Computer-assisted assessment of human sperm morphology: usefulness in predicting fertilizing capacity of human spermatozoa.
The usefulness of sperm morphology to predict the outcome of human sperm fertilizing capacity was examined. Semen samples from 50 male patients attending the infertility clinic of a tertiary referral institution were studied. Sperm morphology was classified both by visual assessment and computer-assisted image analysis. In addition, morphometric analysis of the spermatozoa was measured by the morphologizer. Multivariate discriminant analysis was used to evaluate the usefulness of these morphology parameters for predicting the outcome of the zona-free hamster oocyte sperm penetration assay. The manually derived percent of spermatozoa with normal and small head were selected to be of discriminating value in predicting the outcome of the zona-free hamster oocyte penetration test. The accuracy of correctly classifying the outcome of zona-free hamster oocyte penetration test by these two parameters in combination was 84%, whereas assessment of sperm morphology with morphometric analysis by the morphologizer selected a total of eight variables, which together predicted sperm fertilizing capacity with 74% accuracy. Addition of the morphologizer-derived parameters to those derived manually did not significantly improve the predictive value. We conclude that the results of the zona-free hamster egg penetration test could be predicted using manual assessment of sperm morphology and computer-assisted morphometric analysis did not add further information.


Environmentally friendly and non-polluting solvent pretreatment of palm samples for polyphenol analysis using choline chloride deep eutectic solvents.
In this work, choline chloride (ChCl) deep eutectic solvents (DESs) were evaluated for the pretreatment of palm samples in the analysis of polyphenols, such as protocatechuic acid, catechins, epicatechin, and caffeic acid. During the enrichment step of the pretreatment, eight DESs comprising ChCl with ethylene glycol (EG), glycerol (Gly), xylitol (Xyl), phenol (Ph), formic acid (FA), citric acid (CiA), oxalic acid (OA), or malonic acid (MA), were prepared and applied to the reflux extraction of polyphenols from palm samples. All the DESs exhibited higher polyphenol extraction efficiency than methanol, and the highest extraction efficiency was obtained using ChCl-FA (1:1, mole ratio). For the purification step of the pretreatment, eight ChCl DES-modified adsorbents were prepared by hydrothermal polymerization and packed into solid-phase extraction (SPE) cartridges, and ChCl-Urea, ChCl-Gly, ChCl-FA, and water, were used as eluents. The ChCl DES-modified adsorbents were characterized by Fourier transform infrared spectroscopy, thermal gravimetric analysis, scanning electron microscopy, and Brunauer-Emmett-Teller surface analysis, and the polyphenols were analyzed by mass spectrometry and high-performance liquid chromatograph-ultraviolet detection. The highest purification efficiency was obtained using the ChCl-Ph DES-modified adsorbent as the SPE packing material and ChCl-Urea-H2O (1:1:5, mole ratio), ChCl-Gly (1:1, mole ratio), ChCl-FA-H2O (1:1:5, mole ratio), and H2O as the eluents. Compared to conventional purification processes that employ commercial C18 or C8 SPE columns with organic solvents as eluents, the ChCl DES-based SPE purification process successfully avoided the use of expensive commercial SPE columns and organic solvents. Furthermore, it isolated a larger amount of the target compounds under the same experimental conditions, and could be applied over five cycles with good reversibility. This work indicates that DESs as green solvents have great potential for the totally green pretreatment of samples during the enrichment and purification processes.


Volumetric evidence of a left laterality effect in epileptic psychosis.
We investigated anatomic alterations and lateralization effect in the mesial temporal lobe structures (amygdala and hippocampus) in epileptic psychosis MRI volumetric measurements. Patients with epileptic psychosis and normal controls were studied. Left hippocampus values were significantly smaller for patients (P<0.001). Hippocampal ratio was significantly greater for patients (P<0.01). Group (patients x normal) was the only factor explaining the statistically significant variation of left hippocampus and hippocampal ratio (P<0.001 and P<0.05). Twenty patients had hippocampal atrophy (4 on the right side, 15 on the left side, and 1 bilateral) associated with mesial temporal sclerosis. These results confirm the existence of anatomic alterations and a left laterality effect in the mesial temporal lobe structures of patients with epileptic psychosis.


Reduction, classification and ranking of motion analysis data: an application to osteoarthritic and normal knee function data.
There are certain major obstacles to using motion analysis as an aid to clinical decision making. These include: the difficulty in comprehending large amounts of both corroborating and conflicting information; the subjectivity of data interpretation; the need for visualization; and the quantitative comparison of temporal waveform data. This paper seeks to overcome these obstacles by applying a hybrid approach to the analysis of motion analysis data using principal component analysis (PCA), the Dempster-Shafer (DS) theory of evidence and simplex plots. Specifically, the approach is used to characterise the differences between osteoarthritic (OA) and normal (NL) knee function data and to produce a hierarchy of those variables that are most discriminatory in the classification process. Comparisons of the results obtained with the hybrid approach are made with results from artificial neural network analyses.


Trends and causes of readmission following peripheral vascular intervention in patients with peripheral vascular disease.
To study the risk factors associated with 30-readmission postperipheral vascular intervention (PVI) in peripheral artery disease (PAD). There has been a paucity of data regarding the trend and predictors of PVI readmission. We performed an observational cohort study of patients admitted with peripheral vascular disease for PVI using the NRD for the years 2010-2014. PVI was defined as angioplasty, atherectomy, and/or stenting of lower limb vessels. A total of 453,278 patients (30-day readmission n = 97,235). The mean age of study population was 68.6 ± 12.2 years and included 43.8% women. The 30-day readmission post-PVI was 21.5% (p = .034). Cardiovascular causes constitute 44% of readmission. Chronic limb ischemia and intermittent claudication were two most common cardiovascular causes constituting 11.7 and 4.9% cases of readmissions. Other cardiac causes of readmissions included heart failure (4.64%), dysrhythmias (1.4%), and acute myocardial infarction (1.7%). The high-risk factors for of all-cause 30-day readmission were hypertension, CLI, diabetes, renal failure, dyslipidemia, smoking, chronic pulmonary disease, and atrial fibrillation (p < .005). Length-of-stay was greater than 5 days for 56.2 and 75.4% paid by Medicare. Our study shows an average yearly readmission rate of 21.5% post-PVI. Chronic comorbidities and prolonged hospitalization were associated with higher risk of readmission.


Antibacterial properties of Ag/TiO2/PDA nanofilm on anodized 316L stainless steel substrate under illumination by a normal flashlight.
The demand of medical materials for rapid and efficient elimination of bacteria has seen a dramatic surge over the past few years. In this study, antibacterial nanofilms with reactive oxygen species were generated by photocatalysis. To prepare these nanofilms, Ag and amorphous TiO2 nanoparticles decorated on polydopamine (PDA) were coated on three-dimensional (3D) nanopore arrays, which was fabricated on a substrate of anodized stainless steel. All the antibacterial tests were conducted with a household flashlight, which may be considered as a practical approach for antibacterial materials. The photoelectrochemical property of the 3D Ag/TiO2/PDA nanofilm on 316L stainless steel (Ag/TiO2/PDA SS) was about 15 times higher than that of the annealed Ag/TiO2/PDA SS, and consequently, it exhibited higher antibacterial activity. The enhanced photoelectrochemical property is attributed to the successful separation of electrons (amorphous TiO2) and holes (Ag nanoparticles). Further, when a plate containing 3D Ag/TiO2/PDA SS was irradiated with visible light just for 10 min, it immediately destroyed the bacteria in 106 CFU/mL without any bacterial colony. After five weeks, there were still no bacterial colonies in the plate corresponding to Ag/TiO2/PDA SS under visible light, while Ag/TiO2/PDA SS in dark had a negligible effect on the bacteria, i.e., the antibacterial mechanism through direct contact and ion dissolution was not efficient. The excellent antibacterial properties of 3D Ag/TiO2/PDA SS illuminated by flashlight provides an efficient, facile, and cost-effective technique for the development of antibacterial medical materials to meet the increasing demand of eliminating bacterial infections.


Regional splanchnic blood flow during sleep in the rabbit.
Regional splanchnic blood flow (rSBF) was measured in rabbits with the radioactive microsphere technique. No statistically significant changes occurred in rSBF or vascular conductances in relation to the different states of the sleep-waking cycle (quiet-wakefulness, synchronized sleep, and desynchronized sleep).


Mapping evidence on ovarian, endometrial, vaginal, and vulva cancer research in Africa: a scoping review protocol.
Globally, cancer is generally recognized as a developmental threat yet most countries in Africa lack capacity to diagnose cancer especially gynecological cancers resulting in late detection and poor outcomes. However, most studies on gynecological cancers in Africa tend to focus on cervical cancer compared to the other gynecological cancers. Therefore, this scoping review will aim to describe the existing literature on the epidemiological burden of ovarian, endometrial, vaginal, and vulva cancers, their risk factors, and potential screening methods/techniques in Africa to identify priority research gaps for further research to inform health policy decisions. The framework promulgated by Arksey and O'Malley and improved by Levac et al. will be used as a guide for this scoping review. A comprehensive search for relevant published studies in PubMed, CINAHL, SCOPUS, Google Scholar, and ScienceDirect with no date limitation to the last search date. The database search strategy will include keywords, Boolean operators, and medical subject heading terms. We will additionally consult the WHO/IARC website, IHME/Global Burden of Disease Study. A snowball approach will also be used to search the reference list of all included studies to obtain relevant papers for possible inclusion in this review. We will include articles that involve African countries, focused on ovarian, endometrial, vaginal, and vulva cancers, their risk factors, and potential screening methods/techniques in any language. We will exclude studies on cervical cancer and other cancers as well as review articles. The abstracts and full-text selection will be conducted by two independent reviewers using this review's eligibility criteria as a guide. All the review selection tools, and the data extraction form will be pilot tested for accuracy and consistency. The data will be organized into thematic areas, summarized and the results communicated narratively. It is anticipated that this review will reveal important literature gaps to guide future research to inform health policy decisions about ovarian, endometrial, and rare gynecological neoplasms in Africa. This review's findings will be disseminated via peer review journals, conferences, and other social media such Twitter and LinkedIn.


