Indications for pediatric liver transplantation. Data from the Heidelberg pediatric liver transplantation program.
Nowadays liver transplantation is an established treatment for children with end-stage liver disease with very good 1- and 5-year survival. This has been achieved through constant improvement of surgical techniques, new immunosuppressive drugs and clinical management. Indications for liver transplantation in infants and children include acute liver failure (ALF), chronic liver failure with pruritus, complications of cholestasis and failure to thrive. In young children, the most common liver disease leading to transplantation is biliary atresia. Biliary atresia accounts for at least 50 percent of all liver transplants in children and is characterized by the failure of the bile ducts to develop normally and drain bile from the liver. Several models to assess prognosis of liver disease have been developed. In acute liver failure leukocyte count, bilirubin, International Normalized Ratio (INR) and age have a strong correlation with outcome. In chronic liver failure, PELD (Pediatric end-stage liver disease) Score and the occurrence of complications of liver disease are important prognostic tools. Since the start of our own paediatric liver transplantation program at the University of Heidelberg in 2003, already 15 Children between 5 months and 14 years have been transplanted. Indications and outcome of these patients are reviewed in this paper.


Acquired childhood aphasia. Outcome 1 year after onset.
The effects of the variables age at onset, cause, severity and bilaterality of lesion, and type of aphasia on course and outcome were investigated in a group of 28 aphasic children. Analysis of spontaneous speech and tests of auditory verbal comprehension were used to determine the presence of aphasia. The severity of the cerebral lesion was assessed using a rating scale for computed tomographic scans. Most of the children had not recovered completely 1 year after onset. Recovery was significantly different according to etiological categories. Complete recovery was seen in the majority of traumatic cases.


Analysis of methylation-driven genes for predicting the prognosis of patients with head and neck squamous cell carcinoma.
To help provide evidence for prognosis prediction and personalized targeted therapy for patients with head and neck squamous cell carcinoma (HNSCC), we investigated prognosis-specific methylation-driven genes in HNSCC. Survival time data, RNA sequencing data, and methylation data for HNSCC patients were downloaded from The Cancer Genome Atlas. The MethylMix R package based on the β mixture model was utilized to screen genes with different methylation statuses in tumor tissues and adjacent normal tissues, and a total of 182 HNSCC-related methylation-driven genes were then identified. A survival prediction scoring model based on multivariate Cox analysis was developed to screen the genes related to the prognosis of HNSCC, and a linear risk model of the methylation status of six genes (INA, LINC01354, TSPYL4, MAGEB2, EPHX3, and ZNF134) was constructed. The prognostic values of the six genes were further independently explored by survival analysis combined with methylation and gene expression analyses. The 5-year survival rate in the high-risk group of patients in the test set was 30.4% (95% CI: 22.7%-40.8%) and that in the low-risk group of patients was 65.5% (95% CI: 56.1%-76.5%). The area under the receiver operating characteristic curve for the model was 0.723, which further verified the specificity and sensitivity of the model. In addition, subsequent combined survival analysis revealed that all six genes could be used as independent prognostic markers and thus might be potential drug targets. The innovative method provides new insight into the molecular mechanism and prognosis of HNSCC.


Complex networks emerging from fluctuating random graphs: analytic formula for the hidden variable distribution.
In analogy to superstatistics, which connects Boltzmann-Gibbs statistical mechanics to its generalizations through temperature fluctuations, complex networks are constructed from fluctuating Erdös-Rényi random graphs. Using a quantum-mechanical method, the exact analytic formula for the hidden variable distribution is presented which describes the nature of the fluctuations and generates a generic degree distribution through the Poisson transformation. As an example, a static scale-free network is discussed and the corresponding hidden variable distribution is found to decay as a power law and to diverge at the origin.


MicroRNA in myogenesis and muscle atrophy.
To understand the impact of microRNA on myogenesis and muscle wasting in order to provide valuable information for clinical investigation. Muscle wasting increases the risk of morbidity/mortality in primary muscle diseases, secondary muscle disorders and elderly population. Muscle mass is controlled by several different signalling pathways. Insulin-like growth factor/PI3K/Akt is a positive signalling pathway, as it increases muscle mass by increasing protein synthesis and decreasing protein degradation. This pathway is directly and/or indirectly downregulated by miR-1, miR-133, miR-206 or miR-125b, and upregulated by miR-23a or miR-486. Myostatin and the transforming growth factor-β signalling pathway are negative regulators that cause muscle wasting. An increase of miR-27 reduces myostatin and increases muscle cell proliferation. Muscle regeneration capacity also plays a significant role in the regulation of muscle mass. This review comprehensively describes the effect of microRNA on myoblasts proliferation and differentiation, and summarizes the varied influences of microRNA on different muscle atrophy. Growing evidence indicates that microRNAs significantly impact muscle growth, regeneration and metabolism. MicroRNAs have a great potential to become diagnostic and/or prognostic markers, therapeutic agents and therapeutic targets.


Activation of GPR40 as a therapeutic target for the treatment of type 2 diabetes.
The stimulation of insulin secretion by glucose can be modulated by multiple nutritive, hormonal, and pharmacological inputs. Fatty acids potentiate insulin secretion through the generation of intracellular signaling molecules and through the activation of cell surface receptors. The G-protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1 (we will use GPR40 in this review), has emerged as an important component in the fatty acid augmentation of insulin secretion. By signaling predominantly through Gαq/11, GPR40 increases intracellular calcium and activates phospholipases to generate diacylglycerols resulting in increased insulin secretion. Synthetic small-molecule agonists of GPR40 enhance insulin secretion in a glucose-dependent manner in vitro and in vivo with a mechanism similar to that found with fatty acids. GPR40 agonists have shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes. Recent phase I and phase II clinical trials in humans have shown that the GPR40 agonist TAK-875 reduces fasting and postprandial blood glucose and lowers HbA1c with efficacy equal to that of the sulfonylurea glimepiride without inducing hypoglycemia or evidence of tachyphylaxis. These data suggest that targeting the GPR40 receptor can be a viable therapeutic option for the treatment of type 2 diabetes.


Futility and unilateral decision making: a different view.
... Resuscitation of PVS patients is futile if the goal is to restore the patient to a cognitive or conscious state but not if the goal is restoration of respiratory function. The judgment of futility in either case is based on nonmedical (as well as medical) values or criteria, i.e., the value of cognitive life vs. the value of noncognitive life. If all of the affected parties concur that noncognitive recovery is a goal not worth achieving, a DNR order should be written. Lacking such concurrence, justification for a DNR order might be found in societal assessment of the burdens and benefits to others (besides the patient) of providing treatment in such circumstances. This is not a decision to be made unilaterally by a single physician, whose values are not necessarily reflective of those of the patient, family members, other physicians, or society at large.


Comparative Effects of Some Medicinal Plants: Anacardium occidentale, Eucalyptus globulus, Psidium guajava, and Xylopia aethiopica Extracts in Alloxan-Induced Diabetic Male Wistar Albino Rats.
Insulin therapy and oral antidiabetic agents/drugs used in the treatment of diabetes mellitus have not sufficiently proven to control hyperlipidemia, which is commonly associated with the diabetes mellitus. Again the hopes that traditional medicine and natural plants seem to trigger researchers in this area is yet to be discovered. This research was designed to compare the biochemical effects of some medicinal plants in alloxan-induced diabetic male Wistar rats using named plants that are best at lowering blood glucose and hyperlipidemia and ameliorating other complications of diabetes mellitus by methods of combined therapy. The results obtained showed 82% decrease in blood glucose concentration after the 10th hour to the fortieth hour. There was significant increase P < 0.05 in the superoxide dismutase activity of the test group administered 100 mg/kg of A. Occidentale. There was no significant difference P > 0.05 recorded in the glutathione peroxidase activity of E. globulus (100 mg/kg) when compared to the test groups of P. guajava (250 mg/kg) and X. aethiopica (250 mg/kg). Catalase activity showed significant increase P < 0.05 in the catalase activity, compared to test groups. While at P > 0.05, there was no significant difference seen between test group and treated groups. Meanwhile, degree of significance was observed in other parameters analysed. The biochemical analysis conducted in this study showed positive result, attesting to facts from previous works. Though these individual plants extracts exhibited significant increase in amelorating diabetes complication and blood glucose control compared to glibenclamide, a synthetic antidiabetic drug. Greater performance was observed in the synergy groups. Therefore, a poly/combined formulation of these plants extracts yielded significant result as well as resolving some other complications associated with diabetics.


Activity of trimethoprim-sulfamethoxazole against middle ear fluid pathogens obtained from Costa Rican children with otitis media.
For many years, trimethoprim-sulfamethoxazole (TMP-SMX) has been recommended as an alternative antimicrobial agent for the treatment of children with otitis media (OM). This study analyzed the in vitro activity of TMP-SMX against respiratory pathogens obtained from middle ear fluid of Costa Rican children 6-60 months of age with acute OM, recurrent OM, therapeutic failures and acute OM at risk for having a resistant pathogen. Between 2002 and 2003, a total of 124 middle ear fluid bacterial isolates were analyzed and compared with historic data from 1992 to 1997. A significant increase in the number of TMP-SMX Streptococcus pneumoniae (P = 0.00008)- and Haemophilus influenzae (P = 0.04)-resistant strains was observed during 2002-2003 when compared with strains from 1992-1997.


Phospholipase D2 Modulates the Secretory Pathway in RBL-2H3 Mast Cells.
Phospholipase D (PLD) hydrolyses phosphatidylcholine to produce phosphatidic acid (PA) and choline. It has two isoforms, PLD1 and PLD2, which are differentially expressed depending on the cell type. In mast cells it plays an important role in signal transduction. The aim of the present study was to clarify the role of PLD2 in the secretory pathway. RBL-2H3 cells, a mast cell line, transfected to overexpress catalytically active (PLD2CA) and inactive (PLD2CI) forms of PLD2 were used. Previous observations showed that the Golgi complex was well organized in CA cells, but was disorganized and dispersed in CI cells. Furthermore, in CI cells, the microtubule organizing center was difficult to identify and the microtubules were disorganized. These previous observations demonstrated that PLD2 is important for maintaining the morphology and organization of the Golgi complex. To further understand the role of PLD2 in secretory and vesicular trafficking, the role of PLD2 in the secretory process was investigated. Incorporation of sialic acid was used to follow the synthesis and transport of glycoconjugates in the cell lines. The modified sialic acid was subsequently detected by labeling with a fluorophore or biotin to visualize the localization of the molecule after a pulse-chase for various times. Glycoconjugate trafficking was slower in the CI cells and labeled glycans took longer to reach the plasma membrane. Furthermore, in CI cells sialic acid glycans remained at the plasma membrane for longer periods of time compared to RBL-2H3 cells. These results suggest that PLD2 activity plays an important role in regulating glycoconjugate trafficking in mast cells.


