Short order nanohole arrays in metals for highly sensitive probing of local indices of refraction as the basis for a highly multiplexed biosensor technology.
A small array of subwavelength apertures patterned in a gold film on glass was characterized for use as a biosensor. It is widely believed that such arrays allow the resonance of photons with surface plasmons in the metallic film. Surface plasmon methods (and other evanescent wave methods) are extremely well suited for the measure of real time biospecific interactions. An extremely high sensitivity of 88,000%/refractive index unit was measured on an array with theoretical active area of .09 microm2. The formation of a biological monolayer was monitored. Both sensitivity and resolution were determined through measurement. The measured resolution, for a sensor with an active area of less than 1.5 microm2, is 9.4 x 10(-8) refractive index units which leads to a calculated sensitivity of 3.45E6%/refractive index unit. These values far exceed theoretical and calculated values of other grating coupled surface plasmon resonance (SPR) detectors and prism based SPR detectors. Because the active sensing area can be quite small (.025 microm2) single molecule studies are possible as well as massive multiplexing on a single chip format.


CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology.
Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.


The enteric neural receptor for 5-hydroxytryptamine.
An enteric neural receptor for serotonin (5-HT) has been characterized. This receptor was assayed, using 3H-5-HT as a radioligand, by rapid filtration of isolated enteric membranes and by radioautography. In addition, intracellular recordings were made from ganglion cells of the myenteric plexus. High affinity, saturable, reversible, and specific binding of 3H-5-HT was demonstrated both to membranes of the dissected longitudinal muscle with adherent myenteric plexus and the mucosa-submucosa. Radioautographs showed these 3H-5-HT binding sites to be in myenteric ganglia and in a broad unresolved band at the mucosal-submucosal interface. Antagonists active at receptors for other neurotransmitters than 5-HT, at either of the two known types of CNS 5-HT receptor, and at 5-HT uptake sites on serotonergic neurons failed to inhibit binding of 3H-5-HT. The structural requirements of analogues for binding to the enteric 5-HT receptor matched the known pharmacology of M or neural 5-HT receptors. A novel 5-HT antagonist was found. This compound, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP), antagonized the action of 5-HT on type II/AH cells of the myenteric plexus but did not affect the release or actions of acetylcholine (nicotinic or muscarinic) or substance P. 5-HTP-DP was also an equally potent displacer of 3H-5-HT from its binding sites on enteric membranes. It is concluded that the sites responsible for specific binding of 3H-5-HT are enteric M or neural 5-HT receptors. These receptors differ from those now known to be present in the CNS.


A comparison of Cell Saver versus ultrafilter during coronary artery bypass operations.
A study was performed to evaluate two blood conservation techniques that can be used with high-volume crystalloid cardioplegia. Twenty-seven patients undergoing coronary artery bypass with high-volume crystalloid cardioplegia were randomized into two groups: In 12 Group I patients the coronary sinus effluent was drained into a Cell Saver and the recovered, washed red cells were then reinfused. In 15 Group II patients the coronary sinus effluent was absorbed systemically and excess volume was removed from the cardiopulmonary bypass circuit by an ultrafilter. These two groups were compared with a retrospective control group in which the cardioplegic solution had been evacuated from the right atrium and discarded. Both the techniques resulted in significant and equivalent red blood cell conservation compared with the retrospective control group. The ultrafilter was associated with less derangement of prothrombin time. More complete potassium removal was provided by the Cell Saver.


Evaluation of aggressive heart rate reduction in patients with stable angina.
There is a strong correlation between heart rate and myocardial ischemia, cardiovascular diseases, and life expectancy in general; however, heart rate has been neglected as an important risk factor as well as a therapeutic opportunity. To investigate the effect of aggressive heart rate reduction (50 ⩽ HR ⩽ 60 bpm) on anti-ischemic and anti-anginal efficacy, left ventricular function, exercise tolerance and quality of life in patients with stable coronary artery disease with or without left ventricular dysfunction during 4 months. A total of 159 patients presented with stable CAD without clinical heart failure symptoms were included in a open-label, non-comparative, prospective clinical study between June 2009 to February 2010 in King Abdul Aziz Specialist Hospital, Taif, KSA, Al Hayah National Hospital, Khamis Mushyt, KSA and Critical care department, Cairo University, Egypt. All included patients were, in addition to the ant ischemic treatment, subjected to aggressive heart rate control starting by beta blocker titrated to the maximum dose as tolerated, then Ivabradine added if the target heart rate is not achieved or rate control started by Ivabradine if beta blockers are contraindicated. Exercise treadmill test (ETT) to assess exercise capacity using time to 1 mm ST-segment depression in milliseconds, ejection fraction (EF) assessed by transthoracic echocardiography and frequency of angina attacks and the use of sublingual nitroglycerin per week during the last week were evaluated during a follow-up for 4 months. The patients were divided into two groups, group-I (patients achieved a resting heart rate between 50 and 60 bpm with heart rate reduction treatment) and group-II (patients with resting HR >60 bpm in spite of maximum treatment for heart rate reduction). The resting heart rate was significantly reduced from 77.98 ± 8.7 at baseline to 60.68 ± 4.34 bpm after 4 months of treatment, P < 0.001. The frequency of angina pectoris attacks had been significantly reduced from 2.14 ± 1.27 to 0.48 ± 0.58 attacks per week, P < 0.001 and the highest significant reduction was observed with group-I. Also, the frequency of use sublingual nitrate therapy was significantly reduced from 1.38 ± 1.1 tablet per week at the last week before the study to 0.12 ± 0.33 tablet per week during the last week after 4 months of treatment, P < 0.001 and the reduction was more significantly with group-I. Exercise treadmill test demonstrated statistically significant increase in the time to 1 mm ST-segment depression from 357.36 ± 66.73 at baseline to 387.96 ± 65.19 ms. after 4 months with P < 0.001. The degree of improvement was significantly higher for group-I (from 358.06 ± 68.81 at baseline to 391.71 ± 69.01 after 4 months with P < 0.001) than that of group-II (from 356.11 ± 64.8 at baseline to 381.27 ± 59.08 after 4 months with P < 0.001). Ejection fraction showed a statistically significant increase from 59.76 ± 6.86 at baseline to 61.04 ± 5.35 after 4 months with P < 0.001. This study indicates that heart rate reduction has been associated with an improvement in quality of life in patients with stable coronary artery disease, presenting new opportunities for treatment.


Corrigendum: Effect of epicardial fat volume on outcomes after left atrial posterior wall isolation in addition to pulmonary vein isolation in patients with persistent atrial fibrillation.
[This corrects the article DOI: 10.3389/fcvm.2022.1005760.].


Effect of innovative microwave assisted freezing (MAF) on the quality attributes of apples and potatoes.
This study considered the effect of low energy microwave assisted freezing (MAF) on freezing time and quality attributes (microstructure, texture, drip loss and colour) of apple and potato. MAF of apples and potatoes was performed by applying constant microwave (MW) power (167 W/kg) and pulsed MW power (500 and 667 W/kg with 10 s pulse width and 20 s pulse interval resulting in an average power of 167 and 222 W/kg) during the freezing process. The temperature profile was monitored during the freezing process, and the microstructure was examined using X-ray micro-tomography and cryo-SEM. Other quality parameters such as texture, drip loss and colour were evaluated with thawed samples. It appeared that the freezing time was not affected by the MAF process. It is the first time that a MAF process is used for freezing plant-based products and showed that the application of microwaves during freezing process caused less freeze damage than the control condition.


Quantitative evaluation of contributions to electron paramagnetic resonance line widths in ferric hemoglobin single crystals.
The contributions to the dipolar broadening of ferric magnetic resonances, from crystals of hemoglobin for which the atomic coordinates are known, have been calculated. The total second moment of the g = 2 resonance so determined is about 50 (MHz)2 or 5.0 G (peak-to-trough), figures consistent with the range of values found from analysis of experimental data. Two-thirds of this second moment comes from the two protons of the H2O molecule coordinated to the iron. Treatment with D2O is predicted to reduce the total second moment at g = 2 to about 25 (MHz)2, whereas the experimental measurements on single crystals show no decrease. If the structure of the tetramer is assumed to be the same when in solution as in the crystal, the total second moment is readily redetermined for hemoglobin in solution; the value so obtained is found to be significantly smaller than that from analysis of the g = 2 resonance measured in frozen solution. These two unexpected observations can be explained in terms of distributions in spin Hamiltonian parameters, the spread depending upon the nature of the sample--crystal or solution, ordinary or heavy water-treated. This distribution in H2O and D2O solutions appears to be about the same, since the measured differences in component line width agree with the calculated difference in dipolar contributions.


Characterization of metabolically labelled antigen following immunoprecipitation with antibody bound on ELISA plates.
Immunoprecipitation is a powerful technique for the immunochemical characterization of antigens. In combination with sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) a number of features, e.g., presence of antigen, rate of synthesis, relative molecular weight of the polypeptide chain or post-translational modifications can be determined. Four different steps are basically involved in the immunoprecipitation procedure: (1) metabolic labelling of the antigen by incubation of viable cells with a radioactive precursor, (2) harvesting of the labelled antigen from the cells by lysis or in the case of secretory proteins from the supernatant, (3) formation and (4) purification of antibody-antigen complexes. The last step relies on secondary agents which bind to the antibody.


[Effect of hypoxia on the expression of urokinase-type plasminogen activator in human tongue squamous cell carcinoma cells (Tca8113)].
To observe the expression of urokinase-type plasminogen activator (uPA) in human tongue squamous carcinoma cells (Tca8113) under hypoxia, in order to explore the relation between hypoxia and invasion and metastasis of oral cancer. Under different hypoxic times(0, 3, 6, 12, 24 h), the expression of uPA protein was examined quantitatively using immunohistochemical technique (IH) and flow cytometry (FCM). Hypoxia promoted the expression of uPA. The longer hypoxic time was, the higher expression of uPA was. Hypoxia can promote invasion and metastasis of oral squamous carcinoma through stimulating the expression of uPA.