Human telomerase activity regulation.
Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells. Thus, it has become a very promising target for anticancer therapy. The cell proliferative potential can be limited by replication end problem, due to telomeres shortening, which is overcome in cancer cells by telomerase activity or by alternative telomeres lengthening (ALT) mechanism. However, this multisubunit enzymatic complex can be regulated at various levels, including expression control but also other factors contributing to the enzyme phosphorylation status, assembling or complex subunits transport. Thus, we show that the telomerase expression targeting cannot be the only possibility to shorten telomeres and induce cell apoptosis. It is important especially since the transcription expression is not always correlated with the enzyme activity which might result in transcription modulation failure or a possibility for the gene therapy to be overcome. This review summarizes the current state of knowledge of numerous telomerase regulation mechanisms that take place after telomerase subunits coding genes transcription. Thus we show the possible mechanisms of telomerase activity regulation which might become attractive anticancer therapy targets.


Gamma-aminobutyric acid secreted from islet beta-cells modulates exocrine secretion in rat pancreas.
To investigate the role of endogenous gamma-amino-butyric acid (GABA) in pancreatic exocrine secretion. The isolated, vascularly perfused rat pancreas was employed in this study to eliminate the possible influences of extrinsic nerves and hormones. Cholecystokinin (CCK; 10 pmol/L) was intra-arterially given to stimulate exocrine secretion of the pancreas. Glutamine, a major precursor of GABA, which was given intra-arterially at concentrations of 1, 4 and 10 mmol/L, dose-dependently elevated the CCK-stimulated secretions of fluid and amylase in the normal pancreas. Bicuculline (10 micromol/L), a GABA(A) receptor antagonist, blocked the enhancing effect of glutamine (4 mmol/L) on the CCK-stimulated exocrine secretions. Glutamine, at concentrations of 1, 4 and 10 mmol/L, dose-dependently increased the GABA concentration in portal effluent of the normal pancreas. The effects of glutamine on the CCK-stimulated exocrine secretion as well as the GABA secretion were markedly reduced in the streptozotocin-treated pancreas. GABA could be secreted from beta-cells into the islet-acinar portal system after administration of glutainine, and could enhance the CCK-stimulated exocrine secretion through GABA(A) receptors. Thus, GABA in islet beta-cells is a hormone modulating pancreatic exocrine secretion.


Characteristic effects of alloying elements on β solidifying titanium aluminides: A review.
The high strength-to-weight ratio property of titanium aluminide (TiAl) based intermetallic alloys makes researchers regard this type of material as a potential replacement for the heavier superalloys of nickel. These alloys have been applied as turbocharger wheels of automobile and turbine blades of aircraft engines. A much recent alloy type of TiAl called the TNM alloy has emerged and primarily amenable to mechanical working; while providing the best combinations of mechanical properties that could be achieved through manufacturing processes with subsequent heat treatments. This is attained by solidifying entirely through the disordered β-phase (A2 structure). Effects of major alloying elements such as strength improvement, microstructural stability and phase formation demand the understanding of these alloying elements addition in TiAl-based intermetallic alloys. This review paper aims at encapsulating several works regarding the effects of major alloying elements on β-solidifying TiAl-based alloys and summarizing the characteristic effects of Si for these types of alloys. An impetus for future works on these types of intermetallic TiAl-based alloys is also presented.


Dynamics of mammalian NER proteins.
Despite detailed knowledge on the genetic network and biochemical properties of most of the nucleotide excision repair (NER) proteins, cell biological analysis has only recently made it possible to investigate the temporal and spatial organization of NER. In contrast to several other DNA damage response mechanisms that occur in specific subnuclear structures, NER is not confined to nuclear foci, which has severely hampered the analysis of its arrangement in time and space. In this review the recently developed tools to study the dynamic molecular transactions between the NER factors and the chromatin template are summarized. First, different procedures to inflict DNA damage in a part of the cell nucleus are discussed. In addition, technologies to measure protein dynamics of NER factors tagged with the green fluorescent protein (GFP) will be reviewed. Most of the dynamic parameters of GFP-tagged NER factors are deduced from different variants of 'fluorescence recovery after photobleaching' (FRAP) experiments and FRAP analysis procedures will be briefly evaluated. The combination of local damage induction, genetic tagging of repair factors with GFP and microscopy innovations have provided the basis for the determination of NER kinetics within living mammalian cells. These new cell biological approaches have disclosed a highly dynamic arrangement of NER factors that assemble in an orderly fashion on damaged DNA. The spatio-temporal analysis tools developed for the study of NER and the kinetic model derived from these studies can serve as a paradigm for the understanding of other chromatin-associated processes.


[Timolol and acetazolamide in the treatment of increased intraocular pressure (author's transl)].
Twenty-four patients with open-angle glaucoma were tested to see if, and to what extent, timolol and acetazolamide produced a supplementary reduction of intraocular pressure. Twelve patients were treated with timolol eye drops, 0.5% b.d over a period of one week and then received one dose i.v. acetazolamide 250 mg which produced a statistically significant drop in intraocular pressure. Twelve patients with open-angle glaucoma who had been treated with acetazolamide 500 mg t.d.s. orally over a period of one week, received one drop of timolol 0.25% which produced a statistically significant additional effect. These results are discussed on the basis of the mode of action of the applied medications.


Low tissue oxygen saturation at emergency center triage is predictive of intensive care unit admission.
Timely recognition of critical patients by emergency center triage is an ongoing challenge. Peripheral tissue oxygen saturation (StO2) measurement has been used to monitor shock patients' responses to resuscitation. Interest has developed in evaluating StO2 as a triage tool, but limited studies have addressed critically ill patients. This is a single-center, retrospective study of 158 emergent cancer patients with hypotension and/or modified systemic inflammatory response syndrome who underwent StO2 spot measurement at triage. Of the 57 patients with StO2 less than 70%, 17 went to the intensive care unit (ICU), whereas only 14 of the 101 patients with StO2 of 70% to 89% (P = .01) went to the ICU. There was no significant difference in non-ICU hospital admission or mortality between the 2 groups. The odds ratio of ICU admission for patients with StO2 less than 70% relative to those with StO2 of 70% to 89% was 2.64 (95% confidence interval, 1.18-5.87) and 2.87 (95% confidence interval, 1.23-6.66) when adjusted for mean arterial pressure, pulse, and temperature. In this patient population, an StO2 less than 70% significantly increased the risk of ICU admission. Tissue oxygen saturation at triage identifies critical patients who may not be recognized by vital signs alone. Tissue oxygen saturation measurement could help providers make earlier decisions regarding hospital resource allocation.


Excess mortality among patients with severe mental disorders and effects of community-based mental healthcare: a community-based prospective study in Sichuan, China.
High-quality primary care reduces premature mortality in the general population, but evidence for psychiatric patients in China is scarce. To confirm excess mortality in patients with severe mental illness (SMI), and to examine the impact of community-based mental healthcare and other risk factors on their mortality. We included 93 655 patients in 2012 and 100 706 in 2013 from the national mental health surveillance system in Sichuan, China to calculate the standardised mortality ratio (SMR). A total of 112 576 patients were followed up from 2009 to 2014 for model analyses. We used growth models to quantify the patterns of change for community management measures, high-risk behaviour, disease stability and medication adherence of patients over time, and then used multilevel proportional hazard models to examine the association between change patterns of management measures and mortality. The SMR was 6.44 (95% CI 4.94-8.26) in 2012 and 7.57 (95% CI 5.98-9.44) in 2013 among patients with SMI aged 15-34 years, and diminished with age. Unfavourable baseline socioeconomic status increased the hazard of death by 38-50%. Positive changes in high-risk behaviour, disease stability and medication adherence had a 54% (95% CI 47-60%), 69% (95% CI 63-73%) and 20% (4-33%) reduction in hazard of death, respectively, versus in those where these were unchanged. High excess mortality was confirmed among younger patients with SMI in Sichuan, China. Our findings on the relationships between community management and socioeconomic factors and mortality can inform community-based mental healthcare policies to reduce excess mortality among patients with SMI.


Narrowly defined taxa on a global scale: The phylogeny and taxonomy of the genera Catriona and Tenellia (Nudibranchia, Trinchesiidae) favours fine-scale taxonomic differentiation and dissolution of the "lumpers & splitters" dilemma.
By applying morphological and molecular data on two genera of the nudibranch molluscs it is shown that the tension between taxonomic practice and evolutionary processes persists. A review of the related genera Catriona and Tenellia is used to demonstrate that the fine-scale taxonomic differentiation is an important tool in the integration of morphological and molecular data. This is highlighted by the hidden species problem and provides strong argument that the genus must be kept as a maximally narrowly-defined entity. Otherwise, we are forced to compare a highly disparate species under the putatively lumped name "Tenellia". We demonstrate this in the present study by applying a suite of delimitation methods and describing a new species of Tenellia from the Baltic Sea. The new species possesses fine-scale morphological distinguishing features, which were not investigated before. The true, narrowly defined genus Tenellia represents a peculiar taxon with a clearly expressed paedomorphic characters and predominantly brackish-water habitats. The phylogenetically related genus Catriona, of which three new species are described here, clearly demonstrates different features. A lumping decision to call many morphologically and evolutionary different taxa as "Tenellia" will downgrade the taxonomic and phylogenetic resolution of the entire family Trinchesiidae to just a single genus. The dissolution of the dilemma of "lumpers & splitters", which still significantly affects taxonomy, will further help to make systematics a true evolutionary discipline.


