyanin pigmentation in immature seeds compared with ban. Immature pab1 ban seeds contained less anthocyanins and flavonols than ban, but showed normal expression of anthocyanin biosynthetic genes. In contrast to pab1, introduction of a flavonol-less mutation into ban did not produce paler immature seeds. Map-based cloning showed that two independent pab1 alleles disrupted the MATE-type transporter gene FFT/DTX35. Complementation of pab1 with FFT confirmed that mutation in FFT causes the pab1 phenotype. During development, FFT promoter activity was detected in the seed-coat layers that accumulate flavonoids. Anthocyanins accumulate in the vacuole and FFT fused to GFP mainly localized in the vacuolar membrane. Heterologous expression of grapevine MATE-type anthocyanin transporter gene partially complemented the pab1 phenotype. These results suggest that FFT acts at the vacuolar membrane in anthocyanin accumulation in the Arabidopsis seed coat, and that our screening strategy can reveal anthocyanin-related genes that have not been found by standard screening.


[Necessity for radiological examinations in children : Children in two levels].
The diagnostics and treatment of pediatric skeletal trauma can be fundamentally different from adults. Based on in-house data the diagnostic approach to the most frequently encountered pediatric injury patterns is discussed. The necessity for a primary X‑ray imaging or computed tomography examination is questioned. Both diagnostic methods cause stochastic radiation damage. Therefore, it is important to perform the safest examination for the child while injuries are correctly diagnosed.


Nanostructured Pimpinella anisum essential oil as novel green food preservative against fungal infestation, aflatoxin B1 contamination and deterioration of nutritional qualities.
Application of synthetic preservatives to control the contamination of stored food commodities with aflatoxin B1 causing considerable loss in nutritional value is a major challenge. However, employment of essential oils for protecting food commodities is much limited due to high volatility, and increased susceptibility to oxidation. Therefore, objective of the present investigation was encapsulation of Pimpinella anisum essential oil in chitosan nanobiopolymer (CS-PAEO-Nm) to improve its bioefficacy, and sensorial suitability for application in food system. The synthesized CS-PAEO-Nm was characterized through SEM, FTIR, and XRD and evaluated for improved biological activity. The CS-PAEO-Nm exhibited improved antifungal (minimum inhibitory concentration = 0.08 μL/mL) and antiaflatoxigenic (minimum aflatoxin inhibitory concentration = 0.07 μL/mL) activities. CS-PAEO-Nm treatment significantly inhibited ergosterol, enhanced leakage of ions and induced impairment in defense enzymes (p < 0.05). In situ minerals and macronutrient preservation, and acceptable sensorial characteristics suggested possible recommendation of nanoencapsulated PAEO as potential safe green food preservative.


Concomitant sensory stimulation during therapy to enhance hand functional recovery post stroke.
Post-stroke hand impairment is prevalent and persistent even after a full course of rehabilitation. Hand diminishes stroke survivors' abilities for activities of daily living and independence. One way to improve treatment efficacy is to augment therapy with peripheral sensory stimulation. Recently, a novel sensory stimulation, TheraBracelet, has been developed in which imperceptible vibration is applied during task practice through a wrist-worn device. The objective of this trial is to determine if combining TheraBracelet with hand task practice is superior to hand task practice alone. A double-blind randomized controlled trial will be used. Chronic stroke survivors will undergo a standardized hand task practice therapy program (3 days/week for 6 weeks) while wearing a device on the paretic wrist. The device will deliver TheraBracelet vibration for the treatment group and no vibration for the control group. The primary outcome is hand function measured by the Wolf Motor Function Test. Other outcomes include the Box and Block Test, Action Research Arm Test, upper extremity use in daily living, biomechanical measure of the sensorimotor grip control, and EEG-based neural communication. This research will determine clinical utility of TheraBracelet to guide future translation. The TheraBracelet stimulation is delivered via a wrist-worn device, does not interfere with hand motion, and can be easily integrated into clinical practice. Enhancing hand function should substantially increase stroke survivors' independence and quality of life and reduce caregiver burden. NCT04569123 . Registered on September 29, 2020.


Intramedullary fixation of the medial column of the foot with a solid bolt in Charcot midfoot arthropathy: a case report.
Medial column fixation for rocker-bottom deformity in Charcot arthropathy is commonly performed. However, implant failure is commonly encountered because of uncontrolled weight bearing by the patient. The aim of this case report is to describe the use of a large solid bolt for fusion of the medial column of the foot in a patient with collapse of the midfoot due to diabetic neuroarthropathy.


Influence of neopterin on the generation of reactive oxygen species in human neutrophils.
Neopterin is synthesized by human monocyte-derived macrophages primarily upon stimulation with the cytokine interferon-gamma. We studied the influence of neopterin on the generation of reactive oxygen species (ROS) in human peripheral blood neutrophils. Radical formation was measured using a biochemiluminometer. Neutrophils were isolated from peripheral blood of healthy donors. The generation of ROS by neutrophils suspended in Earl's solution (pH=7.4) at 37 degrees C was investigated by monitoring of chemiluminescence using luminol and lucigenin as light emitters. Neopterin induced chemiluminescence in suspensions of neutrophils in the presence of luminol, but not of lucigenin. Neopterin affected only adhesive cells. Addition of neopterin into the suspension of the cells involving D-mannitol, L-histidine and diazabicyclo[2.2.2]octane (DABCO) decreased luminol-dependent chemiluminescence (LDCL) of the neutrophils. The action of superoxide dismutase (SOD) and 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) reduced neopterin-induced LDCL of neutrophils. Data suggest that neutrophils respond on exposure to neopterin with additional generation of singlet oxygen, hydroxyl radical and nitric oxide by nicotinamide adenine dinucleotide phosphate (NADPH)-independent pathways.