Characterization of a linear epitope within the human pancreatic 64-kDa glutamic acid decarboxylase and its autoimmune recognition by sera from insulin-dependent diabetes mellitus patients.
A 2.0-kb cDNA coding for the full-length 64-kDa human glutamic acid decarboxylase (GAD64) was isolated from a pancreatic carcinoma cDNA library by oligonucleotide screening, polymerase-chain-reaction amplification and subsequently characterized by sequence analysis. Five overlapping fragments of GAD64 cDNA were constructed into the vector pH6EX3, allowing the highly efficient expression of corresponding fusion proteins with a histidine hexapeptide as an affinity ligand at their N-termini in Escherichia coli. The recombinant GAD64 fragments were analysed by Western blotting using sera from patients with early onset of insulin-dependent diabetes mellitus (IDDM). We found that at least 20% of the patients with an onset of IDDM have developed autoantibodies which can specifically recognize a linear antigenic epitope within the GAD64. With a selected IDDM serum, an antigenic epitope was localized in a region of 31 amino acids located at the C-terminus of GAD64, using epitope mapping techniques, and it was characterized. The possibility of using recombinant GAD64 for the development of an immunoassay for a predictive diagnosis of IDDM is discussed.


Sesquiterpene lactones and other constituents from Hymenoxys richardsonii and H. subintegra.
Two Hymenoxys species afforded, in addition to known compounds, three new pseudoguaianoloides, a new sesquiterpene glucoside and a new butyrolactone. This is the first report of an eudesmane from the genus Hymenoxys. The structures were elucidated by high-field NMR and chemical transformations.


The prevention of endometrial cancer in postmenopausal women with progestogens.
Due to adverse publicity alleging an increased risk of endometrial cancer with estrogen therapy, a prospective study was begun in 1976 to determine the incidence of this disease in postmenopausal women. During 5,025 patient-years of observation in 1976-1977, 6 adenocarcinomas of the endometrium were diagnosed for an incidence of 1.2:1,000 postmenopausal women per year. No endometrial malignancies were detected in 2,552 patient years of therapy with estrogens and progestogens. In 1,028 patient-years of observation where estrogens only was the therapy, there were 3 endometrial cancers for an incidence of 2.9:1,000. Adenocarcinoma of the endometrium was found in 2 of the untreated group, which gave an incidence of 3.0:1,000. The sixth endometrial cancer occurred in a patient using estrogen vaginal cream. During this same period, 139 perimenopausal and postmenopausal women were treated with progestogens for endometrial hyperplasia. The hyperplasia was reversed to normal endometrium in 133 patients (95.7%). Hyperplasia is a precancerous lesion and should be treated with either progestogens or hysterectomy. All postmenopausal women with a uterus should be given the Progestogen Challenge Test and the progestogen continued each month as long as bleeding follows. These methods will prevent most endometrial cancers.


The effects of an epidemic on prenatal investments, childhood mortality and health of surviving children.
The potential death toll from an epidemic is larger than the number of deaths directly associated with the infection. In this study, we find that prenatal exposure to a cholera epidemic in Peru increased childhood mortality and that surviving children were more likely to be underweight and to suffer from diarrhea. We further find that a significant part of this mortality happened during the first day of life, and that prenatal exposure to cholera decreased prenatal care and institutional deliveries, suggesting that the mortality and possibly other longer-term effects were partially driven by a reduction in prenatal investments.


Spiritual dimensions of a mind-body group for people with severe mental illness.
In a mind-body group designed to address issues of well-being for people with severe mental disorders, experiences with spiritual themes of optimal functioning and ultimate meaning emerged with surprising clarity.


Foraging behaviour of Lesser Sheathbills Chionis minor exploiting invertebrates on a sub-Antarctic island.
During winter (May through October) many Lesser Sheathbills Chionis minor at Marion Island in the sub-Antarctic were obliged to leave their preferred foraging habitat in penguin colonies to forage for invertebrates on the island's coastal plain. The study describes factors affecting feeding success, time budgets and predation risk of the sheathbills which exploited these small, patchily dispersed prey. The birds appeared to select prey ≧1 mm in diameter, and ignore smaller, common invertebrates.Sheathbills were highly selective of foraging habitat. During 17 censuses made through the winter, 97% of the 1,504 birdsightings were at only eight of the 19 available vegetation types. Multiple regression analysis revealed that prey density was the most important criterion in habitat preference, followed by plant canopy height and distance of the habitat from the sea. These variables accounted for 78% of the variance of habitat use. Focal-animal observations in a sample of habitats showed that feeding success was correlated with prey density and distance from the sea. Tall vegetation impeded the locomotion and foraging of sheathbills. The sheathbills reduced predation risk from skuas Catharacta lonnbergi and travelling time by foraging near the shore. The spatial distribution of prey within vegetation types was apparently unimportant in habitat selection.During winter 83% of the sheathbills in the study foraged communally and 98% roosted communally. Flocks occurred only on good quality habitat and flocking probably facilitated habitat selection. Feeding success increased initially with increasing flock size but decreased in flocks greater than 15 birds, which was attributed to localized prey deletions. The sheathbills spent 88% of the daytime foraging; and feeding, looking around and walking comprised 99% of foraging time. Feeding time increased with increasing flock size, looking around decreased but walking was unaffected. Aggression was rare, was unaffected by flock size and did not significantly affect feeding. A probability model showed that sheathbills could greatly reduce predation risk by flocking but the benefits would not improve much in flocks greater than eight birds.The habitat selection, time budgets and feeding success of adults, subadults and juveniles were very similar.The exploitation of terrestrial invertebrates by sheathbills was interpreted as an expansion of the population's trophic niche to tap an underexploited resource on a species-poor island.


A randomised trial of granulocyte-macrophage colony-stimulating factor for neonatal sepsis: childhood outcomes at 5 years.
We performed a randomised trial in very preterm, small for gestational age (SGA) babies to determine if prophylaxis with granulocyte macrophage colony stimulating factor (GM-CSF) improves outcomes (the PROGRAMS trial). GM-CSF was associated with improved neonatal neutrophil counts, but no change in other neonatal or 2-year outcomes. As subtle benefits in outcome may not be ascertainable until school age we performed an outcome study at 5 years. 280 babies born at 31 weeks of gestation or less and SGA were entered into the trial. Outcomes were assessed at 5 years to determine neurodevelopmental and general health status and educational attainment. We found no significant differences in cognitive, general health or educational outcomes between 83 of 106 (78%) surviving children in the GM-CSF arm compared with 81 of 110 (74%) in the control arm. Mean mental processing composite (equivalent to IQ) at 5 years were 94 (SD 16) compared with 95 (SD 15), respectively (difference in means -1 (95%CI -6 to 4), and similar proportions were in receipt of special educational needs support (41% vs 35%; risk ratio 1.2 (95% CI 0.8 to 1.9)). Performance on Kaufmann-ABC subscales and components of NEPSY were similar. The suggestion of worse respiratory outcomes in the GM-CSF group at 2 years was replicated at 5 years. The administration of GM-CSF to very preterm SGA babies is not associated with improved or more adverse neurodevelopmental, general health or educational outcomes at 5 years. ISRCTN42553489.


Overexpression of HSPA1A enhances the osteogenic differentiation of bone marrow mesenchymal stem cells via activation of the Wnt/β-catenin signaling pathway.
HSPA1A, which encodes cognate heat shock protein 70, plays important roles in various cellular metabolic pathways. To investigate its effects on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), its expression level was compared between undifferentiated and differentiated BMSCs. Rat HSPA1A overexpression in BMSCs increased osteoblast-specific gene expression, alkaline phosphatase activity, and mineral deposition in vitro. Moreover, it upregulated β-catenin and downregulated DKK1 and SOST. The enhanced osteogenesis due to HSPA1A overexpression was partly rescued by a Wnt/β-catenin inhibitor. Additionally, using a rat tibial fracture model, a sheet of HSPA1A-overexpressing BMSCs improved bone fracture healing, as determined by imaging and histological analysis. Taken together, these findings suggest that HSPA1A overexpression enhances osteogenic differentiation of BMSCs, partly through Wnt/β-catenin.


The Vero cell receptor for the hepatitis B virus small S protein is a sialoglycoprotein.
The Vero (African green monkey kidney-derived) cell line is capable of binding recombinant hepatitis B surface antigen (rHBsAg) particles containing only the small surface (S) protein of hepatitis B virus (HBV). This binding activity appears to be due to a single major population of receptors (M. E. Peeples et al., Virology 160, 135-142 (1987]. Since infectious HBV particles also contain the small S protein, it is possible that the Vero cell receptor might also function as an HBV receptor. The initial physical characterization of this receptor is reported here. Treatment of Vero cells with each of four proteases reduced their binding activity by 70% or greater, indicating that the receptor is partially protein in nature. Binding activity was also reduced by pretreating cells with neuraminidase or low levels of sodium periodate, indicating that sialic acid also plays a major role in the receptor activity. Consistent with this interpretation, N-acetylneuraminic acid and N-acetylneuraminyl-lactose were able to competitively inhibit rHBsAg particle attachment to Vero cells. The protein nature of the Vero cell receptor was confirmed by the demonstration that chymotrypsin treatment which resulted in 70% loss of binding had little effect on the cell sialic acid content. Therefore, the Vero cell receptor for rHBsAg particles is a sialoglycoprotein.