Design, synthesis, and evaluation of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.
Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti-HIV potency in TZM-bl and MT-4 cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC50 values ranging from 2.45 nM to 5.36 nM, and 14c (EC50 = 2.45 nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC50 = 10.6 nM), being comparable with ETR (EC50 = 9.80 nM) and 3.5-fold more potent than that of compound 7 (EC50 = 37.3 nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC50 = 0.0589 μM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by molecular dynamics simulation. Overall, we envision that the "dual-site"-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti-HIV-1 agents.


Cellular responses and proteomic analysis of Escherichia coli exposed to green tea polyphenols.
The purpose of this study was to characterize the cellular response and proteomic analysis of Escherichia coli exposed to tea polyphenols (TPP) extracted from Korean green tea (Camellia sinensis L). TPP showed a dose-dependent bactericidal effect on E. coli. Analysis of cell-membrane fatty acids of E. coli cultures treated with TPP identified unique changes in saturated and unsaturated fatty acids, whereas scanning electron microscopic analysis demonstrated the presence of perforations and irregular rod forms with wrinkled surfaces in cells treated with TPP. Two-dimensional polyacrylamide gel electrophoresis of soluble protein fractions from E. coli cultures exposed to TPP showed 17 protein spots increased or decreased by TPP. Nine upregulated proteins were identified (including GroEL and proteins involved in cellular defense, such as GyrA, RpoS, SodC, and EmrK), whereas the expression of eight proteins was downregulated by exposure to TPP (including proteins involved in carbon and energy metabolism, such as Eno, SdhA, and UgpQ, as well as those involved in amino-acid biosynthesis, such as GltK and TyrB). These results provide clues for understanding the mechanism of TPP-induced stress and cytotoxicity on E. coli.


Wideband 2-D sparse array optimization combined with multiline reception for real-time 3-D medical ultrasound.
Three-dimensional (3-D) ultrasound medical imaging provides advantages over a traditional 2-D visualization method. However, the use of a 2-D array to acquire 3-D images may result in a transducer composed of thousands of elements and a large amount of data in the front-end, making it impractical to implement high volume rate imaging and individually control all elements with the scanner. This paper proposes an original approach, valid for wideband operations centered on the design center frequency, to maintain a limited number of active elements and firing events, while preserving high resolution and volume rate. A 7 MHz 2-D array is composed of two circular concentric subparts. In the inner footprint the elements are distributed following a regular grid, while in the outer subpart a sparse non-grid solution is adopted. The inner circular dense array is composed of 256 elements with a pitch of 0.5λ. The overall footprint, delimited by the outer subpart, is equivalent to a 256-element array with a pitch of 1.5λ. All the elements of the inner subpart are activated in transmission. Following an optimization procedure, both subparts, including a subset of the elements placed in the inner footprint (i.e., sparse on-the-grid array) and the elements spread over the outer subpart (i.e., sparse off-the-grid array) are used to receive. A total number of 256 elements, defined by the sum of elements distributed in the inner and outer subparts, is fixed in reception. The proposed approach implies a multiline reception strategy, where for each transmission 3 × 3 firing events occur in reception. The sparse receive array is optimized by using a simulated annealing optimization. An original cost function is designed specifically to achieve successful results in wideband conditions. The receive array is optimized in order to obtain consistent results for different signal bandwidths of the excitation pulse. For all the desired bandwidths, the optimized array will provide the recovery of the lower lateral resolution of the transmission phase and, at the same time, a significant reduction of the undesired side lobe raised in the 3-D two-way beam pattern. The 3-D two-way beam pattern analysis reveals that the proposed solution is able to guarantee a lateral resolution of 1.35 mm at a focus depth of 25 mm for the three fractional signal bandwidths of interest (i.e., 30%, 50% and 70%) considered in the optimization process. The undesired side lobes are successfully suppressed especially when, as a consequence of the multiline strategy, non-coincident steering angles are used in transmission and reception. Moreover, thanks to the firing scheme adopted, a high-volume rate of 63 volumes per second may be achieved at the focus depth. The volume rate decreases to 32 volumes per second at twice the focal depth. Phantom image simulations show that the proposed method maintains a satisfactory and almost uniform image quality in terms of resolution and contrast for all the signal bandwidths of interest.


Protoporphyrinogen oxidase and porphobilinogen deaminase in variegate porphyria.
Two enzymes of the haem biosynthetic pathway were investigated in patients with variegate porphyria. Protoporphyrinogen oxidase in cultures of Epstein-Barr virus transformed lymphoblasts from twenty-seven patients showed a mean maximal velocity (Vmax) of 0.39 +/- 0.08+ nmol of protoporphyrin mg protein-1 h-1, a 52% reduction (P less than 0.001) from a non-porphyric control group (0.82 +/- 0.10). Km values (1.00 +/- 0.27 microM) did not differ significantly (P greater than 0.05) from control values in any of the patients. The mean Vmax of porphobilinogen deaminase in the cultures was 1.50 +/- 0.18 nmol of uroporphyrin mg protein-1 min-1, a 24% reduction (P less than 0.001) from controls (1.94 +/- 0.14). Mean porphobilinogen deaminase activity in the erythrocytes of twenty-one patients with variegate porphyria was 8.37 +/- 1.99 nmol of uroporphyrin 1 erythrocytes-1 s-1, a 28% reduction (P less than 0.001) from normal (11.98 +/- 2.11). The reduced activities of these two enzymes comply with the expression of variegate porphyria during its quiescent and acute phases.


Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a γ-secretase-independent manner.
Presenilins are ubiquitous, intramembrane proteins that function in Alzheimer's disease (AD) as the catalytic component of the γ-secretase complex. Familial AD mutations in presenilin are known to exacerbate lysosomal pathology. Hence, we sought to elucidate the function endogenous, wild-type presenilins play in autophagy-mediated protein degradation. We report the finding that genetic deletion or knockdown of presenilins alters many autophagy-related proteins demonstrating a buildup of autophagosomes, indicative of dysfunction in the system. Presenilin-deficient cells inefficiently clear long-lived proteins and fail to build up autophagosomes when challenged with lysosomal inhibitors. Our studies further show that γ-secretase inhibitors do not adversely impact autophagy, indicating that the role of presenilins in autophagy is independent of γ-secretase activity. Based on our findings, we conclude that endogenous, wild-type presenilins are necessary for proper protein degradation through the autophagosome-lysosome system by functioning at the lysosomal level. The role of presenilins in autophagy has many implications for its function in neurological diseases such as AD.


A longitudinal examination of the interpersonal theory of suicide for predicting suicidal ideation among LGBTQ+ youth who utilize crisis services: The moderating effect of gender.
Despite high rates of suicide among LGBTQ+ youth, the interpersonal theory of suicide (IPTS) has rarely been examined in this population. The current study utilized a longitudinal design to examine whether perceived burdensomeness and thwarted belongingness independently and simultaneously predicted higher levels of suicidal ideation over time in a sample of LGBTQ+ youth who utilized crisis services. We also investigated whether gender identity moderated these associations. A total of 592 youth (12-24 years old) who had contacted a national crisis hotline for LGBTQ+ youth completed two assessments 1-month apart. Perceived burdensomeness and thwarted belongingness independently predicted greater suicidal ideation 1 month later; however, only perceived burdensomeness remained prospectively associated with suicidal ideation when both factors were tested in the same model. Gender identity moderated the associations between IPTS factors and suicidal ideation, such that both perceived burdensomeness and thwarted belongingness were associated with greater suicidal ideation 1 month later for sexual minority cisgender young women and transgender/genderqueer individuals, but not for sexual minority cisgender young men. The IPTS helps explain increases in suicidal ideation over time among LGBTQ+ youth and therefore can be used to inform suicide prevention and intervention approaches for this population.


Spin-labeling of Escherichia coli membrane by enzymatic synthesis of phosphatidylglycerol and divalent cation-induced interaction of phosphatidylglycerol with membrane proteins.
Escherichia coli membrane particulate fraction has been spin-labeled by incubating with sn-glycerol-3-phosphate, CTP, palmitoyl CoA and 12-nitroxide stearoyl CoA. Incorporation of the spin-labeled acyl chain into phosphatidyl-glycerol was confirmed. ESR spectrum of the spin-labeled phosphatidylglycerol in E. coli membrane consisted at least of two components; one due to the labels undergoing rapid anisotropic motions and the other due to strongly immobilized labels (the overall splitting value, approx. 58 G). The relative intensity of the two components was dependent on the concentration of divalent cations. The immobilized component decreased on treatment of the membrane with EDTA and increased on addition of Mg2+ or Ca2+. The spectrum at 1 mM Mg2+ or Ca2+ consisted almost only of the immobilized component. Spin-labeled phosphatidylglycerol in total lipid membrane showed ESR spectrum due to mobile labels and the spectrum was not affected appreciably by the divalent cations. The results suggest the divalent cation-mediated interaction of phosphatidylglycerol with proteins in E. coli membrane. Phosphoenolpyruvate-dependent uptake of methyl-alpha-D-glucoside was markedly accelerated by Mg2+. Ca2+ was not effective for the enhancement. The divalent cation-induced interaction of phosphatidylglycerol with proteins was discussed in relation to the sugar transport.


