Perturbation of reaction-intermediate partitioning by a site-directed mutant of ribulose-bisphosphate carboxylase/oxygenase.
To explore the roles of active-site Glu48 of ribulose-bisphosphate carboxylase/oxygenase from Rhodospirillum rubrum, the E48Q mutant has been characterized with respect to kinetics and product distribution. Although the kcat for carboxylase activity is only 0.6% of the wild-type value, the mutant retains full activity in catalyzing the conversion of the carboxylated reaction intermediate to 3-phosphoglycerate and retains 10% of the normal activity in catalyzing the enolization of ribulose bisphosphate. Thus, the mutant is preferentially impaired in the carboxylation step. Partitioning of the enediol(ate) intermediate during turnover of ribulose bisphosphate is perturbed dramatically in the case of the mutant protein. Whereas the wild-type enzyme displays a CO2/O2 specificity factor of 11, the corresponding parameter of the mutant is only 0.3, thereby signifying a shift of the relative reactivity of the enediol(ate) in favor of O2. The mutant protein is also unable to protect the enediol(ate) against misprotonation with consequential conversion of ribulose bisphosphate to xylulose bisphosphate. This side reaction, undetected with wild-type R. rubrum enzyme, proceeds as rapidly as carboxylation of D-ribulose 1,5-bisphosphate by the E48Q mutant. Formation of xylulose bisphosphate by the mutant does not appear to account for the decline in carboxylase activity that occurs during the course of an assay. These studies demonstrate the multiple functionalities of Glu48 in the facilitation of catalysis and in directing intermediate partitioning in the preferred direction.


Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade.
Multiple myeloma is an incurable plasma cell malignancy. Patients who fail conventional therapy are frequently treated with hematopoietic stem cell transplantation (HSCT), which results in reduced tumor burden, but the patients subsequently relapse from sites of chemotherapy-resistant disease. Using the 5T33 murine model of myeloma and a previously successful immunotherapy regimen consisting of autologous (syngeneic) HSCT and cell-based vaccine administration, we were unable to improve survival of myeloma-bearing mice. The 5T33 tumor line, similar to malignant plasma cells from myeloma patients, expresses high levels of programmed death receptor ligand-1 (PD-L1), which binds to the inhibitory receptor, PD-1. We observed that T cells from myeloma-bearing mice express high levels of PD-1, which has also been observed in patients with multiple myeloma. These PD-1(+) T cells were exhausted and produced IL-10. Based on these observations, we combined HSCT with whole-cell vaccination and PD-L1 blockade. Inhibition of the PD-1/PD-L1 pathway with HSCT and whole-cell vaccination increased the survival of myeloma-bearing mice from 0% to 40%. These data demonstrate a role for PD-L1 in suppressing immune responses to myeloma and suggest that blockade of this pathway may enhance immunotherapy for this disease.


Association of dietary diversity and cognition in preschoolers in rural China.
We sought to investigate the cognition of preschoolers in rural China and examine the relationship between dietary diversity and cognition. We performed a cross-sectional survey analysis. In 1334 preschoolers ages 3 to 5, from 26 preschools in two nationally designated poverty counties in Hunan Province in China, we calculated the dietary diversity score (DDS) using a 24-h recall method. To measure children's cognitive ability, we assessed the Working Memory Index and Verbal Comprehension Index on the Mandarin-language version of the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition. Multiple linear regression models were used to estimate the association between DDS and cognitive test scores. A total of 22% of children had a Working Memory Index that was either extremely low or borderline, and 31% of children had a Verbal Comprehension Index that was either extremely low or borderline. The mean (± SD) DDS was 5.65 ± 1.30. Those preschoolers with medium DDS (5 or 6) or high DDS (7 to 9) scored higher on both Working Memory Index-respectively, mean difference (MD), 1.327; 95% confidence interval (CI), 0.246-3.901; and MD, 2.067, 95% CI, 0.261-4.641-and Verbal Comprehension Index-MD, 0.168; 95% CI, 0.072-2.135; and MD, 0.398; 95% CI, 0.032-2.137-than did those with low DDS (0 to 4). Consuming a more diverse diet may contribute to better cognition in preschoolers. Future research is needed to better understand the possible causal effect of dietary diversity on cognitive development.


Amputation for soft-tissue sarcoma.
Soft-tissue sarcomas are a group of rare malignant tumours, many of which arise in the limbs. Most are treated with a combination of wide local excision and radiotherapy, but a small number--including proximal, large, high-grade, or recurrent tumours, or those involving major neurovascular structures--necessitate major amputation including forequarter or hindquarter amputation. These uncommon operations should remain in the surgical armamentarium for carefully selected patients. Those being considered for amputation should be referred to a tertiary sarcoma unit for examination of all other options, such as limb-salvage surgery, tumour downstaging with chemotherapy or radiotherapy (perhaps with subsequent limb-salvage surgery), or novel techniques such as isolated limb perfusion. Only after careful assessment should amputation be carried out. Outcomes after major amputation are highly variable, but such procedures can confer useful palliation to patients with distressing symptoms (pain, bleeding, fungation), long-term disease-free survival with reasonable function in carefully selected patients, and cure in some.


Lumbar spine teratoma with associated neuroendocrine tumour (NET) in a 37-year-old woman.
Spinal teratoma with associated neuroendocrine tumour (NET) is a rare entity. To date there have been only three such cases reported in the literature. Information available to clinicians regarding clinical presentation, behaviour of this tumour over time, management options and follow-up, are as a consequence very limited. We present a case of a 37-year-old woman who was found to have an incidental lumbar spine teratoma with NET after presenting with a one-week history of acute lower back pain and radiculopathy. Magnetic resonance imaging (MRI) of the lumbosacral spine demonstrated an acute disc prolapse at the L4/5 level as well as incidental lesion at the L1/2 level causing effacement of the conus medullaris. Lumbar laminectomy with gross total resection of the intradural extramedullary lesion at the L1/2 level was performed with histopathology confirming the teratoma with NET. The objective of our case is to report our experience with this unique tumour and potential management implications.


Role of electrostatic interactions in two-dimensional self-assembly of tobacco mosaic viruses on cationic lipid monolayers.
We explore two-dimensional self-assembly of tobacco mosaic viruses (TMVs) on a substrate-supported, fluid lipid monolayer by manipulating the electrostatic interactions, with specific focus on the effects of the cationic lipid concentration in the monolayer and the presence of Ca(2+) ions in the surrounding bulk solution. The TMV assemblies were characterized by grazing-incidence X-ray scattering and atomic force microscopy, and the inter-particle interaction quantified through X-ray scattering data analysis. In the absence of Ca(2+) ions, we found that higher charge densities on the lipid monolayer led to poorer in-plane order, which may be attributed to faster adsorption kinetics, due to the surface potential that increases with charge density. At the same time, higher lipid-charge densities also resulted in weaker repulsion between TMVs, due to partial screening of Coulomb repulsion by mobile cationic lipids in the monolayer. The lipid-charge dependence was diminished with increasing concentration of Ca(2+) ions, which also led to tighter packing of TMVs. The results indicate that Ca(2+) ions strengthen the screening of Coulomb repulsion between TMVs and consequently enhance the role of attractive forces. Control experiments involving Na(+) ions suggest that the attractive inter-TMV interaction has contributions from both the van der Waals force and the counter-ion-induced attraction that depends on ion valence.


[Potential implication of the IgA-pIgR system in idiopathic pulmonary fibrosis].
Idiopathic pulmonary fibrosis (IPF) is a lethal respiratory disease characterized by the excessive deposition of extracellular matrix in the alveolar zones. The bronchiolar epithelium has been implicated in the development of this disease and is capable of secreting IgA into the airway lumen thanks to its expression of the polymeric immunoglobulin receptor. Several elements indicate a dysregulation of this system, such as raised serum IgA levels in IPF patients and the pro-fibrotic effect of IgA on several key cell types. Our work aims at studying the underlying mechanisms so as to better understand the role of IgA mucosal immunity in this disease.


Genome editing in large animal models.
Although genome editing technologies have the potential to revolutionize the way we treat human diseases, barriers to successful clinical implementation remain. Increasingly, preclinical large animal models are being used to overcome these barriers. In particular, the immunogenicity and long-term safety of novel gene editing therapeutics must be evaluated rigorously. However, short-lived small animal models, such as mice and rats, cannot address secondary pathologies that may arise years after a gene editing treatment. Likewise, immunodeficient mouse models by definition lack the ability to quantify the host immune response to a novel transgene or gene-edited locus. Large animal models, including dogs, pigs, and non-human primates (NHPs), bear greater resemblance to human anatomy, immunology, and lifespan and can be studied over longer timescales with clinical dosing regimens that are more relevant to humans. These models allow for larger scale and repeated blood and tissue sampling, enabling greater depth of study and focus on rare cellular subsets. Here, we review current progress in the development and evaluation of novel genome editing therapies in large animal models, focusing on applications in human immunodeficiency virus 1 (HIV-1) infection, cancer, and genetic diseases including hemoglobinopathies, Duchenne muscular dystrophy (DMD), hypercholesterolemia, and inherited retinal diseases.


Isolated bone infarct of the calcaneus after fracture.
The calcaneus has a rich vascular supply; therefore, avascular necrosis of the calcaneus is extremely rare. We report the first case of bone infarct of the calcaneus 9 months after a fracture. We also review the literature on osteonecrosis of the calcaneus to offer potential mechanisms for bone infarction in the calcaneus after a fracture.


18F-Labeled Cyclized α-Melanocyte-Stimulating Hormone Derivatives for Imaging Human Melanoma Xenograft with Positron Emission Tomography.
Since metastatic melanoma is deadly, early diagnosis thereof is crucial for managing the disease. We recently developed α-melanocyte-stimulating hormone (αMSH) derivatives, [68Ga]Ga-CCZ01048 and [18F]CCZ01064, that target the melanocortin 1 receptor (MC1R) for mouse melanoma imaging. In this study, we aim to evaluate [18F]CCZ01064 as well as a novel dual-ammoniomethyl-trifluoroborate (AmBF3) derivative, [18F]CCZ01096, for targeting human melanoma xenograft using μPET imaging. The peptides were synthesized on solid phase using Fmoc chemistry. Radiolabeling was achieved in a one-step 18F-19F isotope-exchange reaction. μPET imaging and biodistribution studies were performed in NSG mice bearing SK-MEL-1 melanoma xenografts. The MC1R density on the SK-MEL-1 cell line was determined to be 972 ± 154 receptors/cell (n = 4) via saturation assays. Using [18F]CCZ01064, moderate tumor uptake (3.05 ± 0.47%ID/g) and image contrast were observed at 2 h post-injection. Molar activity was determined to play a key role. CCZ01096 with two AmBF3 motifs showed comparable sub-nanomolar binding affinity to MC1R and much higher molar activity. This resulted in improved tumor uptake (6.46 ± 1.42%ID/g) and image contrast (tumor-to-blood and tumor-to-muscle ratios were 30.6 ± 5.7 and 85.7 ± 11.3, respectively) at 2 h post-injection. [18F]CCZ01096 represents a promising αMSH-based μPET imaging agent for human melanoma and warrants further investigation for potential clinical translation.