Maxillary Sinus Floor Augmentation with Porcine-Apatite Xenograft: A Prospective Case Series Study.
This study clinically and histologically evaluated the outcome of a porcineapatite xenograft used to elevate the maxillary sinus floor in a severely atrophic ridge. A two-stage crestal window sinus elevation protocol was conducted in 24 patients with crestal bone ≤ 2 mm. Highly porous porcine carbonate apatite moistened with saline solution was placed in the elevated sinus cavity as the sole grafting material. Bone core biopsy samples were taken at 6, 9, and 12 months after sinus augmentation surgery (at implant placement). Treatment outcomes were assessed using microCT (μCT) and histologic analysis. Statistical analysis was performed using nonparametric Kruskal-Wallis test, followed by post-hoc Dunn multiple comparison test. At 6 months after implant placement, all implants achieved good primary stability (insertion torque ≥ 30 Ncm) and successfully osseointegrated. The residual graft amount (mean ± SE) was low (11.91% ± 1.99%) at 6 months and further decreased (6.11% ± 2.64%) by 12 months. On the contrary, the amount of new bone detected was 18.94% ± 4.08% at 6 months and was significantly (P < .05) increased (40.16% ± 5.27%) at 12 months. Histologic assessment revealed osteoclasts actively resorbing the graft as well as osteoblasts actively forming new bone. In the severely atrophic maxilla, the porcine-apatite xenograft promotes new bone formation while being slowly absorbed. Within the limited sample size, the porcine-apatite xenograft seems to be a good graft material for crestal window sinus augmentation.


Rapid and quantitative assay system for measuring anti-infectious bursal disease virus antibody using monoclonal antibody bound to polystyrene latex microspheres.
A monoclonal antibody (MAb) to infectious bursal disease virus (IBDV) that has virus-neutralizing activity was bound to polystyrene latex microspheres The microspheres agglutinated with extracts of bursae from chickens infected with IBDV. Agglutination was inhibited in a competitive manner by adding serum obtained from IBDV-infected chickens. The level of agglutination-inhibition depended on the serum antibody titer against IBDV. The reaction was visually accomplished within 5 minutes. The titer of this rapid assay showed a close relationship with that of the virus-neutralization test.


Neoadjuvant Intra-Arterial Cytoreductive Chemotherapy for Lacrimal Gland Adenoid Cystic Carcinoma: A Long-Term Follow-up Study of a Trimodal Strategy.
To report the therapeutic efficacy of integrating neoadjuvant chemotherapy with conventional bimodal therapies for lacrimal gland adenoid cystic carcinoma by providing an additional 8 years of follow-up data on the same cohort of patients whose cumulative 10-year disease-free survival outcomes were reported in 2013. Non-randomized, retrospective, interventional case series. Nineteen consecutive patients treated with neoadjuvant intra-arterial cytoreductive chemotherapy (IACC), orbital exenteration, chemoradiotherapy, and adjuvant intravenous chemotherapy at a single institution were included. Analyses were undertaken of locoregional recurrences and distant metastases, disease-free survival time, TNM tumor stage at presentation, response to IACC, and prognostic impact of positive resection margins. The main outcome measures were overall survival, disease-free survival, disease relapse, positive tumor resection margins, and tumor stage at presentation. Eight patients with an intact lacrimal artery (group 1), 7 with AJCC stage T4a-c, had significantly better overall survival (87.5% versus 14.3% at 15 years), disease-specific mortality, and recurrences (all < .001, log-rank test) than prior conventionally treated patients from the Bascom Palmer Eye Institute. Group 1 was superior to group 2, patients lacking an intact lacrimal artery, concerning overall survival (P = .042) and recurrence (P = .017), but with no significant difference in disease-specific mortality (P = .23). Group 2 was associated with a significantly lower cause-specific mortality than the institutional comparator group (P = .039). Prior tumor resection with lateral wall osteotomy and failure to adhere to all protocol elements were adverse prognostic factors for suboptimal outcomes. Positive tumor margins increased the risk of all-cause mortality 4.1 times (P = .036, stratified Cox proportional hazards regression) and disease-specific mortality 8.0 times (P = .043, stratified Cox proportional hazards regression) than a patient with negative margins. Extended follow-up supplemented with AJCC staging data supports neoadjuvant IACC as an integral component of a trimodal treatment strategy in patients with an intact lacrimal artery. Protocol elements implemented as designed appear to have improved overall survival and decreased disease relapse in this cohort. This extended long-term IACC dataset suggests that a critical bar of at least 15 years of follow-up is appropriate for assessing the efficacy of current conventional and future globe-sparing bimodal therapies.


New potent calcimimetics: I. Discovery of a series of novel trisubstituted ureas.
Starting from Fendiline and R-568, we identified a novel series of urea compounds as positive allosteric modulators of the calcium sensing receptor (CaSR), as part of a program to identify novel therapeutics for secondary hyperparathyroidism. Initially identified disubstituted ureas were converted to trisubstituted urea lead 20e, which was further modified to increase in vivo potency. Replacing a carbomethoxy substituent by various bioisosteres led to compound 46 which exhibited potent in vitro and in vivo activity after oral administration.


Inhibition of human parainfluenza virus type 3 infection by novel small molecules.
Human parainfluenza virus type 3 (HPIV3) is an important respiratory tract pathogen of infants and children. There are no vaccines or antivirals currently approved for prevention or treatment of HPIV3 infection. Towards developing an antiviral therapy to combat HPIV3 infection, we have established a green fluorescent protein (GFP)-tagged HPIV3 infected-cell assay and used it for screening of a small molecule library obtained from ChemBridge Diver. Two novel small molecules (C5 and C7) which shared structural similarities were identified and their inhibitory effects on HPIV3 were confirmed in CV-1 and human lung epithelium A549 cells by plaque assay, Western blot and Northern blot analyses. C5 and C7 effectively prevented the cytopathic effect in cells infected with HPIV3, achieving IC(50) values of 2.36 microM and 0.08 microM, respectively, for infectious virus production. The inhibition appears to be at the primary transcriptional level of HPIV3 life cycle based on sequential time course test, binding and internalization assays, and finally by a minigenome transcription assay in cells as well as measuring viral transcripts in cells in the presence of anisomycin. Interestingly, vesicular stomatitis virus (VSV), another member of mononegavirales order, was also inhibited by these compounds, whereas poliovirus-a picornavirus was not. Use of these inhibitors has a strong potential to develop novel antiviral agents against this important human pathogen.


HF2: a double-stranded DNA tailed haloarchaeal virus with a mosaic genome.
HF2 is a haloarchaeal virus infecting two Halorubrum species (Family Halobacteriaceae). It is lytic, has a head-and-tail morphology and belongs to the Myoviridae (contractile tails). The linear double-stranded DNA genome was sequenced and found to be 77 670 bp in length, with a mol% G+C of 55.8. A total of 121 likely open reading frames (ORFs) were identified, of which 37 overlapped at start and stop codons. The predicted proteins were usually acidic (average pI of 4.8), and less than about 12% of them had homologues in the sequence databases. Four complete tRNA-like sequences (tRNA-Arg, -Asx, -Pro and -Tyr) and an incomplete tRNA-Thr were detected. A transcription map showed that most of the genome was transcribed and that the synthesis of transcripts occurred in a highly organized and reproducible pattern over a 5 h infection cycle. Transcripts often spanned multiple ORFs, suggesting that viral genes were organized into operons. The predicted ORF and observed transcript directions matched well and showed that transcription is mainly directed inwards from the genome termini, meeting at about 45-48 kb, and this was also a turning point in a cumulative GC-skew plot. The low point in cumulative GC-skew, near the left end, was a region rich in short repeats and lacking ORFs, which is likely to be an origin of replication. The HF2 genome is a mosaic of components from widely different sources, demonstrating clearly that viruses of haloarchaea, like their bacteriophage counterparts, are vectors for the exchange and transmission of genetic material between wide taxonomic distances, even across domains.


Coil occlusion for patent ductus arteriosus larger than 3 mm.
Coil occlusion of patent ductus arteriosus (PDA) is now widely accepted as the first-line treatment, but there are few reports of age-dependent differences in the complications associated with this technique. Sixteen patients (11 adults, 5 children) with a PDA larger than 3 mm, who underwent coil occlusion at Sapporo Medical University Hospital between September 1995 and August 2004, were enrolled. Immediate and intermediate outcomes and complications were analyzed. Procedural success rate was 72.7% (8/11) in the children and 100% (5/5) in the adults. Coil migration occurred in 4 children and 1 adult, and 3 adult patients had hemolysis. Hemolysis was more frequent in adults than in children even though the residual shunt was trivial.


Paraphyly changes understanding of timing and tempo of diversification in subtribe Hakeinae (Proteaceae), a giant Australian plant radiation.
Subtribe Hakeinae (526 spp.) represents a large Australian plant radiation central to our understanding of that flora's evolution and ecology. It contains Grevillea-the third largest plant genus in Australia and a group inferred to have among the highest diversification rates in the angiosperms. However, we lack a robust phylogenetic framework for understanding subtribe Hakeinae and recognize that Grevillea lacks an unambiguous synapomorphy supporting its monophyly. We used four plastid and one nuclear DNA region from a taxonomically even sampling of a third of the species to infer a time-calibrated phylogeny of Hakeinae and absolute diversification rates of major clades. We developed the R package addTaxa to add unsampled taxa to the tree for diversification rate inference. Grevillea is paraphyletic with respect to Hakea and Finschia. Under most parameter combinations, Hakea contains the major clade with the highest diversification rate in Hakeinae, rather than Grevillea. The crown age of the Grevillea+Hakea+Finschia crown group is about double that of prior estimates. We demonstrate that the paraphyly of Grevillea considerably enlarges the number of Australian descendants from its most recent common ancestor but has also misled investigators who considered a single operational taxonomic unit as adequate to represent the genus for inferences of diversification rate and timing. Our time-calibrated phylogeny can form the basis of future evolutionary, comparative ecology, and biogeography studies involving this large Australian plant radiation, as well as nomenclatural changes.


Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers.
Modafinil has been reported to produce a concentration-related suppression of CYP2C9 activity in vitro in primary cultures of human hepatocytes. To determine whether this effect occurs in vivo, the pharmacokinetics of (S)-warfarin was investigated after single oral doses of racemic warfarin (5 mg; COUMADIN) in a placebo-controlled, single-blind, single-period study in 28 volunteers. Subjects received an oral dose of warfarin prior to administration of modafinil (200 mg for 7 days, followed by 400 mg for 21 days) or placebo and they received another after 4 weeks of treatment. Treatment with modafinil did not significantly alter the pharmacokinetics of (S)- or (R)-warfarin relative to placebo. Since (S)-warfarin is predominantly metabolized via CYP2C9, the results indicate that the marked suppression of CYP2C9 activity in vitro does not translate into a similar effect clinically. However, limitations arising from investigation of single doses of warfarin preclude global conclusions about the potential for more subtle interactions after chronic warfarin administration.


[Effect of sodium butyrate on the interferon sensitivity of normal or cells transformed by murine sarcoma virus].
Sodium butyrate enhances the sensitivity of MSV transformed murine cells to interferon, but does not influence the response of normal cells. Sodium butyrate might act in transformed cells by restoring the different elements of the cytoskeletal system.


Why is suicide incidence among doctoral students so high? ---A study of China's doctoral tutorial system.
The annual incidence of suicide among Chinese doctoral students remains high. We reviewed the statistics for doctoral student suicides over the past 12 years and administered a questionnaire survey and interviews to relatives and friends of doctoral students who committed suicide. The results indicated that suicide among doctoral students is closely related to academic pressure, the teacher-student relationship, and the academic environment, reflecting the current condition of China's doctoral tutorial system. This study provides a theoretical basis for society to understand Chinese doctoral student suicide and the Chinese doctoral tutorial system as well as the relationship between the two. Our results may serve as a warning to the academic community to prevent the worsening of the suicide contagion.


Superior two-year results of externally unsupported polyester compared to supported grafts in above-knee bypass grafting: a multicenter randomised trial.
The aim of this study was to compare externally supported thin wall knitted polyester (P-EXS) and externally unsupported thin wall knitted polyester (P-non-EXS) for above-knee (AK) femoro-popliteal bypass grafting. A prospective multicenter randomised clinical trial. Between 1999 and 2008, 265 AK femoro-popliteal bypass grafts (6 mm in diameter) were performed, including 136 P-EXS and 129 P-non-EXS. The selection of patients was based on the presence of disabling claudication or critical ischaemia. Follow-up took place at 3, 6, 12, 18, and 24 months and included clinical examination and duplex ultrasonography. The main end points of this study were primary patency rates at one and two years. Secondary end points were mortality, and primary assisted and secondary patency rates. Cumulative patency rates were calculated with life-table analysis and log-rank testing. The 1-year primary, primary assisted and secondary patency rates were 65%, 70% and 84%, respectively, for P-EXS and 76% (p = 0.05), 82% (p = 0.03) and 88% (p = 0.35), respectively, for P-non-EXS. Two-year primary, primary assisted and secondary patency rates were 45%, 57% and 70%, respectively, for P-EXS and 62% (p = 0.003), 75% (p = 0.005) and 84% (p = 0.02), respectively, for P-non-EXS. The overall mortality rate after two years was 11.3%. In above-knee femoro-popliteal bypass grafting patency rates of externally supported knitted polyester grafts were inferior to their unsupported counterpart. ISRCTN: At the time this study started this number was not the standard.


Further studies on the influence of interferon on pokeweed mitogen induced Ig-synthesis in vitro.
Preincubation with pure interferon beta, but not partially purified interferon alpha, increased immunoglobulin production from non-fractionated peripheral blood mononuclear cells stimulated by pokeweed mitogen. Preincubation of B lymphocytes, but not T lymphocytes or monocytes, with pure interferon beta also increased immunoglobulin synthesis. It is concluded that interferon has a direct effect on B lymphocytes in enhancing immunoglobulin production.


A semisynthetic Atg3 reveals that acetylation promotes Atg3 membrane binding and Atg8 lipidation.
Acetylation of Atg3 regulates the lipidation of the protein Atg8 in autophagy. The molecular mechanism behind this important biochemical event remains to be elucidated. We describe the first semi-synthesis of homogeneous K19/K48-diacetylated Atg3 through sequential hydrazide-based native chemical ligation. In vitro reconstitution experiments with the semi-synthetic proteins confirm that Atg3 acetylation can promote the lipidation of Atg8. We find that acetylation of Atg3 enhances its binding to phosphatidylethanolamine-containing liposomes and to endoplasmic reticulum, through which it promotes the lipidation process.


Stress and gonadal steroid influences on alcohol drinking and withdrawal, with focus on animal models in females.
Sexually dimorphic effects of alcohol, following binge drinking, chronic intoxication, and withdrawal, are documented at the level of the transcriptome and in behavioral and physiological responses. The purpose of the current review is to update and to expand upon contributions of the endocrine system to alcohol drinking and withdrawal in females, with a focus on animal models. Steroids important in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes, the reciprocal interactions between these axes, the effects of chronic alcohol use on steroid levels, and the genomic and rapid membrane-associated effects of steroids and neurosteroids in models of alcohol drinking and withdrawal are described. Importantly, comparison between males and females highlight some divergent effects of sex- and stress-steroids on alcohol drinking- and withdrawal-related behaviors, and the distinct differences in response emphasize the importance of considering sex in the development of novel pharmacotherapies for the treatment of alcohol use disorder.


Brain-wide distribution of reporter expression in five transgenic tetracycline-transactivator mouse lines.
The spatial pattern of transgene expression in tetracycline-controlled mouse models is governed primarily by the driver line used to introduce the tetracycline-controlled transactivator (tTA). Detailed maps showing where each tTA driver activates expression are therefore essential for designing and using tet-regulated models, particularly in brain research where cell type and regional specificity determine the circuits affected by conditional gene expression. We have compiled a comprehensive online repository of serial microscopic images showing brain-wide reporter expression for five commonly used tTA driver lines. We have spatially registered all images to a common three-dimensional mouse brain anatomical reference atlas for direct comparison of spatial distribution across lines. The high-resolution images and associated metadata are shared via the web page of the EU Human Brain Project. Images can be inspected using an interactive viewing tool that includes an optional overlay feature providing anatomical delineations and reference atlas coordinates. Interactive viewing is supplemented by semi-quantitative analyses of expression levels within anatomical subregions for each tTA driver line.


Mycosis fungoides: is it a Borrelia burgdorferi-associated disease?
Mycosis fungoides (MF) is the most frequently found cutaneous T-cell lymphoma with an unknown aetiology. Several aetiopathogenetic mechanisms have been postulated, including persistent viral or bacterial infections. We looked for evidence of Borrelia burgdorferi (Bb), the aetiologic agent of Lyme disease (LD), in a case study of MF patients from Northeastern Italy, an area with endemic LD. Polymerase chain reaction for the flagellin gene of Bb was used to study formalin-fixed paraffin-embedded lesional skin biopsies from 83 patients with MF and 83 sex- and age-matched healthy controls with homolocalised cutaneous nevi. Borrelia burgdorferi-specific sequence was detected in 15 out of 83 skin samples of patients with MF (18.1%), but in none out of 83 matched healthy controls (P<0.0001). The Bb positivity rates detected in this study support a possible role for Bb in the aetiopathogenesis of MF in a population endemic for LD.


Macrophage activation syndrome as initial presentation of systemic lupus erythematosus.
Macrophage activation syndrome (MAS) is known to be a severe and potentially life-threatening complication of rheumatic disorder, especially systemic juvenille rheumatoid arthritis. It is very rare for MAS to be an initial presentation of systemic lupus erythematosus (SLE). Here, we report a 14-year-old girl in whom MAS developed as an initial presentation of SLE. With early diagnosis and administration of cyclosporine A, she had a fair outcome. Further testing showed positive anti-dsDNA about 8 months later.


Mapping multidimensional content representations to neural and behavioral expressions of episodic memory.
Human neuroimaging studies have shown that the contents of episodic memories are represented in distributed patterns of neural activity. However, these studies have mostly been limited to decoding simple, unidimensional properties of stimuli. Semantic encoding models, in contrast, offer a means for characterizing the rich, multidimensional information that comprises episodic memories. Here, we extensively sampled four human fMRI subjects to build semantic encoding models and then applied these models to reconstruct content from natural scene images as they were viewed and recalled from memory. First, we found that multidimensional semantic information was successfully reconstructed from activity patterns across visual and lateral parietal cortices, both when viewing scenes and when recalling them from memory. Second, whereas visual cortical reconstructions were much more accurate when images were viewed versus recalled from memory, lateral parietal reconstructions were comparably accurate across visual perception and memory. Third, by applying natural language processing methods to verbal recall data, we showed that fMRI-based reconstructions reliably matched subjects' verbal descriptions of their memories. In fact, reconstructions from ventral temporal cortex more closely matched subjects' own verbal recall than other subjects' verbal recall of the same images. Fourth, encoding models reliably transferred across subjects: memories were successfully reconstructed using encoding models trained on data from entirely independent subjects. Together, these findings provide evidence for successful reconstructions of multidimensional and idiosyncratic memory representations and highlight the differential sensitivity of visual cortical and lateral parietal regions to information derived from the external visual environment versus internally-generated memories.


Ultra-light polylactic acid/combination composite foam: A fully biodegradable flame retardant material.
In this study, low-density polylactic acid (PLA) flame retardant foams were prepared using lignin fiber (LF), ammonium polyphosphate (APP), resorcinol bis(diphenyl phosphate) (RDP) and SiO2 aerogel. LF, RDP and SiO2 aerogel alone did not improved the flame retardancy of PLA composites; however, APP alone required a higher addition of amount to achieve a better flame retardancy. The synergistic effect between the four can improve the flame retardancy of PLA at a lower addition level. The intumescent flame retardant system composed of LF/APP/RDP/SiO2 aerogel can not only form a dense carbon layer on the surface of the material when burning to improve the flame retardant performance, but also improve the thermal stability of PLA, increase the degradation temperature and reduce the thermal weight loss rate. The final PLA flame retardant foam (density: 0.022 g/cm3) prepared by supercritical foaming can reach V-0 rating in UL-94 vertical combustion test, and the limiting oxygen index (LOI) can reach 30.5 %.