The evolution and adaptive potential of transcriptional variation in sticklebacks--signatures of selection and widespread heritability.
Evidence implicating differential gene expression as a significant driver of evolutionary novelty continues to accumulate, but our understanding of the underlying sources of variation in expression, both environmental and genetic, is wanting. Heritability in particular may be underestimated when inferred from genetic mapping studies, the predominant "genetical genomics" approach to the study of expression variation. Such uncertainty represents a fundamental limitation to testing for adaptive evolution at the transcriptomic level. By studying the inheritance of expression levels in 10,495 genes (10,527 splice variants) in a threespine stickleback pedigree consisting of 563 individuals, half of which were subjected to a thermal treatment, we show that 74-98% of transcripts exhibit significant additive genetic variance. Dominance variance is also prevalent (41-99% of transcripts), and genetic sources of variation seem to play a more significant role in expression variance in the liver than a key environmental variable, temperature. Among-population comparisons suggest that the majority of differential expression in the liver is likely due to neutral divergence; however, we also show that signatures of directional selection may be more prevalent than those of stabilizing selection. This predominantly aligns with the neutral model of evolution for gene expression but also suggests that natural selection may still act on transcriptional variation in the wild. As genetic variation both within- and among-populations ultimately defines adaptive potential, these results indicate that broad adaptive potential may be found within the transcriptome.


An in vivo animal model of gene therapy for leukocyte adhesion deficiency.
Leukocyte adhesion deficiency (LAD) is an inherited disorder of leukocyte function that is caused by defects in the CD18 gene and is associated with diminished cell surface expression of CD11/CD18 proteins. We have developed an in vivo model for gene therapy of LAD. Recombinant retroviruses were used to transduce a functional human CD18 gene into murine bone marrow cells which were transplanted into lethally irradiated syngeneic recipients. A reliable flow cytometric assay for human CD18 in transplant recipients was developed based on: (a) the availability of human specific CD18 monoclonal antibodies and (b) the observation that human CD18 can form chimeric heterodimers with murine CD11a on the cell surface. Human CD18 was detected on leukocytes in a substantial number of transplant recipients for at least 6 mo suggesting that the gene had been transduced into stem cells. Expression was demonstrated in several lineages of a variety of hematopoietic tissues, but was consistently highest and most frequent in granulocytes. Murine granulocytes demonstrated appropriate posttranscriptional regulation of human CD18 in response to activation of protein kinase C. No apparent untoward effects of human CD18 expression were noted in transplant recipients. These studies suggest a specific strategy for LAD gene therapy that may be effective and safe.


Structure-Dependent Electron Transfer Rates for Dihydrophenazine, Phenoxazine, and Phenothiazine Photoredox Catalysts Employed in Atom Transfer Radical Polymerization.
Organic photocatalysts (PCs) are gaining popularity in applications of photoredox catalysis, but few studies have explored their modus operandi. We report a detailed mechanistic investigation of the electron transfer activation step of organocatalyzed atom transfer radical polymerization (O-ATRP) involving electronically excited organic PCs and a radical initiator, methyl 2-bromopropionate (MBP). This study compares nine N-aryl modified PCs possessing dihydrophenazine, phenoxazine, or phenothiazine core chromophores. Transient electronic and vibrational absorption spectroscopies over subpicosecond to nanosecond and microsecond time intervals, respectively, track spectroscopic signatures of both the reactants and products of photoinduced electron transfer in N,N-dimethylformamide, dichloromethane, and toluene solutions. The rate coefficients for electron transfer exhibit a range of values up to ∼1010 M-1 s-1 influenced systematically by the PC structures. These rate coefficients are an order of magnitude smaller for catalysts with charge transfer character in their first excited singlet (S1) or triplet (T1) states than for photocatalysts with locally excited character. The latter species show nearly diffusion-limited rate coefficients for the electron transfer to MBP. The derived kinetic parameters are used to model the contributions to electron transfer from the S1 state of each PC for different concentrations of MBP. Comparisons of singlet and triplet reactivity for one of the phenoxazine PCs reveal that the rate coefficient kET(T1) = (2.7 ± 0.3) × 107 M-1 s-1 for electron transfer from the T1 state is 2 orders of magnitude lower than that from the S1 state, kET(S1) = (2.6 ± 0.4) × 109 M-1 s-1. The trends in bimolecular electron transfer rate coefficients are accounted for using a modified Marcus theory for dissociative electron transfer.


Validation and Quality Assessment of the Kilimanjaro Cancer Registry.
Global cancer burden has increasingly shifted to low- and middle-income countries and is particularly pronounced in Africa. There remains a lack of comprehensive cancer information as a result of limited cancer registry development. In Moshi, Tanzania, a regional cancer registry exists at Kilimanjaro Christian Medical Center. Data quality is unknown. Our objective was to evaluate the completeness and quality of the Kilimanjaro Cancer Registry (KCR). In October 2015, we conducted a retrospective review of KCR by validating the internal consistency of registry records with medical and pathology records. We randomly sampled approximately 100 total registry cases. Four reviewers not associated with the KCR manually collected data elements from medical records and compared them with KCR data. All 100 reviewed registry cases had complete cancer site and morphology included in the registry. Six had a recorded stage. For the majority (n = 92), the basis of diagnosis was pathology. Pathology reports were found in the medical record for 40% of patients; for the remainder, these were stored separately in the pathology department. Of sampled registry cases, the KCR and medical records were 98% and 94% concordant for primary cancer site and morphology, respectively. For 28%, recorded diagnosis dates were within 14 days of what was found in the medical record, and for 32%, they were within 30 days. The KCR has a high level of concordance for classification and coding when data are retrieved for validation. This parameter is one of the most important for measuring data quality in a regional cancer registry.


Lysosomal enzyme activity and fibroblast stimulation of lavage from guinea pigs exposed to silica dust.
Guinea pigs were exposed to silica dust for 3 weeks and examined up to 1 year thereafter. The activity of several lysosomal enzymes in lung lavage fluid (LLF) increased from 8 weeks after cessation of exposure whereas the level in aveolar macrophages decreased. Collagen synthesis in fibroblast cultures exposed to LLF was also increased except at 24 weeks after exposure. The results indicate that 8 weeks and later after cessation of exposure to silica dust there are cellular changes in the lung which can be related to the exposure, although typical silicotic lesions were not observed till 1 year after the exposure.


Use of pamidronate in chronic and acute bone loss conditions.
Involutional osteoporosis (OP), Osteogenesis imperfecta (OI) and Reflex sympathetic dystrophy syndrome (RSDS) are conditions in which an increase in bone resorption has been described. It therefore seems logical to prescribe a potent inhibitor of bone resorption like pamidronate (APD) in a patient suffering from any of these conditions. In our experience, oral as well as intravenous APD therapy was able to increase significantly bone mineral density (BMD) in patients with OP. This increase was more marked at the lumbar spine than at the proximal femur. With cyclical intermittent APD therapy, a plateauing effect in the BMD results during the third year appeared. After weaning from APD therapy, a remanent effect was observed: no loss of bone apparently occurred for at least two years, but the biological remodeling parameters re-increased earlier. The protective action on OP fractures has still to be clearly demonstrated, however. In children with OI, oral APD therapy has produced a dramatic increase in bone mass, without adversely interfering with the growth spur. The effect on fracture rate is still debatable in such a protean condition. Intravenous APD administered daily for twelve days has provoked a dramatic improvement in patients with long lasting RSDS which had resisted to various well-accepted therapies. However, this was an open trial, and these favorable preliminary results should be confirmed in a double-blind study.


Does nocturnality drive binocular vision? Octodontine rodents as a case study.
Binocular vision is a visual property that allows fine discrimination of in-depth distance (stereopsis), as well as enhanced light and contrast sensitivity. In mammals enhanced binocular vision is structurally associated with a large degree of frontal binocular overlap, the presence of a corresponding retinal specialization containing a fovea or an area centralis, and well-developed ipsilateral retinal projections to the lateral thalamus (GLd). We compared these visual traits in two visually active species of the genus Octodon that exhibit contrasting visual habits: the diurnal Octodon degus, and the nocturnal Octodon lunatus. The O. lunatus visual field has a prominent 100° frontal binocular overlap, much larger than the 50° of overlap found in O. degus. Cells in the retinal ganglion cell layer were 40% fewer in O. lunatus (180,000) than in O. degus (300,000). O. lunatus has a poorly developed visual streak, but a well developed area centralis, located centrally near the optic disk (peak density of 4,352 cells/mm(2)). O. degus has a highly developed visual streak, and an area centralis located more temporally (peak density of 6,384 cells/mm(2)). The volumes of the contralateral GLd and superior colliculus (SC) are 15% larger in O. degus compared to O. lunatus. However, the ipsilateral projections to GLd and SC are 500% larger in O. lunatus than in O. degus. Other retinorecipient structures related to ocular movements and circadian activity showed no statistical differences between species. Our findings strongly suggest that nocturnal visual behavior leads to an enhancement of the structures associated with binocular vision, at least in the case of these rodents. Expansion of the binocular visual field in nocturnal species may have a beneficial effect in light and contrast sensitivity, but not necessarily in stereopsis. We discuss whether these conclusions can be extended to other mammalian and non-mammalian amniotes.


Current perspectives on herb-drug interactions in the European regulatory landscape.
Herb-drug interactions have turned out not to be a major issue in the European regulatory landscape. For a minority of herbal preparations, herb-drug interactions are clinically relevant, e.g., between high-dose St.John's wort extracts and a number of chemical substances. The inclusion of adequate information on such interactions into the package leaflet is important for the safe use of the products. Information on potential interactions is also part of the official HMPC monographs. However, only for some herbal preparations described in these monographs, such a potential is known. Thus, in accordance with the relevant European guidance documents, potential interactions should be assessed critically for their clinical relevance, and a balanced assessment is required when regulatory documents are established or regulatory measures are implemented.