Cytotoxic rotenoid glycosides from the seeds of Amorpha fruticosa.
Four new rotenoid glycosides, namely amorphaside A-D (1-4), along with four known ones (5-8) were isolated from the seeds of Amorpha fruticosa. Their chemical structures and absolute configurations were elucidated by HRESIMS, NMR and CD spectra, as well as deduction from biosynthesis route. The sugar units were determined by acid hydrolysis, appropriate derivatization and HPLC analysis. The in vitro anti-proliferative activities of all compounds were evaluated against MCF-7 and HCT-116 cell lines. The results showed that compounds 1-3 had no effect on cell proliferation in the two cell lines even with the concentration of 50 μM, and compounds 4, 7 and 8 had selective cytotoxicity against MCF-7 with IC50 values of 3.90, 0.95 and 34.08 μM, respectively, while compounds 5 and 6 both showed significant cytotoxicity to the two cell lines with IC50 values less than 2.00 μM, even better than the positive control cisplatin. These preliminary results indicated that compounds 5 and 6 might be valuable to anticancer drug candidates.


Concentrations and distribution of chlorinated paraffins in Belgian foods.
This study reports on concentrations of short- and medium-chain chlorinated paraffins (SCCPs and MCCPs, respectively) in a wide range of food samples (n = 211) purchased in Belgium during 2020. Samples were analysed by gas chromatography-mass spectrometry (GC-MS) and quantified using chlorine content calibration. ∑SCCPs were present above LOQ in 25% of samples with an overall range of <LOQ to 58 ng/g wet weight (ww), while ∑MCCPs were identified in 66% of samples ranging from <LOQ to 250 ng/g ww. ∑MCCP concentrations were greater than those of ∑SCCPs in all 48 samples in which both groups were detected with an average ∑MCCP/∑SCCP ratio of 5.8 (ranging from 1.3 to 81). In general, the greatest CP concentrations were observed in foods classified as animal and vegetable fats and oils and sugar and confectionary for both SCCPs and MCCPs. Significant correlations between lipid content in food samples and CP levels illustrated the role of lipids in accumulating CPs within foodstuffs, while industrial processing, food packaging and environmental conditions are each likely to contribute to overall CP loads. Selected samples (n = 20) were further analysed by liquid chromatography-high resolution MS (LC-HRMS) to investigate homologue profiles and the occurrence of long-chain CPs (LCCPs). LCCPs were detected in 35% of the 20 subset samples while the HRMS results for SCCPs and MCCPs matched closely with those obtained by GC-MS. This study reveals the widespread occurrence of SCCPs and MCCPs in Belgian food and indicates that LCCPs may represent a substantial contribution to overall CP levels in foodstuffs.


Preferentially enhancing anti-cancer isothiocyanates over glucosinolates in broccoli sprouts: How NaCl and salicylic acid affect their formation.
Broccoli (Brassica oleracea L. var. italica) sprouts contain glucosinolates (GLs) that when hydrolysed yield health promoting isothiocyanates such as sulforaphane (SF). SF content can be increased by salt (NaCl) stress, although high salt concentrations negatively impact plant growth. Salicylic acid (SA) treatments can attenuate the negative effects of salt on growth. To test whether sprout isothiocyanate content could be elevated without sprout growth being compromised, broccoli seed were germinated and grown for seven days in salt (0, 80 and 160 mM) alone and in combination with 100 μM SA. Increasing concentrations of salt lowered transcript accumulation of GL biosynthetic genes which was reflected in lowered content of Gluconapin, 4-methoxyglucobrassicin and neoglucobrassicin glucosinolates. Other glucosinolates such as glucoraphanin did not alter significantly. Salt (160 mM) increased transcript abundance of the GL hydrolytic gene MYROSINASE (BoMYO) and its cofactor EPITHIOSPECIFIER MODIFIER1 (BoESM1) whose encoded product directs MYROSINASE to produce isothiocyanate rather than nitrile forms. SF content was increased 6-fold by the 160 mM salt treatment, but the salt treatment reduced percentage seed germination, slowed seed germination, and reduced sprout hypocotyl elongation. This growth inhibition was prevented if 100 μM SA was included with the salt treatment. These findings suggest that the increase in SF production by salt occurs in part because of increased transcript abundance of genes in the hydrolytic pathway, which occurs independently of the negative impact of salt on sprout growth.


The effect of lactobacillus cell size on its probiotic characteristics.
Screening for probiotic characteristics is usually associated with a series of assays and a large number of isolates to be tested, which can be sometimes costly and frustrating. For this reason, finding some indicators to predict the probiotic potential would be of great significance. In this study, 10 Lactobacillus strains including L. sakei, L. reuteri, L. delbrueckii subsp. lactis, L. delbrueckii subsp. delbrueckii, L. plantarum, L. acidophilus, L. rhamnosus, L. paracasei, L. salivarius, and L. gasseri were characterized by cell morphology and growth properties. The strains were then examined in terms of some probiotic characteristics including resistance to acid and bile conditions, ability to adhesion to intestinal epithelial cells, antioxidant activity, aggregation characteristics, antibacterial activity, hemolytic activity, and resistance to different antibiotics. Correlations between different quantitative features were analyzed using Pearson's coefficient (r). Results of this study provided first-time evidence for the effects of cell length on probiotic features. Based on statistical analysis, long Lactobacillus strains had often higher antioxidant and aggregation activities. Moreover, these long strains were usually more sensitive to acid and bile conditions and resulted in a lower CFU yield compared to short strains. By conducting morphological tests at the first step of screening, some strains would gain higher priority because of predicting a high performance in some of the desired characteristics. Therefore, the cost and time required for the subsequent tests would be significantly reduced.


Split distal flexor pollicis longus tenodesis: long-term results.
A thumb lacking intrinsic muscle function but having extrinsic flexion will hyperflex in the interphalangeal joint giving a positive Froment's sign. This can effectively be prevented with split flexor pollicis longus tenodesis. The mean postoperative range of motion in the IP joint of 39 hands was 28 (18) degrees and 23 (20) degrees six and 12 months postoperatively. The procedure makes arthrodesis (temporary or permanent) superfluous. This procedure can be recommended strongly.


Clinical practice guidelines for acute otitis media in children: a systematic review and appraisal of European national guidelines.
To appraise European guidelines for acute otitis media (AOM) in children, including methodological quality, level of evidence (LoE), astrength of recommendations (SoR), and consideration of antibiotic stewardship. Systematic review of the literature. Three-pronged search of (1) databases: Medline, Embase, Cochrane library, Guidelines International Network and Trip Medical Database; (2) websites of European national paediatric associations and (3) contact of European experts. Data were collected between January 2017 and February 2018. National guidelines of European countries for the clinical management of AOM in children aged <16 years. Data were extracted using tables constructed by the research team. Guidelines were graded using AGREE II criteria. LoE and SoR were compared. Guidelines were assessed for principles of antibiotic stewardship. AOM guidelines were obtained from 17 or the 32 countries in the European Union or European Free Trade Area. The mean AGREE II score was ≤41% across most domains. Diagnosis of AOM was based on similar signs and symptoms. The most common indication for antibiotics was tympanic membrane perforation/otorrhoea (14/15; 93%). The majority (15/17; 88%) recommended a watchful waiting approach to antibiotics. Amoxicillin was the most common first-line antibiotic (14/17; 82%). Recommended treatment duration varied from 5 to 10 days. Seven countries advocated high-dose (75-90 mg/kg/day) and five low-dose (30-60 mg/kg/day) amoxicillin. Less than 60% of guidelines used a national or international scale system to rate level of evidence to support recommendations. Under half of the guidelines (7/17; 41%) referred to country-specific microbiological and antibiotic resistance data. Guidelines for managing AOM were similar across European countries. Guideline quality was mostly weak, and it often did not refer to country-specific antibiotic resistance patterns. Coordinating efforts to produce a core guideline which can then be adapted by each country may help improve overall quality and contribute to tackling antibiotic resistance.


Recycling and reutilization of cytotoxic molecules, a new type of energy conservation of NK cells?
Natural killer (NK) cells play critical roles in defense against tumors and viral infections. They exert their cytotoxic functions through the secretion of granules containing cytotoxic molecules, such as perforin and granzymes. These cytotoxic molecules are stored within dual-functional organelles, known as secretory lysosomes. Target cell recognition induces the formation of an "immunological synapse", between the NK cell and its target, into which cytotoxic granules release their contents. However the post-exocytosis regulation of the process is still largely unknown. Recent research and the data accumulated therefrom lead to new hypotheses that suggest that, not unlike synaptic vesicle recycling in neuronal terminals, NK cells also recycle not just their secretory lysosome membranes but their correlated cytotoxic molecules (perforin and granzymes). The newly endocytosed vesicles are used to replenish the "reserve pool" of vesicles for continued NK cell serial killings. These hypotheses, if proved to be correct, will significantly improve our understanding of NK cell cytotoxicity mechanisms and might even suggest new NK cell-based therapies that rely on NK serial killing abilities for overcoming tumors.


Expression of the membrane attack complex of complement and its inhibitors during human liver allograft transplantation.
In order to test the possible role of activated complement in human liver allograft rejection, we evaluated the expression of the membrane attack complex of complement, its soluble inhibitors clusterin and vitronectin and its membrane inhibitor protectin during the evolution of liver transplants. An indirect immunoperoxidase technique was applied to biopsy specimens obtained from liver allografts in 16 patients without complications, nine with acute rejection, four with chronic rejection and five with biliary complications. Two types of membrane attack complex deposition were observed: (a) extracellular deposits in portal tracts and perisinusoidal matrix, associated with clusterin and vitronectin, similar to those found in the normal liver; and (b) intra-portal vascular deposits, devoid of clusterin and vitronectin. Vascular membrane attack complex deposition was detected in four clinically stable patients, three patients with chronic rejection and two patients with biliary complications. In clinically stable patients, vascular membrane attack complex deposition was restricted to large portal vessels and was detected in a minority of portal tracts. In patients with chronic rejection or biliary complications, vascular membrane attack complex deposition was detected along both large and small portal vessels and was present in the majority of portal tracts. Protectin induction on hepatocytes was detected in 33 cases. Our results suggest that membrane attack complex deposition is unlikely to play a major role in the pathogenesis of acute liver allograft rejection but may contribute to the vascular and biliary lesions observed in chronic rejection.