Free-breathing pediatric chest MRI: Performance of self-navigated golden-angle ordered conical ultrashort echo time acquisition.
To assess the feasibility and performance of conical k-space trajectory free-breathing ultrashort echo time (UTE) chest magnetic resonance imaging (MRI) versus four-dimensional (4D) flow and effects of 50% data subsampling and soft-gated motion correction. Thirty-two consecutive children who underwent both 4D flow and UTE ferumoxytol-enhanced chest MR (mean age: 5.4 years, range: 6 days to 15.7 years) in one 3T exam were recruited. From UTE k-space data, three image sets were reconstructed: 1) one with all data, 2) one using the first 50% of data, and 3) a final set with soft-gating motion correction, leveraging the signal magnitude immediately after each excitation. Two radiologists in blinded fashion independently scored image quality of anatomical landmarks on a 5-point scale. Ratings were compared using Wilcoxon rank-sum, Wilcoxon signed-ranks, and Kruskal-Wallis tests. Interobserver agreement was assessed with the intraclass correlation coefficient (ICC). For fully sampled UTE, mean scores for all structures were ≥4 (good-excellent). Full UTE surpassed 4D flow for lungs and airways (P < 0.001), with similar pulmonary artery (PA) quality (P = 0.62). 50% subsampling only slightly degraded all landmarks (P < 0.001), as did motion correction. Subsegmental PA visualization was possible in >93% scans for all techniques (P = 0.27). Interobserver agreement was excellent for combined scores (ICC = 0.83). High-quality free-breathing conical UTE chest MR is feasible, surpassing 4D flow for lungs and airways, with equivalent PA visualization. Data subsampling only mildly degraded images, favoring lesser scan times. Soft-gating motion correction overall did not improve image quality. 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:200-209.


Perfluorooctane sulfonate and bisphenol A induce a similar level of mast cell activation via a common signaling pathway, Fyn-Lyn-Syk activation.
Perfluoroalkyl compounds (PFCs) as food contaminants are widely distributed persistent organic pollutants (POPs) and have been suggested to induce immune dysfunction. However, their effects on immune function are not conclusive. Mast cells play a central role in allergic and non-allergic inflammatory responses. Therefore, we have examined the effects of PFCs (PFHxS, PFOA, PFOS) on mast cell-mediated inflammatory responses using in vitro mouse bone marrow-derived mast cells (BMMCs) and human mast cells (HMC-1) and in vivo mice model. The effects of PFCs were compared with those of bisphenol A (BPA), a well-studied environmental pollutant. Among PFCs tested, PFOS had the highest effects. Both PFOS and BPA increased degranulation and production of inflammatory eicosanoids in mast cells at a similar level, which subsequently led to increased skin edema and serum LTC4 and PGD2 in mice. Both PFOS and BPA increased not only downstream signaling (PLCγ1, AKT, ERK), but also upstream signaling (Fyn, Lyn, Syk/LAT) in mast cells. Taken together, PFOS and BPA induce mast cell-mediated inflammatory responses via a common signaling pathways. Our results may help establish the scientific basis for understanding the etiology of mast cell-mediated inflammatory responses and improve the immune dysfunction risk assessment for emerging POPs such as PFCs.


Paracetamol hepatotoxicity and microsomal function.
The effect of paracetamol-induced hepatotoxicity in rats (650 mg/kg) on microsomal function was examined. Paracetamol treatment resulted in lowered Na(+),K(+)-ATPase activity in the microsomes with decrease in V(max) of the low affinity high V(max) component II. However, the temperature kinetics was not influenced significantly. The total phospholipid and cholesterol contents as well as lipid peroxidation in the microsomes were unchanged. However, content of acidic phospholipids: phosphatidylserine and phosphatidylinositol decreased by 50% with a reciprocal increase in the sphingomyelin content; the lysophosphoglyceride content increased by 12-fold. The microsomal membrane appeared to be more fluidized following paracetamol treatment. Paracetamol treatment also resulted in a significant reduction in the sulfhydryl groups content.


Viral loads, lymphocyte subsets and cytokines in asymptomatic, mildly and critical symptomatic patients with SARS-CoV-2 infection: a retrospective study.
Tens of million cases of coronavirus disease-2019 (COVID-19) have occurred globally. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. The aim of the present study is to investigate the laboratory characteristics of the viral load, lymphocyte subset and cytokines in asymptomatic individuals with SARS-CoV-2 infection in comparison with those in symptomatic patients with COVID-19. From January 24, 2020, to April 11, 2020, 48 consecutive subjects were enrolled in this study. Viral loads were detected by RT-PCR from throat-swab, sputum and feces samples. Lymphocyte subset levels of CD3 + , CD4 + , and CD8 + T lymphocytes, B cells and NK cells were determined with biological microscope and flow cytometric analysis. Plasma cytokines (IL2, IL4, IL5, IL6, IL8, IL10, TNF-α, IFN-α and IFN-γ) were detected using flow cytometer. Analysis of variance (ANOVA), Chi-square or Fisher's exact test and Pearson's Correlation assay was used for all data. Asymptomatic (AS), mild symptoms (MS) and severe or critical cases (SCS) with COVID-19 were 11 (11/48, 22.9%), 26 (54.2%, 26/48) and 11 cases (11/48, 22.9%), respectively. The mean age of AS group (47.3 years) was lower than SCS group (63.5 years) (P < 0.05). Diabetes mellitus in AS, MS and SCS patients with COVID-19 were 0, 6 and 5 cases, respectively, and there was a significant difference between AS and SCS (P < 0.05). No statistical differences were found in the viral loads of SARS-CoV-2 between AS, MS and SCS groups on admission to hospital and during hospitalization. The concentration of CD 3 + T cells (P < 0.05), CD3 + CD4 + T cells (P < 0.05), CD3 + CD8 + T cells (P < 0.01), and B cells (P < 0.05) in SCS patients was lower than in AS and MS patients, while the level of IL-5 (P < 0.05), IL-6 (P < 0.05), IL-8 (P < 0.01) and IL-10 (P < 0.01), and TNF-α (P < 0.05) was higher. The age was negatively correlated with CD3 + T cells (P < 0.05), CD3 + CD4 + T cells (P < 0.05), and positively correlated with IL-2 (P < 0.001), IL-5 (P < 0.05), IL-6 (P < 0.05) IL-8 (P < 0.05), and IL-10 (P < 0.05). The viral loads were positively correlated with IL-2 (P < 0.001), IL-5 (P < 0.05), IL-6 (P < 0.05) IL-8 (P < 0.05) and IL-10 (P < 0.05), while negatively correlated with CD 3 + T cells (P < 0.05) and CD3 + CD4 + T cells (P < 0.05). The viral loads are similar between asymptomatic, mild and severe or critical patients with COVID-19. The severity of COVID-19 may be related to underlying diseases such as diabetes mellitus. Lymphocyte subset and plasma cytokine levels may be as the markers to distinguish severely degrees of disease, and asymptomatic patients may be as an important source of infection for the COVID-19.


Cavity preparation by Er-YAG laser on pulpal temperature rise.
To measure the intrapulpal temperature changes in vitro, during cavity preparation and caries removal, using the Opus 20 Er-YAG laser plotted as a function of the laser energy and pulse rate. Class I and V cavity preparations were made in 175 fresh extracted caries-free human teeth and caries removal was carried out in 42 carious extracted teeth by the Opus 20 Er-YAG laser. K-type thermocouples were inserted into the pulp chambers filled with heat conducting paste. Lasing was carried out at different irradiation energies and pulse frequencies, using air-water spray. Temperature changes in the pulp chamber were measured during lasing. In all groups tested, the maximum temperature rise was lower than 5.5 degrees C, which is considered as critical value for pulp vitality. The highest temperature values were measured during Cl I preparations (3.13 degrees C +/- 1.54 - 4.11 degrees C +/- 1.29), medium values were in Cl V in enamel (2.38 degrees C +/- 1.37 - 4 degrees C +/- 1.07) and the lowest were in cementum (2.10 degrees C +/- 0.61 - 3.61 degrees C +/- 1.15) and during caries removal (1.21 degrees C +/- 0.46 - 3.51 degrees C +/- 0.68).


Evaluation of treatment response and resistance in metastatic renal cell cancer (mRCC) using integrated 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI); The REMAP study.
Tyrosine kinase inhibitors are the first line standard of care for treatment of metastatic renal cell carcinoma (RCC). Accurate response assessment in the setting of antiangiogenic therapies remains suboptimal as standard size-related response criteria do not necessarily accurately reflect clinical benefit, as they may be less pronounced or occur later in therapy than devascularisation. The challenge for imaging is providing timely assessment of disease status allowing therapies to be tailored to ensure ongoing clinical benefit. We propose that combined assessment of morphological, physiological and metabolic imaging parameters using 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) will better reflect disease behaviour, improving assessment of response/non-response/relapse. The REMAP study is a single-centre prospective observational study. Eligible patients with metastatic renal cell carcinoma, planned for systemic therapy, with at least 2 lesions will undergo an integrated 18F-FDG PET and MRI whole body imaging with diffusion weighted and contrast-enhanced multiphasic as well as standard anatomical MRI sequences at baseline, 12 weeks and 24 weeks of systemic therapy allowing 18F-FDG standardised uptake value (SUV), apparent diffusion co-efficient (ADC) and normalised signal intensity (SI) parameters to be obtained. Standard of care contrast-enhanced computed tomography CT scans will be performed at equivalent time-points. CT response categorisation will be performed using RECIST 1.1 and alternative (modified)Choi and MASS criteria. The reference standard for disease status will be by consensus panel taking into account clinical, biochemical and conventional imaging parameters. Intra- and inter-tumoural heterogeneity in vascular, diffusion and metabolic response/non-response will be assessed by image texture analysis. Imaging will also inform the development of computational methods for automated disease status categorisation. The REMAP study will demonstrate the ability of integrated 18F-FDG PET-MRI to provide a more personalised approach to therapy. We suggest that 18F-FDG PET/MRI will provide superior sensitivity and specificity in early response/non-response categorisation when compared to standard CT (using RECIST 1.1 and alternative (modified)Choi or MASS criteria) thus facilitating more timely and better informed treatment decisions. The trial is approved by the Southeast London Research Ethics Committee reference 16/LO/1499 and registered on the NIHR clinical research network portfolio ISRCTN12114913 .