[Texture analysis based on contrast-enhanced MRI can predict treatment response to neoadjuvant chemotherapy of breast cancer].
Objective: To investigate whether texture analysis based on contrast-enhanced MRI can predict pathological complete response of locally advanced breast cancer undergoing neoadjuvant chemotherapy(NAC). Methods: Forty-seven patients with breast cancer undergone neoadjuvant chemotherapy from January 2015 to February 2016 were divided into pathological complete response (pCR) group or non-pathological complete response (non-pCR) group based on surgical pathology. Their parameters of texture analysis based on MRI before neoadjuvant chemotherapy and after 2 cycles of treatment were analyzed. Parameters(Energy, Entropy, Inertia, Correlation, Inverse Difference Moment)before and after 2 cycles of NAC between pCR and non-pCR groups were compared using Student t or Wilcoxon rank sum test. The diagnostic performance of different parameters was judged by the receiver-operating characteristic (ROC) curve analysis. Results: The post-NAC value was significantly different from that of pre-NAC (all P<0.05). Pre-treatment parameters (Energy, Entropy, Inertia, Correlation, Inverse Difference Moment) were 78.58×10(-5)(55.64×10(-5), 135.23×10(-5)), 10.06 ± 1.02, 7 993.91±2 428.10, (4.76±0.99) ×10(-5) and (18.10±4.13) ×10(-3) in pCR group, and 76.84×10(-5) (48.68×10(-5), 154.15×10(-5)), 10.28±1.26, 7 184.77 (4 938.03, 9 974.04), (5.21±2.01) ×10(-5) and (17.68±5.87) ×10(-3) in non-pCR group. No significant difference was found between both groups. (P>0.05 for all). At the end of the second cycle of NAC, parameters(Energy, Entropy, Inertia, Correlation, Inverse Difference Moment) were (542.11±361.04) ×10(-5,) 7.95±1.28, 16 765.08±97 06.56, (0.43±0.07) ×10(-5,) and (12.18±9.82) ×10(-3) in pCR group, and 133.00×10(-5) (79.80×10(-5,) 239.00×10(-5)), 9.29±1.46, 7 916.64(6 418.89, 10 934.40), (0.38±0.08) ×10(-5) and (14.80±5.06) ×10(-3) in non-pCR group. At the end of the second cycle of NAC, there was significant difference in the parameters (Energy, Entropy, Inertia, Correlation) and Δparameters (ΔEnergy, ΔEntropy, ΔInertia, ΔInverse Difference Moment) between both groups (P<0.05 for all). The area under curve (AUC) of post-treatment ΔEntropy was 0.81, which was the largest one among parameters. Sensitivity of ΔEntropy for predicting pCR was 75.0% and specificity was 85.7%, respectively. Conclusion: Texture analysis based on dynamic contrast-enhanced MRI can predict early treatment response in primary breast cancer.


Understanding the mechanism and origins of stereoconvergence in nickel-catalyzed hydroarylation of 1,3-dienes with aryl boronates.
Nickel-catalyzed stereoselective hydroarylation is one of the most efficient methods to access functionalized arenes. Herein, computational studies have been applied to reveal the mechanism and origins of ligand-controlled enantioselectivity of Ni-catalyzed hydroarylation of 1,3-dienes using ethanol as the hydrogen source. DFT calculations show that the hydroarylation of (E)-diene takes place via concerted hydronickelation aided by boronate leading to an alkylnickel(II) intermediate, which further undergoes transmetallation and C-C reductive elimination to deliver the final chiral alkylarene. The hydronickelation is found to be the rate-determining step and is irreversible. The enantioselectivity is dominated by the transmetallation step, in which the ligand-substrate interactions are analyzed to unveil the source of stereocontrol. Besides, mechanistic studies demonstrate that the (Z)-diene initially reacts to offer a (S)-Z-alkyl-Ni(II) species, which preferably undergoes facile isomerization via σ-π-σ-π-σ interconversion to the (R)-E-alkyl-Ni(II) complex rather than the transmetallation step, thus ultimately generating the same (R)-alkylarene product as (E)-diene. Overall, the mechanistic understanding will be useful for the further advancement of asymmetric hydroarylation of dienes.


[Mesectodermal leiomyoma. Unusual tumor of the ciliary body].
Mesectodermal leiomyoma is a benign tumor of smooth muscle of the ciliary body, which is derived from the neural crest. We report the case of a 35-year-old Mexican woman with visually impaired and blurred vision of the right eye of 2 months duration. The clinical and imaging presuntional diagnosis was adenoma of the non pigmented epithelium of the ciliary body and it was surgically resected. Microscopically, the tumor was composed of cells with round nuclei and scant cytoplasm without atypia or mitosis, arranged in a fibrillary background. The immunohistochemical markers for vimentin, muscle specific actin, smooth muscle actin and calponin were strongly positive in the cytoplasm of the neoplastic cells, while for glial fibrillary acidic protein and S-100 protein were negative in the same cellular population. Mesectodermal leiomyoma of the ciliary body is benign tumor of smooth muscle extremely rare in this location. Until now, there are just 25 previous reported cases in the literature and, the main differential diagnosis is uveal malignant melanoma, therefore some eyes were enucleated. The ultrabiomicroscopy, A and B-scan imaging studies are useful in the evaluation, however, is mandatory the microsocpic examination with routine and histochemical stains as well as the use of immunohistochemical markers such as vimentin, specific muscle actin, smooth muscle actin andcalponin to stablish the smooth muscle origin of this neoplasm, and rule out other malignant neoplams such as malignant melanoma.


Mechanism of RNA-binding protein Lin28 in neuronal ferroptosis after intracerebral haemorrhage.
Intracerebral haemorrhage (ICH) is a highly risky cerebrovascular disease with poor prognosis. Lin-28 homolog A (Lin28) has been identified as a crucial regulator in ICH. This study aims to analyse the mechanism of Lin28 in neuronal ferroptosis after ICH and provide theoretical basis for ICH treatment. An ICH mouse model was established via injection of collagenase VII, followed by neurological impairment assessment, and haematoxylin-eosin staining. An in vitro ICH model was established using hemin treatment. Next, cell viability and ferroptosis parameters were detected via cell counting kit-8, assay kits, enzyme-linked immunosorbent assay and western blot. Lin28 expression and tripartite motif-containing 37 (Trim37) mRNA level were detected via western blot and quantitative real-time polymerase chain reaction (qRT-PCR). The binding relationship of Lin28 and Trim37 was verified. ICH mice exhibited neuronal ferroptosis and upregulation of Lin28. Lin28 inhibition alleviated neurological impairment, manifested by decreased hematoma, oedema, neuronal necrosis, glial cell swelling, intracellular vacuoles and inflammatory cell infiltration, reduced Fe2+ concentration and reactive oxygen species content, and increased glutathione and glutathione peroxidase 4 activity. In the hemin-induced HT-22 cells, Lin28 inhibition promoted cell viability and alleviated neuronal ferroptosis. Lin28 bound to Trim37 mRNA to stabilize the mRNA level of Trim37. Overexpression of Trim37 reversed the alleviating role of silencing Lin28 in neuronal ferroptosis after ICH. Overall, Lin28 stabilized the mRNA level of Trim37 to aggravate neuronal ferroptosis after ICH.


Correlation of effector function with phenotype and cell division after in vitro differentiation of naive MART-1-specific CD8+ T cells.
Adoptive transfer of antigen-specific CD8+ T cells may represent an effective strategy for immunotherapy of tumors such as melanoma, but is limited by the number and functionality of in vitro expanded T cells. Here, we document that although ELAGIGILTV-specific CD8+ T cells from different donors initially possessed a naive phenotype, after antigen-induced in vitro expansion two distinct phenotypes correlating with cell proliferation rate emerged in the different donors. Those cultures achieving fewer cumulative population doublings (CPDs) were cytotoxic and displayed a CD45RA+CCR7- phenotype. In contrast, cultures reaching higher CPDs were non-cytotoxic T cells with a CD45RA-CCR7- phenotype. Thus, the generation of larger numbers of ELAGIGILTV-specific CD8+ T cells correlates negatively with the acquisition of a CD45RA+CCR7- phenotype and cytotoxic capacity. A better understanding of the differentiation pathways of cytotoxic T cells to obtain optimally efficient cells for adoptive transfer will allow the development of new immunotherapy protocols.


2020 guidelines for conducting plastic reconstructive short-term surgical projects in low-middle income countries.
Many low- or middle-income countries (LMICs) continue to suffer from a lack of safe and timely essential and emergency surgery despite growing attention to this problem. Short-term surgical projects (STSPs) continue to play an important role in addressing LMIC unmet surgical need and strengthening local healthcare systems. Guidelines here present recommendations for performing plastic reconstructive STSPs for pediatric patients in a safe, ethical, and effective manner. These guidelines represent consensus physician expert opinions, assembled collaboratively by members of Volunteers in Plastic Surgery and the Society for Pediatric Anesthesia's global health committee, with broad input from physicians practicing daily in LMICs. Organizations must partner with hosts to thoughtfully plan and carefully execute STSPs. We outline crucial items to STSP success, including choice of host facility, team selection, patient selection, staffing, ensuring proper equipment and supplies, disinfecting reusable equipment, creation of a safety culture, and data collection for quality assessment/improvement and research. Patient factors are discussed and recommendations given for developing exclusion criteria, as well as for determining which patients and procedures may require the team to include expertise in pediatric anesthesia or critical care. We recommend that educational opportunities for hosts are sought and advanced to optimize education/training at both the resident and post-trainee levels. Host education during STSPs has become crucial as LMICs ramp up training at a time when their surgical volumes remain grossly behind well-resourced countries. Recommendations here aim to assist organizations, hosts, and volunteers as they navigate the enormously complex and ever changing STSP environment. Patient safety and transfer of knowledge and skills should be central concerns of all who participate in this highly rewarding endeavor.