Prevention of febrile convulsions with dipropylacetate (Depakine).
In 47 children followed for 1 year after the first "simple" febrile convulsion, dipropylacetate (Depakine, 20 mg/kg) was as effective in preventing new febrile convulsions (a single recurrence in 4% of 47 children) as was phenobarbital (5 mg/kg) or primidone (25 mg/kg) (a single recurrence in 4% of 47 children), and there were no side effects. Of 47 untreated children followed for 1 year, 55% had 1 to 4 new febrile convulsions. All medications were given in divided doses morning and evening.


Preoperative periodontal treatment and its effects on postoperative infection in cardiac valve surgery.
Oral infection control is important for patients undergoing cardiac valve replacement (CVR) as prophylaxis for postoperative complications. This study examined the changes in oral health status by preoperative periodontal treatment and its effects on postsurgical complications in CVR patients. We recruited 64 patients undergoing CVR who received preoperative periodontal treatment at our hospital as the intervention group and retrospectively reviewed the medical records of 38 patients who had undergone CVR surgery without dental intervention as the control group. Oral health status was assessed at the first visit to our dental office, 1 day before surgery, and >7 days after surgery. Days of high fever, antibiotics use, and postoperative hospitalization were recorded for the intervention and control groups for statistical comparisons. In the intervention group, oral health status significantly improved from the initial visit to >7 days after surgery. There were significantly fewer days of high fever (>37.5°C) in the intervention group than in the control group, with comparable results for other events. This study's findings suggest that preoperative periodontal treatment can improve oral health status surrounding CVR surgery and could be the contributor of the reduction in the risk of postoperative infection.


Trauma-Informed Care: A Missing Link in Addressing Burnout.
The Covid-19 pandemic and national movements for health equity have highlighted the impact of trauma on public health as well as on health worker well-being. As burnout rates across healthcare climb, we seek creative and effective solutions. Current anti-burnout strategies focus on much needed systems solutions for employee success; however, they often lack a trauma-informed approach. Trauma is highly prevalent in society at large, and health workers are further exposed to trauma in the course of their professional studies and duties. Common symptoms of burnout may actually be manifestations of traumatic stress. Trauma-informed care (TIC) is a strategic framework and growing social movement for providing quality care to survivors of individual, interpersonal, collective, and structural trauma. Importantly, TIC has practical applications to address our healthcare burnout epidemic. In this perspective piece, an expert describes a trauma-informed lens through which to view burnout solutions using SAMHSA's 4 Rs of a trauma-informed approach: 1) Realize the widespread impact of trauma, 2) Recognize the signs and symptoms in patients and staff, 3) Respond by integrating knowledge about trauma into practice, and actively 4) Resist re-traumatization. Moving forward, key stakeholders must collaborate to build and refurbish efficient systems alongside a trauma-informed organizational model. TIC can transform the healthcare experience for patients and employees alike by fostering community, empowerment, and healing.


Sources of heavy metal contamination in Swedish wood waste used for combustion.
In this paper, wood waste (RWW) recovered for heat production in Sweden was studied. Previous research has concluded that RWW contains elevated amounts of heavy metals, causing environmental problems during waste management. This study extends previous work on RWW by analysing which pollution sources cause this contamination. Using existing data on the metal contents in various materials, and the amounts of these materials in RWW, the share of the elevated amounts of metals in RWW that these materials explain was quantified. Six different materials occurring in RWW were studied and the results show that they explain from 70% to 100% of the amounts of arsenic, chromium, lead, copper and zinc in RWW. The most important materials contributing to contamination of RWW are surface-treated wood, industrial preservative-treated wood, plastic and galvanised fastening systems. These findings enable the development and evaluation of strategies aiming to decrease pollution and resource loss from handling RWW. It is argued that source separation and measures taken further downstream from the generation site, such as treatment, need to be combined to substantially decrease the amount of heavy metals in RWW.


LDL apheresis in Japan.
LDL apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH). Currently, plasma exchange, double membrane filtration, and selective LDL adsorption are available in Japan, and selective LDL adsorption is most common method. LDL apheresis can prevent atherosclerosis progression even in homozygous (HoFH). However, in our observational study, HoFH who started LDL apheresis from adulthood had poor prognosis compared with patients who started from childhood. Therefore, as far as possible, HoFH patients need to start LDL apheresis from childhood. Although indication of LDL apheresis in heterozygous FH (HeFH) has been decreasing with the advent of strong statin, our observational study showed that HeFH patients who were discontinued LDL apheresis therapy had poor prognosis compared with patients who were continued apheresis therapy. These results suggest that high risk HeFH need to be treated by LDL apheresis even if their LDLC is controlled by lipid-lowering agents. However, by launching new class of lipid lowering agents, that is, PCSK-9 antibody and MTP inhibitor, indication of LDL-apheresis in FH may be changed near the future. LDL-apheresis can provide symptom relief of peripheral artery disease (PAD). Therefore, PAD patients who have insufficient effect by other therapeutic approach including revascularization are also treated by LDL apheresis. Thus, LDL apheresis is still one of good therapeutic options for severe atherosclerotic diseases in Japan.


The Influence of Grandparents on Children's Dietary Health: A Narrative Review.
To examine and synthesise recent evidence on the role of grandparents in shaping children's dietary health. The influence of grandparents on children's dietary health was evident across studies. Grandparents frequently provide their grandchildren with meals and snacks, and engage in many of the same feeding practices used by parents. Although grandparents report providing their grandchildren with healthy foods, the provision of treat foods high in sugar or fat was a common finding. This provision led to family conflict, with the indulgent behaviours of grandparents seen by parents as a barrier to healthy eating. Grandparents are exerting significant influence on child dietary health. Efforts are needed to ensure these care providers are considered key stakeholders in the promotion of healthy eating and are targeted in policies and programs addressing children's diets. Research that determines how to best support grandparents to foster healthy behaviours in children is critical.


Validity of the calculation of non-sex hormone-binding globulin-bound estradiol from total testosterone, total estradiol and sex hormone-binding globulin concentrations in human serum.
Recent evidences indicate that biologically available serum testosterone (T) and estradiol (E2) include not only the free fractions but also most of the albumin-bound fractions. These two serum T or E2 fractions constitute most of non-sex hormone-binding globulin (SHBG)-bound T or E2, respectively. It has been reported that the estimation of serum non-SHBG-bound T gives identical results when it is assayed experimentally or when it is calculated by a formula derived from the law of mass action assuming two binding systems (T-SHBG and T-albumin). In the present work, we have compared the results of the experimental measurement of non-SHBG-bound E2 with the calculated value derived by an equation based on the law of mass action considering four binding systems (E2-SHBG, T-SHBG, E2-albumin, T-albumin). It was found that the two estimations of non-SHBG-bound E2 correlated closely in normal men (r = 0.80), normal women (r = 0.90) and hirsute women (r = 0.98). When compared with a more complex calculation which includes 21 steroids and 3 binding proteins results also agreed closely. Values for the different T and E2 fractions in these groups of subjects are given. These calculations could be used, not only for clinical research, but also in clinical practice as an useful tool for evaluation of the sex hormone status of patients.


Expression of the MAGE gene family in human lymphocytic leukemia.
The MAGE gene family, encoding tumor-rejection antigens recognized by cytotoxic T lymphocytes, is frequently expressed in human solid cancers. However, its expression in leukemia has not been well studied. We have investigated MAGE gene expression at the mRNA level in human leukemia. The MAGE gene family was expressed in 17 of 34 (50%) examples of T cell leukemia (12/21 patients' peripheral blood mononuclear cells and 5/13 cell lines), in 7 of 16 (44%) cases of B cell leukemia (1/8 and 6/8 respectively), but in none of 23 myelomonocytic leukemia cases (0/16 and 0/7), as evaluated by the primers common to the MAGE-1, -3, -4 (-4a and/or -4b), and -6 genes and the semi-quantificative reverse transcription/polymerase chain reaction method. None of a panel of normal lymphoid cells expressed the MAGE gene family. As revealed by the primers specific for each of the MAGE genes, the MAGE-1, -2, -3, -4 or -6 gene was expressed in 8, 8, 6, 2, or 6 respectively out of 23 types of leukemia cell lines. Expression of the MAGE-1 protein in both the cell lines and patients' cells was confirmed by immunoblot analysis with the polyclonal antibody to recombinant MAGE-1 protein. Cellular MAGE-4 protein in the cell lines was measured by an enzyme-linked immunosorbent assay with the polyclonal and monoclonal antibodies to recombinant MAGE-4b protein. In summary, the MAGE gene family was found to be expressed in the substantial proportion of T cell leukemias, but in no case of myelomonocytic leukemia. Antigens coded by the MAGE gene family could be important molecules for understanding specific immunity against lymphocytic leukemia.


Allergy clinics in times of the SARS-CoV-2 pandemic: an integrated model.
Almost the entire World is experiencing the Coronavirus-Disease-2019 (COVID-19) pandemic, responsible, at the end of May 2020, of more than five million people infected worldwide and about 350,000 deaths. In this context, a deep reorganization of allergy clinics, in order to ensure proper diagnosis and care despite of social distancing measures expose, is needed. The reorganization of allergy clinics should include programmed checks for severe and poorly controlled patients, application of digital medicine service for mild-to-moderate disease in well-controlled ones, postponement of non urgent diagnostic work-ups and domiciliation of therapies, whenever possible. As far as therapies, allergen immunotherapy (AIT) should not be stopped and sublingual immunotherapy (SLIT) fits perfectly for this purpose, since a drug home-delivery service can be activated for the entire pandemic duration. Moreover, biologic agents for severe asthma, chronic spontaneous urticaria and atopic dermatitis should be particularly encouraged to achieve best control possible of severe disease in times of COVID-19 and, whenever possible, home-delivery and self-administration should be the preferred choice. During COVID-19 pandemic, allergists have the responsibility of balancing individual patients' needs with public health issues, and innovative tools, such as telemedicine and digital medicine services, can be helpful to reduce the risk of viral spreading while delivering up-to-date personalized care.