Molecular insights of hyaluronic acid-hydroxychloroquine conjugate as a promising drug in targeting SARS-CoV-2 viral proteins.
In-silico anti-viral activity of Hydroxychloroquine (HCQ) and its Hyaluronic Acid-derivative (HA-HCQ) towards different SARS-CoV-2 protein molecular targets were studied. Four different SARS-CoV-2 proteins molecular target i.e., three different main proteases and one helicase were chosen for In-silico anti-viral analysis. The HA-HCQ conjugates exhibited superior binding affinity and interactions with all the screened SAR-CoV-2 molecular target proteins with the exception of a few targets. The study also revealed that the HA-HCQ conjugate has multiple advantages of efficient drug delivery to its CD44 variant isoform receptors of the lower respiratory tract, highest interactive binding affinity with SARS-CoV-2 protein target. Moreover, the HA-HCQ drug conjugate possesses added advantages of good biodegradability, biocompatibility, non-toxicity and non-immunogenicity. The prominent binding ability of HA-HCQ conjugate towards Mpro (PDB ID 5R82) and Helicase (PDB ID 6ZSL) target protein as compared with HCQ alone was proven through MD simulation analysis. In conclusion, our study suggested that further in-vitro and in-vivo examination of HA-HCQ drug conjugate will be useful to establish a promising early stage antiviral drug for the novel treatment of COVID-19.


Ultrastructural studies on the midgut of biting midge Forcipomyia nigra (Winnertz) (Diptera: Ceratopogonidae).
Biting midges belonging to the genus Forcipomyia are known to be hematophagous, predatory or saprophagous. Different stages of Forcipomyia nigra midges were investigated to provide a description of midgut ultrastructure. Larvae feeding on decaying organic matter possess simple, straight alimentary tracts whose middle regions are the longest. TEM studies of the larval midgut epithelium reveal that digestive cells show different ultrastructure depending on their age. The older cells with electron-dense cytoplasm degenerate while the younger ones with electron-lucent cytoplasm remain active in digestion. In saprophagous females, the ultrastructure of midgut epithelium changes according to the age of flies. Oogenesis induces degeneration of digestive cells and utilization of reserve material accumulated by them. The midgut epithelia of male midges consist of digestive and regenerative cells that show no evidence of cell degeneration as observed in females. Our results demonstrate differences between midgut digestive cells of males and females.


Critical scaffolding regions of the tumor suppressor Axin1 are natively unfolded.
The Wnt pathway tumor-suppressor protein Axin coordinates the formation of a critical multiprotein destruction complex that serves to downregulate β-catenin protein levels, thereby preventing target gene activation. Given the lack of structural information on some of the major functional parts of Axin, it remains unresolved how the recruitment and positioning of Wnt pathway kinases, such as glycogen synthase kinase 3β, are coordinated to bring about β-catenin phosphorylation. Using various biochemical and biophysical methods, we demonstrate here that the central region of Axin that is implicated in binding glycogen synthase kinase 3β and β-catenin is natively unfolded. Our results support a model in which the unfolded nature of these critical scaffolding regions in Axin facilitates dynamic interactions with a kinase and its substrate, which in turn act upon each other.


Postural responses to a moving room in children with and without developmental coordination disorder.
Children (10 or 11 years old) with and without developmental coordination disorder (DCD) were exposed to imposed optic flow in a moving room. We manipulated the amplitude and frequency of oscillatory room motion, and we evaluated the coupling of standing body sway with room oscillations. The results revealed that standing sway of both children with and without DCD was influenced by room motion. However, children with DCD responded differently than children without DCD to specific combinations of room motion amplitude and frequency. We conclude that DCD can influence a child's use of imposed optic flow for postural control and that these effects are situation-specific rather than being systemic.


The association between inhaled corticosteroid and the risks of SARS-COV-2 infection: A systematic review and meta-analysis.
The effect of inhaled corticosteroid (ICS) on the risk of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection is unclear. We performed a systematic review and meta-analysis of clinical studies that assessed the association between the use of ICS and the risk of SARS-COV-2 infection. PubMed, Web of Science, Scopus, Cochrane Library and Google Scholar were searched to January 1st, 2023. ROBINS-I was used to assess risk of bias of included studies. The outcome of interest was the risk of SARS-COV-2 infection in patients and odds ratio (OR) with 95% confidence interval (95% CI) were calculated using Comprehensive Meta-analysis software version 3. Twelve studies involving seven observational cohort studies, three case-control studies, and two cross-sectional studies were included in this meta-analysis. Overall, compared to non-ICS use, the pooled odds ratio (OR) of the risk of SARS-COV-2 infection was 0.997 (95% confidence interval [CI] 0.664-1.499; p = 0.987) for patients with ICS use. Subgroup analyses demonstrated no statistical significance in the increased risk of SARS-COV-2 infection in patients with ICS monotherapy or in combination with bronchodilators (pooled OR=1.408; 95% CI=0.693-2.858; p = 0.344 in ICS monotherapy, and pooled OR=1.225; 95% CI=0.533-2.815; p = 0.633 in ICS combination, respectively). In addition, no significant association was observed between ICS use and the risk of SARS-COV-2 infection for patients with COPD (pooled OR=0.715; 95% CI=0.415-1.230; p = 0.225) and asthma (pooled OR=1.081; 95% CI=0.970-1.206; p = 0.160). The use of ICS, either monotherapy or in combination with bronchodilators, does not have impact on the risk of SARS-COV-2 infection.


Ectopic ependymal cells in striatum accompany neurogenesis in a rat model of stroke.
Stroke-induced neurogenesis originates from a neural stem cell (NSC) niche in subventricular zone (SVZ). In mice, NSCs are concentrated in a so-called "neurogenic spot" in the lateral angle area of SVZ. We aimed to identify the "neurogenic spot" in the rat SVZ and to characterize the cellular changes in the ependymal cell compartment in this area at different time points after middle cerebral artery occlusion. The majority of ependymal cells outlining the ventricular wall did not proliferate, and their numbers in the "neurogenic spot" declined at 6 and 16weeks after stroke. Cells with the ultrastructural properties of ependymal cells were detected in the adjacent striatum. The number of these ectopic ependymal cells (EE cells) correlated positively with the magnitude of lateral ventricular enlargement and negatively with the ependymal cell number in the "neurogenic spot". EE cells were found along blood vessels, accumulated in the pericyst regions, and participated in scar formation but did not incorporate BrdU. We provide the first evidence for the occurrence of EE cells in the ischemic striatum following stroke.


Cp*Rh(III)-catalyzed regioselective cyclization of aromatic amides with allenes.
A new Cp*Rh(III)-catalyzed regioselective cyclization reaction of aromatic amides with allenes is reported. The use of allenyl derivatives bearing a directing-group assistant as a reaction promoter was the key to the success of this protocol. In this catalytic system, N-(pivaloyloxy)benzamide substrates react with allenes via Rh-σ-alkenyl intermediates, while N-(pivaloyloxy) indol substrates react via Rh-π-allyl intermediates. These reactions were characterized by mild reaction conditions, a broad substrate scope, and high functional-group compatibility to yield several high-value isoquinolinone and pyrimido[1,6-a]indol-1(2H)-one skeleton-containing compounds. The synthetic applications and primary mechanisms were also investigated.


Amortized Bayesian inference on generative dynamical network models of epilepsy using deep neural density estimators.
Whole-brain modeling of epilepsy combines personalized anatomical data with dynamical models of abnormal activities to generate spatio-temporal seizure patterns as observed in brain imaging data. Such a parametric simulator is equipped with a stochastic generative process, which itself provides the basis for inference and prediction of the local and global brain dynamics affected by disorders. However, the calculation of likelihood function at whole-brain scale is often intractable. Thus, likelihood-free algorithms are required to efficiently estimate the parameters pertaining to the hypothetical areas, ideally including the uncertainty. In this study, we introduce the simulation-based inference for the virtual epileptic patient model (SBI-VEP), enabling us to amortize the approximate posterior of the generative process from a low-dimensional representation of whole-brain epileptic patterns. The state-of-the-art deep learning algorithms for conditional density estimation are used to readily retrieve the statistical relationships between parameters and observations through a sequence of invertible transformations. We show that the SBI-VEP is able to efficiently estimate the posterior distribution of parameters linked to the extent of the epileptogenic and propagation zones from sparse intracranial electroencephalography recordings. The presented Bayesian methodology can deal with non-linear latent dynamics and parameter degeneracy, paving the way for fast and reliable inference on brain disorders from neuroimaging modalities.


An adaptor from translational to transcriptional control enables predictable assembly of complex regulation.
Bacterial regulators of transcriptional elongation are versatile units for building custom genetic switches, as they control the expression of both coding and noncoding RNAs, act on multigene operons and can be predictably tethered into higher-order regulatory functions (a property called composability). Yet the less versatile bacterial regulators of translational initiation are substantially easier to engineer. To bypass this tradeoff, we have developed an adaptor that converts regulators of translational initiation into regulators of transcriptional elongation in Escherichia coli. We applied this adaptor to the construction of several transcriptional attenuators and activators, including a small molecule-triggered attenuator and a group of five mutually orthogonal riboregulators that we assembled into NOR gates of two, three or four RNA inputs. Continued application of our adaptor should produce large collections of transcriptional regulators whose inherent composability can facilitate the predictable engineering of complex synthetic circuits.


Desmopressin oral lyophilisate in young children: new insights in pharmacokinetics and pharmacodynamics.
To study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability. Open label, non-randomised, interventional PK and PD trial. Single-centre study. Children (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5-8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month. After a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration. Non-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated. The PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (Vd/F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated. For the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated. NTC02584231.


Thermography: a reevaluation.
This is a brief review of the physical and physiologic aspects and theories of thermography and its clinical use in musculoskeletal conditions. Thermography is a simple, non-invasive procedure with a potential for usefulness. However, the majority of clinical studies to date have not been performed independent of other examinations with controlled verification, nor are there standards of normal available for comparison. Thermography should not be offered to the public as a confirmed and reliable tool for the diagnosis and management of musculoskeletal problems. It is still experimental, and its clinical use cannot be justified until appropriate data support it.