The actin-bundling protein fascin is involved in the formation of dendritic processes in maturing epidermal Langerhans cells.
Dendritic cells (DC) are characterized by their unique potential to prime naive T cells. Epidermal Langerhans cells (LC), the DC resident in the epidermis, gain this immunostimulatory capacity following Ag contact in vivo or during in vitro culture of epidermal cell suspensions. To analyze differential gene expression in maturing LC, we constructed a highly representative cDNA library of cultivated LC (cLC) in lambda ZAP II containing 18 x 10(6) independent clones. This library was screened with freshly isolated Langerhans cell (fLC)- and cLC-derived probes for cLC-specific cDNAs. The cDNAs identified were sequenced and analyzed by database searches. Two cDNA fragments were identified as fragments of fascin, indicating that fascin is differentially expressed in LC. By competitive RT-PCR, we confirmed that fascin is highly expressed in cLC cultivated for 1, 2, and 3 days, while no signals were obtained with fLC. Western blot and immunofluorescence analysis revealed cLC-specific expression of fascin on the protein level as well. Fascin is known to be involved in the organization of the actin cytoskeleton in cytoplasmatic extensions of nerve growth cones. Its differential expression in maturing LC coincides with the formation of numerous dendritic projections in LC. Their formation was inhibited by incubation of LC with fascin antisense oligonucleotides during cultivation. Therefore, we conclude that fascin is necessary for the formation of the dendritic processes of maturing Langerhans cells and may thus influence T cell-LC interaction.


Sex in the 90s: SRY and the switch to the male pathway.
In mammals the male sex determination switch is controlled by a single gene on the Y chromosome, SRY. SRY encodes a protein with an HMG-like DNA-binding domain, which probably acts as a local organizer of chromatin structure. It is believed to regulate downstream genes in the sex determination cascade, although no direct targets of SRY are clearly known. More genes in the pathway have been isolated through mutation approaches in mouse and human. At least three genes, SRY itself, SOX9, and DAX1, are dosage sensitive, providing molecular evidence that the sex determination step operates at a critical threshold. SRY initiates development of a testis from the bipotential cells of the early gonad. The dimorphic male and female pathways present a rare opportunity to link a pivotal gene in development with morphogenetic mechanisms that operate to pattern an organ and the differentiation of its cells. Mechanisms of testis organogenesis triggered downstream of SRY include pathways of cell signaling controlling cell reorganization, cell proliferation, cell migration, and vascularization.


Characterizing the neuroendocrine and ovarian defects of androgen receptor-knockout female mice.
Homozygous androgen receptor (AR)-knockout (ARKO) female mice are subfertile due to both intra- and extraovarian (neuroendocrine) defects as defined by ovary transplantation. Using ARKO mice, this study set out to reveal the precise AR-regulated pathways required for optimal androgen-regulated ovulation and fertility. ARKO females exhibit deficient neuroendocrine negative feedback, with a reduced serum luteinizing hormone (LH) response to ovariectomy (OVX) (P < 0.01). Positive feedback is also altered as intact ARKO females, at late proestrus, exhibit an often mistimed endogenous ovulatory LH surge. Furthermore, at late proestrus, intact ARKO females display diminished preovulatory serum estradiol (E2; P < 0.01) and LH (P < 0.05) surge levels and reduced Kiss1 mRNA expression in the anteroventral periventricular nucleus (P < 0.01) compared with controls. However, this reduced ovulatory LH response in intact ARKO females can be rescued by OVX and E2 priming or treatment with endogenous GnRH. These findings reveal that AR regulates the negative feedback response to E2, E2-positive feedback is compromised in ARKO mice, and AR-regulated negative and positive steroidal feedback pathways impact on intrahypothalamic control of the kisspeptin/GnRH/LH cascade. In addition, intraovarian AR-regulated pathways controlling antral to preovulatory follicle dynamics are disrupted because adult ARKO ovaries collected at proestrus have small antral follicles with reduced oocyte/follicle diameter ratios (P < 0.01) and increased proportions of unhealthy large antral follicles (P < 0.05) compared with controls. As a consequence of aberrant follicular growth patterns, proestrus ARKO ovaries also exhibit fewer preovulatory follicle (P < 0.05) and corpora lutea numbers (P < 0.01). However, embryo development to the blastocyst stage is unchanged in ARKO females, and hence, the subfertility is a consequence of reduced ovulations and not altered embryo quality. These findings reveal that the AR has a functional role in neuroendocrine regulation and timing of the ovulatory LH surge as well as antral/preovulatory follicle development.


Effect of orally ingested diosgenin into diet on skin collagen content in a low collagen skin mouse model and its mechanism of action.
Influence on collagen content with oral ingestion of diosgenin (Dios) was investigated in established low collagen skin mouse model. And its mechanism of action was investigated using primary cultured fibroblasts. Hairless mice were fed a low protein diet with Dios for 8weeks and the contents of collagen in skin were determined by measuring the content of hydroxyproline (Hyp). In primary cultured fibroblasts, the numbers of fibroblast were determined by incubating with Dios for 120h; the contents of Hyp were determined by incubating with Dios for 24 or 72h using fibroblasts of confluent state; the expressions of messenger ribonucleic acid (mRNA) were determined by incubating with Dios for 24h. Oral ingestion of Dios in the diet for 8weeks led to a dose-dependent increase in the Hyp content as collagen content of skin. In proliferating of primary cultured fibroblasts, Dios treatment led to a decrease of adenosine 5'-triphosphate content indicating decrease of the cell number. In the cells reached to confluent, although increase of Hyp content in the control indicating progress of fibroblasts differentiation were observed, the content of Hyp remained unchanged with Dios treatment. Finally, addition of Dios led to a decrease the α-tubulin and c-fos mRNA expressions relating to the cell cycle. It is concluded that Dios can improve skin collagen content by shifting the dynamics of the fibroblasts from proliferation to differentiation via cell cycle arrest.


SUDEP: The First Case Series in Turkey.
Sudden unexpected death in epilepsy (SUDEP) is defined as the sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death of patients with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, and in whom postmortem examinations do not reveal a toxicological or anatomic cause for death. In this study, data on patients who passed away under observation in the epilepsy clinic due to sudden, unexpected death have been compiled, and we also aim to emphasize the importance of SUDEP in Turkey. This study was performed with a total of nine cases. Data were obtained from hospital records, information given by the families of patients, the database of the General Directorate for Civil Services of the Ministry of Internal Affairs of Turkey, and from the Ankara Metropolitan Municipality Cemetery Information System. As the basis of classification and definition, the proposals suggested by Nashef et al., which were made to the International League Against Epilepsy (ILAE) in 2011, were taken into consideration. Eight of the patients were classified as probable SUDEP and one of them as possible SUDEP; the mean age at SUDEP was 33 years, and the average follow-up period was 19.7 years. In these cases, except for known risk factors (generalized tonic-clonic seizures, nocturnal seizures, severe epilepsy, more frequent seizures, younger age at the onset of epilepsy, unwitnessed seizures, polytherapy, and mental handicap), a different risk factor was not identified. This study is the first case series on SUDEP in Turkey. Postmortem studies are the most important shortcoming of the study. However, the importance of the topic is highlighted by presenting the available data. SUDEP deserves more attention during the daily practice of neurologists, pediatric neurologists, forensic physicians, and family physicians. If death is sudden and unexpected in a patient with epilepsy, SUDEP should be considered, regardless of the clear causes of death.


Vitamin E and athletic performance.
Vitamin E has been of interest to sports people for many years, with reports of its dietary supplementation in the 1950s. In the last decade there has been a resurgence in the interest in the relationship between vitamin E and athletic performance and animal studies have demonstrated that endurance is reduced in vitamin E deficiency. Much of the recent research has centred around the antioxidant properties of vitamin E and it seems that these properties are in part responsible for the improvement of aerobic power of humans at medium to high altitude venues following supplementation of the vitamin. However, there have been no similar reports relating to sea-level performance. On the other hand, one recent study has indicated that supplementation of vitamin E to athletes consuming the recommended daily intake (RDI) elicited a reduction in indicators of muscle damage following an exercise bout. Furthermore, vitamin E is implicated in maintenance of both optimal immune function and optimal blood viscosity, both factors being important in athletes' ability to train and compete, but it remains to be seen whether supplementation over the RDI has any beneficial effects. So, there seems 'little doubt that vitamin E deficiency will impair athletic performance and there is also some evidence that supplementation of vitamin E on top of the RDI may provide some advantage for the intensely training athlete, especially those training at altitude.


Coordination of Tetravalent Actinides (An=ThIV , UIV , NpIV , PuIV ) with DOTA: From Dimers to Hexamers.
Three tetravalent actinide (AnIV ) hexanuclear clusters with the octahedral core [An6 (OH)4 O4 ]12+ (AnIV =UIV , NpIV , PuIV ) were structurally characterized in the solid state and in aqueous solution by using single-crystal X-ray diffraction, X-ray absorption, IR, Raman, and UV/Vis spectroscopy. The observed structure, [An6 (OH)4 O4 (H2 O)8 (HDOTA)4 ]⋅HCl/HNO3 ⋅n H2 O (An=U(I), Np(II), Pu(III)), consists of a AnIV hexanuclear pseudo-octahedral cluster stabilized by DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) ligands. The six actinide atoms are connected through alternate μ3 -O2- and μ3 -OH- groups. Extended X-ray absorption fine structure (EXAFS) investigations combined with UV/Vis spectroscopy provide evidence for the same local structure in moderate acidic and neutral aqueous solutions. The synthesis mechanism was partially elucidated and the main physicochemical properties (pH range stability, solubility, and protonation constant) of the cluster were determined. The results underline the importance of: 1) considering such polynuclear species in thermodynamic models, and 2) competing reactions between hydrolysis and complexation. It is interesting to note that the same synthesis route with thorium(IV) led to the formation of a dimer, Th2 (H2 O)10 (H2 DOTA)2 ⋅4 NO3 ⋅x H2 O (IV), which contrasts to the structure of the other AnIV hexamers.


Influence of farm resource endowment on possibilities for sustainable development: a case study for vegetable farms in South Uruguay.
In different parts of the world, there is an urgent need for redesigning and innovating farming systems. Such a process may be supported by model-based explorations that enable ex-ante evaluation of a broad range of alternatives. Since a variety of viable patterns of farm development exists related to farm resource endowment and farmer's strategy, model-based explorations should be able to capture the existing variation in resource endowment and strategies in order to have impact on strategic farm management. In this paper, we present an overview of the model-based explorative method based on the MILP model Farm Images, applied to explore options for sustainable development of vegetable farms in Canelón Grande, Uruguay. The method is used to gain insight into the impact of current farm resource endowment on the possibilities for sustainable development and on the resource use efficiency at farm scale. We maximized farm income for 128 different farm types in an environment-oriented scenario and in an income-oriented scenario. Farm types were defined by combining 4 farm sizes, 2 labor endowments, 4 irrigation endowments, 2 soil quality combinations and 2 mechanization levels. The results demonstrate a strong impact of farm resource endowment on possibilities for sustainable development, as well as synergy between labor, land and irrigated area on resource-use efficiency at farm scale. Farms with 10ha of land or less, representing 47% of the farms in the Canelón Grande region, could only achieve a family income higher than the average income of Uruguayan families when the irrigated area was ca. 40% of the farm area. The achievement of environmental targets was less costly in terms of income on farms with a low rather than high labor availability per unit area and on farms with irrigation facilities.