Transplantation without growth factor: engraftment kinetics after stem cell transplantation for primary systemic amyloidosis (AL).
Stem cell transplantation is increasingly used in the management of immunoglobulin light-chain amyloidosis (AL). It is considered the standard of care to administer growth factors to accelerate neutrophil recovery after transplantation. However, unique toxicities occur with growth factor use in patients with AL who receive a stem cell transplant. We report a cohort of patients who underwent transplantation without receiving posttransplantation growth factors. In total, 282 patients received a stem cell transplant. A neutrophil count of 500/mul was achieved in 50, 75 and 90% of patients at 14, 16 and 22 days, respectively. A platelet count of 20 000/mul was achieved in 50, 75 and 90% of patients at 14, 20 and 31 days, respectively. Non-staphylococcal bacteremia was detected in 16% of patients. The median hospital stay was 9 days. It is feasible and reasonable to withhold growth factor therapy after autologous stem cell transplantation in patients with AL.


The Use of Expert Elicitation among Computational Modeling Studies in Health Research: A Systematic Review.
Expert elicitation (EE) has been used across disciplines to estimate input parameters for computational modeling research when information is sparse or conflictual. We conducted a systematic review to compare EE methods used to generate model input parameters in health research. PubMed and Web of Science. Modeling studies that reported the use of EE as the source for model input probabilities were included if they were published in English before June 2021 and reported health outcomes. Studies were classified as "formal" EE methods if they explicitly reported details of their elicitation process. Those that stated use of expert opinion but provided limited information were classified as "indeterminate" methods. In both groups, we abstracted citation details, study design, modeling methodology, a description of elicited parameters, and elicitation methods. Comparisons were made between elicitation methods. Studies that conducted a formal EE were appraised on the reporting quality of the EE. Quality appraisal was not conducted for studies of indeterminate methods. The search identified 1520 articles, of which 152 were included. Of the included studies, 40 were classified as formal EE and 112 as indeterminate methods. Most studies were cost-effectiveness analyses (77.6%). Forty-seven indeterminate method studies provided no information on methods for generating estimates. Among formal EEs, the average reporting quality score was 9 out of 16. Elicitations on nonhealth topics and those reported in the gray literature were not included. We found poor reporting of EE methods used in modeling studies, making it difficult to discern meaningful differences in approaches. Improved quality standards for EEs would improve the validity and replicability of computational models. We find extensive use of expert elicitation for the development of model input parameters, but most studies do not provide adequate details of their elicitation methods.Lack of reporting hinders greater discussion of the merits and challenges of using expert elicitation for model input parameter development.There is a need to establish expert elicitation best practices and reporting guidelines.


Effects of beta-carboline-3-carboxylic acid ethyl ester on suppressed and non-suppressed responding in the rhesus monkey.
The effects of the putative 'anxiogenic' compound beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) were studied on non-suppressed and suppressed responding of rhesus monkeys. Responding was maintained under a fixed-interval 2 min schedule of food presentation (non-suppressed responding) and a fixed-interval 2 min schedule of food presentation where each 10th response produced a 3-5 mA footshock (suppressed responding). Rates of suppressed responding were 60-90% lower than those for non-suppressed responding. beta-CCE reliably decreased non-suppressed responding over the range of 0.03-0.3 mg/kg (ED50 approximately 0.04 mg/kg) while consistent decreases in suppressed responding were not obtained in all animals until doses of 1-3 mg/kg (ED50 approximately 2 mg/kg) were given. Doses of beta-CCE greater than 0.01 mg/kg slightly increased blood pressure, moderately increased heart rate and greatly increased plasma ACTH levels for both types of response. In contrast, diazepam increased suppressed responding without affecting non-suppressed responding at low doses (0.3-1 mg/kg), while higher doses were required to decrease suppressed responding. Diazepam had little effect on blood pressure or mean heart rate. Ro 15-1788 (1 mg/kg) blocked the rate-decreasing effects of beta-CCE on non-suppressed responding, suggesting the decrease is mediated via a benzodiazepine recognition site. These results show that under conditions where relatively low doses of diazepam have an anxiolytic effect (i.e. selectively increase rates of suppressed responding), relatively low doses of beta-CCE selectively decrease non-suppressed responding, questioning current notions of how to define an anxiogenic drug effect.


[Ultrastructure of the embryonic and larval sub-aortic blastema of Rana dalmatine (Amphibia, Anuran)].
In early stages of development, the sub-aortic blastema is formed by cells of a uniform appearance filled up with lipidic inclusions. As early as stage 36, four different types of cells are present; numerous leucocytes, cells with mitochondria with tubulo-vesicular saccules, cells with granules, and cells with dense cytoplasm.


Studies on the physiology of pollen and pollen tube growth. 1. pinus roxburghii.
Pollen grains and pollen tubes of Pinus roxburghii were subjected to histochemical technique with a view to determining the distributional pattern of reserve substances (ascorbic acid, proteins starch, polysaccharides, nucleic acids) and some enzymes (acid phosphatase, glucose-6-phosphatase, peroxidase, esterase, cytochrome oxidase, succinate dehydrogenase). An attempt is made to correlate the activity of different enzymes in relation to pollen tube growth.


Effect of dibutyryl cyclic adenosine monophosphate on active amino acid transport in Streptomyces hydrogenans.
The active uptake of 2-aminoisobutyric acid (AIB) and several other amino acids in resting cells of Streptomyces hydrogenans was found to be stimulated by exogenously added adenosine cyclic monophosphate (cAMP). The uptake of glycerol, sorbose, and pyrimidine nucleosides remained unaffected. Among the various cAMP derivatives tested, the dibutyryl derivative was found to be most effective, followed by monobutyryl cAMP, and cAMP. Dibutyryl cGMP was also found to stimulate AIB transport, and its effectivity was as good as that of dibutyryl cAMP. The effect of dibutyryl cAMP is time dependent and attains its maximum after 40--60 min of incubation at 30 degrees C in K-Na-phosphate buffer. Dibutyryl cAMP-dependent transport stimulation has a high temperature coefficient and is prevented by rifamycin SV or chloramphenicol. The rate of leucine incorporation into protein was rapidly increased upon addition of dibutyryl cAMP. Kinetic studies reveal that the stimulation of AIB transport is characterized by an increase in maximum uptake rate and an unaltered apparent Michaelis constant. Analysis of the unidirectional fluxes show that both influx and efflux are enhanced by dibutyryl cAMP. It is concluded that exogenous dibutyryl cAMP stimulates de novo synthesis of certain proteins including the transport catalysts for various amino acids.


Photodynamic therapy using SnET2 for basal cell nevus syndrome: a case report.
A 26-year-old man with basal cell nevus syndrome presented to the Rocky Mountain Cancer Center (Denver, Colorado) for treatment of several basal cell carcinomas with photodynamic therapy using tin ethyl etiopurpurin (SnET2). The patient was of northern European descent, had type I skin (always burns, never tans), and had a 10-year history of multifocal basal cell carcinomas. The patient had a family history of Gorlin's syndrome (basal cell nevus syndrome); the syndrome had been diagnosed in this patient in 1985. The patient was enrolled in a Phase I/II clinical trial. He was given 1.2 mg/kg (94 mg total) of SnET2 via intravenous infusion; he returned to the clinic the following day for red light application. Thirteen lesions, in 12 treatment fields, were illuminated with light totaling 200 J/cm2 at a fluence of 150 mW/cm2. At the 3-month follow-up examination, all tumors were graded as having a complete response by modified AIDS Clinical Trial Guidelines oncologic standards. No evidence of recurrence has been noted during the 6-month follow-up period.


Coexistence of bulimia nervosa and mania: a literature review and case report.
A literature review of the relationship between bulimia and affective disorder showed that the evidence from empirical research and case report studies suggests that a sizeable subgroup of bulimics suffer from bipolar disorder as well as bulimia and may benefit from antimanic medications such as lithium. A case report is presented of a bulimic patient with manic symptoms who was successfully treated with lithium. However, the use of lithium should be avoided with any patient who is purging, since it may exacerbate the loss of intracellular potassium, thereby increasing the risk of cardiac toxicity.


Amyloidogenic Nanoplaques in Cerebrospinal Fluid: Relationship to Amyloid Brain Uptake and Clinical Alzheimer's Disease in a Memory Clinic Cohort.
Aggregation of amyloid-β (Aβ) is an early pathological event in Alzheimer's disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF). The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD. Nanoplaque levels in the CSF from 54 memory clinic patients were compared between sub-groups classified by 18F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD. Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype. The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients.


Beyond RGD; nanoclusters of syndecan- and integrin-binding ligands synergistically enhance cell/material interactions.
Biomaterials are a powerful platform for directing cellular behaviour. Herein, we employed a biomimetic strategy to synthesize a low-fouling polymer functionalized with nano-scale clusters of ligands that bind both integrin and syndecan-4 receptors, as both receptor types are critical in focal adhesion signalling and mechanotransduction. Our results demonstrate that the presence of both ligand types synergistically increases the adhesion of human umbilical vein endothelial cells (more than a two fold increase after 4 h) and increases the rate of surface endothelialization compared to surfaces functionalized with only one ligand type. Additionally, we observe that the mixed population of ligands regulates endothelial cell migration, likely due to improved focal adhesion formation as observed through confocal microscopy. Furthermore, we illustrate that only endothelial cells cultured on these mixed ligand surfaces exhibit the appropriate morphological changes - elongation and alignment in the direction of flow - when exposed to laminar shear flow, and neither of the individual ligands alone is sufficient. These results illustrate that both receptor types must be engaged for optimum cell-material interactions and are mandatory for appropriate mechanotransduction. The results presented in this manuscript will be critical for the development of next generation biomedical devices and tissue engineering scaffolds.