Seroepidemiologic investigations of human hepatitis caused by A, B, and a possible third virus.
Seroepidemiologic studies were made of normal subjects in populations in the United States and Costa Rica and in family outbreaks of hepatitis in Costa Rica. Hepatitis A affected a majority of children of very young age in Costa Rica, while such experience in persons of high socioeconomic status in the United States did not occur before middle life. Persons of low socioeconomic status (paid plasma donors) and residents and attendants of institutions for the mentally retarded showed a far greater incidence of hepatitis A antibody than did their counterparts in the open community. Hepatitis A and B epidemics occurred in families in Costa Rica with rapid spread to other susceptible members of the group. The disease was clinically apparent in roughly half the cases, whether the responsible agent be hepatitis A or B. Five cases of nonhepatitis A or B (hypothetical hepatitis C) were found and all but one of them were subclinical.


Leukocyte integrins.
Lymphocytes, monocytes and granulocytes, which are collectively known as 'leukocytes', circulate primarily within the vascular system and lymphoid tissue but are found in essentially all tissues of the body. This mobile lifestyle necessitates the constant making and breaking of adhesive contacts with targets in their immediate environment. The adhesion receptors termed integrins, which are expressed in abundance by leukocytes, are well suited to carry out the transient interactions in which these cells engage. Major advances in the leukocyte integrin field this year have been the realization of the extensive roles for alpha 4 integrins in leukocyte function, the solution of the crystal structure of an I domain and its identification as a major ligand-binding site, and the initial understanding of how divalent cations may function in an active integrin.


Isolation, fermentation, and formulation of entomopathogenic fungi virulent against adults of Diaphorina citri.
Mycopesticides are important for integrated management of the Asian citrus psyllid, Diaphorina citri. However, there are few reports on the fermentation and formulation for mycopesticides with high virulence against D. citri. From four different locations in South China, 12 fungal strains were isolated and classified into Beauveria bassiana (two isolates), Fusarium fujikuroi (five isolates), and Cordyceps javanica (five isolates) based on the phylogenetic analysis of ITS1-5.8S rDNA-ITS4 and morphology of colonies and conidia. Based on the highest initial virulence (86.52 ± 2.35%) and best growth characteristics, F-HY002-ACPHali was further optimized for biphasic fermentation (7.85 ± 2.62 × 109 g-1 dry substrate) with soybean meal + cottonseed flour (1:1) as the solid substrate and full light as the light/dark cycle. Furthermore, the oil-based conidial formulation was optimized with sesame oil as an effective carrier, which significantly enhanced conidial shelf life up to 16 weeks at 26 °C and 4 °C, thermo-stress (50 °C) and UV-B stress resistance, and virulence against adults of D. citri with increased mortalities and decreased LT50 in comparison to that of unformulated conidia. Our results not only provide a valuable native strain with high virulence against adults of D. citri, but also imply the soybean meal + cottonseed flour as valuable solid substrate, full-light exposure as environmental stimuli for solid-state fermentation, and the sesame oil as an effective carrier for the formulation of the C. javanica. These findings will facilitate the development of a potential mycopesticide for the biological control of Asian citrus psyllid.


Acoustic measurements are useful therapeutic indicators of patients with dysphonia-related to reflux.
The objective is to study the usefulness of acoustic measurements as therapeutic outcomes for patients with dysphonia related to laryngopharyngeal reflux (LPR). From September 2019 to April 2021, 120 patients with LPR at the hypopharyngeal-esophageal multichannel intraluminal impedance pH-monitoring (HEMII-pH) were prospectively recruited from three University Hospitals. They were divided in two groups regarding the presence of dysphonia. The treatment consisted of a combination of diet, proton-pump inhibitors, magaldrate and alginate for 3-6 months. The following clinical and acoustic evaluations were studied regarding groups at baseline, 3- and 6-month posttreatment: reflux symptom score (RSS), reflux sign assessment (RSA), percent jitter, percent shimmer and noise-to-harmonic ratio (NHR). A total of 109 patients completed the evaluations, accounting for 49 dysphonic and 60 non-dysphonic individuals. HEMII-pH, gastrointestinal endoscopy, baseline clinical and acoustic features were comparable between groups. RSS and RSA significantly improved from pre- to 3-month posttreatment in both groups. Jitter, Shimmer and NHR significantly improved from pre- to 3-month posttreatment in dysphonic patients, without additional 3- to 6-month posttreatment changes. Acoustic parameters did not change throughout treatment in patients without dysphonia. Acoustic measurements may be an interesting indicator of treatment in LPR patients who reported dysphonia. In this group of individuals, the evolution of acoustic parameters was consistent with the evolution of symptoms and findings.


Mobile phone-based interactive voice response as a tool for improving access to healthcare in remote areas in Ghana - an evaluation of user experiences.
To investigate and determine the factors that enhanced or constituted barriers to the acceptance of an mHealth system which was piloted in Asante-Akim North District of Ghana to support healthcare of children. Four semi-structured focus group discussions were conducted with a total of 37 mothers. Participants were selected from a study population of mothers who subscribed to a pilot mHealth system which used an interactive voice response (IVR) for its operations. Data were evaluated using qualitative content analysis methods. In addition, a short quantitative questionnaire assessed system's usability (SUS). Results revealed 10 categories of factors that facilitated user acceptance of the IVR system including quality-of-care experience, health education and empowerment of women. The eight categories of factors identified as barriers to user acceptance included the lack of human interaction, lack of update and training on the electronic advices provided and lack of social integration of the system into the community. The usability (SUS median: 79.3; range: 65-97.5) of the system was rated acceptable. The principles of the tested mHealth system could be of interest during infectious disease outbreaks, such as Ebola or Lassa fever, when there might be a special need for disease-specific health information within populations.


Cav1.2 channels mediate persistent chronic stress-induced behavioral deficits that are associated with prefrontal cortex activation of the p25/Cdk5-glucocorticoid receptor pathway.
Chronic stress is known to precipitate and exacerbate neuropsychiatric symptoms, and exposure to stress is particularly pathological in individuals with certain genetic predispositions. Recent genome wide association studies have identified single nucleotide polymorphisms (SNPs) in the gene CACNA1C, which codes for the Cav1.2 subunit of the L-type calcium channel (LTCC), as a common risk variant for multiple neuropsychiatric conditions. Cav1.2 channels mediate experience-dependent changes in gene expression and long-term synaptic plasticity through activation of downstream calcium signaling pathways. Previous studies have found an association between stress and altered Cav1.2 expression in the brain, however the contribution of Cav1.2 channels to chronic stress-induced behaviors, and the precise Cav1.2 signaling mechanisms activated are currently unknown. Here we report that chronic stress leads to a delayed increase in Cav1.2 expression selectively within the prefrontal cortex (PFC), but not in other stress-sensitive brain regions such as the hippocampus or amygdala. Further, we demonstrate that while Cav1.2 heterozygous (Cav1.2+/-) mice show chronic stress-induced depressive-like behavior, anxiety-like behavior, and deficits in working memory 1-2 days following stress, they are resilient to the effects of chronic stress when tested 5-7 days later. Lastly, molecular studies find a delayed upregulation of the p25/Cdk5-glucocorticoid receptor (GR) pathway in the PFC when examined 8 days post-stress that is absent in Cav1.2+/- mice. Our findings reveal a novel Cav1.2-mediated molecular mechanism associated with the persistent behavioral effects of chronic stress and provide new insight into potential Cav1.2 channel mechanisms that may contribute to CACNA1C-linked neuropsychiatric phenotypes.


PEPC of sugarcane regulated glutathione S-transferase and altered carbon-nitrogen metabolism under different N source concentrations in Oryza sativa.
Phosphoenolpyruvate carboxylase (PEPC) plays an important role in the primary metabolism of higher plants. Several studies have revealed the critical importance of PEPC in the interaction of carbon and nitrogen metabolism. However, the function mechanism of PEPC in nitrogen metabolism is unclear and needs further investigation. This study indicates that transgenic rice expressing the sugarcane C4-PEPC gene displayed shorter primary roots and fewer crown roots at the seedling stage. However, total nitrogen content was significantly higher in transgenic rice than in wild type (WT) plants. Proteomic analysis revealed that there were more differentially expressed proteins (DEPs) responding to nitrogen changes in transgenic rice. In particular, the most enriched pathway "glutathione (GSH) metabolism", which mainly contains GSH S-transferase (GST), was identified in transgenic rice. The expression of endogenous PEPC, GST and several genes involved in the TCA cycle, glycolysis and nitrogen assimilation changed in transgenic rice. Correspondingly, the activity of enzymes including GST, citrate synthase, 6-phosphofructokinase, pyruvate kinase and ferredoxin-dependent glutamate synthase significantly changed. In addition, the levels of organic acids in the TCA cycle and carbohydrates including sucrose, starch and soluble sugar altered in transgenic rice under different nitrogen source concentrations. GSH that the substrate of GST and its components including glutamic acid, cysteine and glycine accumulated in transgenic rice. Moreover, the levels of phytohormones including indoleacetic acid (IAA), zeatin (ZT) and isopentenyladenosine (2ip) were lower in the roots of transgenic rice under total nutrients. Taken together, the phenotype, physiological and biochemical characteristics of transgenic rice expressing C4-PEPC were different from WT under different nitrogen levels. Our results revealed the possibility that PEPC affects nitrogen metabolism through regulating GST, which provide a new direction and concepts for the further study of the PEPC functional mechanism in nitrogen metabolism.


Distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene-expression analysis.
The present study aims at a platform-independent confirmation of previously obtained cDNA microarray results on inflammatory breast cancer (IBC) using Affymetrix chips. Gene-expression data of 19 IBC and 40 non-IBC specimens were subjected to clustering and principal component analysis. The performance of a previously identified IBC signature was tested using clustering and gene set enrichment analysis. The presence of different cell-of-origin subtypes in IBC was investigated and confirmed using immunohistochemistry on a TMA. Differential gene expression was analysed using SAM and topGO was used to identify the fingerprints of a pro-metastatic-signalling pathway. IBC and non-IBC have distinct gene-expression profiles. The differences in gene expression between IBC and non-IBC are captured within an IBC signature, identified in a platform-independent manner. Part of the gene-expression differences between IBC and non-IBC are attributable to the differential presence of the cell-of-origin subtypes, since IBC primarily segregated into the basal-like or ErbB2-overexpressing group. Strikingly, IBC tumour samples more closely resemble the gene-expression profile of T1/T2 tumours than the gene-expression profile or T3/T4 tumours. We identified the insulin-like growth factor-signalling pathway, potentially contributing to the biology of IBC. Our previous results have been validated in a platform-independent manner. The distinct biological behaviour of IBC is reflected in a distinct gene-expression profile. The fact that IBC tumours are quickly arising tumours might explain the close resemblance of the IBC gene-expression profile to the expression profile of T1/T2 tumours.