[Health-quality problems of paddy soil in the Taihu region].
The concept of soil health quality was discussed from the angle of sustainable and safe agricultural production and nutritive agricultural products. Based on the data of 13 higher-yield rice-farms and its corresponding irrigated rivers in the Taihu region, problems of health quality occurred in paddy soil were discussed. Owing to the high application of inorganic fertilizers in those farms, high available P and N were observed in paddy soil and river sediments. The contents of heavy metals such as Pb, Cu, Ni and Co in paddy soil were still at the level of background values. However, it was found that some rivers were seriously polluted by Cu, Zn and Pb. Several cases of point-source pollution of heavy metal were found in paddy soil in the region. The contents of DDT and HCH in soils and river sediments were lower than their maximum allowable concentrations. The results of lower selenium content in agricultural product owing to lower content in paddy soil indicted that the Taihu region is a selenium-deficient area.


[Inhibition of human ovarian cancer cell growth by prostaglandin D2].
The effects of prostaglandin D2 (PGD2) on human ovarian tumor growth were examined in vitro and in vivo by using a cell line, designated HR, derived from patients with serous cystadenocarcinoma of the ovary. The cell proliferation was dose-dependently inhibited by PGD2 between concentrations of 0.1 and 4.0 micrograms/ml after 24 hrs, 48 hrs and 72 hrs of contact time. Concentrations of PGD2 required for 50% inhibition of the cell proliferation were 2.0, 1.1 and 0.55 micrograms/ml with 24, 48 and 72 hrs of contact time, respectively. From the results of 51Cr-release assay, the inhibition of cell proliferation by PGD2 was considered to result from the direct cytotoxic effects. The incorporations of 3H-thymidine, 3H-uridine and 3H-valine were inhibited in a dose-dependent fashion with more than 1.0 micrograms/ml of PGD2. Tumor growth in nude mice treated with 0.3 mg/mouse PGD2 was significantly inhibited, compared to that of untreated nude mice. In untreated nude mice the tumor growth curve was parallel to the changes in the plasma alpha-hydroxybutyrate dehydrogenase (HBD). In both PGD2-treated groups with 0.1 mg/mouse and 0.3 mg/mouse, the HBD activity markedly decreased on the 14th and the 21st day after inoculation. The 50% survival time in untreated mouse, 0.1 mg/mouse and 0.3 mg/mouse PGD2-treated groups was 52 days, 55 days and 67 days, each respectively.


Optimization of biofiltration for odor control: model calibration, validation, and applications.
A dynamic model that describes the biofiltration process for hydrogen sulfide removal from wastewater treatment plant air emissions was calibrated and validated using pilot- and full-scale biofilter data obtained from the Cedar Rapids (Iowa) Water Pollution Control Facilities. After calibration, the model was found to predict the dynamic effluent concentrations of the pilot- and full-scale biofilters well, with the measured data falling within 58 to 80% of the model output values. In addition, the model predicted the trend of the field data, even under field conditions of changing input concentration and at effluent concentrations below 1 ppm by volume. The model demonstrated that increasing gas residence time and temperature and decreasing influent concentration decreases effluent concentration. In addition, model simulations showed that a longer residence time is required to treat dynamic loading increases, indicating that biofilter design should account for the maximum influent concentration. These results can be used to help design and operate biofilters for controlling odorous and hazardous air emissions.


Unique antimicrobial effects of platelet-rich plasma and its efficacy as a prophylaxis to prevent implant-associated spinal infection.
Platelet-rich-plasma (PRP) has attracted great attention and has been increasingly used for a variety of clinical applications including orthopedic surgeries, periodontal and oral surgeries, maxillofacial surgeries, plastic surgeries, and sports medicine. However, very little is known about the antimicrobial activities of PRP. PRP is found to have antimicrobial properties both in vitro and in vivo. In vitro, the antimicrobial properties of PRP are bacterial-strain-specific and time-specific: PRP significantly (80-100 fold reduction in colony-forming units) inhibits the growth of methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Group A streptococcus, and Neisseria gonorrhoeae within the first few hours but it has no significant antimicrobial properties against E. coli and Pseudomonas. The antimicrobial properties of PRP also depend on the concentration of thrombin. In vivo, an implant-associated spinal infection rabbit model is established and used to evaluate the antimicrobial and wound-healing properties of PRP. Compared to the infection controls, PRP treatment results in significant reduction in bacterial colonies in bone samples at all time points studied (i.e. 1, 2, and 3 weeks) and significant increase in mineralized tissues (thereby better bone healing) at postoperative weeks 2 and 3. PRP therefore may be a useful adjunct strategy against postoperative implant-associated infections.


Delayed neuropathy after organophosphorus insecticide (Dipterex) poisoning: a clinical, electrophysiological and nerve biopsy study.
Clinical, electrophysiological and histological findings in four patients accidentally poisoned with the organophosphorus insecticide Dipterex are reported. Three to five weeks after insecticide ingestion signs of a distal sensorimotor (preponderantly motor) neuropathy occurred. The patients complained of paraesthesia in the lower limbs, and two of them of very disagreeable pricking sensation in the soles of the feet, responsive to carbamazepine. They showed distal weakness mainly of the legs, footdrop , difficult gait and muscle hypotonia. Ankle jerk was abolished while other tendon reflexes persisted. Two months or even later after poisoning, knee jerks in all the patients were very brisk and more and less accompanied by other pyramidal signs (patellar clonus, abolishment of abdominal cutaneous reflexes, Babinski's sign). Clinical, electrophysiological and nerve biopsy data revealed a "dying-back" neuropathy in our patients. Distal muscle fatigue was confirmed by failure of neuromuscular transmission on repetitive nerve stimulation.


Artery length sensitivity in patient-specific cerebral aneurysm simulations.
The reconstruction of aneurysm geometry is a main factor affecting the accuracy of hemodynamics simulations in patient-specific aneurysms. We analyzed the effects of the inlet artery length on intra-aneurysmal flow estimations by using 10 ophthalmic aneurysm models. We successively truncated the inlet artery of each model, first at the cavernous segment and second at the clinoid segment. For each aneurysm, we obtained 3 models with different artery lengths: the originally segmented geometry with the longest available inlet from scans and 2 others with successively shorter artery lengths. We analyzed the velocity, wall shear stress, and the oscillatory shear index inside the aneurysm and compared the 2 truncations with the original model. We found that eliminating 1 arterial turn resulted in root mean square errors of <18% with no visual differences for the contours of the flow parameters in 8 of the 10 models. In contrast, truncating at the second turn led to root mean square errors between 18% and 32%, with consistently large errors for wall shear stress and the oscillatory shear index in 5 of the 10 models and visual differences for the contours of the flow parameters. For 3 other models, the largest errors were between 43% and 55%, with large visual differences in the contour plots. Excluding 2 arterial turns from the inlet artery length of the ophthalmic aneurysm resulted in large quantitative differences in the calculated velocity, wall shear stress, and oscillatory shear index distributions, which could lead to erroneous conclusions if used clinically.


FBXW7 tumor suppressor regulation by dualspecificity tyrosine-regulated kinase 2.
FBXW7 is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a main tumor suppressor due to its ability to control proteasome-mediated degradation of several oncoproteins such as c-Jun, c-Myc, Cyclin E1, mTOR, and Notch1-IC. FBXW7 inactivation in human cancers results from a somatic mutation or downregulation of its protein levels. This work describes a novel regulatory mechanism for FBXW7 dependent on the serine/threonine protein kinase DYRK2. We show that DYRK2 interacts with and phosphorylates FBXW7 resulting in its proteasome-mediated degradation. DYRK2-dependent FBXW7 destabilization is independent of its ubiquitin ligase activity. The functional analysis demonstrates the existence of DYRK2-dependent regulatory mechanisms for key FBXW7 substrates. Finally, we provide evidence indicating that DYRK2-dependent regulation of FBXW7 protein accumulation contributes to cytotoxic effects in response to chemotherapy agents such as Doxorubicin or Paclitaxel in colorectal cancer cell lines and to BET inhibitors in T-cell acute lymphoblastic leukemia cell lines. Altogether, this work reveals a new regulatory axis, DYRK2/FBXW7, which provides an understanding of the role of these two proteins in tumor progression and DNA damage responses.


Copper-Catalyzed Electrophilic Etherification of Arylboronic Esters with Isoxazolidines.
A copper-catalyzed electrophilic etherification of arylboronic esters is reported. Isoxazolidines are utilized as easily available and stable [RO]+ surrogates to give 1,3-amino aryl ethers. The O-selective arylation of isoxazolidines takes place without causing competitive N-arylation. In contrast to previously reported anionic conditions, our copper-catalyzed conditions are mild enough to achieve high functional group tolerance. Preliminary mechanistic studies and DFT calculations support that the reaction proceeds via a transmetalation/oxidative addition pathway, followed by a Lewis acid-promoted reductive elimination to induce the crucial O-selectivity.


Extracting atoms from molecular electron densities via integral equations.
The observation that a molecular electron density is close to the superposition of its constituent atoms leads naturally to the idea of modeling a density by a sum of nuclear-centered, spherically symmetric functions. The functions that are optimal in a least-squares sense are known as Stewart atoms. Previous attempts to construct Stewart atoms by expanding them in an auxiliary basis have been thwarted by slow convergence with respect to the size of the auxiliary basis used. We present a method for constructing Stewart atoms via convolution integrals which bypasses the need for an auxiliary basis, and is able to produce highly accurate approximations to Stewart atoms.


July 2021 civil unrest: South African diagnostic radiography students' experiences.
South Africa (SA), in 2021, experienced a wave of civil unrest following political events that led to mass looting and the destruction of property. Civil unrests, among other disruptions, have been seen to cause ripple effects on healthcare education, particularly for radiography students who undergo work integrated learning within hospitals and universities, even during these times of unrest. This study aimed to explore and describe the undergraduate diagnostic radiography students' experience of the civil unrest that occurred in SA in 2021. The study was conducted across five universities in South Africa, offering the diagnostic radiography programme. A qualitative, interpretive phenomenological design was employed as it enabled the researchers to facilitate focus group interviews to gain insight into the lived experiences of the students during this time. Four themes emerged from the study data, namely: (1) Negative effects on students' emotional and psychological well-being, (2) Academic and clinical support mechanisms during disruptions, (3) The influence of disruptions on clinical training, (4) Recommendations to support students for future disruptions. The participants from this study described the negative effects that the civil unrest had on their emotional and mental well-being. There is a need for increased support mechanisms during times of disruptions from universities across South Africa. The findings highlight the ripple effects that disruptions, such as civil unrests, have on radiography students. This can assist universities to relook at their institutional support structures, in order to enhance the current support given to students across universities in times of disruptions.