Analysis of some commonly found inhalants using gas chromatography-mass spectrometry (GC MS) - Effect of substrates on the identification of inhalants.
Inhalant abuse is a serious and ever-evolving problem for our society. Inhalants are abused more commonly by teenagers and adolescents. Inhalants such as glue, paint thinners, correction fluid, and nail paint remover are easily available in the market which makes them readily abused. Out of various methods of abuse, huffing (placing a piece of cloth soaked with inhalant is placed in the mouth), bagging (placing head in a polythene bag containing inhalant), and ballooning (balloons filled with inhalant are used for inhaling vapors through the mouth) are most common. Inhalant abuse results in multiple target organ dysfunction with neuritis and brain damage due to the dissolution of the myelin sheath. In acute poisoning cases, it might cause death due to asphyxia and sudden sniffing syndrome. In such cases, various articles containing traces of inhalants could be retrieved from the scene of incidence and to detect these traces become an important facet of the investigation. However, it might be difficult due to the rapid evaporation of inhalants and the formation of reaction product species. In the present study, an attempt has been made to study the effect of three substrates (balloon, cloth, polythene) on component profiles of four paint thinners and four nail paint removers. The study suggests that although some components are retained, there is the formation of a large number of reaction product species and these must be taken into consideration before furnishing the opinion. These reaction product species might also be inhalant specific which must be further explored.


The influence of socioeconomic status on the reporting of regional and widespread musculoskeletal pain: results from the 1958 British Birth Cohort Study.
This study aims to determine to what extent the reporting of pain in adulthood varies by adult socioeconomic status, whether there are additional long-term effects of socioeconomic status in childhood and whether any such relationships are mediated through adult psychological ill health. A prospective cohort study (the 1958 British Birth Cohort Study) was conducted. Participants were recruited, at birth, in 1958 and were followed-up throughout childhood and adulthood, most recently at 45 years when information was collected on regional and widespread pain, and various potential mediating factors. The prevalence of shoulder, forearm, low back, knee and chronic widespread pain at 45 years generally increased with lower adult social class. Persons in the lowest social class (compared to the highest) experienced nearly a threefold increase in the risk of chronic widespread pain: relative risk: 2.9 (95% CI 1.8 to 4.6). The strength of association varied between 1.5 and 2.0 for regional pains. Childhood social class also demonstrated a relationship with most regional pains and chronic widespread pain. With the exception of forearm pain, the magnitude of effect of childhood social status on reporting of pain in adulthood was less than that of adult social status. On multivariable analysis these relationships were partly explained by poor adult mental health, psychological distress, adverse life events and lifestyle factors. These results emphasise the importance and potential impact of measures to reduce social adversity, which will have the effect of improving musculoskeletal health in adult life and other major causes of morbidity.


Effect of alirocumab on cataracts in patients with acute coronary syndromes.
Some data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels. The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab. Over median follow-up of 2.8 years (interquartile range 2.3 - 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 - 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values < 25 mg/dL (0.65 mmol/L), the incidence of cataracts was 71/4305 (1.6%), versus 60/4305 (1.4%) in propensity score-matched patients from the placebo group (HR 1.10, CI 95% 0.78 - 1.55). In patients treated with alirocumab with ≥ 2 LDL-C values < 15 mg/dL (0.39 mmol/L), the incidence of cataracts was 13/782 (1.7%), versus 36/2346 (1.5%) in matched patients from the placebo group (HR 1.03, CI 95% 0.54 - 1.94). Treatment with alirocumab versus placebo, added to statin, did not influence the incidence of cataracts, even when achieved LDL-C levels on alirocumab were very low. Longer follow-up studies might be necessary to exclude the long-term effects on the incidence or progression of cataracts. ClinicalTrials.gov Identifier: NCT01663402 .


Synthesis of zidovudine prodrugs with broad-spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS.
A series of prodrugs of zidovudine has been synthesized in an effort to enhance spectrum of chemotherapeutic properties for the effective treatment of HIV/AIDS. The 5'-OH function of zidovudine was esterified with ciprofloxacin, norfloxacin, isoniazide, pyrazinamide acetic acid. The anti-HIV-1 activity of the esters was determined in CEM cell-line and zidovudine ester bearing pyrazinamide acetic acid was found to be the most potent compound with EC50 of<0.0636 microM, CC50 of>1000 microM and selectivity index (SI) of>15,723. Zidovudine prodrug bearing ciprofloxacin and norfloxacin moiety showed 100% inhibition against Mycobacterium tuberculosis H37Rv at 6.25 microg/ml. The prodrugs were also found to exhibit antibacterial activity against 24 pathogenic bacteria. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterase with t1/2 ranging from 20 to 240 min.


A haploscope based binocular pupillometer system to quantify the dynamics of direct and consensual Pupillary Light Reflex.
This study described the development of a haploscope-based pupillometer for the parametrization of the Pupillary Light Reflex (PLR), and its feasibility in a set of 30 healthy subjects (light or dark-colored irides) and five patients diagnosed with Relative Afferent Pupillary Defect (RAPD). Our supplementary aim focused on evaluating the influence of iris colour on the PLR to decide whether a difference in PLR parameters should be anticipated when this system is used across ethnicities. All the participants underwent a customized pupillometry protocol and the generated pupil traces, captured by an eye tracker, were analyzed using exponential fits to derive PLR parameters. A Pupil Response Symmetry (PRS) coefficient was calculated to predict the presence of RAPD. The mean (SD) Initial PD during dilation (3.2 (0.5) mm) and the minimum PD during constriction (2.9 (0.4) mm) in the light iris group had a statistically significant (p < 0.001) higher magnitude compared to the dark iris group. The normal limits of the PRS coefficient ranged from - 0.20 to + 1.07 and all RAPD patients were outside the calculated normal limits. This proposed system, analysis strategies, and the tested metrics showed good short-term repeatability and the potential in detecting pupil abnormalities in neuro-ophthalmic diseases.