Promising Applications of Nanoparticles in the Treatment of Hearing Loss.
Hearing loss is one of the most common disabilities affecting both children and adults worldwide. However, traditional treatment of hearing loss has some limitations, particularly in terms of drug delivery system as well as diagnosis of ear imaging. The blood-labyrinth barrier (BLB), the barrier between the vasculature and fluids of the inner ear, restricts entry of most blood-borne compounds into inner ear tissues. Nanoparticles (NPs) have been demonstrated to have high biocompatibility, good degradation, and simple synthesis in the process of diagnosis and treatment, which are promising for medical applications in hearing loss. Although previous studies have shown that NPs have promising applications in the field of inner ear diseases, there is still a gap between biological research and clinical application. In this paper, we aim to summarize developments and challenges of NPs in diagnostics and treatment of hearing loss in recent years. This review may be useful to raise otology researchers' awareness of effect of NPs on hearing diagnosis and treatment.


Naloxonazine actions in vivo.
Naloxonazine is a relatively selective mu 1 affinity label in binding studies. Like naloxazone, naloxonazine has proven valuable in vivo in establishing a role for mu 1 sites in specific opiate actions. We now report a detailed characterization of naloxonazine's actions in mice and rats. Naloxonazine antagonized morphine analgesia for greater than 24 h without altering lethality. This prolonged action could not be easily explained by a slow rate of elimination since the terminal elimination half-life was estimated at less than 3 h. Furthermore, these actions were associated with a wash-resistant inhibition of binding lasting 24 h which was relatively selective for mu 1 sites. At a fixed morphine dose, increasing naloxonazine doses lowered peak tailflick latencies in a biphasic manner, suggesting that morphine analgesia consisted of both mu 1 (naloxonazine-sensitive) and a non-mu 1 (naloxonazine-insensitive) components. The ratio of mu 1 to non-mu 1 analgesia was greater at low morphine doses, implying that morphine activated mu 1 analgesic mechanisms with higher affinity. Our studies also emphasized that naloxonazine has reversible actions similar to those of naloxone; only its irreversible actions are relatively mu 1-selective. In addition, the selectivity of naloxonazine's irreversible actions is dose-dependent. High naloxonazine doses will irreversibly antagonize receptors other than mu 1.


Pharmacodynamic modeling of the effects of lanreotide Autogel on growth hormone and insulin-like growth factor 1.
Acromegaly arises from excessive levels of growth hormone (GH), many of whose effects are mediated by stimulation of secretion of insulin-like growth factor 1 (IGF-1). Synthetic somatostatin analogues inhibit GH secretion. The objective of the study was to develop a population pharmacodynamic model describing the relationship between serum concentrations of lanreotide (C(P)) and its GH and IGF-1 effects in patients with acromegaly receiving lanreotide Autogel (LA) at doses of 60, 90, or 120 mg by deep subcutaneous route every 28 days. Data were analyzed from 104 patients. The GH and IGF-1 profiles were fit simultaneously using the population approach with NONMEM. The GH vs C(P) and the IGF-1 vs GH relationships were described using inhibitory I(max) and E(max) models, respectively. Results indicated that lanreotide cannot abolish GH completely. C(P) levels of 3.4 ng/mL are required to achieve percentages of hormonal control (GH and IGF-1) of 21% and 36% in not treated and previously treated patients. If the focus is only GH, a C(P) of 3.4 ng/mL corresponds to 33% and 56% controlling rates. Simulations showed that there is a possible clinical benefit if the highest dose of 120 mg LA is administered to patients who are not well controlled by lower doses of LA.


Can we rely on the multiplex ligation-dependent probe amplification method (MLPA) for prenatal diagnosis?
The major aneuploidies that are diagnosed prenatally involve the autosomal chromosomes 13, 18, and 21, as well as sex chromosomes, X and Y. Because multiplex ligation-dependent probe amplification (MLPA) is rapid and non-invasive, it has replaced traditional culture methods for the screening and diagnosis of common aneuploidies in some countries. To evaluate the sensitivity and specificity of MLPA in a cross-sectional descriptive study for the detection of chromosomal aneuploidies in comparison to other methods. Genomic DNA was extracted from the peripheral blood samples of 10 normal controls and the amniotic fluid of 55 patients. Aneuploidies screening of chromosomes 13, 18, 21, X and Y were carried out using specific MLPA probe mixes (P095-A2). For comparison purposes, samples were also tested by Quantitative Fluorescent-PCR (QF-PCR) and routine chromosomal culture method. Using this specific MLPA technique and data-analyzing software (Genemarker v1.85), one case was diagnosed with 45, X (e.g. Monosomy X or Turner's Syndrome), and the remaining 54 cases revealed normal karyotypes. These results were concordant with routine chromosomal culture and QF-PCR findings. The experiment demonstrates that MLPA can provide a rapid and accurate clinical method for prenatal identification of common chromosomal aneuploidies with 100% sensitivity and 100% specificity.


The role of the Consultant Radiographer in facilitating rapid access to palliative radiotherapy.
The fast track pathway for palliative radiotherapy was created to facilitate rapid access to radiotherapy for symptom relief and improved quality of life. The fast track pathway has a target of 5 days from the decision to treat to starting treatment. This study is a quantitative analysis of all patients referred and treated with palliative radiotherapy between the 1st September 2018 and 30th September 2019. The number of working days overall from referral to treatment and at each stage of the radiotherapy pathway was recorded and evaluated. The electronic referral system was amended to include the treatment priority option of 'fast track' for all patients with the selected treatment intent of 'palliative'. The data was acquired using the electronic referral system reporting tool. Results demonstrate a reduction in average pathway timing from 14 days to 3 days for volume planned patients, and 13 days to 2 days for virtual simulation patients referred into the fast track pathway. The routine priority palliative pathway also demonstrated a decrease in time from decision to treat to treatment, despite this not being an initial objective. Reducing pathway time from referral to treatment is achievable through the introduction of a fast track treatment priority pathway. Rapid access to treatment was facilitated through the electronic referral system fast track option, the creation of a separate fast track care path in Aria, the use of fast track alerts in Aria, and reserved planning scan and treatment appointments. Rapid access to palliative radiotherapy facilitates alleviation of symptoms and improved quality of life. To improve the efficiency of the palliative radiotherapy service, a streamlined pathway and the commitment of the radiotherapy team is required.


Reevaluating the pathogenicity of the variations c.439 G>A and c.2132 C>T in the PLA2G6 gene.
The phospholipase A2 group VI (PLA2G6) gene encodes for a Ca2+-independent PLA2, which is localized in the cytosol, in the endoplasmic reticulum and in the mitochondrial membrane, plays a major role in phospholipid remodelling. Mutations within this gene have been reported to cause different phenotypes: infantile-onset neuroaxonal dystrophy associated with brain iron accumulation and adult-onset parkinsonian syndrome. In the present study, we analysed the PLA2G6 gene sequence in an asymptomatic young woman that was referred to our laboratory by a geneticist for an history of infantile neuroaxonal dystrophy in her little maternal cousin in whom the results of the genetical analysis were not available. We found two variants in the PLA2G6 gene (NM_003560.4, c.439 G>A and c.2132 C>T, p.Ala147Thr and p.Pro711Leu) previously reported as pathogenic. These results prompted us to perform a segregation analysis in the parents of this woman and we only found the presence of both variants in the asymptomatic 56-year-old patient's mother. Our molecular genetic testing clearly indicates that the c.439 G>A and c.2132 C>T variations identified in the PLA2G6 gene are positioned in cis and are not responsible for infantile neuroaxonal dystrophy which is an autosomal recessive disease.


Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches.
Insulin is a peptide secreted by the pancreas and plays an important role in the regulation of glucose metabolism in peripheral tissues. Although the role of insulin in the periphery is well understood, less is known about its multifactorial role in the brain. However, emerging evidence from human and animal studies indicate that insulin influences cerebral bioenergetics, enhances synaptic viability and dendritic spine formation, and increases turnover of neurotransmitters, such as dopamine. Insulin also has a role in proteostasis, influencing clearance of the amyloid β peptide and phosphorylation of tau, which are hallmarks of Alzheimer's disease. Insulin also modulates vascular function through effects on vasoreactivity, lipid metabolism, and inflammation. Through these multiple pathways, insulin dysregulation could contribute to neurodegeneration. Thus, new approaches to restore cerebral insulin function that could offer therapeutic benefit to adults with Alzheimer's disease, vascular cognitive impairment, or related disorders are being investigated.


[Prevention of bone loss in a patient receiving androgen deprivation therapy].
Bone loss is a frequent side effect of androgen deprivation therapy, which leads to a significant number of pathologic fractures. Prevention of osteoporosis aims at reducing skeletal-related events. The RANK ligand antibody denosumab and bisphosphonates are used for this indication. Denosumab has been shown to increase bone density and to reduce the incidence of fractures at any location by 72%. Bone density can also be increased by bisphosphonates; however, there is no conclusive evidence so far that the fracture rate can be reduced significantly. Therefore guidelines do not recommend use of these substances for this indication.


Patient-reported outcomes of sleep, mood and quality of life after treatment of chronic hepatitis C infection using direct-acting antiviral agents.
The aim was to investigate the effect of hepatitis C virus (HCV) infection treatment with direct-acting antiviral (DAA) drugs on patients' mood, sleep quality and quality of life (QoL). Chronic HCV-infected patients receiving DAAs were evaluated prospectively. Patients were evaluated before the beginning of treatment and 12-24 weeks after finishing their treatment duration using the Pittsburgh Sleep Quality Index, Beck depression inventory questionnaire and SF-36 health-related QoL questionnaires. A total of 120 patients with a mean age of 41.03 ± 7.68 years were evaluated (68.3% males). The mean follow-up duration was 141.79 ± 27.88 days after finishing the treatment. Significant improvement in the scores of sleep quality (5.13 ± 1.5 vs. 3.43 ± 1.35), mood (12.77 ± 4.02 vs. 9.27 ± 3.14) and QoL (77.49 ± 5.15 vs. 83.95 ± 3.39) post treatment compared with pretreatment were observed (p < 0.05). Changes in patients' sleep and mood were not related to their QoL change (p > 0.05). DAAs for the treatment of HCV have a significant effect on improving their sleep, mood and QoL. The changes in sleep quality, mood and QoL of patients were independent and were not affected by each other.