Modelling the time at which overcrowding and feed interruption emerge on the swine premises under movement restrictions during a classical swine fever outbreak.
A stochastic risk model was developed to estimate the time elapsed before overcrowding (TOC) or feed interruption (TFI) emerged on the swine premises under movement restrictions during a classical swine fever (CSF) outbreak in Indiana, USA. Nursery (19 to 65 days of age) and grow-to-finish (40 to 165 days of age) pork production operations were modelled separately. Overcrowding was defined as the total weight of pigs on premises exceeding 100% to 115% of the maximum capacity of the premises, which was computed as the total weight of the pigs at harvest/transition age. Algorithms were developed to estimate age-specific weight of the pigs on premises and to compare the daily total weight of the pigs with the threshold weight defining overcrowding to flag the time when the total weight exceeded the threshold (i.e. when overcrowding occurred). To estimate TFI, an algorithm was constructed to model a swine producer's decision to discontinue feed supply by incorporating the assumptions that a longer estimated epidemic duration, a longer time interval between the age of pigs at the onset of the outbreak and the harvest/transition age, or a longer progression of an ongoing outbreak would increase the probability of a producer's decision to discontinue the feed supply. Adverse animal welfare conditions were modelled to emerge shortly after an interruption of feed supply. Simulations were run with 100 000 iterations each for a 365-day period. Overcrowding occurred in all simulated iterations, and feed interruption occurred in 30% of the iterations. The median (5th and 95th percentiles) TOC was 24 days (10, 43) in nursery operations and 78 days (26, 134) in grow-to-finish operations. Most feed interruptions, if they emerged, occurred within 15 days of an outbreak. The median (5th and 95th percentiles) time at which either overcrowding or feed interruption emerged was 19 days (4, 42) in nursery and 57 days (4, 130) in grow-to-finish operations. The study findings suggest that overcrowding and feed interruption could emerge early during a CSF outbreak among swine premises under movement restrictions. The outputs derived from the risk model could be used to estimate and evaluate associated mitigation strategies for alleviating adverse animal welfare conditions resulting from movement restrictions.


Transferring knowledge during dyadic interaction: The role of the expert in the learning process.
Physical interaction between man and machines is increasing the interest of the research as well as the industrial community. It is known that physical coupling between active persons can be beneficial and increase the performance of the dyad compared to an individual. However, the factors that may result in performance benefits are still poorly understood. The aim of this work is to investigate how the different initial skill levels of the interacting partners influence the learning of a stabilization task. Twelve subjects, divided in two groups, trained in couples in a joint stabilization task. In the first group the couples were composed of two naive, while in the second a naive was trained together with an expert. Results show that training with an expert results in the greatest performance in the joint task. However, this benefit is not transferred to the individual when performing the same task bimanually.


Self-inflicted burns: a sporadic phenomenon.
Self-inflicted burns are a regular cause of admission to burn units. Historically, a full moon has been associated with mental instability. Circadian rhythms and seasonal changes are known to influence human affect. Such cosmic effects, however, have not yet been studied for self-inflicted burns. In this regard, the results of a retrospective analysis of 184 self-inflicted burns admitted during a 20-year period to the Birmingham Burns Centre are presented. The analysis fails to show a connection between the timing of self-inflicted burns and cosmic events. Such incidents are random, not influenced by the day of the week, first or second half of the month, seasonal variation or phase of the lunar cycle.


Lymphocytes in neuroprotection, cognition and emotion: is intolerance really the answer?
Clinical, epidemiological and therapeutic studies indicate that some human depression is associated with proinflammatory cytokines, chronic inflammatory disorders, and inflammation-inducing lifestyle factors. Moreover depression can be induced by administration of proinflammatory cytokines, including IL-2 or IFN-α. However, recent studies in specific pathogen-free (SPF) rodents suggest a different--and potentially contradictory--relationship between immune processes and mental health. These studies suggest that effector T cells specific for central nervous system (CNS) antigens can assist recovery from an array of environmental insults ranging from nerve injury to psychological stress, while in contrast, regulatory T cells (Treg) oppose such recovery. Indeed, some reported effects of this so-called "protective autoimmunity" seem of direct relevance to depressive disorders. These findings pose a dilemma for those intending to manipulate inflammatory pathways as a treatment for depression. Should we administer anti-inflammatory treatments, or should we induce self-reactive T cells? We re-examine the rodent findings and outline immunological peculiarities of SPF rodents, the abnormal properties of their regulatory T cells, and the impact of gut microbiota. We find that "protective autoimmunity" is likely to be relevant only to very clean SPF animals that lack normal levels of activated T cells, CNS T cell traffic and mature Treg. The data indicate that even in SPF models the effectors of beneficial effects are not the proinflammatory autoimmune cells themselves, but rather unidentified regulatory cells. This reinterpretation of findings relevant to "protective autoimmunity" suggests that ongoing, and planned, clinical trials of anti-inflammatory strategies to treat depressive disorders are justified.


Organocatalyzed Multicomponent Synthesis of Isoxazolidin-5-ones.
An unprecedented multicomponent organocatalyzed Knoevenagel-aza-Michael-cyclocondensation reaction between Meldrum's acid, hydroxylamines, and aldehydes afforded a straightforward entry to a large array of racemic and syn-diastereoenriched isoxazolidinones as synthetically useful scaffolds. This process revealed a markedly facile aza-Michael-cyclocondensation sequence as a key domino reaction between RCO2NHOH and transient alkylidene Meldrum's acid upon Brønsted base catalysis.


Hydrophilic surface modification of poly(methyl methacrylate)-based ocular prostheses using poly(ethylene glycol) grafting.
Ocular prostheses are custom-made polymeric inserts that can be placed in anophthalmic sockets for cosmetic rehabilitation. Prosthetic eye wearers have reduced tear amount, and they often experience dry eye symptoms including dryness, irritation, discomfort, and discharge. Most modern ocular prostheses are made of poly(methyl methacrylate) (PMMA), which is highly hydrophobic. Previous research has shown that improving the wettability of contact lens materials decreases its wearers discomfort by increasing lubrication. Therefore, hydrophilic modification of PMMA-based ocular prostheses might also improve patient discomfort by improving lubrication. We modified the surfaces of PMMA-based ocular prostheses using poly(ethylene glycol) (PEG), which is hydrophilic. To do this, we used two strategies. One was a "grafting from" method, whereby PEG was polymerized from the PMMA surface. The other was a "grafting to" method, which involved PEG being covalently bonded to an amine-functionalized PMMA surface. Assessments involving the water contact angle, ellipsometry, and X-ray photoelectron spectroscopy indicated that PEG was successfully introduced to the PMMA surfaces using both strategies. Scanning electron microscopy and atomic force microscopy images revealed that neither strategy caused clinically significant alterations in the PMMA surface morphology. In vitro bacterial adhesion assessments showed that the hydrophilic modifications effectively reduced bacterial adhesion without inducing cytotoxicity. These results imply that hydrophilic surface modifications of conventional ocular prostheses may decrease patient discomfort and ocular prosthesis-related infections.


Enantioselective Intramolecular C-H Insertion of Donor and Donor/Donor Carbenes by a Nondiazo Approach.
The first enantioselective intramolecular C-H insertion and cyclopropanation reactions of donor- and donor/donor-carbenes by a nondiazo approach are reported. The reactions were conducted in a one-pot manner without slow addition and provided the desired dihydroindole, dihydrobenzofuran, tetrahydrofuran, and tetrahydropyrrole derivatives with up to 99 % ee and 100 % atom efficiency.


Is there a placental microbiota? A critical review and re-analysis of published placental microbiota datasets.
The existence of a placental microbiota is debated. The human placenta has historically been considered sterile and microbial colonization was associated with adverse pregnancy outcomes. Yet, recent DNA sequencing investigations reported a microbiota in typical human term placentas. However, this detected microbiota could represent background DNA or delivery-associated contamination. Using fifteen publicly available 16S rRNA gene datasets, existing data were uniformly re-analyzed with DADA2 to maximize comparability. While Amplicon Sequence Variants (ASVs) identified as Lactobacillus, a typical vaginal bacterium, were highly abundant and prevalent across studies, this prevalence disappeared after applying likely DNA contaminant removal to placentas from term cesarean deliveries. A six-study sub-analysis targeting the 16S rRNA gene V4 hypervariable region demonstrated that bacterial profiles of placental samples and technical controls share principal bacterial ASVs and that placental samples clustered primarily by study origin and mode of delivery. Contemporary DNA-based evidence does not support the existence of a placental microbiota.ImportanceEarly-gestational microbial influences on human development are unclear. By applying DNA sequencing technologies to placental tissue, bacterial DNA signals were observed, leading some to conclude that a live bacterial placental microbiome exists in typical term pregnancy. However, the low-biomass nature of the proposed microbiome and high sensitivity of current DNA sequencing technologies indicate that the signal may alternatively derive from environmental or delivery-associated bacterial DNA contamination. Here we address these alternatives with a re-analysis of 16S rRNA gene sequencing data from 15 publicly available placental datasets. After identical DADA2 pipeline processing of the raw data, subanalyses were performed to control for mode of delivery and environmental DNA contamination. Both environment and mode of delivery profoundly influenced the bacterial DNA signal from term-delivered placentas. Aside from these contamination-associated signals, consistency was lacking across studies. Thus, placentas delivered at term are unlikely to be the original source of observed bacterial DNA signals.


[Viral transfer of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gene therapy].
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces carcinoma cell death through the extrinsic pathway of apoptosis. Preclinical trials of gene therapy have been conducted using viral transfer of the TRAIL transgene into prostate, bladder, breast, kidney, liver, non-small cell lung cancer and also glioblastoma cells. Experiments in vitro demonstrated the extensive apoptosis of target cells as well as frequent disease regression or remission. TRAIL transfer did not show any side effects, opposite to chemotherapy. Encouraging results of TRAIL-related gene therapy were observed in rheumatoid arthritis and type 1 diabetes. Adenoviral vectors (AdV) encoding TRAIL are the most promising tool in anti-tumor therapy. They have undergone numerous modifications by increasing transfection efficiency and transgene expression in target cells. However, only one clinical phase I trial has been performed. AdV encoding the TRAIL transgene caused local inflammation and apoptosis in patients with prostate cancer.