Genetic mapping, distribution, and properties of an aconitase isozyme in Anopheles albimanus (Diptera:Culicidae).
Electrophoretic analysis of the developmental stages and tissues of Anopheles albimanus showed that qualitatively similar allozymes of aconitase (Acon-2) occur at all stages, and the enzyme is widespread in every larval and adult tissues. Relative heat stabilities of the allozymes were investigated by electrophoresis of heated aqueous extracts and by heating the enzyme in situ in acrylamide gels after electrophoretic separation in Tris-citrate and Tris-maleate buffer systems. The pupal aconitase in the crude extract is more stable to heat than the larval and adult enzyme. The presence of citrate ions in the gel increased the stability of aconitase to heat. Studies of substrate specificities indicated that cis-aconitic acid is the best substrate but citric acid can also serve as a substrate. Zymograms developed with isocitric acid as a substrate showed no aconitase electromorphs and produced only isocitrate dehydrogenase bands. Aconitase has a pH optimum of 8.0 and this enzyme is completely inhibited if treated in situ with ethylenediaminetetra-acetic acid (EDTA), p-chloromercuribenzoate (PCMB), and urea at concentrations higher than 5 mM, 5 X 10(-5) M, and 2 M, respectively. Acon-2(100) and Acon-2(105) do not respond differently to the above treatments. Genetic crosses involving a holandric translocation, pericentric inversions, visible mutants, and allozyme markers were analyzed to map the aconitase (Acon-2) locus on the left arm of chromosome 3. The gene sequence (and map distances) on 3L is centromere-esterase-8 (Est-8)-2-esterase-4 (Est-4)-25-esterase-2 (Est-2)-9-Acon-2-5-phosphoglucomutase (Pgm)-7-esterase-6 (Est-6).


[The limping child. Differential radiologic diagnosis of acute gait disorder in childhood and adolescence].
Limping is a common and often challenging problem in children and adolescents. A limp is defined as asymetric deviation from a normal gait pattern. A systematic approach is necessary to determine the cause of the limp, so the radiologist should combine a thorough history, clinical information and pertinent radiologic testing. The possible differential diagnosis is extensive and includes many pathologies of the lower extremity and spine like trauma, infection, neoplasia, furthermore inflammatory, developmental and congenital disorders. In cases with knee or tight pain, an underlying hip condition should be considered. The childs age can narrow the possible differential diagnoses, because certain entities are age-related. Despite this wide bandwidth of entities, potential catastrophic causes like septic arthritis and malignant disease should be excluded first. Plain radiographs are often diagnostic. The choice of further imaging modalities like ultrasonography, magnetic resonance imaging, computed tomography and bone scan should be guided by the history and clinical findings.


The worldwide prevalence of burnout syndrome among bank employees: a systematic review and meta-analysis protocol.
Burnout is a syndrome caused by chronic stress in the workplace that has not been successfully managed. Although prevalence of burnout is well documented in different fields, little is known about this syndrome in the context of banking work. The objective of this review will be to assess worldwide pooled prevalence of burnout syndrome among bank employees. This is a study protocol for a systematic review. We will search the following electronic databases (from their inception onwards): PubMed/MEDLINE, SCOPUS, Web of Science, PsycINFO, ERIC, EBSCOhost, Emerald Insight, and Google Scholar. Grey literature will be identified through searching SCOPUS, Google Scholar, ProQuest databases, and websites of related organizations. We will consider studies that include any type of employee in the banking industry and report extractable prevalence estimates of burnout. Two reviewers will independently screen all citations, full-text articles, and abstract data. The study methodological quality (or bias) will be appraised using an appropriate tool. If feasible, we will conduct random effect meta-analysis of prevalence data. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g., setting, sex, burnout assessment method, country, and work hours). This systematic review will assess the worldwide prevalence of burnout syndrome among bank employees. The results of this study will be published in a peer-reviewed journal. As it presents an analysis of published literature, the study does not require ethical approval. PROSPERO CRD42020213565.


RESP18, a novel endocrine secretory protein transcript, and four other transcripts are regulated in parallel with pro-opiomelanocortin in melanotropes.
The homogeneous nature of the rat intermediate pituitary makes it a powerful model system in which to study peptide hormone secretion. Adult male rats were treated with bromocriptine, a dopamine agonist, or haloperidol, a dopamine antagonist, for 3 weeks. In cDNA libraries prepared from the neurointermediate pituitaries of these rats, pro-opiomelanocortin (POMC) expression exhibited the expected decrease in response to bromocriptine, and increase in response to haloperidol. We report the identification of six transcripts that are coregulated with POMC in the intermediate pituitary by these dopaminergic agents. In addition to demonstrating parallel dopamine-regulated expression of carboxy-peptidase E, chromogranin B, binding protein/glucose-regulated protein, and tenascin, two novel regulated transcripts are described. The expression of one of these novel transcripts, RESP18, is limited to neural and endocrine tissue. The RESP18 transcript is approximately 800 nucleotides in length; its cognate translation product is 20 +/- 1 kDa, contains a putative signal sequence, and has many characteristics of a secreted protein. Cell-free translation experiments in the presence of microsomal membranes demonstrate that the 20 +/- 1-kDa RESP18 protein is cleaved to an 18 +/- 1-kDa protein and sequestered within the lumen of the rough endoplasmic reticulum. Tissue in situ hybridization analysis shows that RESP18 mRNA is highly expressed in both the intermediate and anterior pituitary, as well as in the paraventricular and supraoptic nuclei of the hypothalamus.


Transverse island flap and double flap procedure in the treatment of congenital epispadias in 32 patients.
According to major reports in the literature satisfactory cosmetic and genital results after correction of male epispadias have been achieved in only 50 per cent of the patients. Since 1976 we have been using the Duckett transverse island flap principle adapted to epispadiac anatomical conditions. The original technique was used in our initial 18 patients and the Asopa double flap technique was performed in the subsequent 14. Excellent results were obtained in both series. However, there was a high percentage of fistulas that required secondary repair. The techniques and results are described.