DNA hypomethylation is prevalent even in low-grade breast cancers.
Hypomethylation of some portions of the genome and hypermethylation of others are very frequent attributes of human cancer. We previously showed that cancer-associated DNA hypomethylation often involves satellite 2 (Sat2), the main DNA component of the large juxtacentromeric (centromere-adjacent) heterochromatin of chromosome 1. In this study, we compared methylation of Sat2 and centromeric satellite DNA (Satalpha) as well as overall genomic methylation in 41 breast adenocarcinomas of known tumor grade and stage, 16 non-neoplastic breast tissues (mostly fibroadenomas), and a variety of normal somatic tissue controls. The cancers were significantly hypomethylated at Sat2 relative to the fibroadenomas or normal somatic tissues and at Satalpha relative to the normal somatic tissues. However, unlike Sat2, Satalpha did not display significant differences in methylation between the cancers and the non-neoplastic breast tissues. Therefore, hypomethylation at Sat2 is a much better marker of breast cancer than is Satalpha hypomethylation. There was a significant association of Sat2 hypomethylation with global DNA hypomethylation in the cancers but not with tumor grade, stage, axillary lymph node involvement, or hormone receptor status. Extensive cancer-associated hypomethylation of juxtacentromeric satellite DNA and global DNA hypomethylation were common even in grade-1 or stage-1 carcinomas, which suggests that demethylation of the genome is an early event in breast carcinogenesis.


Recovery of Platinum-Group Metals from an Unconventional Source of Catalytic Converter Using Pressure Cyanide Leaching and Ionic Liquid Extraction.
The fast depletion of critical metals in natural reserves against their increasing demands in advanced technology application presents the necessity to exploit the end-of-life/waste materials as unconventional resources. Due to a higher accumulation of platinum-group metals (PGMs) in exhausted autocatalytic converters, their recycling through an integrative bio-solvo-chemical technique has been studied. PGMs were efficiently dissolved in bio-cyanide solution produced by Chromobacterium violaceum. The autoclave leaching was optimized in the conditions of temperature, 150°C; pO2, 200 psi; and time, 120 min, yielding > 90% PGMs' dissolution. PGMs' separation from cyanide leach liquor was performed using an ionic liquid, Cyphos IL101. Under optimum conditions (i.e., ionic liquid concentration, 0.15 mol/L; extraction pH, 10.4; and temperature, 25°C), Pt and Pd were selectively stripping with > 99% efficiency in 0.1 mol/L (acidic) thiourea and 1.0 mol/L HNO3 solution, respectively, leaving Rh in the raffinate.


IgG (Gm) allotypes and multiple sclerosis in a French population: phenotype distribution and quantitative abnormalities in CSF with respect to sex, disease severity, and presence of intrathecal antibodies.
The association of a given Gm allotype or phenotype with MS susceptibility, as previously described in some Caucasian populations, was not observed in a large French MS group, whether or not considering the possible influence of sex or disease severity. This result could be related to variations in geographical distribution of Gm alleles and MS susceptibility gene(s) or suggests the simultaneous involvement of Gm and other genetic system(s). In contrast, the corresponding CSFs exhibited already known MS-associated abnormalities of IgG1 (G1m) allotype contents, which therefore did not merely result from a Gm-associated MS susceptibility. These quantitative abnormalities were not sex dependent, but may fluctuate with MS severity. The G1m allotype levels in each CSF were not correlated with titers of various intrathecal antibodies but with the number of antibody specificities detected, a picture arguing for a polyclonal, non-antigen-specific activation of G1m allotype-producing B cells present in MS brain.


[Delayed surgical treatment of traumatic injury of the thoracic aorta].
Two cases of traumatic aneurysm of the thoracic aorta associated with blunt chest trauma are described. We underwent the operation for the aorta at 23 days in case 1 and 39 days in case 2 after the injury. Immediate repair may be thought to be the first choice for acute traumatic injury of the thoracic aorta, but delayed surgery can be achieved more safely in the patients, especially with associated injury.


Bonding, Aromaticity and Isomerization of Furfuraldehyde through Off-Nucleus Isotropic Magnetic Shielding.
Off-nucleus isotropic magnetic shielding (σiso (r)) and multi-points nucleus independent chemical shift (NICS(0-2 Å)) index were utilized to find the impacts of the isomerization of gas-phase furfuraldehyde (FD) on bonding and aromaticity of FD. Multidimensional (1D to 3D) grids of ghost atoms (bqs) were used as local magnetic probes to evaluate σiso (r) through gauge-including atomic orbitals (GIAO) at density functional theory (DFT) and B3LYP functional/6-311+G(d,p) basis set level of theory. 1D σiso (r) responses along each bond of FD were examined. Also, a σiso (r) 2D-scan was performed to obtain σiso (r) behavior at vertical heights of 0-1 Å above the FD plane in its cis, transition state (TS) and trans forms. New techniques for evaluating 2D σiso (r) cross-sections are also included. Our findings showed that bonds in cyclic and acyclic parts of FD are dissimilar. Unlike the C-O bond of furanyl, the C=O bond of the formyl group is magnetically different. C-C and C-H bonds in furanyl are found similar to those in aromatic rings. A unique σiso (r) trend was observed for the C2 -C6 bond during FD isomerization. Based on NICS(0-2 Å) values, the degree of aromaticity follows the order of cis FD<trans FD<furan<TS FD.


Does blood on "dirty" instruments interfere with the effectiveness of sterilization technologies?
We evaluated the robustness of sterilization technologies when spores and bacteria were placed on "dirty" instruments and overlaid with blood. The results illustrate that steam sterilization is the most effective sterilization technology with the largest margin of safety, followed by ethylene oxide and hydrogen peroxide gas plasma.


Safety evaluation of self-expanding metallic biliary stents eluting gemcitabine in a porcine model.
Palliative biliary decompression by metal stent is the treatment of choice for unresectable malignant biliary obstruction; however, conventional stents provide only mechanical palliation and exert no anti-tumor effects. Gemcitabine (GEM) has been reported to be more effective in unresectable pancreatic cancer and biliary cancer compared with other chemotherapeutic drugs. We evaluated the safety of a GEM-eluting stent by analyzing histologic responses of the porcine bile duct. Stents containing GEM (0%, 10%, 15%, and 20% [w/v]) were surgically inserted into bile ducts of pigs (each group, n = 2). The animals were euthanized after 4 weeks, and the stented bile duct segment underwent gross and microscopic examination. Laboratory assay was performed for aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, and gamma-glutamyl transferase (γ-GTP). Moderate to severe inflammation was observed in the bile ducts in contact with stents containing 15 and 20% GEM, compared with no inflammation with 0% GEM and mild inflammation with 10% GEM. Fibrous reactions observed in the submucosal layer did not differ among groups. Transmural necrosis and perforations were not observed in any animal. No abnormal laboratory test findings were directly caused by GEM. Our newly developed GEM eluting stents can be used safely in normal bile ducts. Our results indicated that 10% GEM produced mild histologic changes in the stented segment and adjacent tissue; this concentration may be appropriate for clinical application.


Change of gastric liquid emptying after highly selective vagotomy and pyloric dilatation for patients with obstructing duodenal ulcer.
Gastric liquid emptying was studied in duodenal ulcer patients with and without stenosis before highly selective vagotomy (HSV) and 1 week, 3 months, and 1 year after. The test meal consisted of 1 mCi of 99m Technetium-diethylene penta-acetic acid (DTPA) in 500 ml of isotonic saline. The patients were divided into 2 groups: group 1 (16 cases) without clinical stenosis, who underwent HSV alone, served as control; group 2 (14 cases) with mild to moderate stenosis, who underwent HSV and transgastric dilatation to 20 mm in diameter. Before HSV, the stenotic group showed a significantly slower liquid emptying than the nonstenotic. Most of the stenotic group could resume a normal diet quickly after operation, but they still had prolonged liquid emptying. At 3 months, the emptying curve of the stenotic patients had approached that of the preoperative controls without a significant difference, while the nonstenotic patients showed an accelerated initial emptying. Although there was a significant improvement with the appearance of accelerated initial emptying at 1 year, the stenotic group still demonstrated slightly slower emptying than the nonstenotic group. A temporary state of preexistent gastric atony due to chronic outlet obstruction may explain the delayed emptying in the early postoperative period; however, minor residual resistance in the fibrotic, scarred tissue was postulated to be persistent despite dilatation, and responsible for the slower emptying of the stenotic than the nonstenotic group at 1 year.


Biosynthesis of galactogen: identification of a beta-(1----6)-D-galactosyltransferase in Helix pomatia albumen glands.
A beta-(1----6)-D-galactosyltransferase has been purified over 2000-fold by affinity chromatography on UDP-p-aminophenyl-Sepharose. The enzyme, from a pellet fraction (8000 x g) of Helix pomatia albumen gland, catalyzes transfer of D-galactose from UDP-galactose to a (1----6) linkage on acceptor H. pomatia galactogen. Three other polymers served as acceptors: beef lung galactan, Lymnaea stagnalis galactogen and arabinogalactan from larch wood. To determine the linkage specificity of the enzyme, it was incubated with UDP-D-galactose and acceptor galactogen that had been tritiated previously by treatment with galactose oxidase and [3H]KBH4. The [3H]galactogen reaction product was recovered, methylated, hydrolyzed and acetylated; tritiated derivatives were identified by mass spectroscopy of effluent fractions separated by gas chromatography. This analysis revealed that (1----6)-linked galactosyl groups had been added to the enzyme-treated acceptor galactogen. Also identified was a hydrolytic enzyme that removed terminal alpha 1,2-linked L-galactosyl residues from H. pomatia galactogen.


PEG-Based Hydrogel Coatings: Design Tools for Biomedical Applications.
Device failure due to undesired biological responses remains a substantial roadblock in the development and translation of new devices into clinical care. Polyethylene glycol (PEG)-based hydrogel coatings can be used to confer antifouling properties to medical devices-enabling minimization of biological responses such as bacterial infection, thrombosis, and foreign body reactions. Application of hydrogel coatings to diverse substrates requires careful consideration of multiple material factors. Herein, we report a systematic investigation of two coating methods: (1) traditional photoinitiated hydrogel coatings; (2) diffusion-mediated, redox-initiated hydrogel coatings. The effects of method, substrate, and compositional variables on the resulting hydrogel coating thickness are presented. To expand the redox-based method to include high molecular weight macromers, a mechanistic investigation of the role of cure rate and macromer viscosity was necessary to balance solution infiltration and gelation. Overall, these structure-property relationships provide users with a toolbox for hydrogel coating design for a broad range of medical devices.