Nuclear Pore Complexes and Nucleocytoplasmic Transport: From Structure to Function to Disease.
Nucleocytoplasmic transport is an essential cellular activity and occurs via nuclear pore complexes (NPCs) that reside in the double membrane of the nuclear envelope. Significant progress has been made during the past few years in unravelling the ultrastructural organization of NPCs and their constituents, the nucleoporins, by cryo-electron tomography and X-ray crystallography. Mass spectrometry and genomic approaches have provided deeper insight into the specific regulation and fine tuning of individual nuclear transport pathways. Recent research has also focused on the roles nucleoporins play in health and disease, some of which go beyond nucleocytoplasmic transport. Here we review emerging results aimed at understanding NPC architecture and nucleocytoplasmic transport at the atomic level, elucidating the specific function individual nucleoporins play in nuclear trafficking, and finally lighting up the contribution of nucleoporins and nuclear transport receptors in human diseases, such as cancer and certain genetic disorders.


Effect of estrogen/gestagen and 24R,25-dihydroxyvitamin D3 therapy on bone formation in postmenopausal women.
The effect of two different estrogen/gestagen regimens and 24R,25-(OH)2-cholecalciferol on bone formation was studied in a randomized trial with 144 healthy postmenopausal women. Urinary excretion (UE) of 99m-technetium-diphosphonate and serum alkaline phosphatase (AP) was determined before and then once a year for 2 years of treatment. Both estimates of bone formation showed highly significant decreases (p less than .001) to normal premenopausal levels in women receiving unopposed 17 beta-estradiol or in a sequential combination with progestagen, whereas unchanged high values were found in the groups receiving 24R,25-(OH)2D3 and placebo. The data show that bone turnover increases in early postmenopausal women concomitantly with the loss of bone mass, and that hormonal substitutional therapy normalizes the total skeletal turnover as well as preventing bone loss.


Identification of amino acid residues of a designed ankyrin repeat protein potentially involved in intermolecular interactions with CD4: analysis by molecular dynamics simulations.
We applied molecular dynamics simulations to investigate the binding properties of a designed ankyrin repeat protein, the DARPin-CD4 complex. DARPin 23.2 has been reported to disturb the human immunodeficiency virus (HIV) viral entry process by Schweizer et al. The protein docking simulation was analysed by comparing the specific ankyrin binder (DARPin 23.2) to an irrelevant control (2JAB) in forming a composite with CD4. To determine the binding free energy of both ankyrins, the MM/PBSA and MM/GBSA protocols were used. The free energy decomposition of both complexes were analysed to explore the role of certain amino acid residues in complex configuration. Interestingly, the molecular docking analysis of DARPin 23.2 revealed a similar CD4 interaction regarding the gp120 theoretical anchoring motif. In contrast, the binding of control ankyrin to CD4 occurred at a different location. This observation suggests that there is an advantage to the molecular modification of DARPin 23.2, an enhanced affinity for CD4.


Biomarkers, regerons, and pathways to lethal cancer.
Cancer is a disease of "outlaw" cells that become mutated in regulatory mechanisms. They have lost normal self controls and relationships to the whole organism. Cancers can progress by several pathways from a normal cell to malignant cancer, from bad to worse. Questions about advisability of treatment for some cancers arise from the possibility that they are arrested during progression and so never become lethal. Techniques could be developed to determine the degree of progression and possibility for successful treatment. This article is intended to suggest a way of looking at cancer. It is not a review so references to research articles are infrequent.


Wind-chill and the seasonal variation of cerebrovascular disease.
The hospital admission rates for patients with specific types of stroke were examined for seasonal variation and correlation with meteorological factors. A seasonal variation in admission rates was found for subarachnoid haemorrhage, thrombo-embolic brain infarction and ill-defined cerebrovascular disease. Overall this seasonality was more strongly associated with the computed chilling effect of the atmosphere than with changes in temperature, humidity or wind speed alone. No seasonal variation was observed for admission rates of intracerebral haemorrhage, transient ischaemic attack or occlusion of precerebral arteries. Intracerebral haemorrhage admission rates exhibited a decrease with time. This evidence suggests that seasonal variation in admission rates exists only for certain pathological types of stroke and this is strongly associated with changes in the chilling effect of the atmosphere.


Photophysics of Soret-excited free base tetraphenylporphyrin and its zinc analog in solution.
Photophysical properties of free base tetraphenylporphyrin and its zinc analog are investigated in detail in solvents of varying polarity by using steady state and time-resolved techniques. Both the porphyrins are excited at the Soret band to have better signal-to-noise ratio. Also, the fluorescence emission measurements are carried out by using dilute solutions (~10(-7)mol/L) of the fluorophores in order to minimize the self-quenching effect. It is observed that the steady state absorption and emission characteristics of the porphyrin molecules are mainly affected by polarizability (via refractive index) rather than polarity (via dielectric constant) of the moderate to highly polar solvents. As the molecules are highly symmetric in the ground state, the associated dipole moments are found to be very low from quantum chemical calculations performed by density functional theory method by using Gaussian 03 package. The dipole moments associated with the first excited singlet state of the porphyrins are computed by applying solvatochromic Stokes' shift method. To the best of our knowledge, this is the first attempt to calculate the excited state dipole moments of the porphyrins used in the present investigations. Also, fluorescence quantum yield, fluorescence lifetime of the first excited singlet state, radiative and non-radiative rate constants of the porphyrins are reported in solvents of varying polarity.


Characterizing the prevalence and contributing factors of sexual violence: A representative cross-sectional study among school-going adolescents in two East African countries.
Sexual violence against minors is a global phenomenon with wide-ranging negative consequences. Global reports suggest that it is a particularly serious issue in East African countries, although research on prevalence and characteristics of violence in these countries is scarce. The aim of this study was to assess sexual violence and its circumstances among Tanzanian and Ugandan adolescents. Two representative samples of secondary school students aged 12-17 from Tanzania and Uganda (N = 1402) were included in this study. Data assessed using standardized questionnaires were analyzed to determine prevalence, characteristics, and contributing factors of sexual violence among youth. We found high levels of sexual violence (27.2 %) exceeding global average estimates of under 20 %. Significantly more sexual violence experiences were reported by boys (29.9 %) than girls (24.6 %) and by older compared to younger adolescents (30.2 % vs. 19.6 %). Peers were the most frequent perpetrator group, named by 47.6 % of those reporting abuse. Several potential contributing factors for victimization were identified, such as rural living area, external financial support, and being in a romantic relationship. Sexual violence is a relevant issue among East African adolescents that occurs in a variety of settings but appears to be most prevalent between peers. Comprehensive sexual education approaches may help to improve the protection of adolescents and to enhance autonomous sexual development.


Pulmonary vasodilation in the rat by insulin in vitro could indicate potential hazard for inhaled insulin.
Hypoxic pulmonary vasoconstriction is an essential mechanism to prevent hypoxaemia in lung diseases. Insulin is known to be a systemic vasodilator but its effect on the pulmonary circulation is not known. Inhaled particulate insulin can generate locally high concentrations in the lung which could be physiologically important. We therefore studied the effects of insulin in vitro on isolated rat pulmonary artery in a small vessel myograph. We have shown that pulmonary artery vasodilatation with insulin occurs in a dose-dependent manner. Pre-constriction with PGF2alpha can be abolished (105.7+/-2.9%, mean+/-SEM) and pre-constriction with hypoxia reduced (68.9+/-6.5%) by pharmacologically relevant concentrations of insulin. The characteristic phasic vasoconstriction by pulmonary vessel to hypoxia is substantially modified, resulting in sustained vasodilatation. These effects could be clinically important for patients using inhaled insulins who have acute or occult chronic lung disease.


Imperfections of elasticity and continental drift.
Imperfection of elasticity in the Earth follows a law that forbids convection and continental drift.


A non-hypocholesterolemic atorvastatin treatment improves vessel elasticity by acting on elastin composition in WHHL rabbits.
Statins are prescribed for their preventative effects within atherosclerosis development. To our knowledge, no study focusing on very low-dose (non-hypolipidemic effect) and long-term atorvastatin treatment in vivo was available. Our aim was to assess the effect of such atorvastatin treatment on the mechanical and functional characteristics of arteries in the context of primary prevention. An atorvastatin treatment (2.5 mg/kg/day) was tested against controls on 34 male 3 to 12 month-old WHHL rabbits. No effect on total cholesterol, triglycerides, HDL or LDL was observed. The arterial stiffness was evaluated on vigil animals by pulse wave velocity (PWV) measurement. Then, in vitro measurements were made to evaluate (1) the endothelial and vascular smooth muscle function, (2) the elasticity of the arterial wall and (3) the composition in collagen and elastin in the aorta. The PWV increasing observed with age in control group was canceled by treatment, creating a significance difference between groups at 12 months (5.17 ± 0.50 vs 2.14 ± 0.34 m s(-1) in control and treated groups respectively). Vasoreactivity modifications can't explain this result but maintain of elasticity with treatment in large arteries was confirm by a static tensile test. A first possible explanation is the change of wall composition with treatment, validated by the percentage of elastin at 12 months, 4.4% lower in the control group compared to the treated group (p < 0.05). This study shows that a non-hypocholesterolemic statin treatment could improve vessel elasticity in the atherosclerotic WHHL model. The great novelty of this work is the vessel wall composition changing associated. This first approach in animal opens the reflection on the use of these low doses in humans. This could be interesting in the context of arterial stiffening with aging, non-hyperlipidemic atherosclerosis or with cholesterol reduce by another therapy or lifestyle modification.