Functional comparison between secretory pathway Ca2+/Mn2+-ATPase (SPCA) 1 and sarcoplasmic reticulum Ca2+-ATPase (SERCA) 1 isoforms by steady-state and transient kinetic analyses.
Steady-state and transient kinetic studies were performed to functionally analyze the overall and partial reactions of the Ca(2+) transport cycle of the human secretory pathway Ca(2+)/Mn(2+)-ATPase 1 (SPCA1) isoforms: SPCA1a, SPCA1b, SPCA1c, and SPCA1d (encoded by ATP2C1, the gene defective in Hailey-Hailey disease) upon heterologous expression in mammalian cells. The expression levels of SPCA1 isoforms were 200-350-fold higher than in control cells except for SPCA1c, whose low expression level appears to be the effect of rapid degradation because of protein misfolding. Relative to SERCA1a, the active SPCA1a, SPCA1b, and SPCA1d enzymes displayed extremely high apparent affinities for cytosolic Ca(2+) in activation of the overall ATPase and phosphorylation activities. The maximal turnover rates of the ATPase activity for SPCA1 isoforms were 4.7-6.4-fold lower than that of SERCA1a (lowest for the shortest SPCA1a isoform). The kinetic analysis traced these differences to a decreased rate of the E(1) approximately P(Ca) to E(2)-P transition. The apparent affinity for inorganic phosphate was reduced in the SPCA1 enzymes. This could be accounted for by an enhanced rate of the E(2)-P hydrolysis, which showed constitutive activation, lacking the SERCA1a-specific dependence on pH and K(+).


Parasitic plants indirectly regulate below-ground properties in grassland ecosystems.
Parasitic plants are one of the most ubiquitous groups of generalist parasites in both natural and managed ecosystems, with over 3,000 known species worldwide. Although much is known about how parasitic plants influence host performance, their role as drivers of community- and ecosystem-level properties remains largely unexplored. Parasitic plants have the potential to influence directly the productivity and structure of plant communities because they cause harm to particular host plants, indirectly increasing the competitive status of non-host species. Such parasite-driven above-ground effects might also have important indirect consequences through altering the quantity and quality of resources that enter soil, thereby affecting the activity of decomposer organisms. Here we show in model grassland communities that the parasitic plant Rhinanthus minor, which occurs widely throughout Europe and North America, has strong direct effects on above-ground community properties, increasing plant diversity and reducing productivity. We also show that these direct effects of R. minor on the plant community have marked indirect effects on below-ground properties, ultimately increasing rates of nitrogen cycling. Our study provides evidence that parasitic plants act as a major driver of both above-ground and below-ground properties of grassland ecosystems.


Interferon-λ1 suppresses invasion and enhances autophagy in human osteosarcoma cell.
The purpose of the present study was to determine whether type III IFN can modulate the autophagic response in human osteosarcoma cell. Human osteosarcoma cell were treated with Interferon-λ1. We investigated that Interferon-λ1 could inhibit the invasive ability of osteosarcoma cells by Matrigel invasion assay. Autophagy were assessed by acridine orange staining, MDC staining and Transmission electron microscopy. In this study, we found that Interferon-λ1 could inhibit the invasive ability of osteosarcoma cells. Acridine orange staining and MDC staining showed that Interferon-λ1 triggered the accumulation of acidic vesicular and autolysosomes in osteosarcoma cell. The acridine orange osteosarcoma cell ratios were 3.6 ± 0.5%, 4.5 ± 0.8%, and 12.4 ± 1.7% after treatment with 1, 10, and 100 ng/mL Interferon-λ1 for 48 h. Osteosarcoma cell cells treated with 100 ng/mL Interferon-λ1 for 48 h developed autophagy some-like characteristics, including single or double-membrane vacuoles containing intact and degraded cellular debris. Interferon-λ1 could inhibit the invasive ability of osteosarcoma cells. Autophagy can be induced in a dose-dependent manner by treatment with Interferon-λ1 in osteosarcoma cell.


Artificial intelligence for radiological paediatric fracture assessment: a systematic review.
Majority of research and commercial efforts have focussed on use of artificial intelligence (AI) for fracture detection in adults, despite the greater long-term clinical and medicolegal implications of missed fractures in children. The objective of this study was to assess the available literature regarding diagnostic performance of AI tools for paediatric fracture assessment on imaging, and where available, how this compares with the performance of human readers. MEDLINE, Embase and Cochrane Library databases were queried for studies published between 1 January 2011 and 2021 using terms related to 'fracture', 'artificial intelligence', 'imaging' and 'children'. Risk of bias was assessed using a modified QUADAS-2 tool. Descriptive statistics for diagnostic accuracies were collated. Nine eligible articles from 362 publications were included, with most (8/9) evaluating fracture detection on radiographs, with the elbow being the most common body part. Nearly all articles used data derived from a single institution, and used deep learning methodology with only a few (2/9) performing external validation. Accuracy rates generated by AI ranged from 88.8 to 97.9%. In two of the three articles where AI performance was compared to human readers, sensitivity rates for AI were marginally higher, but this was not statistically significant. Wide heterogeneity in the literature with limited information on algorithm performance on external datasets makes it difficult to understand how such tools may generalise to a wider paediatric population. Further research using a multicentric dataset with real-world evaluation would help to better understand the impact of these tools.


Activated microglia-derived macrophage-like cells exacerbate brain edema after ischemic stroke correlate with astrocytic expression of aquaporin-4 and interleukin-1 alpha release.
Brain edema following brain infarction affects mobility and mortality. The mechanisms underlying this process remain to be elucidated. Animal studies have shown that aquaporin-4 (AQP4) expression in astrocytes increases after stroke, and its deletion significantly reduces brain swelling. Recently, two kinds of cells, resident microglia-derived macrophage-like cells (MG-MΦ) and bone marrow-derived macrophages (BM-MΦ), have been reported to accumulate in the ischemic core and stimulate adjacent astrocytes. Therefore, we hypothesized that these cells play crucial roles in the expression of AQP4 and ultimately lead to exacerbated brain edema. To verify this hypothesis, we investigated the role of MG- or BM-MΦ in brain edema using a rat model of transient middle cerebral artery occlusion and rat astrocyte primary cultures. AQP4 expression significantly increased in the peri-infarct tissue at 3-7 days post-reperfusion (dpr) and in the core tissue at 5 and 7 dpr, which synchronized with the expression of Iba1, Il1a, Tnf, and C1qa mRNA. Interleukin (IL)-1α treatment or coculture with MG- and BM-MΦ increased AQP4 expression in astrocytes, while an IL-1 receptor type I antagonist reduced these effects. Furthermore, aggravated animals exhibited high expression of Aqp4 and Il1a mRNA in the ischemic core at 7 dpr, which led to the exacerbation of brain edema. MG-MΦ signature genes were highly expressed in the ischemic core in aggravated rats, while BM-MΦ signature genes were weakly expressed. These findings suggest that IL-1α produced by MG-MΦ induces astrocytic AQP4 expression in the peri-infarct and ischemic core tissues, thereby exacerbating brain edema. Therefore, the regulation of MG-MΦ may prevent the exacerbation of brain edema.