Probabilistic approach to polychlorinated biphenyl (PCB) exposure through eel consumption in recreational fishermen vs. the general population.
Concentrations of the sum of the seven indicator PCBs (Sigma7 iPCBs) measured in non-commercial European eel (Anguilla anguilla L.) in Flanders are high: in 80% of all sampled localities, the Belgian PCB standard for fish was exceeded. The objective of this study was to assess the intake of the Sigma7 iPCBs through consumption of eel by recreational fishermen and to compare it to the intake of a background population. The median estimated intake for recreational fishermen varied between 18.4 and 237.6 ng iPCBs kg(-1) bw day(-1), depending on the consumption scenario, while the estimated intake of the background population (consumers only) was 4.3 ng iPCBs kg(-1) bw day(-1). Since the levels of intake via eel for two intake scenarios were, respectively, 50 and 25 times higher than the intake of the background population, the body burden (BB) might be proportionally higher and reach levels of toxicological relevance. The intake of the seven iPCBs via consumption of self-caught eel in Flanders is at a level to cause serious concern. The Flemish catch-and-release obligation for eel, established in 2002, should be maintained and supervised (more) carefully.


Judo training program improves brain and muscle function and elevates the peripheral BDNF concentration among the elderly.
Programmed exercise interventions modulating both physical fitness and cognitive functions have become a promising tool to support healthy aging. The aim of this experiment was to determine the effect of a 12-week judo training (JEX) on cognitive processing and muscle function among the elderly. Forty participants were divided into two groups: the JEX group and the control group (CTL). Before and after 12-week of JEX, participants performed a battery of physiological and psychological tests. The peripheral level of brain-derived neurotrophic factor (BDNF) was analyzed. A 12-week JEX intervention led to improved Stroop performance reflected by a shortening of the response time related to Stroop "naming" interference. In addition, the peripheral concentration of BDNF was significantly increased following the JEX compared with the CTL group. In response to JEX, balance and lower limb strength significantly increased. The current results suggest that JEX could have beneficial effects on cognitive functions, denoted by elevated peripheral BDNF, as well as on balance and strength abilities. A combination of positive effects with respect to movement and cognition makes JEX an ideal preventive lifestyle modification for the aging population.


Anti-androgen flutamide affects gonadal development and reproduction in medaka (Oryzias latipes).
The effects of an anti-androgenic chemical on the reproduction of medaka (Oryzias latipes) were examined. Six mating pairs of medaka were exposed to flutamide (FLU) at measured concentrations of 0.101, 0.202, 0.397, 0.787, or 1.56 mg/L for 3 weeks. During the exposure period, one female died in the 1.56-mg/L treatment group, but no lesions or pathological abnormalities were observed. The fecundity and fertility of paired medaka were significantly decreased at 1.56 mg/L compared with those of the controls. Histological examination showed intersex gonads (testis-ova) in males exposed to FLU at 0.202, 0.397, and 0.787 mg/L. However, concentrations of hepatic vitellogenin (Vtg) in both sexes were not statistically different from those in the controls. These results demonstrate that FLU affected gonadal development in male medaka and reproductive capacity in paired medaka. This is the first report of testis-ova in male medaka exposed to FLU.


Quality of life among Oral Potentially Malignant Disorder (OPMD) patients: A prospective study.
The purpose of this study was to evaluate the quality of life among the Oral Potentially Malignant Disorder (OPMD) patients during diagnosis, at one month and 3 months after intervention (surgical or conservative). The University of Washington Quality of Life version (4UWQOL v4) and World Health Organization (WHO-BREF) were repeatedly administered on 54 OPMD patients. The results of Friedman's ANOVA showed a statistically significant change in the mean scores for pain, activity, speech, shoulder, taste, saliva, mood, and anxiety domains of UWQOL with time, (p-value <0.05); while physical health, social relationships, environment domains of WHO- BREF have shown significant changes in their respective mean scores. The assessment of Quality of Life (QOL) should routinely be done by the clinicians. If the clinicians start considering the QOL as the primary outcome of a treatment protocol, it will enhance patients' identity, well-being, and personality.


Carboamination of Unactivated Alkenes through Three-Component Radical Conjugate Addition.
Two-component Giese type radical additions are highly practical and established reactions. Herein, three-component radical conjugate additions of unactivated alkenes to Michael acceptors are reported. Amidyl radicals, oxidatively generated from α-amido oxy acids using redox catalysis, act as the third reaction component which add to the unactivated alkenes. The adduct radicals engage in Giese type additions to Michael acceptors to provide, after reduction, the three-component products in an overall alkene carboamination reaction. Transformations which can be conducted under practical mild conditions feature high functional group tolerance and broad substrate scope.


Gold Nanoparticle-Based Enzyme-Assisted Cyclic Amplification for the Highly-Sensitive Detection of miRNA-21.
Because microRNAs (miRNAs) are biological indicators for the diagnosis, treatment, and monitoring of tumors, cancers, and other diseases, it is significant to develop a rapid, sensitive, and reliable miRNA detection platform. In this study, based on miRNA-21 detection, DNA-a with a 3' end overhang and Texas Red fluorophore-labeled 5' end was designed, which reacts with miRNA-21 and hybridizes with exonuclease III (Exo III), where the part connected to miRNA-21 is hydrolyzed, leaving a-DNA. At the same time, miRNA-21 is released to participate in the following reaction, to achieve cyclic amplification. a-DNA reacts with DNA-b conjugated to gold nanoparticles to achieve fluorescence quenching, with the quenching value denoted as F; additionally, after adding DNA-d and linked streptavidin immunomagnetic beads (SIBs), fluorescence recovery was achieved using DNA-c, with the recovered fluorescence recorded as F0. By comparing the difference in the fluorescence (F0 - F) between the two experiments, the amount of DNA-a hydrolyzed to produce a-DNA was established to determine the target miRNA-21 content. Under optimized conditions, by comparing the changes in the fluorescence signal, the developed strategy shows good sensitivity and repeatability, with a detection limit of 18 pM, good discriminative ability and selectivity, and promise for the early diagnosis of breast and intestinal cancers.


Mechanical power of ventilation is associated with mortality in neurocritical patients: a cohort study.
This study aimed to determine the predictive relevance of mechanical power in the clinical outcomes (such as ICU mortality, hospital mortality, 90-day mortality, length of ICU stay, and number of ventilator-free days at day 28) of neurocritical patients. This is a retrospective cohort analysis of an open-access clinical database known as MIMIC-III. The study included patients who had sustained an acute brain injury and required invasive ventilation for at least 24 h. Demographic parameters, disease severity scores (Glasgow coma scale), comorbidities, vital signs, laboratory parameters and ventilator parameters were collected within the first 24 h of ICU admission. The main outcome was the relationship between MP and ICU mortality. A total of 529 patients were selected for the study. The critical value of MP was 12.16 J/min, with the area under the curve (AUC) of the MP was 0.678 (95% CI 0.637-0.718), and compared to the GCS scores, the MP performed significantly better in discrimination (DeLong's test: p < 0.001). Among these patients elevated MP was associated to higher ICU mortality (OR 1.11; 95% CI 1.06-1.17; p < 0.001), enhanced the risk of hospital mortality, prolonged ICU stay, and decreased the number of ventilator-free days. In the subgroup analysis, high MP was associated with ICU mortality regardless of ARDS (OR 1.01, 95% CI 1.00-1.02, p = 0.009; OR 1.01, 95% CI 1.00-1.02, p = 0.018, respectively) or obesity (OR 1.01, 95% CI 1.00-1.02, p = 0.012; OR 1.01, 95% CI 1.01-1.02, p < 0.001, respectively). In neurocritical care patients undergoing invasive ventilation, elevated MP is linked to higher ICU mortality and a variety of other clinical outcomes.


Involvement of protein kinase A in the induction of arginase in murine bone marrow-derived macrophages.
Arginase is induced in bone marrow-derived macrophages by agents that increase the intracellular concentrations of cAMP (Br-cAMP, prostaglandin E2) and, in their presence, the LPS induced NO synthesis is down regulated. Moreover, interleukin 10 which induces arginase in macrophages is able to increase the cAMP-dependent protein kinase A activity. In contrast, suppressors of NOS synthesis like protein kinase C inhibitors and calmodulin antagonists (W7), or NO activators (A23187) have no effect on the induction of arginase by LPS. These results strongly suggest that PKA is involved in the induction of arginase and supports the hypothesis that there is a reciprocal regulation of these two enzymes that drives the macrophages towards opposite functional states.


Production Process Development of Pseudorabies Virus Vaccine by Using a Novel Scale-Down Model of a Fixed-Bed Bioreactor.
In this study, a novel tube-fixed-bed bioreactor which consists of a TubeSpin bioreactor 50 tube and 0.44 g macrocarriers was developed as the scale-down model of a fixed-bed bioreactor. The adherent Vero cell-based pseudorabies virus (PRV) production process was tested in this novel model. The Vero cells grew well in the tube-fixed-bed bioreactor, and the cell density reached 5.8 × 106 cells/mL after 7 days of culture. The PRV production parameters (time of infection, multiplicity of infection, and harvest process) were optimized in the tube-fixed-bed bioreactor. Then the optimized process (time of infection = 3 days, multiplicity of infection = 0.001 and multiple harvest process) was scaled up 25-fold to an Xcell 1-L laboratory-scale fixed-bed bioreactor and 125-fold to an Xcell 5-L fixed-bed bioreactor successfully. The total PRV harvest in the Xcell 1-L bioreactor at 5 days after infection (dpi) was 10.25 log10 TCID50 which corresponds to 177,827 doses of vaccine. The total PRV harvest in the Xcell 5-L bioreactor at 5 dpi was 11.13 log10 TCID50 which corresponded to 1,348,962 doses of vaccine. The comparable growth curve, metabolism, and PRV production profile of the scaled-up bioreactors confirmed the feasibility and scalability of the tube-fixed-bed bioreactor as a scale-down model of the fixed-bed bioreactor for virus production process development.


Computed tomography combined with gastroscopy for assessment of pancreatic segmental portal hypertension.
Pancreatic segmental portal hypertension (PSPH) is the only type of portal hypertension that can be completely cured. However, it can easily cause varicose veins in the esophagus and stomach and hemorrhage in the digestive tract. To explore the application of computed tomography (CT) to examine the characteristics of PSPH and assess the risk level. This was a retrospective analysis of CT images of 22 patients diagnosed with PSPH at our center. Spearman correlation analysis was performed using the range of esophageal and gastric varices (measured by the vertical gastric wall), the ratio of the width of the splenic portal vein to that of the compression site (S/C ratio), the degree of splenomegaly, and the stage determined by gastroscopy. This study examined whether patients experienced gastrointestinal bleeding within 2 wk and combined CT and gastroscopy to explore the connection between bleeding and CT findings. The range of esophageal and gastric varices showed the best correlation in the diagnosis of PSPH (P < 0.001), and the S/C ratio (P = 0.007) was correlated with the degree of splenomegaly (P = 0.021) and PSPH (P < 0.05). This study revealed that male patients were more likely than females to progress to grade 2 or grade 3 as determined by gastroscopy. CT demonstrated excellent performance, with an area under the curve of 0.879. CT can be used to effectively analyze the imaging signs of PSPH, and CT combined with gastroscopy can effectively predict the risk level of gastrointestinal bleeding.