Porcine-pancreatic alpha amylase hydrolysis of substrates containing 6-deoxy-D-glucose and 6-deoxy-6-fluoro-D-glucose and the specificity of subsite binding.
Hydrolysis of 6-deoxyamylose and mono-6-deoxy-6-fluorocyclomaltoheptaose by porcine-pancreatic alpha amylase produces low-molecular-weight modified products, which have been analyzed by chemical and chromatographic techniques. Results for both substrates show that modified D-glucose and two isomers of modified maltoses are produced in the enzyme reaction. In addition, the formation of maltoses modified in the nonreducing residue is more favored than the formation of maltoses modified in the reducing residue. These results indicate that productive binding of 6-fluoro- and 6-deoxy-D-glucose residues is permitted at subsites 1 through 4 of the amylase-active site but that binding of these modified residues may be less favorable at subsite 3, the subsite at which catalytic attack occurs.


The role of family planning in recent rapid fertility declines in developing countries.
World Fertility Survey data for ten developing countries are used to examine the respective roles of development and family planning in influencing the regulation of fertility. The findings show that high proportions of women at all socioeconomic levels in the countries studied wanted no more children, including large proportions among rural, poor, and uneducated women with few children. The data also show that despite the limitations of underdevelopment, in countries with strong family planning programs knowledge and use of contraception was high. These findings confirm that there is a large unmet demand for family planning and point to the importance of continued allocation of funds to support service programs.


Fulminant myocarditis in a patient with a lung adenocarcinoma after the third dose of modern COVID-19 vaccine. A case report and literature review.
Introduction COVID-19 disease has caused a global health and economic crisis. The introduction of the different COVID-19 vaccines has resulted in a significant decrease in the morbidity and mortality associated with this disease. Adverse effects have been reported, including cardiological ones such as myocarditis or pericarditis after administration. Likewise, tyrosine kinase inhibitor drugs such as osimertinib used in lung cancer patients with epidermal growth factor receptor (EGFR) mutation are associated with heart failure or prolongation of the QT interval. Case report 62-year-old woman diagnosed in September 2019 of lung adenocarcinoma stage IV with bilateral lung and lymph node involvement, carrier of an EGFR mutation (Ex19Del) on treatment with osimertinib. She attended emergency department for fever and hypotension 24 h after administration of the third dose of Moderna® COVID-19 vaccine in the context of acute myocarditis with evidence of severe left ventricular (LV) dysfunction in cardiogenic shock. She required vasoactive support, non-invasive mechanical ventilation, corticotherapy, immunoglobulins and subsequent ventricular support with Impella, with improvement of the clinical picture after 3 days. Cardiac magnetic resonance imaging (MRI) showed evidence of global myocardial oedema compatible with acute myocarditis. Coronary CT showed a lesion in the anterior descending coronary artery requiring revascularization. A few days later, she presented febrile symptoms with isolation of Staphylococcus aureus in the central line catheter and antibiotherapy with cloxacillin was started, with subsequent resolution of the infectious symptoms. Conclusion This is an exceptional and controversial case of fulminant myocarditis probably related to the Modern COVID-19 vaccine in a patient diagnosed with metastatic lung adenocarcinoma on treatment with osimertinib. An increasing number of cases of myocarditis and pericarditis have been reported following vaccination with COVID-19 mRNA vaccines. In addition, retrospective data have shown an increased risk of QT prolongation and heart failure in patients treated with tyrosine kinase inhibitors. Hence, the need for close monitoring of cardiac function during treatment of these patients. Future studies will be necessary to evaluate unknown adverse reactions of these vaccines and their possible interaction with other antineoplastic drugs.


Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion.
The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.


Dynamic decision policy reconfiguration under outcome uncertainty.
In uncertain or unstable environments, sometimes the best decision is to change your mind. To shed light on this flexibility, we evaluated how the underlying decision policy adapts when the most rewarding action changes. Human participants performed a dynamic two-armed bandit task that manipulated the certainty in relative reward (conflict) and the reliability of action-outcomes (volatility). Continuous estimates of conflict and volatility contributed to shifts in exploratory states by changing both the rate of evidence accumulation (drift rate) and the amount of evidence needed to make a decision (boundary height), respectively. At the trialwise level, following a switch in the optimal choice, the drift rate plummets and the boundary height weakly spikes, leading to a slow exploratory state. We find that the drift rate drives most of this response, with an unreliable contribution of boundary height across experiments. Surprisingly, we find no evidence that pupillary responses associated with decision policy changes. We conclude that humans show a stereotypical shift in their decision policies in response to environmental changes.


The Nuclear Matrix Protein SAFB Cooperates with Major Satellite RNAs to Stabilize Heterochromatin Architecture Partially through Phase Separation.
Interphase chromatin is hierarchically organized into higher-order architectures that are essential for gene functions, yet the biomolecules that regulate these 3D architectures remain poorly understood. Here, we show that scaffold attachment factor B (SAFB), a nuclear matrix (NM)-associated protein with RNA-binding functions, modulates chromatin condensation and stabilizes heterochromatin foci in mouse cells. SAFB interacts via its R/G-rich region with heterochromatin-associated repeat transcripts such as major satellite RNAs, which promote the phase separation driven by SAFB. Depletion of SAFB leads to changes in 3D genome organization, including an increase in interchromosomal interactions adjacent to pericentromeric heterochromatin and a decrease in genomic compartmentalization, which could result from the decondensation of pericentromeric heterochromatin. Collectively, we reveal the integrated roles of NM-associated proteins and repeat RNAs in the 3D organization of heterochromatin, which may shed light on the molecular mechanisms of nuclear architecture organization.


The effect of medicaid expansion on access to healthcare, health behaviors and health outcomes between expansion and non-expansion states.
In 1965, Medicaid was implemented with the goal of providing insurance to low-income individuals. In 2010, the Patient Protection Affordable Care Act (PPACA) standardized and expanded the eligibility criteria for the Medicaid program across the United States. In 2012, the constitutionality of this expansion was challenged and the Supreme Court rules that states were only required to expand their Medicaid program if they wanted to utilize the additional funds allotted by the federal government. This research paper examines the effects of the expansion by looking at health data in expansion and non-expansion states. Specifically, this study compares metrics designed to gauge healthcare access, health behaviors and health outcomes to determine if expansion has had positive overall effect on expansion states. We conclude that expansion states have demonstrated improved access to healthcare and improved health outcomes than the non-expansion states. Changes in health behaviors reflect mixed results - HIV screenings are higher in expansion states but participation in flu vaccinations show no statistical significance difference between the two groups. Given the results of this analysis, we conclude that Medicaid expansion is an effective policy for states to pursue in order to further the original objectives of Medicaid by improving the health of low-income recipients.


Stochastic epigenetic dynamics of gene switching.
Epigenetic modifications of histones crucially affect eukaryotic gene activity, while the epigenetic histone state is largely determined by the binding of specific factors such as the transcription factors (TFs) to DNA. Here, the way in which the TFs and the histone state are dynamically correlated is not obvious when the TF synthesis is regulated by the histone state. This type of feedback regulatory relation is ubiquitous in gene networks to determine cell fate in differentiation and other cell transformations. To gain insights into such dynamical feedback regulations, we theoretically analyze a model of epigenetic gene switching by extending the Doi-Peliti operator formalism of reaction kinetics to the problem of coupled molecular processes. Spin-1 and spin-1/2 coherent-state representations are introduced to describe stochastic reactions of histones and binding or unbinding of TFs in a unified way, which provides a concise view of the effects of timescale difference among these molecular processes; even in the case that binding or unbinding of TFs to or from DNA is adiabatically fast, the slow nonadiabatic histone dynamics gives rise to a distinct circular flow of the probability flux around basins in the landscape of the gene state distribution, which leads to hysteresis in gene switching. In contrast to the general belief that the change in the amount of TF precedes the histone state change, flux drives histones to be modified prior to the change in the amount of TF in self-regulating circuits. Flux-landscape analyses shed light on the nonlinear nonadiabatic mechanism of epigenetic cell fate decision making.


Interventional neuroradiologic treatment of head and neck lesions.
Treatment of diseases involving the head and neck is most challenging because of the high density of vital structures in this region, the need to preserve function, and aesthetic requirements. Technical advances in needles, catheters, guide wires, and embolic materials have broadened the scope of interventional neuroradiologic procedures. Endovascular therapy can serve as a valuable adjunct to conventional surgical treatment for head and neck masses. In addition, it is now the treatment of choice for a variety of vascular lesions, such as arteriovenous malformations, arteriovenous fistulas, and pseudoaneurysms. In this article, examples from the spectrum of applications of endovascular therapy in the head and neck region are presented along with a discussion of therapeutic considerations.


Total facial nerve injury during mandibular distraction osteogenesis.
Over the last 10-15 years, usage of internal mandibular distraction systems has increased in the pediatric population, particularly for craniofacial syndromes. Mandibular distraction osteogenesis (MDO) has been shown to be effective in avoiding tracheostomy or achieving early decannulation in patients with micro-retrognathic mandibles in hemifacial microsomia or Pierre Robin sequence. As the frequency of the application of MDO has increased, so has the awareness and management of subsequent complications from the procedure. In this study, we discuss a complication involving paresis and eventual recovery of cranial nerve (CN) VII after the application of an MDO internal device at our institution in two cases. We also review the literature and propose multiple anatomic considerations that can impact more than just the marginal branch of CN VII. This study is a retrospective case study from our institution and a review of the literature. Pubmed was queried for terms singularly and in combination including "mandibular distraction osteogenesis", "facial nerve", "cranial nerve", "complications", "micrognathia", "retrognathia". After reviewing the results, studies discussing complications of MDO that involved CN VII were reviewed and included. In the literature review and our retrospective review, CN VII injuries from MDO vary in their length and timing of onset. Management of this complication depended on the timing of onset and ranged from conservative management to removal of the distraction device. Majority (7/9) of the cases resolved to an eventual House-Brackmann of 0/6 with conservative measures. Total facial nerve injury in association with MDO, has been scarcely reported, though the facial nerve is at great risk given its intimate location near the mandible particularly in neonates. It is encouraging that though it could be a devastating complication, out of all the cases reported, the large majority resolve with a combination of time and steroids.