Self-assembling micelle-like nanoparticles based on phospholipid-polyethyleneimine conjugates for systemic gene delivery.
With few exceptions, where local administration is feasible, progress towards broad clinical application of gene therapies requires the development of effective delivery systems. Here we report a novel non-viral gene delivery vector, 'micelle-like nanoparticle' (MNP) suitable for systemic application. MNP were engineered by condensing plasmid DNA with a chemical conjugate of phospholipid with polyethylenimine (PLPEI) and then coating the complexes with an envelope of lipid monolayer additionally containing polyethylene glycol-phosphatidyl ethanolamine (PEG-PE), resulting in spherical 'hard-core' nanoparticles loaded with DNA. MNP allowed for complete protection of the loaded DNA from enzymatic degradation, resistance to salt-induced aggregation, and reduced cytotoxicity. MNP also demonstrated prolonged blood circulation and low RES accumulation. Intravenous injection of MNP loaded with plasmid DNA encoding for the Green Fluorescence Protein (GFP) resulted in an effective transfection of a distal tumor. Thus, MNP provide a promising tool for systemic gene therapy.


Prevalence of preoperative opioid usage and its impact on postoperative outcomes: a retrospective cohort study.
Preoperative opioid treatment increases postoperative adverse events. This study was aimed to analyze preoperative opioid prevalence in countries with low opioid consumption. Additionally, the effect of low opioid usage on postoperative outcomes was also investigated. We conducted this single center retrospective cohort analysis in a Japanese university-affiliated hospital to investigate opioid usage and its impact on the duration of postoperative hospitalization and in-hospital mortality. Adult patients who underwent general anesthesia between 2015 and 2020 were included. We extracted the patients' characteristics, surgical information and postoperative outcomes. Subgroup analysis to address opioid dose effect was performed in high and low dose opioid subgroups. Among 20,306 inpatients, 535 (2.63%) patients used opioids preoperatively. Tramadol was the most frequently used opioid. The median morphine equivalent (MME) dose was 15 mg/day. Median duration of hospitalization was 18 and 9 days in the opioid and non-opioid groups, and in-hospital mortality was 2.06% and 0.42%. Multivariable regression analysis demonstrated that preoperative opioid use was associated with a longer duration of hospitalization and in-hospital mortality. Subgroup analysis demonstrated longer durations of hospitalization in both high (> 30 mg/day MME) and low (≤ 30 mg/day MME) dose opioid groups, while higher in-hospital mortality was seen only in the high dose opioid group. Preoperative opioid usage was one-tenth of the United States average. Despite its low prevalence and small dosage, preoperative opioid usage was associated with poor postoperative outcomes. Dedicated perioperative interventions to prevent opioid-associated adverse events should be developed even in countries with low opioid consumption.


Public and professional attitudes to transplanting alcoholic patients.
The discrepancy between the number of people who might benefit from liver transplantation continues to exceed the availability of donor livers available, so rationing of grafts must occur. Alcoholic liver disease (ALD) is an excellent indication for liver transplantation, with outcomes at least as good as for other indications.ALD remains a controversial indication for liver transplantation. There is no robust evidence that public disquiet over distribution of donor livers to those with ALD (even if they return to alcohol) greatly affects organ donation, although this does not mean there is no consequence of such disquiet. Numerous surveys of the general public, patients, and health care professionals indicate the these patients are thought to have lower priority for access to available liver grafts. Public education is required to demonstrate that patients with ALD are carefully selected for liver transplantation and available grafts are used with attention to equity, justice, and utility.


Central lead administration induces natriuretic and kaliuretic effects in rats.
The aim of the present experiments was to discern whether central acute lead injections affect brain control of renal function. Adult Wistar male rats received third-ventricle injections of lead acetate in three different doses (0.03, 0.3, and 3.0 nmol/rat). Lead acetate induced a significant increase in renal excretion of sodium and potassium. Pretreatment with losartan, a selective angiotensin II AT1 receptor antagonist (10.8 nmol/rat into the third ventricle 10 min before central lead injection), inhibits lead-induced natriuretic and kaliuretic effects. In addition, pretreatment with gadolinium, a calcium-channel blocker (0.3 nmol/rat into the third ventricle 20 min before central lead administration), reversed the increase in renal excretion of sodium and potassium provoked by central lead administration. Taken together, the data presented here suggest that lead injected into the third ventricle increases renal excretion of sodium and potassium by a mechanism that depends on the functional integrity of central angiotensin II AT1 receptors and calcium channels.


Fertility estimates in the Tunisian all-acrocentric and Robertsonian populations of the house mouse and their chromosomal hybrids.
The reproductive features of wild all-acrocentric and 2n = 22 Robertsonian (Rb) house mice (M. m. domesticus) from Tunisia were studied. The aim was to examine the possibility of a reproductive selective advantage associated with chromosomal change as well as to measure the effect of heterozygosity for a large number of Rb fusions on the fertility of hybrids. Results showed that litter sizes were significantly smaller in Rb than in all-acrocentric mice. This difference, which may represent a favourable demographic strategy related to the habitat segregation observed in the Tunisian mice, needs to be studied further. The F1 hybrids between the two chromosomal races showed a significantly reduced reproductive success and litter size (respectively, 53 per cent and 60 per cent less than either parental race). Analysis of the testicular histology of F1 and backcross males showed in some cases a breakdown of spermatogenesis. The degree of this disturbance was not related to the level of chromosomal heterozygosity suggesting that genetic incompatibilities between the two genomes might be involved. The strong reduction in fertility measured in these hybrids represents a reproductive isolating mechanism effectively reducing gene flow between the all-acrocentric and 22Rb mice populations of Tunisia.