Assignment of phosphorylation sites in buffalo beta-casein by fast atom bombardment mass spectrometry.
Fast atom bombardment mass spectrometry has been applied to the localization of phosphorylation sites in buffalo beta-casein. Two complementary strategies of identification are described. Phosphorylated residues in the tryptic peptide Tp 1 have been assigned by measuring the masses of peptide fragments obtained by enzymatic degradations. The phosphoserine residue in peptide Tp 2 has been identified by determining the intact molecular weight and confirmed by partial sequence information. This rapid and sensitive procedure appears of a great interest in structural studies of a wide range of post-translational modifications in proteins.


Biallelic variants in CPAMD8 are associated with primary open-angle glaucoma and primary angle-closure glaucoma.
This study aims to assess the contribution of biallelic CPAMD8 variants in patients with different forms of glaucoma, especially primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), based on a systematic analysis of exome sequencing (ES). Potentially pathogenic CPAMD8 variants were selected from the ES data of 5307 subjects with various eye conditions through multiple bioinformatics analyses. Of the 5307 subjects, 1221 probands had different forms of primary glaucoma. The genotype-phenotype correlation was assessed by a systematic review of biallelic CPAMD8 variants that including our data and data from the literature. The expression profile of CPAMD8 in human tissues was determined at the mRNA and protein levels. Biallelic CPAMD8 variants, including one frameshift and six missense variants, were exclusively present and significantly enriched in patients with glaucoma (one with juvenile open-angle glaucoma (JOAG), two with POAG and two with PACG) compared with none of the 4086 probands with other eye conditions in this cohort (p=4.1E-07). The effect of variants in these patients is relatively mild compared with that reported in patients with anterior segment dysgenesis or primary congenital glaucoma. CPAMD8 mRNA was highly expressed in the optic nerve, ciliary body, retina and iris, whereas the CPAMD8 protein was mainly detected in the nonpigmented epithelium of the iris and ciliary process, determined by immunohistochemistry. The data from this study not only provide further evidence to support the association of biallelic CPAMD8 variants with JOAG but also suggest that biallelic CPAMD8 variants might be associated with POAG and PACG.


Diagnosis of perioperative myocardial necrosis following coronary artery surgery--a reappraisal of isoenzyme analysis.
Although the routine determination of CK-MB activity is widely used after coronary artery bypass grafting (CABG), the diagnosis of a perioperative myocardial necrosis remains arbitrary. The intention of the present study was to develop discriminative enzymatic parameters of CK-MB activity in a collective of 710 patients following CABG. Patients were grouped according to their postoperative electrocardiogram (ECG). For each patient, the time activity curve of CK-MB was determined. The total amount of CK-MB was calculated by integrating the area beneath the CK-MB activity curve. Patients presenting with an unchanged postoperative ECG (group I) or a new bundle branch block with uncompromised haemodynamics (group IIa) had an uniform and low profile of CK-MB activity. Serial CK-MB activities as well as the integrated CK-MB area of these two collectives were significantly different (P less than 0.001) from values determined for patients with bundle branch block and low cardiac output (group II b) or patients with new Q waves (group III). After 24h, the 90th percentile of serial CK-MB activities of group I had declined to 18 U/l and was clearly exceeded by 90% of all patients that belonged to either group IIb or III. The 90th percentile of CK-MB areas for group I showed a value of 801 U/l x h. CK-MB areas above 801 U/l x h were seen in about 50% of all patients of group IIa.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of phase transition temperature of liposomes on preparation of fullerene-encapsulated liposomes by the fullerene-exchange reaction.
It is shown that the fullerene-exchange reaction from the cyclodextrin cavity to liposomes, to prepare lipid membrane-incorporating fullerenes, occurred above the phase transition temperature (T(m)) of liposomes.


Aftermath of fortnightly universal testing for severe acute respiratory corona virus-2 infection in maintenance hemodialysis patients.
Asymptomatic maintenance hemodialysis patients with acute respiratory corona virus-2 (SARS-COV-2) are missed with pre-dialysis screening without testing. The possible ideal strategy of testing each patient before each shift with reverse transcription polymerase chain reaction (RT-PCR) is not feasible. We aimed to study the effectiveness of fortnightly screening with RT-PCR for SARS-CoV-2 in curbing transmission. Between July 1, 2020 and September 30, 2020, all 273 patients receiving hemodialysis were subjected to fortnightly testing for SARS-Cov-2 in the unit to detect asymptomatic patients. The cost and effectiveness of universal testing in preventing transmission were analyzed using susceptible-infectious-removed (SIR) modeling assuming R0 of 2.2. Of 273 MHD patients, 55 (20.1%) found infected with SARS-CoV-2 over 3 months. Six (10.9%) were symptomatic, and 49 (89.1%) asymptomatic at the time of testing. Six (10.9%) asymptomatic patients develop symptoms later, and 43 (78.2%) remained asymptomatic. A total of seven (6.1%) HCWs also tested positive for the virus. Fortnightly universal testing is cost-effective, and SIR modeling proved effective in preventing person-to-person transmission. Repeated universal testing in maintenance hemodialysis patients detected 89% of asymptomatic SARS-CoV-2 patients over 3 months and appeared to be an effective strategy to prevent person-to-person transmission in the dialysis unit.


No association between partial depopulation and Campylobacter spp. colonization of Dutch broiler flocks.
To determine whether an association exists between partial depopulation of a flock and increased Campylobacter colonization in that flock. Data from 1737 flocks of two Dutch integrators were used. Flocks that experienced partial depopulation were defined as 'exposed' and those that did not as 'nonexposed'. Multivariable modelling was accomplished with, in addition to 'exposure', the independent variables 'age of broilers at slaughter' and 'season' to adjust for possible confounding. The response variable was 'Campylobacter colonization'. The odds ratio (OR) for partial depopulation for integrator A was 0.8 [95% CI (0.4, 1.8)]; for integrator B the OR = 0.8 [95% CI (0.5, 1.3)]. Age and season were confounders: the difference in Campylobacter status between exposed and nonexposed flocks of integrator A could be explained by both variables; for integrator B, only season was associated with Campylobacter status. We found no significant association between partial depopulation and an increased risk of Campylobacter colonization among broiler flocks at final depopulation. This study demonstrates that Campylobacter colonization in a broiler flock is not influenced by the partial depopulation of that flock.


Nitrogen doped porous carbon coated antimony as high performance anode material for sodium-ion batteries.
Sb holds the promise of being a high performance anode for sodium ion batteries(SIBs), while effective preparation of decent antimony(Sb) based anode materials for sodium storage is still under exploration. Herein, we propose a simple approach to achieve a high performance anode, using polyaniline as the carbon source and SbCl3as the metal source. Synergetic polymerization and hydrolysis reactions combined with subsequent thermal reduction endow Sb/C-PANI electrode possessing ultrafine Sb nanoparticles symmetrically distributed in the nitrogen(N) doped porous carbon matrix. The Sb/C-PANI electrode exhibits excellent sodium storage performance, featured for a high reversible capacity of 469.5 mAh g-1after 100 cycles at 100 mA g-1and 336.5 mAh g-1after 300 cycles under 500 mA g-1. Such impressive performance will advance the development of Sb based anode materials for sodium storage. The present approach provides a compatible strategy for preparation of anode materials with high reversible capacity and long lifespan.


Impact of highly active antiretroviral therapy on individual AIDS-defining illness incidence and survival in Australia.
To determine the effect of highly active antiretroviral therapy (HAART) on incidence of initial AIDS-defining illnesses (ADIs) and survival after individual ADIs. Australian AIDS notification data over the period 1993 to 2000 were examined. Analyses were based on all initial ADIs. To examine the impact of HAART, two periods of AIDS diagnosis were chosen: pre-HAART (1993-1995) and HAART (1996-2000). Comparisons between these two periods included proportion of individual ADIs, median CD4 lymphocyte counts at and survival following AIDS and individual ADIs. Median survival was based on Kaplan-Meier estimates, with examination of factors influencing survival in a Cox proportional hazards model. Over the period 1993 to 2000 in Australia, 5017 initial ADIs were diagnosed among 4351 AIDS cases. At AIDS diagnosis, changes from the pre-HAART (1993-1995) to HAART (1996-2000) periods included an increased proportion of Pneumocystis carinii pneumonia (PCP) (25.9% to 30.4%; p =.001), AIDS dementia complex (5.2% to 6.8%; p = 0.029), non-Hodgkin lymphoma (NHL) (4.4% to 6.3%; p =.005), and tuberculosis (0.5% to 2.7%; p <.0005). Median survival following AIDS increased from 19.6 months for AIDS cases diagnosed in 1993 to 1995 to 39.6 months for AIDS cases diagnosed in 1996 to 2000 (p <.0005). Median survival was stable for NHL (7.5-8.8 months; p =.26), but increased significantly for almost all other ADIs. An increased proportion of PCP relative to other ADIs suggests an increasing proportion of AIDS patients not receiving specific prophylaxis, presumably because of "late" HIV diagnosis. Survival following almost all ADIs has increased in the era of HAART, although the prognosis after NHL remains extremely poor.


Field Efficacy of Metarhizium rileyi Applications Against Spodoptera frugiperda (Lepidoptera: Noctuidae) in Maize.
The efficacy of the fungus Metarhizium rileyi (Farlow) Kepler, S. A. Rehner & Humber (Hypocreales: Clavicipitaceae) against the fall armyworm Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) and the impact on the community of epigeans predators as well as the natural occurrence of native fungal strains were evaluated after sequential sprays in maize. In the first season, the infestation was lower than 0.2 larvae per plant throughout the three fungal sprays and no significant difference was observed in the number of infected larvae among treatments. In the second season, insect population reached an average of 0.8 larvae per plant between the second and third sprays and the number of larvae succumbed by M. rileyi was higher in fungal-treated plots in the following weeks. Molecular characterization of the collected isolates on mummified larvae revealed the introduction of a new isolate did not eliminate the native strain on the fungal-treated plots. In both seasons, the diversity and abundance of predator species in the plots were not affected by any of the treatments. We showed that applications of selected strains of M. rileyi early in the season have no significant impact on the occurrence of natural enemies in maize.