A pilot study for a non-invasive system for detection of malignancy in canine subcutaneous and cutaneous masses using machine learning.
Early diagnosis of cancer enhances treatment planning and improves prognosis. Many masses presenting to veterinary clinics are difficult to diagnose without using invasive, time-consuming, and costly tests. Our objective was to perform a preliminary proof-of-concept for the HT Vista device, a novel artificial intelligence-based thermal imaging system, developed and designed to differentiate benign from malignant, cutaneous and subcutaneous masses in dogs. Forty-five dogs with a total of 69 masses were recruited. Each mass was clipped and heated by the HT Vista device. The heat emitted by the mass and its adjacent healthy tissue was automatically recorded using a built-in thermal camera. The thermal data from both areas were subsequently analyzed using an Artificial Intelligence algorithm. Cytology and/or biopsy results were later compared to the results obtained from the HT Vista system and used to train the algorithm. Validation was done using a "Leave One Out" cross-validation to determine the algorithm's performance. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the system were 90%, 93%, 88%, 83%, and 95%, respectively for all masses. We propose that this novel system, with further development, could be used to provide a decision-support tool enabling clinicians to differentiate between benign lesions and those requiring additional diagnostics. Our study also provides a proof-of-concept for ongoing prospective trials for cancer diagnosis using advanced thermodynamics and machine learning procedures in companion dogs.


A case of rapidly progressive upper limb ischemic necrosis in a patient with COVID-19.
For more than a year, health systems all over the world have been combating the global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first described in the city of Wuhan in China, presenting as an atypical infection of the lower respiratory tract. COVID-19 is characterized by multisystemic involvement, and mortality is attributed mainly to the respiratory system involvement, which may lead to severe acute respiratory distress syndrome and respiratory failure. Several COVID-19-associated complications are being increasingly reported, including arterial and venous thromboembolic events that may lead to amputation of the affected limbs. So far, a large number of reports have described hypercoagulability crises leading to amputation of the lower limbs. However, a search of the National Library of Medicine (MEDLINE) revealed no cases of urgent upper limb amputation in COVID-19 patients. This article describes a novel case of upper limb ischemia in a COVID-19 patient, with rapid progression to hand necrosis, requiring urgent through-arm amputation of the upper limb. This case emphasizes the need for anticoagulant therapy in COVID-19 patients and to maintain a constant awareness of the possible thromboembolic COVID-19-related sequelae.


Could plasma cystatin C be useful as a marker of hemodialysis low molecular weight proteins removal?
Plasma cystatin (pCyst) is a well-assessed tool for measuring renal function, and it could also play a part in hemodialysis adequacy. pCyst and other uremic toxins (urea, creatinine, parathyroid hormone, prolactin) were assessed before and after a dialysis session in 18 hemodialysis patients: 7 on bicarbonate hemodialysis (BHD) and 11 on mixed convective dialysis (MCD; 6 standard hemodiafiltration and 5 acetate-free biofiltration). Plasma levels and reduction ratios (RR) were then compared between the BHD and MCD groups. The mean pre-dialysis pCyst level is nearly the same in both groups (5.3 +/- 0.8 vs. 5.7 +/- 1 mg/l, p = ns), although a substantial decrease occurs after MCD only (mean 2.4 +/- 1 vs. 6.2 +/- 2.2 mg/l after BHD, p = 0.002). The mean pCyst RR (PCRR) of 55.5% after MCD is poorly related to prolactin and urea RR, fairly comparable to parathyroid hormone RR and very close to creatinine RR (58.4%). Only MCD removes pCyst, but the amount of removal is different for other low molecular weight proteins (prolactin and parathyroid hormone) and similar for creatinine, a classic 'little molecule'. In view of the discrepancy of these findings, the use of pCyst in hemodialysis still seems premature and needs further studies.


Cryptococcus neoformans in a child with CSF rhinorrhoea: A cytopathological diagnosis.
Cryptococcosis is caused by Cryptococcus neoformans and is fatal in children. The fungus is known to enter respiratory tract by inhalation and localizes in lungs in immunocompetent host. Patients with immunocompromised state facilitate dissemination of disease. However, disseminated cases have been described in immunocompetent HIV-negative individuals. CSF rhinorrhoea as a predisposing cause of cryptococcal meningitis has been rarely reported. We hereby describe C. neoformans directly spreading to the meninges in 1 year child due to CSF rhinorrhoea and the fungus was detected on fluid cytology.


Sawtooth contrast sensitivity: effects of mean illuminance and low temporal frequencies.
Temporal contrast sensitivity was measured for mirror-image sawtooth (rapid-on and rapid-off) and sine waveforms for a 1.8 deg foveal target. In one experiment, contrast sensitivity was measured for 2-26 Hz stimuli at target mean illuminance levels of 5-1260 td. At 5 td, contrast sensitivity functions for sawtooth and sine waveforms, expressed in terms of the Fourier fundamental amplitude, are equivalent. At higher light levels, sawtooth sensitivity increasingly exceeds sine sensitivity and rapid-off (decremental) sawtooths show progressively greater sensitivity than rapid-on (incremental) sawtooths. This pattern of results was obtained for two color-normal observers and for a deuteranopic observer. In a second experiment, sawtooth and sine sensitivity was tested at 500 td with an extended low-frequency range, to 0.5 Hz. Rapid-off and rapid-on sensitivities declined only slightly at low temporal frequencies in contrast with sine sensitivity. To interpret our data, we evaluate two single-pathway models (last-stage asymmetric detector and compressive response-intensity non-linearity) and a dual-pathway model in which incremental and decremental waveforms are detected by separate ON and OFF visual mechanisms.


Eupatolide inhibits lipopolysaccharide-induced COX-2 and iNOS expression in RAW264.7 cells by inducing proteasomal degradation of TRAF6.
Inula britannica is a traditional medicinal plant used to treat bronchitis, digestive disorders, and inflammation in Eastern Asia. Here, we identified eupatolide, a sesquiterpene lactone from I. britannica, as an inhibitor of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Eupatolide inhibited the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) as well as iNOS and COX-2 protein expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Eupatolide dose-dependently decreased the mRNA levels and the promoter activities of COX-2 and iNOS in LPS-stimulated RAW264.7 cells. Moreover, eupatolide significantly suppressed the LPS-induced expression of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) reporter genes. Pretreatment of eupatolide inhibited LPS-induced phosphorylation and degradation of I kappaB alpha, and phosphorylation of RelA/p65 on Ser-536 as well as the activation of mitogen-activated protein kinases (MAPKs) and Akt in LPS-stimulated RAW264.7 cells. Eupatolide induced proteasomal degradation of tumor necrosis factor receptor-associated factor-6 (TRAF6), and subsequently inhibited LPS-induced TRAF6 polyubiquitination. These results suggest that eupatolide blocks LPS-induced COX-2 and iNOS expression at the transcriptional level through inhibiting the signaling pathways such as NF-kappaB and MAPKs via proteasomal degradation of TRAF6. Taken together, eupatolide may be a novel anti-inflammatory agent that induces proteasomal degradation of TRAF6, and a valuable compound for modulating inflammatory conditions.


Perception of forces exerted by jaw and thumb.
By comparing the results of force matching between the jaw and the thumbs, whether subjects have any knowledge about the magnitude of exerted forces irrespective of the motor system was studied. Subjects were asked to match isometric forces of their own choice exerted by flexion of one of the thumbs with the jaw, and the other way around. The results were compared with control experiments in which subjects matched forces exerted by flexion of one of the thumbs with the other thumb and vice versa. None of the subjects was able to match correctly in all experimental conditions. All subjects displayed inconsistent matching behaviour, showing a mixture of correct matching and mismatching. This holds both for absolute matches (in N), and for matches relative to the maximal forces. The results show that knowledge about the magnitude of exerted forces is different for the jaw and the thumbs. Sensations about isometric forces exerted by the jaw or the thumbs are different within each subject and from subject to subject.


Iatrogenic uterine injury leading to uterine arteriovenous malformation.
The incidence of acquired uterine arteriovenous malformation has risen significantly because of increased instrumentation. Hysterectomy used to be the treatment of choice, but currently uterine artery embolisation is the preferred treatment. Here, the case of a 34-year-old woman who presented with uncontrolled uterine bleeding after iatrogenic uterine injury and who underwent successful management is described.


Evaluation of pediatric upper extremity peripheral nerve injuries.
The evaluation of motor and sensory function of the upper extremity after a peripheral nerve injury is critical to diagnose the location and extent of nerve injury as well as document functional recovery in children. The purpose of this paper is to describe an approach to the evaluation of the pediatric upper extremity peripheral nerve injuries through a critical review of currently used tests of sensory and motor function. Outcome studies on pediatric upper extremity peripheral nerve injuries in the Medline database were reviewed. The evaluation of the outcome in children less than 10 years of age with an upper extremity peripheral nerve injury includes careful observation of preferred prehension patterns, examination of muscle atrophy and sudomotor function, provocative tests, manual muscle testing and tests of sensory threshold and tactile gnosis. The evaluation of outcome in children with upper extremity peripheral nerve injuries warrants a unique approach.