Rapamycin induces differentiation of glioma stem/progenitor cells by activating autophagy.
Glioma stem/progenitor cells (GSPCs) are considered to be responsible for the initiation, propagation, and recurrence of gliomas. The factors determining their differentiation remain poorly defined. Accumulating evidences indicate that alterations in autophagy may influence cell fate during mammalian development and differentiation. Here, we investigated the role of autophagy in GSPC differentiation. SU-2 cells were treated with rapamycin, 3-methyladenine (3-MA) plus rapamycin, E64d plus rapamycin, or untreated as control. SU-2 cell xenografts in nude mice were treated with rapamycin or 3-MA plus rapamycin, or untreated as control. Western blotting and immunocytochemistry showed up-regulation of microtubule-associated protein light chain-3 (LC3)-II in rapamycin-treated cells. The neurosphere formation rate and the number of cells in each neurosphere were significantly lower in the rapamycin treatment group than in other groups. Real-time PCR and immunocytochemistry showed down-regulation of stem/progenitor cell markers and up-regulation of differentiation markers in rapamycin-treated cells. Transmission electron microscopy revealed autophagy activation in rapamycin-treated tumor cells in mice. Immunohistochemistry revealed decreased Nestin-positive cells and increased GFAP-positive cells in rapamycin-treated tumor sections. These results indicate that rapamycin induces differentiation of GSPCs by activating autophagy.


Inhibitors of tubulin polymerization: synthesis and biological evaluation of hybrids of vindoline, anhydrovinblastine and vinorelbine with thiocolchicine, podophyllotoxin and baccatin III.
A series of novel hybrid compounds obtained by the attachment of anhydrovinblastine, vinorelbine, and vindoline to thiocolchicine, podophyllotoxin, and baccatin III are described. Two types of diacyl spacers are introduced. The influence of the hybrid compounds on tubulin polymerization is reported. The results highlight the importance of the length of the spacer. Immunofluorescence microscopy and flow cytometry measurements that compound with the best in vitro activity could disrupt microtubule networks in cell and prevent the formation of the proper spindle apparatus, thereby causing cell cycle arrest in the G2/M phase. The newly synthesized compounds were tested in the human lung cancer cell line A549.


When nitrosative stress hits the endoplasmic reticulum: Possible implications in oxLDL/oxysterols-induced endothelial dysfunction.
Oxidized LDL (oxLDL) and oxysterols are known to play a crucial role in endothelial dysfunction (ED) by inducing endoplasmic reticulum stress (ERS), inflammation, and apoptosis. However, the precise molecular mechanisms underlying these pathophysiological processes remain incompletely understood. Emerging evidence strongly implicates excessive nitric oxide (NO) production in the progression of various pathological conditions. The accumulation of reactive nitrogen species (RNS) leading to nitrosative stress (NSS) and aberrant protein S-nitrosylation contribute to NO toxicity. Studies have highlighted the involvement of NSS and S-nitrosylation in perturbing ER signaling through the modification of ER sensors and resident isomerases in neurons. This review focuses on the existing evidence that strongly associates NO with ERS and the possible implications in the context of ED induced by oxLDL and oxysterols. The potential effects of perturbed NO synthesis on signaling effectors linking NSS with ERS in endothelial cells are discussed to provide a conceptual framework for further investigations and the development of novel therapeutic strategies targeting ED.


Recovery of pregnancy mediated bone loss during lactation.
It is uncertain whether bone is routinely mobilised during pregnancy to provide calcium for the fetus and whether this is of a magnitude to cause osteoporosis. We have made sequential measurements of lumbar spine and hip bone mineral density (BMD) in 60 normal women before conception and then during the subsequent pregnancy out to one year after delivery. During pregnancy there was a significant fall in the BMD at the spine (1.53%), total hip (1.15%), and trochanter (3.90%) but not at the femoral neck. After delivery the women who breast-fed (n=34) showed a significant fall in BMD at all measurement sites (P<0.001) with the greatest change at the spine (4.7 +/- 3.1%) with 38% of women showing a change >5%. The women who bottle fed (n=10) increased or maintained BMD at all sites with the mixed feeders (n=16) showing an intermediate response. There was no consistent relationship between the change during pregnancy and lactation but 47% of the breast-feeders lost >5% at either the lumbar spine or trochanter. There was a good correlation between the change in BMD at these two sites (r=0.48, P<0.001). At 1 year after delivery all but 7 women had returned to within 5% of the preconceptual value at the spine and trochanter but the recovery at the total hip was less complete. Several women became transiently osteoporotic (T score below -2.5) at either spine or hip during reproduction of whom three started pregnancy with a normal BMD.


Is coordination of two-joint leg muscles during load lifting consistent with the strategy of minimum fatigue?
The purpose of this study was to examine if strong correlations reported for a back lift task between activity (EMG) of two-joint rectus femoris (RF), hamstrings (HA), and gastrocnemius (GA) and the difference in the joint moments could be predicted by minimizing an objective function of minimum fatigue. Four subjects lifted barbell weights (9 and 18 kg) using a back lift technique at three speeds normal, slow, and fast. Recorded ground reaction forces and coordinates of the leg joints were used to calculate the resultant joint moments. Surface EMG of five muscles crossing the knee joint were also recorded. Forces of nine muscles were calculated using static optimization and a minimum fatigue criterion. Relationships (i) (RF EMG-HA EMG) vs (knee moment hip moment) and (ii) GA EMG vs. (ankle moment knee moment) were closely related (coefficients of determination were typically 0.9 and higher). Qualitatively similar relationships were predicted by minimizing fatigue. Gastrocnemius and hamstrings had the agonistic action at both joints they cross during load lifting, and their activation and predicted forces increased with increasing flexion knee moments and extension ankle and hip moments. The rectus femoris typically had the antagonistic action at the knee and hip, and its activation and predicted force were low. Patterns of predicted muscle forces were qualitatively similar to the corresponding EMG envelopes (except in phases of low joint moments where accuracy of determining joint moments was presumably poor). It was suggested that muscle coordination in load lifting is consistent with the strategy of minimum muscle fatigue.