Utility of gum-elastic bougie for tracheal intubation during chest compressions in a manikin: a randomized crossover trial.
The utility of the gum-elastic bougie (GEB) as an assistive device for tracheal intubation during chest compressions has not been sufficiently validated. This study aimed to compare the utility of the GEB during chest compressions on an adult manikin. Seventeen novice physicians performed tracheal intubation on an adult manikin using the GEB with or without chest compressions. Intubation success rate, intubation time, subjective difficulty of laryngoscopy, and tube passage through the glottis were measured. P < .05 was considered as significantly different. All novice physicians successfully secured the airway without chest compression with and without the GEB. In contrast, during chest compressions, 7 failed without the GEB, whereas only 1 failed with the GEB (P = .007). Intubation time was significantly longer with chest compressions regardless of GEB use (P < .001). Both laryngoscopy and tube passage through the glottis were perceived as significantly more difficult with chest compressions, regardless of GEB use (P < .001). Subjective difficulty of tube passage through the glottis during chest compression was perceived as significantly more easy by GEB application (P < .001). These findings suggest that the GEB facilitates tracheal intubation during chest compressions performed by novice physicians in adult simulations.


Left Ventricular Longitudinal Strain as a Marker for Point of No Return in Hypertensive Heart Failure Treatment.
There are currently no therapies that can improve prognosis in cases of heart failure (HF) with preserved ejection fraction (EF). We hypothesized that there is a point of no return after which no response to treatment is noted and that for the prevention of hypertensive HF this point may be determined by left ventricle (LV) strain, in the prevention of hypertensive HF. Here an angiotensin-converting enzyme inhibitor (ACE-I) was initiated based on myocardial strain imaging and its effects were determined in an animal model. Thirty-two male Dahl salt-sensitive rats, age 6 weeks, were divided into six experimental groups and compared with low-salt (n = 8) and high-salt control groups (n = 8). In the early treatment group, ACE-I was administered from the age of 6 weeks (n = 4); in the longitudinal strain (LS) group, at 10-12 weeks when LS impairment was >-21% (n = 4); in the circumferential strain (CS) group, at 16-18 weeks when CS impairment was >-18% (n = 4); and in the EF group, at 20 weeks when EF was <55% (n = 4). Subsequently, all rats were sacrificed at 23 weeks age, the LV and lung weight were measured, and pathologic analyses were performed. At 23 weeks of age, the lung and LV weights increased in the high-salt control, EF, and CS groups, whereas the lung and LV weights in the LS and early groups were similar to those in the low-salt control group. The percentage of area of subendocardial fibrosis was >6% in the high-salt control, EF, and CS groups and <3% in the LS, early, and low-salt groups. Serial echocardiography demonstrated LS improvement in the LS group; however, the CS and EF groups showed no differences. Heart failure-related lung congestion was prevented when ACE-I was administered soon after LS impairment, accompanied by suppression of cardiac hypertrophy and fibrosis, thereby suggesting that the point of no return of myocardial remodeling due to hypertension was present after LS but before CS impairment.


Does implant surface hydrophilicity influence the maintenance of surface integrity after insertion into low-density artificial bone?
To evaluate the influence of hydrophilicity on the surface integrity of implants after insertion in low-density artificial bone and to determine the distribution of titanium (Ti) particles along the bone bed. Forty-eight dental implants with different designs (Titamax Ex, Facility, Alvim, and Drive) and surface treatments (Neoporos® and Aqua™) were inserted into artificial bone blocks with density compatible with bone type III-IV. Hydrophobic Neoporos® surfaces were obtained by sandblasting and acid etching while hydrophilic Aqua™ surfaces were obtained by sandblasting, acid etching, and storage in an isotonic 0.9% NaCl solution. The surface integrity was evaluated by Scanning Electron Microscope (SEM) and the surface roughness parameters (Sa, Sp, Ssk, Sdr, Spk, Sk, and Svk) and surface area were measured with Laser Scanning Confocal Microscopy before and after installation. Bone beds were inspected with Digital Microscopy and micro X-Ray Fluorescence (μ-XRF) to analyze the metallic element distribution along the bone bed. Acqua™ implants had higher initial Sa and a pronounced reduction of Sa and Sp during insertion, compared to NeoPoros® implants. After insertion, Sa and Sp of Acqua™ and NeoPoros® implants equalized, differing only between designs of Acqua™ implants. Surface damage was observed after insertion, mainly in the apical region. Facility implants that are made of TiG5 released fewer debris particles, while the highest Ti intensity was detected in the cervical region of the Titamax Ex Acqua™ and Drive Acqua™ implants. Physicochemical modifications to achieve surface hydrophilicity created a rougher surface that was more susceptible to surface alterations, resulting in more Ti particle release into the bone bed during surgical insertion. The higher Ti intensities detected in the cervical region of bone beds may be related to peri-implantitis and marginal bone resorption.


The non-filter function of orb webs in spiders.
Experiments with artificial webs show that there is no correlation between prey size and mesh width. The number of prey items per thread increases with mesh width. Spiders with narrow-meshed webs catch more prey, whilst spiders with wide-meshed webs save more spinning material.


Iron rich self-assembly micelles on the Doce River continental shelf.
After the Fundão iron ore mining dam rupture in November 2015, yellow/ocher emulsions never before reported on the continental shelf adjacent to the Doce River began to be seen, both in coalesced and foam forms. XRD analyses pointed to a prevailing composition of iron and kaolinite with a substantial contribution of an organic-metallic compound, measured in multiple periods over 2 years of sampling. Optical microscopy images allowed the identification of micelles composed of nanoparticles of iron oxyhydroxide making up this emulsion. The generation of dendritic snowflake-shaped microcrystals on fiber filters after water sample filtration and heating confirmed the presence of micelles composed of iron oxyhydroxide nanoparticles enveloped by organic polymers. After losing water, the micelles may act as a self-assembly template seed, where the polymer acts in the oriented adsorption of nanoparticles according to their crystallographic structure. The study brought to light the distinct behavior of a portion of the tailings material, which has already been reported to not have the same flocculation process as the clay minerals previously found in the suspended particulate material (SPM) before the dam rupture.


Circulating matrix metalloproteinases and their inhibitors in hypertension.
Growing experimental evidence indicates that matrix metalloproteinases (MMPs) are implicated in many cardiovascular diseases including hypertension and its chronic complications. It is now clear that MMPs have many more substrates other than components of the extracellular matrix. In fact, intracellular targets now include those associated with the cardiovascular system. Clinical studies have suggested that circulating MMPs may predict cardiovascular morbidity and mortality. It is highly probable that increased MMPs may predispose hypertensive patients to additional complications and clinical sequelae. In this article, we review the basic principles linking MMP activity with hypertension and summarize clinical studies examining two specific MMPs (MMP-2 and -9) in hypertension. We also discuss how antihypertensive drugs may affect MMPs and their endogenous inhibitors, i.e., tissue inhibitors of matrix metalloproteinases (TIMPs). Circulating MMPs may predict increased risk of developing cardiovascular complications associated with hypertension. As such, patients could benefit from early pharmacologic intervention including use of MMP inhibitors.


Genomic organization of an avermectin receptor subunit from Haemonchus contortus and expression of its putative promoter region in Caenorhabditis elegans.
Avermectins and milbemycins are believed to exert their anthelmintic effects by binding to glutamate-gated chloride channels (GluCls). Two GluCl subunits have been localized in the pharynx in Caenorhabditis elegans, and the pharynx has been implicated as a major target for avermectins in C. elegans. However, in parasitic nematodes, the pharyngeal localization of the GluCl subunits needs to be determined. The HcGluCla gene encoding an alpha-type GluCl subunit has been cloned from Haemonchus contortus previously. To investigate the expression site of the HcGluCla gene we have isolated a 1439bp 5'-flanking region and determined the genomic organization of this gene. The HcGluCla gene is composed of 12 exons separated by 11 introns and spans approximately 7.3kb of genomic DNA. Analysis of the 1439bp 5'-flanking region of the HcGluCla gene revealed that it contained TATA, CCAAT boxes, and several other consensus transcriptional factor recognition sequences. The 1439bp 5'-flanking region and the first exon and intron and part of the second exon of the HcGluCla gene were fused to green fluorescence protein (GFP) reporter gene and microinjected into the gonads of C. elegans. After microinjection of the construct into C. elegans, four stable transformed lines were established and assayed for GFP expression. The transformed animals exhibited fluorescence in the two pairs of MC and M2 pharyngeal neurons, but no expression was detected in the muscle cells. Expression of HcGluCla in pharyngeal neurons suggests a mechanism for the effects of avermectins and milbemycins on pharyngeal function in parasitic nematodes.


The European Federation of the Pharmaceutical Industry and Associations' Research and Animal Welfare Group: Assessing and benchmarking 'Culture of Care' in the context of using animals for scientific purpose.
The European Federation of Pharmaceutical Industries and Associations' Research and Animal Welfare group members reflected on the concept of a Culture of Care in relation to animal care and use and on differences in its understanding and application across European pharmaceutical companies. The term 'Culture of Care' is used across different regions and organizations but rarely with any defined indicators to support working practice. The European Federation of Pharmaceutical Industries and Associations' Research and Animal Welfare group has developed a framework to help organizations identify gaps or potential areas for improvement in support of a positive Culture of Care. The framework is a tool that identifies five areas of focus for a Culture of Care: company values; strategic approach at establishment level; implementation structures; staff support; and animal care and procedures. The framework is intended as an aid for continuous improvement, highlighting where indicators of good practice are present. We expect it to provide points of reflection and ideas for those looking to implement a Culture of Care in a structured way, while facilitating a professional and strategic approach. To prevent it supporting a 'tick-box' exercise, the framework must not be used as an auditing tool, but as a starting point for consideration and discussion about how care manifests within the context and constraints of individual establishments.