Liquid-based hybridization assay with real-time detection in miniaturized array platforms.
An assay for the fluorescent detection of short oligonucleotide probe hybridization in miniaturized high-density array platforms is presented. It combines hybridization in solution with real-time fluorescent detection, which involves measurement of fluorescence increase by means of an induced fluorescence resonance energy transfer. The feasibility of this approach using DNA or RNA as a target, and short DNA- as well as LNA (locked nucleic acid)-modified oligonucleotides as probes is shown. The presented approach could potentially contribute to a significant increase in the throughput of large-scale genomic applications, such as oligofingerprinting and genotyping, and also reduce material consumption.


[Diagnostic keys for disseminated eczema: experience of a Dermatitis Contact unit (2003-2019)].
The aim of this study was to establish the diagnoses of patients with disseminated eczema and analyze the allergens involved in disseminated eczema due to allergic contact dermatitis. We analyzed the data from patients with a diagnosis of disseminated / generalized eczema who had undergone anamnesis, physical examination and patch tests in a Contact Dermatitis consultation from 2003 to 2019. Allergic contact dermatitis was the most frequent diagnosis, folowed by atopic dermatitis, asteatotic eczema, and gravitational eczema. The allergens most frequently involved in allergic contact dermatitis were isothiazolinones, topical medications, paraphenylenediamine, and fragrances. Allergic contact dermatitis caused almost half of the cases of disseminated eczema. It would be therefore advisable for patients with disseminated eczema to be assessed at a Contact Dermatitis unit and undergo patch tests.


The influence of gut microbiome on bone health and related dietary strategies against bone dysfunctions.
The link between the gut microbiome and bone health has begun to attract widespread interest in recent years. The gut microbiome are vital in many diseases involving bone loss. Probiotics, prebiotics, and dietary supplements have been suggested to protect bone health by altering the composition of the gut microbiota. Notably, studying the relationship between the gut microbiome and bone health can provide a basis for the prevention and treatment of bone diseases. This review focuses on the link between the gut microbiome and bone diseases, exploring current knowledge of the mechanisms by which gut bacteria affect bone health. In addition, the influences of dietary supplements on the interactions between the gut microbiome and bone health are discussed. This knowledge will promote new ideas for gut microbiota-mediated dietary interventions in patients with bone diseases.


Mucinous Rectal Adenocarcinoma in a Urutu Snake (Bothrops alternatus).
A 15-year-old captive female Urutu snake (Bothrops alternatus) was presented with anorexia, apathy, dehydration, pale mucous membranes and marked enlargement of the caudal third of the coelomic cavity. Radiographs and ultrasonography were suggestive of faecal impaction or neoplasia. Post-mortem findings consisted of solid faecal impaction of the intestines, secondary to obstruction caused by a rectal tumour. Cytological examination of impression smears of the tumour revealed polygonal to round neoplastic cells arranged in clusters in an abundant extracellular mucinous matrix. Histologically, there was transmural growth of neoplastic epithelial cells arranged in small nests or individually and immersed in abundant extracellular mucin lakes. The neoplastic cells were immunopositive for cytokeratin. Clinical and pathological aspects indicated a diagnosis of mucinous rectal adenocarcinoma.


Vascular changes in peripheral corneal destructive disease.
A clinical classification of peripheral corneal destructive disease is presented. These syndromes all start within 2 mm of the limbus and are accompanied by varying degrees of vaso-occlusion of the adjacent limbal vascular networks. Close observation of the configuration, integrity and pattern of the limbal vessels can indicate whether the disease is active, quiescent or brought under control with treatment.


Erythrocyte sedimentation rate kinetics as a marker of treatment response and predictor of prognosis in Chinese metastatic renal cell carcinoma patients treated with sorafenib.
Previous prognostic factor models for metastatic renal cell carcinoma (mRCC) have not included erythrocyte sedimentation rate (ESR). We designed the present study to evaluate the prognostic value of ESR for mRCC patients treated with sorafenib. Sorafenib was given to 83 patients with clear cell mRCC. Serum ESR was tested before treatment and every 4 weeks after first administration of sorafenib. Oncological evaluation was carried out every 8 weeks. Analyzed factors included age, sex, performance status, method of nephrectomy, number of metastatic organs, anemia, lactate dehydrogenase, corrected calcium, albumin, baseline ESR level and ESR kinetics status. Kaplan-Meier and Cox regression analyses on progression-free survival (PFS) were carried out. Baseline ESR levels ranged from 3 to 154 mm/h, and 43 (41.0%) patients had an ESR level higher than 40 mm/h. Median PFS was 10.0 months (95% CI 7.6-12.4 months). Dividing the cohort into three groups according to ESR kinetics status, median PFS was 27 months in the decreased ESR group, 12 months in the stable ESR group and 6 months in the increased ESR group. Performance status, time from diagnoses to sorafenib treatment, number of metastatic organs and ESR kinetics were independent predictors for PFS in multivariable Cox regression model analysis, with an area under the curve of 0.865 in a binary logistic regression model of 12-month PFS probability. ESR kinetics can be useful to monitor the treatment response and to predict PFS for mRCC patients treated with sorafenib as second-line therapy.


Associations of Systolic Blood Pressure and Diastolic Blood Pressure With the Incidence of Coronary Artery Disease or Cerebrovascular Disease According to Glucose Status.
To determine associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with new-onset coronary artery disease (CAD) or cerebrovascular disease (CVD) according to glucose status. Examined was a nationwide claims database from 2008 to 2016 on 593,196 individuals. A Cox proportional hazards model identified risks of CAD and CVD events among five levels of SBP and DBP. During the study period 2,240 CAD and 3,207 CVD events occurred. Compared with SBP ≤119 mmHg, which was the lowest quintile of SBP, hazard ratios (95% CI) for CAD/CVD in the 4 higher quintiles (120-129, 130-139, 140-149, ≥150 mmHg) gradually increased from 2.10 (1.73-2.56)/1.46 (1.27-1.68) in quintile 2 to 3.21 (2.37-4.34)/4.76 (3.94-5.75) in quintile 5 for normoglycemia, from 1.39 (1.14-1.69)/1.70 (1.44-2.01) in quintile 2 to 2.52 (1.95-3.26)/4.12 (3.38-5.02) in quintile 5 for borderline glycemia, and from 1.50 (1.19-1.90)/1.72 (1.31-2.26) in quintile 2 to 2.52 (1.95-3.26)/3.54 (2.66-4.70) in quintile 5 for diabetes. A similar trend was observed for DBP across 4 quintiles (75-79, 80-84, 85-89, and ≥90 mmHg) compared with ≥74 mmHg, which was the lowest quintile. Results indicated that cardiovascular risks gradually increased with increases in SBP and DBP regardless of the presence of and degree of a glucose abnormality. Further interventional trials are required to apply findings from this cohort study to clinical practice.


Goat milk proteins enriched with Agaricus blazei Murrill ss. Heinem extracts: Electrophoretic, FTIR, DLS and microstructure characterization.
This study aimed to characterize mixtures of goat milk proteins and Agaricus blazei Murrill (ABM) extracts (aqueous, AE and polysaccharides, PE). The mixtures showed stable particles with ζ-potential more negative than -41.1 mV. The addition of AMB extracts to goat milk did not result in a significant particle size change, whereas their addition to heated goat milk significantly increased mean particle diameter (from 194 nm to 225 nm). Fourier Transform Infrared Spectroscopy (FTIR) showed that ABM extracts provoked changes in the secondary structure of goat milk proteins and interactions between polysaccharides and milk proteins predominantly via hydrogen and/or glycoside bonds and hydrophobic interactions. The milk protein profiles revealed proteolytic activity in mixtures with AE resulting in the formation of five new polypeptides. The different microstructures of mixtures with AE and PE were found by Scanning Electron Microscopy (SEM). A schematic representation of possible milk proteins-ABM extracts interactions has been given.


Prevalence of lactose intolerance and nutrients intake in an older population regarded as lactase non-persistent.
Energy and nutrient intakes of community-dwelling older adults in Indonesia are inadequate whereby milk consumption is among the lowest in the world. Lactose intolerance is probably one of the reasons for such low milk consumption, but information on the burden of this problem and its consequences for dietary intake is lacking. We obtained data on the prevalence of lactose intolerance and dietary intakes in Indonesian older outpatients, thereby comparing dairy users and non-dairy users. A cross-sectional study was conducted in 2019 involving 103 community-dwelling older adults in the outpatient geriatric clinic, Dr. Cipto Mangunkusumo Hospital, Jakarta. A structured questionnaire was used to categorize participants as dairy- or non-dairy users. Food records were collected to assess nutrients intake from the diet. The prevalence of lactose intolerance (LI) was estimated based on the results of the hydrogen breath test (HBT) and on symptoms of lactose malabsorption. The difference in LI prevalence between dairy- and non-dairy user group was presented as a prevalence ratio (with 95% confidence interval). Chi-square tests, t-test, and Mann-Whitney tests were used to evaluate differences in demographic and clinical characteristics, as well as in nutrient intake profiles between dairy and non-dairy users. The prevalence of lactose intolerance amounted to 66% (57-75%), 54% (37-70%), and 73% (61-84%) in the total population, dairy- and non-dairy users, respectively. Lactose intolerance tended to be higher among non-dairy users (PR 1.36 95% CI 0.99-1.89). On the other hand, we found no pronounced differences in symptoms of lactose intolerance between dairy and non-dairy users. The overall mean protein, calcium, vitamin D, and vitamin B12 intakes of the older adults were low. Intakes of protein, calcium, vitamin D and vitamin B12 were higher among dairy than among non-dairy users. This study uncovered the large size of the lactose intolerance problem in Indonesian older adults. Especially in non-dairy users, the intakes of proteins and some micronutrients are a concern. Strategies to tackle lactose intolerance are most relevant as to open the door for more nutrient-dense foods in the diet of Indonesian older adults.


The HIV protein, GP120, activates nuclear protein kinase C in nuclei from lymphocytes and brain.
Nuclear pool(s) of protein kinase C (PKC) may be a common target for hormones and growth factors which affect the trophic state of cells. The data presented demonstrate a time and dose-dependent activation of nuclear PKC by the HIV coat protein, gp120, in isolated nuclei from rat spleen and hippocampus. This gp120-stimulated PKC response was blocked by specific PKC inhibitors, a monoclonal antibody to PKC, and a monoclonal antibody directed against the murine T4 analog, L3T4. It is suggested that the gp120 interaction with the nuclear trophic factor-PKC system may impair normal gene expression, and thus result in the clinical symptoms associated in AIDS infection.