Satellite-based assessment of water use and leaf area efficiencies of dryland conifer forests along an aridity gradient.
Dryland forests worldwide are increasingly threatened by drought stress due to climate change. Understanding the relationships between forest structure and function is essential for managing dryland forests to adapt to these changes. We investigated the structure-function relationships in four dryland conifer forests distributed along a semiarid to subhumid climatic aridity gradient. Forest structure was represented by leaf area index (LAI) and function by gross primary productivity (GPP), evapotranspiration (ET), and the derived efficiencies of water use (WUE = GPP/ET) and leaf area (LAE = GPP/LAI). Estimates of GPP and ET were based on the observed relationships between high-resolution vegetation indices from VENμS and Sentinel-2A satellites and flux data from three eddy covariance towers in the study regions between November 2015 to October 2018. The red-edge-based MERIS Terrestrial Chlorophyll Index (MTCI) from VENμS and Sentinel-2A showed strong correlations to flux tower GPP and ET measurements for the three sites (R2cal > 0.91, R2val > 0.84). Using our approach, we showed that as LAI decreased with decreasing aridity index (AI) (i.e., dryer conditions), estimated GPP and ET decreased (R2 > 0.8 to LAI), while WUE (R2 = 0.68 to LAI) and LAE increased. The observed global-scale patterns are associated with a variety of forest vegetation characteristics, at the local scale, such as tree species composition and density. However, our results point towards a canopy-level mechanism, where the ecosystem-LAI and resultant proportion of sun-exposed vs. shaded leaves are primary determinants of WUE and LAE along the studied climatic aridity gradient. This work demonstrates the importance of high-resolution (spatially and spectrally) remote sensing data conjugated with flux tower data for monitoring dryland forests and understanding the intricate structure-function interactions in their response to drying conditions.


Ellagic acid through attenuation of neuro-inflammatory response exerted antidepressant-like effects in socially isolated mice.
Recent studies have been demonstrated that neuroinflammation plays a crucial role in the pathophysiology of depression. Therefore, anti-inflammatory medications could be regarded as a potentially effective treatments for depression. Ellagic acid (EA) is a natural polyphenol with antioxidant and anti-inflammatory properties. This study aimed to evaluate the antidepressant-like effect of EA in a mouse model of social isolation stress (SIS), considering its potential anti-neuroinflammatory properties. In this study, 48 male mice were divided into six groups (n = 8), including saline-treated control (socially conditioned (SC)) group and SIS (isolation conditioned (IC)) groups treated with saline or EA at doses of 12.5, 25, 50, and 100 mg/kg, respectively. Saline and EA were administrated intraperitoneally for 14 constant days. Immobility time in the forced swimming test (FST) and grooming activity time in the splash test were measured. The gene expression of inflammatory cytokines relevant to neuroinflammation was assessed in the hippocampus by real-time PCR. Results showed that SIS significantly increased immobility time in the FST and reduced grooming activity time in the splash test. In addition, the expression of inflammatory genes, including TNF-α, IL-1β, and TLR4 increased in IC mice's hippocampi. Findings showed that EA decreased immobility time in the FST and increased grooming activity time in the splash test. Moreover, EA attenuated neuroimmune-response in the hippocampus. In conclusion, finding determined that EA, through attenuation of neuroinflammation in the hippocampus, partially at least, exerted an antidepressant-like effect in the mouse model of SIS.


Metabolism of diethylstilbestrol in the C3H mouse: chromatographic systems for the quantitative analysis of DES metabolic products.
Initial excretion studies with orally administered [monoethyl-1-3H] DES demonstrated the feces to be the principal mode of elimination of DES in the C3H mouse. Metabolic studies with tritiated DES and/or [UL-14C] DES were performed with orally dosed C3H high (MTV+) and low (MTV-) titer MMTV female mice. Extraction and partitioning of the fecal radioactivity demonstrated 77 to 86% (n = 4) to be benzene soluble and the remainder H2O soluble. The principal product in the organic phase following Sephadex LH-20 and HPLC purification was DES. The aqueous phase was resolved by LH-20 into two conjugate fractions that were partially hydrolyzed by beta-glucuronidase. The principal aglycone was chromatographically identical with authentic DES. The urinary conjugates were resolved into six fractions. The four major fractions were 80% hydrolyzable with beta-glucuronidase. Two of these fractions had trans-DES as the principal aglycone, whereas the other two had a major peak similar to but not chromatographically coincident with cis-DES. In certain experiments mice were sequentially dosed with tritium (24 hr) followed by a 14C dose (24 hr). Two mice (MTV+) were also previously fed 1000 ppb DES prior to these experiments. The tritated and 14C products were combined and analyzed simultaneously. This experiment did not reveal significant differences in the metabolism due to the modes of radioactive labeling, MMTV titer, or the prior feeding of DES. The developed methodology was judged to purify quantitatively 90% or more of the DES radioactive products.


Enzymatic modification of daidzin using heterologously expressed amylosucrase in Bacillus subtilis.
Amylosucrases (ASase, EC 188.8.131.52) from Deinococcus geothermalis (DGAS) and Neisseria polysaccharea (NPAS) were heterologously expressed in Bacillus subtilis. While DGAS was successfully expressed, NPAS was not. Instead, NPAS was expressed in Escherichia coli. Recombinant DGAS and NPAS were purified using nickel-charged affinity chromatography and employed to modify daidzin to enhance its water solubility and bioavailability. Analyses by LC/MS revealed that the major products of transglycosylation using DGAS were daidzein diglucoside and daidzein triglucoside, whereas that obtained by NPAS was only daidzein diglucoside. The optimal bioconversion conditions for daidzein triglucoside, which was predicted to have the highest water-solubility among the daidzin derivatives, was determined to be 4% (w/v) sucrose and 250 mg/L daidzin in sodium phosphate pH 7.0, with a reaction time of 12 h. Taken together, we suggest that the yield and product specificity of isoflavone daidzin transglycosylation may be modulated by the source of ASase and reaction conditions.