Prevalence and Factors Associated with the Utilization of Dental Care Services among Factory Workers in Nava Nakorn Industrial Estate, Pathumthani Province, Thailand.
The present study aimed to find out the utilization prevalence of dental care services among factory workers over a period of one year and factors associated with utilization of dental care services. This was a cross-sectional analytic study. The study population was factory workers in Nava Nakorn Industrial Estate randomly sampled using Probability Proportion to Size Cluster Sampling Method. The tool was a questionnaire about utilization of dental care services. Among the sample group of 1,500 workers from 16 factories, almost 2/3 (63.9%) had never used any dental care services in the previous year while only 36.1% did. A multivariable logistic regression analysis showed that workplace, accommodation, tooth decay, toothache history, transportation, experience in using social security fund for dental care services, availability and accessibility of dental care services, brushing teeth regularly after meals, using dental care services regularly in a dental clinic, and agreement with the idea that a tooth extraction and medication by a dentist could reduce the risk of progression of disease, statistical significance (p-value < 0.05), were factors associated with the utilization of dental care services at R2 (The Nagelkerke R Square) 0.38. That the prevalence of the factory workers who did not use dental care services during the last one year was 63.9 percent. This study identified three groups of factors associated with the utilization of dental care services as: 1) Predisposing factors, 2) Enabling factors, and 3) Need factors.


Organoid Establishment of Long-Term Culture Using Primary Mouse Hepatocytes and Evaluation of Liver Function.
Primary hepatocytes and various animal models have traditionally been used in liver function tests to assess the effects of nutrients. However, these approaches present several limitations such as time consumption, high cost, the need for facilities, and ethical issues in primary mouse hepatocytes and animal models. In this study, we constructed liver organoids from primary mouse hepatocytes (OrgPH) to replace primary hepatocytes and animal models. We isolated primary mouse hepatocytes from 6- to 10-week-old male C57BL/6J mice using the two-step collagenase method, and generated liver organoids by clustering the cells in Matrigel. To assess the hepatic function of OrgPH, we examined specific liver markers and gene expressions related to hepatic glucose, ethanol, and cholesterol metabolism. Over a 28-day culture period, liver-specific markers, including Alb, Arg1, G6pc, and Cyp1a1, increased or remained stable in the OrgPH. However, they eventually decreased in primary hepatocytes. Glucose and ethanol metabolism-related gene expression levels exhibited a similar tendency in AML12 cells and OrgPH. However, the expression levels of cholesterol metabolism-related genes displayed an opposite trend in OrgPH compared with those in AML12 cells. These results agree with those of previous studies involving in vivo models. In conclusion, our study indicates that OrgPH can retain liver function and mimic the hepatocytic physiology of mouse in vivo models. Therefore, organoids originating from primary mouse hepatocytes are potentially useful as an animal-free method for evaluating the safety and toxicity of health functional foods and a replacement for animal models.


Is there any correlation between restriction fragment length polymorphism of the L-MYC gene and metastasis of human nonsmall cell lung cancer?
A potential molecular marker associated with cancer susceptibility as well as metastasis, prognosis and adverse survival, is the L-myc gene. The studies of lung cancer patients from different populations have yielded controversial results. We studied 64 nonsmall cell lung cancer (NSCLC) patients and 37 healthy controls of Turkish origin for L-myc gene polymorphism. Our aim was to test the hypothesis that there was association between L-myc S allele in NSCLC and predisposition to the disease and TNM stage indicating tumor size, node classification and metastasis. Polymerase chain reaction restriction fragment length polymorphism and agarose gel electrophoresis were used to determine the L-myc oncogene genotypes. We found no significant difference, both in the distribution of the LL, LS and SS genotypes and in the allelic frequencies, between the patient group and the control group; that is, the frequencies of L-myc alleles were, L and S, 0.59 and 0.41, 0.60 and 0.40, respectively. Our data between the patient group and the control group; that is, the frequencies of L-myc alleles were, L and S, 0.59 and 0.41, 0.60 and 0.40, respectively. Our data concerning age, sex, size of tumors, histological type of tumors showed no significant association with L-myc genotype. However, a higher frequency of L-myc S allele in the squamous cell carcinoma compared to other histological groups was found, although this difference was not statistically significant. No association was found between the L-myc RFLP and increased risk of metastasis either to the lymph nodes or to other organs. Our results suggested that L-myc gene polymorphism was not a suitable prognostic marker of metastatic development in Turkish NSCLC patients.


Pediatric resuscitation: lessons learned and future directions.
The science of resuscitation has had significant and meaningful advances over the past fifty years, with resultant improvements in outcomes for both adult and pediatric populations. This article aims to describe some of the recent advances in pediatric resuscitation, including aspects of care affecting the management of cardiac arrest and sepsis, and to give a glimpse into technologies and methodologies that may be utilized to improve outcomes for children in the near future.


The small-voxel tracking algorithm for simulating chemical reactions among diffusing molecules.
Simulating the evolution of a chemically reacting system using the bimolecular propensity function, as is done by the stochastic simulation algorithm and its reaction-diffusion extension, entails making statistically inspired guesses as to where the reactant molecules are at any given time. Those guesses will be physically justified if the system is dilute and well-mixed in the reactant molecules. Otherwise, an accurate simulation will require the extra effort and expense of keeping track of the positions of the reactant molecules as the system evolves. One molecule-tracking algorithm that pays careful attention to the physics of molecular diffusion is the enhanced Green's function reaction dynamics (eGFRD) of Takahashi, Tănase-Nicola, and ten Wolde [Proc. Natl. Acad. Sci. U.S.A. 107, 2473 (2010)]. We introduce here a molecule-tracking algorithm that has the same theoretical underpinnings and strategic aims as eGFRD, but a different implementation procedure. Called the small-voxel tracking algorithm (SVTA), it combines the well known voxel-hopping method for simulating molecular diffusion with a novel procedure for rectifying the unphysical predictions of the diffusion equation on the small spatiotemporal scale of molecular collisions. Indications are that the SVTA might be more computationally efficient than eGFRD for the problematic class of non-dilute systems. A widely applicable, user-friendly software implementation of the SVTA has yet to be developed, but we exhibit some simple examples which show that the algorithm is computationally feasible and gives plausible results.


Systemic levels of G-CSF and interleukin-6 determine the angiogenic potential of bone marrow resident monocytes.
There is considerable interest in the potential of cell-based approaches to mediate therapeutic angiogenesis for acute and chronic vascular syndromes. Using a mouse model of HLI, we showed previously that adoptive transfer of a small number of donor monocytes enhanced revascularization significantly. Herein, we provide data suggesting that the BM resident monocytes sense systemic signals that influence their future functional capacity. Specifically, following induction of distant ischemia, the angiogenic capacity of BM resident monocytes is reduced markedly. We provide evidence that G-CSF and IL-6 represent such "conditioning" signals. Systemic levels of G-CSF and IL-6 are increased significantly following induction of HLI. Accordingly, BM resident monocytes from ischemic mice exhibited increased pSTAT3 and STAT3 target gene expression. Finally, G-CSFR(-/-) and IL-6(-/-) mice were resistant to the deleterious effects of ischemic conditioning on monocyte angiogenic potential. RNA expression profiling suggested that ischemia-conditioned monocytes in the BM up-regulate the well-described M2 polarization markers Chi3l4 and Lrg1. Consistent with this observation, M2-skewed monocytes from SHIP(-/-) mice also had impaired angiogenic capacity. Collectively, these data show that G-CSF and IL-6 provide signals that determine the angiogenic potential of BM resident monocytes.


The chameleon-like nature of zwitterionic micelles: the intrinsic relationship of anion and cation binding in sulfobetaine micelles.
The rate of specific hydrogen ion-catalyzed hydrolysis of 2-( p-heptoxyphenyl)-1,3-dioxolane and acid-base equilibrium of 4-carboxy-1-n-dodecylpyridinium in zwitterionic micelles of SB3-14, C14H29NMe2+(CH2)3SO3(-) are controlled by NaClO4, which induces anionic character and uptake of H3O+ in the micelles. Other salts, e.g., NaF, NaCl, NaBr, NaNO3, NaI, NaBF4, have similar, but smaller, effects on the uptake of H3O+. Salt effects upon zeta potentials of SB3-14 micelles, estimated by capillary electrophoresis, are anion specific, and the anion order is similar to that of the rates of acid hydrolysis and of acid-base equilibria. Fluorescence quenching shows that the micellar aggregation number is not very sensitive to added salts, consistent with electrophoretic evidence. These specific anion effects follow the Hofmeister series and are related to anion hydration free energies.


Diverse effects of pinacidil on KATP channels in mouse skeletal muscle in the presence of different nucleotides.
The potassium channel opener pinacidil relaxes smooth muscle and exerts cardioprotective effects. The aim of the study was to investigate the actions of pinacidil on ATP sensitive potassium channels (KATP channels) in mammalian skeletal muscle and to explore the interrelations of this drug with various nucleotides. Single skeletal muscle fibres were prepared enzymatically from flexor digitorum brevis muscles of adult mice. Membrane patches of the inside-out configuration were excised in a Ca(2+)-free solution, and currents through single KATP channels were recorded at -40 mV. The cytoplasmic face of the patch was exposed to a K(+)-rich solution with MgCl2 (1 mM), and pinacidil (0.1 or 0.4 mM) and the nucleotides (0.1 mM) were added to this internal solution. KATP channels were not activated by pinacidil in the presence of the nonhydrolysable ATP analogue AMP-PNP, in contrast to the reported channel activation by pinacidil and ATP. KATP channels had a high activity in the control and were blocked by ADP; the subsequent addition of pinacidil did not enhance the open probability of KATP channels. Pinacidil in the presence of a mixture of AMP-PNP and ADP activated KATP channels. The diverse effects of pinacidil are interpreted with a model of the KATP channel containing a binding site for pinacidil and two sites for nucleotides, one activatory (A) site and one inhibitory (I) site. Occupation of the A site by ATP or ADP activates the channel, while occupation of the I site by ATP, AMP-PNP, ADP closes the channel. Pinacidil activates the channel and displaces blockers from the I site only if the A site is occupied.


Changes in serum selenium, copper, zinc levels and cu/zn ratio in patients with pulmonary tuberculosis during therapy.
The effectiveness and success of antituberculosis therapy is mainly measured by its ability to identify the organism in the sputum. In certain cases, available tuberculosis tests are not satisfactory and do not provide enough information on the effectiveness of antituberculosis therapy. Copper (Cu), zinc (Zn), and selenium (Se) are the essential elements that play a crucial role in the immune system. The serum levels of these elements vary in many diseases including tuberculosis. In this study, we investigate whether the serum levels of Cu, Zn, and Se change during antituberculosis therapy. We have included 22 pulmonary tuberculosis cases that were newly diagnosed with positive sputum and 18 healthy subjects. At the beginning and 2 mo after therapy, serum levels of Cu, Zn, and Se were measured by atomic absorption spectrometry. Despite Se and Cu levels not being affected during the treatment, we found that there was a significant increase in the levels of Zn and a decrease in the Cu/Zn ratio. Serum Zn levels and the Cu/Zn ratio could be used as a valuable laboratory tool for the clinicians to assess response to therapy or effectiveness of the ongoing antituberculosis therapy.


Decolorization of anthraquinone-type dye by bilirubin oxidase-producing nonligninolytic fungus Myrothecium sp. IMER1.
The decolorization of an anthraquinone dye, Remazol Brilliant Blue R (RBBR), was carried out using a new isolated nonligninolytic fungus, strain Myrothecium sp. IMER1. In potato dextrose broth (PDB) containing RBBR, this strain was able to grow and decolorize the dye efficiently at pHs ranging from 4.0 to 9.0, and the optimal pH and temperature were pH 7.0 and 28 degrees C. A decolorization efficiency of approximately 90% was achieved by cultivation for 7 d at an initial dye concentration of 80 mg l(-1). The adsorption of the dye by cells was observed at the beginning of the decolorization, then the color became faint and finally disappeared when bilirubin oxidase (BOX) was released by the strain. Additionally, the visual observation and ultraviolet- visible (UV-VIS) spectral analysis demonstrated that decolorization involved biosorption and biodegradation. Native polyacrylamide gel electrophoresis of crude enzyme and purified BOX confirmed that BOX, which is an important extracellular oxidoreductase, played a major role in decolorization. Furthermore, purified BOX was demonstrated to degrade RBBR and other dyes by in vitro enzymatic experiments. Our results suggest that both the strain and its extracellular BOX have promising applications in dye effluent decolorization.


Health-related quality of life and its associated factors among outpatients with heart failure: a cross-sectional study.
Heart Failure (HF) is a chronic disease associated with life-limiting symptoms that could negatively impact patients' health-related quality of life (HRQOL). This study aimed to evaluate HRQOL and explore the factors associated with poor HRQOL among patients with HF in Jordan. This cross-sectional study used the validated Arabic version of the Minnesota Living with Heart Failure Questionnaire to assess HRQOL in outpatients with HF visiting cardiology clinics at two public hospitals in Jordan. Variables were collected from medical records and custom-designed questionnaires, including socio-demographics, biomedical variables, and disease and medication characteristics. Ordinal regression analysis was used to explore variables associated with poor HRQOL among HF patients. Ordinal regression analysis showed that the number of HF medications (P < 0.05) and not taking a loop diuretic (P < 0.05) significantly increased HRQOL, while the number of other chronic diseases (P < 0.05), stage III/IV of HF (P < 0.01), low monthly income (P < 0.05), and being unsatisfied with the prescribed medications (P < 0.05) significantly decreased HRQOL of HF patients. Although the current study demonstrated low HRQOL among patients with HF in Jordan, HRQOL has a considerable opportunity for improvement in those patients. Variables identified in the present study, including low monthly income, higher New York Heart Association (NYHA) classes, a higher number of comorbidities, and/or taking a loop diuretic, should be considered in future intervention programs, aiming to improve HRQOL in patients with HF.


Report on the AAPM deep-learning spectral CT Grand Challenge.
This Special Report summarizes the 2022 AAPM Grand Challenge on Deep-Learning spectral Computed Tomography (DL-spectral CT) image reconstruction. The purpose of the challenge is to develop the most accurate image reconstruction algorithm possible for solving the inverse problem associated with a fast kilovolt switching dual-energy CT scan using a three tissue-map decomposition. Participants could choose to use a deep-learning (DL), iterative, or a hybrid approach. The challenge is based on a 2D breast CT simulation, where the simulated breast phantom consists of three tissue maps: adipose, fibroglandular, and calcification distributions. The phantom specification is stochastic so that multiple realizations can be generated for DL approaches. A dual-energy scan is simulated where the x-ray source potential of successive views alternates between 50 and 80 kilovolts (kV). A total of 512 views are generated, yielding 256 views for each source voltage. We generate 50 and 80 kV images by use of filtered back-projection (FBP) on negative logarithm processed transmission data. For participants who develop a DL approach, 1000 cases are available. Each case consists of the three 512 × 512 tissue maps, 50 and 80-kV transmission data sets and their corresponding FBP images. The goal of the DL network would then be to predict the material maps from either the transmission data, FBP images, or a combination of the two. For participants developing a physics-based approach, all of the required modeling parameters are made available: geometry, spectra, and tissue attenuation curves. The provided information also allows for hybrid approaches where physics is exploited as well as information about the scanned object derived from the 1000 training cases. Final testing is performed by computation of root-mean-square error (RMSE) for predictions on the tissue maps from 100 new cases. Test phase submission were received from 18 research groups. Of the 18 submissions, 17 were results obtained with algorithms that involved DL. Only the second place finishing team developed a physics-based image reconstruction algorithm. Both the winning and second place teams had highly accurate results where the RMSE was nearly zero to single floating point precision. Results from the top 10 also achieved a high degree of accuracy; and as a result, this special report outlines the methodology developed by each of these groups. The DL-spectral CT challenge successfully established a forum for developing image reconstruction algorithms that address an important inverse problem relevant for spectral CT.


Front air bag nondeployments in frontal crashes fatal to drivers or right-front passengers.
Public concern has arisen about the reliability of front air bags because Fatality Analysis Reporting System (FARS) data indicate many nondeployed air bags in fatal frontal crashes. However, the accuracy of air bag deployment, the variable in question, is uncertain. This study aimed to provide more certain estimates of nondeployment incidence in fatal frontal crashes. Fatally injured passenger vehicle drivers and right-front passengers in frontal crashes were identified in two U.S. databases for calendar years 1998-2006 and model years 1994-2006: FARS, a census of police-reported fatal crashes on public roads, and National Automotive Sampling System/Crashworthiness Data System (NASS/CDS), a probability sample of tow-away crashes. NASS/CDS contains subsets of fatal crashes in FARS and collects detailed data using crash investigators. Front air bag deployment coding for front-seat occupant fatalities was compared in FARS and NASS/CDS, and case reviews were conducted. Among FARS frontal deaths with available deployment status (N = 43,169), front air bags were coded as not deployed for 18 percent of front occupants. In comparison, NASS/CDS (N = 628) reported 9 percent (weighted estimate) nondeployment among front occupants killed. Among crashes common to both databases, NASS/CDS reported deployments for 45 percent of front occupant deaths for which FARS had coded nondeployments. Detailed case reviews of NASS/CDS crashes indicated highly accurate coding for deployment status. Based on this case review, 8 percent (weighted estimate) of front occupant deaths in frontal crashes appeared to involve air bag nondeployments; 1-2 percent of front occupant deaths represented potential system failures where deployments would have been expected. Air bag deployments appeared unwarranted in most nondeployments based on crash characteristics. FARS data overstate the magnitude of the problem of air bag deployment failures; steps should be taken to improve coding. There are inherent uncertainties in judgments about whether or not air bags would be expected to deploy in some crashes. Continued monitoring of air bag performance is warranted.


No Delay in Age of Crawling, Standing or Walking with Pavlik Harness Treatment: A Prospective Cohort Study.
Pavlik harness treatment is the standard of care for developmental dysplasia of the hip in infants younger than 6 months. The effect of Pavlik harness treatment on the achievement of motor milestones has not previously been reported. In this prospective cohort study, 35 patients were prospectively enrolled to participate and received questionnaires with sequential clinical visits monitoring treatment of their developmental dysplasia of the hip. One-sample Student t-tests assessed differences in milestone attainment age, and the Benjamini-Hochberg procedure was conducted to decrease the false discovery rate. Post hoc power analyses of each test were conducted. The age of achievement of eight early motor milestones were recorded and compared with a previously published cohort of healthy infants. Infants treated with a Pavlik harness achieved four early motor milestones markedly later than the reported age of achievement in a historical control group. These milestones included "roll supine" (5.3 vs. 4.5 months; P = 0.039), "roll prone" (5.7 vs. 5.0 months; P = 0.039), "sit" (6.4 vs. 5.2 months; P < 0.001), and "crawl on stomach" (7.7 vs. 6.6 months; P = 0.039). However, there was no difference in time to achievement of later motor milestones of "crawl on knees," "pull to stand," and "independent walking." Several early motor milestones were achieved at a statistically significantly later time than historical control subjects not treated in a Pavlik harness. Despite statistical significance, the small delays in early motor milestones were not thought to be clinically significant. No differences were observed in the later motor milestones, including knee crawling, standing, and independent walking. Clinicians and parents may be reassured by these findings. Therapeutic Level II-prospective study.


Place field detection using grid-based clustering in a large-scale computational model of the rat dentate gyrus.
Place cells are neurons in the hippocampus that are sensitive to location within an environment. Simulations of a large-scale, computational model of the rat dentate gyrus using grid cell input have been performed resulting in granule cells that express multiple place fields. The typical method of detecting place fields using a global threshold on this data is unreliable as the characteristics of the place fields from a single neuron can be highly variable. A grid-based implementation of DENCLUE has been developed to calculate local thresholds to identify each place field. An adaptive binning algorithm used to smooth the rate maps was combined with the DENCLUE implementation to adaptively choose the size of the smoothing kernel and reduce the number of free parameters of the total algorithm. A sensitivity analysis was performed using the threshold parameter to demonstrate the robustness of using local thresholds as opposed to using a single global threshold in detecting the place fields resulting from the large-scale simulation. The analysis supports the use of applying local thresholds for place field detection and will be used to further investigate the role of granule cells in hippocampal function.