Applications of Transition-Metal-Catalyzed Asymmetric Allylic Substitution in Total Synthesis of Natural Products: An Update.
Metal-catalyzed asymmetric allylic substitution (AAS) reaction is one of the most synthetically useful reactions catalyzed by metal complexes for the formation of carbon-carbon and carbon-heteroatom bonds. It comprises the substitution of allylic substrates with a wide range of nucleophiles or SN 2'-type allylic substitution, which results in the formation of the above-mentioned bonds with high levels of enantioselective induction. AAS reaction tolerates a broad range of functional groups, thus has been successfully applied in the asymmetric synthesis of a wide range of optically pure compounds. This reaction has been extensively used in the total synthesis of several complex molecules, especially natural products. In this review, we try to highlight the applications of metal (Pd, Ir, Mo, or Cu)-catalyzed AAS reaction in the total synthesis of the biologically active natural products, as a key step, updating the subject from 2003 till date.


Herpes simplex type 2 encephalitis concurrent with known cerebral metastases.
A 62-year-old woman developed neurologic deficits 7 months after pulmonary lobectomy for alveolar cell carcinoma of the lung. CT scan of the head demonstrated two metastases with marked peritumoral edema. Administration of Decadron, chemotherapy and 3,000 rad cranial radiation resulted in dramatic improvement of dysphasia and right hand paresis. Almost 2 months later, rhythmic, involuntary movements of the left hand developed. There was progression to multifocal seizures, grand mal seizures, postictal depression, status epilepticus, and coma, with death 9 days after onset of the movement disorder. Bronchoalveolar carcinoma was widely disseminated in lungs and bones, and as three metastases in brain. Bland "ischemic" necrosis in a pseudolaminar pattern was present in the neocortex. Innumerable Cowdry type A intranuclear inclusion bodies were seen in neurons, astrocytes, and oligodenodroglia. Immunofluorescence demonstrated Herpes simplex virus type 2 antigen and electron microscopy revealed virions with the morphology of the Herpes group. The case is significant for (1) the concurrence of intracranial metastases and Herpes simplex encephalitis, and (2) the causal agent, Herpes simplex virus type 2. The implication for the clinical neurocientist is the potential in a patient with systemic cancer, for the causation of neurologic complications by more than one factor or mechanism.


Computerized segmentation of whole-body bone scintigrams and its use in automated diagnostics.
Bone scintigraphy or whole-body bone scan is one of the most common diagnostic procedures in nuclear medicine used in the last 25 years. Pathological conditions, technically poor image resolution and artefacts necessitate that algorithms use sufficient background knowledge of anatomy and spatial relations of bones in order to work satisfactorily. A robust knowledge based methodology for detecting reference points of the main skeletal regions that is simultaneously applied on anterior and posterior whole-body bone scintigrams is presented. Expert knowledge is represented as a set of parameterized rules which are used to support standard image-processing algorithms. Our study includes 467 consecutive, non-selected scintigrams, which is, to our knowledge the largest number of images ever used in such studies. Automatic analysis of whole-body bone scans using our segmentation algorithm gives more accurate and reliable results than previous studies. Obtained reference points are used for automatic segmentation of the skeleton, which is applied to automatic (machine learning) or manual (expert physicians) diagnostics. Preliminary experiments show that an expert system based on machine learning closely mimics the results of expert physicians.


Connective tissue growth factor regulates retinal neovascularization through p53 protein-dependent transactivation of the matrix metalloproteinase (MMP)-2 gene.
The role of connective tissue growth factor (CTGF/CCN2) in pathological angiogenesis in the retina is unknown. CTGF/CCN2 stimulates retinal neovascularization through transactivation of p53 target genes such as matrix metalloproteinase (MMP)-2. CTGF/CCN2 effects on abnormal vessel formation in the retina are mediated by p53 and MMP-2. CTGF/CCN2 and its downstream effectors are potential targets in the development of new antiangiogenic treatments. Pathological angiogenesis in the retina is driven by dysregulation of hypoxia-driven stimuli that coordinate physiological vessel growth. How the various components of the neovascularization signaling network are integrated to yield pathological changes has not been defined. Connective tissue growth factor (CTGF/CCN2) is an inducible matricellular protein that plays a major role in fibroproliferative disorders. Here, we show that CTGF/CCN2 was dynamically expressed in the developing murine retinal vasculature and was abnormally increased and localized within neovascular tufts in the mouse eye with oxygen-induced retinopathy. Consistent with its propitious vascular localization, ectopic expression of the CTGF/CCN2 gene further accelerated neovascularization, whereas lentivirus-mediated loss-of-function or -expression of CTGF/CCN2 harnessed ischemia-induced neovessel outgrowth in oxygen-induced retinopathy mice. The neovascular effects of CTGF/CCN2 were mediated, at least in part, through increased expression and activity of matrix metalloproteinase (MMP)-2, which drives vascular remodeling through degradation of matrix and non matrix proteins, migration and invasion of endothelial cells, and formation of new vascular patterns. In cultured cells, CTGF/CCN2 activated the MMP-2 promoter through increased expression and tethering of the p53 transcription factor to a highly conserved p53-binding sequence within the MMP-2 promoter. Concordantly, the neovascular effects of CTGF/CCN2 were suppressed by p53 inhibition that culminated in reduced enrichment of the MMP-2 promoter with p53 and decreased MMP-2 gene expression. Our data identified new gene targets and downstream effectors of CTGF/CCN2 and provided the rational basis for targeting the p53 pathway to curtail the effects of CTGF/CCN2 on neovessel formation associated with ischemic retinopathy.