Water-lipid interactions in native bone by high-resolution solid-state NMR spectroscopy.
The study of structural and dynamical properties of lipid and its associated interaction with different components of bone is essential to understand its role at a different level of bone homeostasis such as bone mineralization and bone metabolism. In this article, we present water-dependent dynamical changes observed in lipids (triglycerides) in its absolute native environment inside bone by high-resolution 1H solid-state nuclear magnetic resonance spectroscopy (ssNMR). Relaxation measurement (T2 measurement) ssNMR experiments were performed at different levels of water network induced by dehydration and H/D exchange in native bone. Our measurements reflect the changes in the local environment and dynamical properties of triglyceride due to different hydration levels. The present study explains the role of water in stabilizing the structural properties of triglycerides in bone hence will help understand its pathological role associated with bone physiology and bone disorders.


Structural design, synthesis, and anti-Trypanosomatidae profile of new Pyridyl-thiazolidinones.
The present work reports the synthesis of a novel series of pyridine-thiazolidinones with anti-Trypanosoma cruzi and leishmanicidal activities (compounds 10-27), derived from 2 or 4-pyridine thiosemicarbazones (1-9). The in vitro assays were performed with Trypanosoma cruzi trypomastigotes and amastigotes, as well as with Leishmania amazonensis promastigotes and amastigotes. The cytotoxicity profile was evaluated using the cell line RAW 264.7. From the 18 pyridine-thiazolidinones, 5 were able to inhibit trypomastigotes. Overall, all compounds inhibited amastigotes, highlighting compounds 15 (0.60 μM), 18 (0.64 μM), 17 (0.81 μM), and 27 (0.89 μM). Compounds 15 and 18 were able to induce parasite cell death through necrosis induction. Analysis by scanning electron microscopy showed that T. cruzi trypomastigotes treated with compounds 15 and 18 induced morphological changes such as shortening, retraction and curvature of the parasite body and leakage of internal content. Regarding the antiparasitic evaluation against Leishmania amazonensis, only compound 27 had a higher selectivity compared to Miltefosine against the amastigote form (IC50 = 5.70 μM). Our results showed that compound 27 presented an antiparasitic activity for both Trypanosoma cruzi and Leishmania amazonensis. After in silico evaluation, it was suggested that the new pyridine-thiazolidinones had an appropriate drug-likeness profile. Our results pointed out a new chemical frame with an anti-Trypanosomatidae profile. The pyridine-thiazolidinones presented here for the first time could be used as a starting point for the development of new antiparasitic agents.


Regional differences of repeatability on visual analogue scale with experimental mechanical pain stimuli.
Pain-VAS is quite subjective as a scale, but has a tendency to assume differences in repeatability in accordance with perceived pain intensity. The aim of the present study was to investigate the repeatability of regional differences with ratings of pain-VAS. Three experimental mechanical stimuli were applied to twenty seven healthy volunteers across four sessions over four weeks within individuals. The same stimuli were also simultaneously measured in the same manner with an electric balance. The magnitude of mechanical stimuli was determined by 100 g, 300 g, and 600 g monofilaments. Standard deviations (SDs) across measurements with an electric balance showed a regular increase with stimulus magnitude, while coefficient variations (CVs) were constant in each stimulus. On the other hand, although SDs across pain-VAS measurements were significantly greater with the 300 g filament than with the 100 g and 600 g filaments, CVs showed a regular decrease in magnitude of stimulus. These results showed that the CVs of repeated measurement with electric balance were consistent regardless of stimulus intensity, in contrast, CVs of pain-VAS decreased with greater pain rating averaged by repeated measurement. These results suggest that a low rating in pain-VAS is inherently less objective, indicating poor repeatability. In contrast, a high rating in pain-VAS is more objective with better repeatability for experimental pain perception.


Prognostic impact of 6 min walk test distance in patients with systolic heart failure: insights from the WARCEF trial.
This study aimed to investigate the impact of baseline 6 min walk test distance (6MWTD) on time to major cardiovascular (CV) events in heart failure with reduced ejection fraction (HFrEF) and its impact in clinically relevant subgroups. In the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial, 6MWTD at baseline was available in 2102 HFrEF patients. Median follow-up was 3.4 years. All-cause death and heart failure hospitalization (HFH) exhibited a significant non-linear relationship with 6MWTD (P = 0.023 and 0.032, respectively), whereas a significant association between 6MWTD and CV death was shown in a linear model [hazard ratio (HR) per 10 m increase, 0.989; P = 0.011]. In linear splines with the best cut-off point at 200 m, the positive effect of a longer 6MWTD on all-cause death and HFH was only observed for 6MWTD > 200 m (HR per 10 m increase, 0.987; P = 0.0036 and 0.986; P = 0.0022, respectively). The associations between 6MWTD and CV outcomes were consistent across clinical subgroups; for age, a significant relationship between 6MWTD and HFH was observed in patients ≥60 years (HR per 10 m increase, 0.98; P < 0.001), but not in patients <60 years (HR per 10 m increase, 1.00; P = 0.98; P = 0.02 for the interaction). In HFrEF, 6MWTD is independently associated with all-cause death, CV death, and HFH. 6MWTD of 200 m is the best cut-off point for predicting these adverse events. The prognostic impact of 6MWTD for HFH was only observed in older patients.


Serious diarrhea with weight loss caused by Capillaria philippinensis acquired in China: a case report.
Diarrhea caused by Capillaria philippinensis (C. philippinensis) has not been reported in any areas with the exception of Taiwan province in China. We herein report the misdiagnosis and subsequent management of a patient with diarrhea caused by C. philippinensis. A 33-year-old woman from the outskirts of Danzhou city, Hainan province, China, had an 11-month history of chronic diarrhea with abdominal pain, edema, hypoalbuminemia, and severe weight loss. The patient was misdiagnosed at an outpatient clinic and one hospital. She was finally correctly diagnosed with C. philippinensis by stool examination. The patient was given a 30-days course of albendazole (400 mg/day) and had an uneventful and stable recovery. Doctors cannot lose sight of patients' dietary histories, must query stool examination results, and need to expand their knowledge of certain nonlocal and global diseases, especially those described in new case reports. Some diagnostic examinations must be performed repeatedly. Hainan province may be the epidemic focus of C. philippinensis.


Special Issue "Advanced Engineering Cementitious Composites and Concrete Sustainability".
Concrete, one of the most often-used building materials today, is the cornerstone of modern buildings all over the world, being used for foundations, pavements, building walls, architectural structures, highways, bridges, overpasses, and so on [...].


Reconstitution and characterization of the human neutrophil N-formyl peptide receptor and GTP binding proteins in phospholipid vesicles.
We have developed a unilamellar phospholipid vesicle system which contains the N-formyl peptide receptor and GTP binding proteins. Several detergents were investigated but only two, octyl glucoside (35 mM) and deoxycholate (7.5 mM), were capable of extracting N-formyl peptide receptor from neutrophil membranes in a form which remained functionally active upon reconstitution into phospholipid vesicles. Extracted proteins were reconstituted into phosphatidylcholine vesicles by passage over a Sephadex G-50-80 column. The reconstituted formylpeptide receptor could bind [3H]FMLP (3H-labeled fMet-Leu-Phe) and [125I]FMLPL-SASD (125I-labeled N-formylmethionylleucylphenylalanyl-N epsilon-(2-(p-azidosalicylamido)ethyl- 1,3'-dithiopropionyl)lysine) while the endogenous G protein could bind [35S]GTP gamma S. Furthermore, the functional interaction of the two proteins was preserved. Addition of the nonhydrolyzable guanine nucleotide, GTP gamma S, shifted the N-formyl peptide receptor from a high- to a low-affinity binding state for ligand. The development of this in vitro reconstitution system should provide a basis to study the mechanism of interaction of the N-formyl peptide receptor and the G protein.


Structural dynamics of the complex of calmodulin with a minimal functional construct of eukaryotic elongation factor 2 kinase and the role of Thr348 autophosphorylation.
The calmodulin (CaM) activated α-kinase, eukaryotic elongation factor 2 kinase (eEF-2K), plays a central role in regulating translational elongation by phosphorylating eukaryotic elongation factor 2 (eEF-2), thereby reducing its ability to associate with the ribosome and suppressing global protein synthesis. Using TR (for truncated), a minimal functional construct of eEF-2K, and utilizing hydrogen/deuterium exchange mass spectrometry (HXMS), solution-state nuclear magnetic resonance (NMR) and biochemical approaches, we investigate the conformational changes accompanying complex formation between Ca2+ -CaM and TR and the effects of autophosphorylation of the latter at Thr348, its primary regulatory site. Our results suggest that a CaM C-lobe surface, complementary to the one involved in recognizing the calmodulin-binding domain (CBD) of TR, provides a secondary TR-interaction platform. CaM helix F, which is part of this secondary surface, responds to both Thr348 phosphorylation and pH changes, indicating its integration into an allosteric network that encompasses both components of the Ca2+ -CaM•TR complex. Solution NMR data suggest that CaMH107K , which carries a helix F mutation, is compromised in its ability to drive the conformational changes in TR necessary to enable efficient Thr348 phosphorylation. Biochemical studies confirm the diminished capacity of CaMH107K to induce TR autophosphorylation compared to wild-type CaM.


A comparison of heat acclimation by post-exercise hot water immersion and exercise in the heat.
To compare heat acclimation adaptations after three and six days of either post-exercise hot water immersion (HWI) or exercise-heat-acclimation (EHA) in recreationally active individuals. Randomised, mixed model, repeated measures. Post-exercise HWI involved a daily 40-min treadmill-run at 65% V̇O2peak in temperate conditions (19 °C, 45% RH) followed by HWI (≤40 min, 40 °C water; n = 9). Daily EHA involved a ≤60-min treadmill-run in the heat (65% V̇O2peak; 33 °C, 40% RH; n = 9), chosen to elicit a similar endogenous thermal stimulus to HWI. A thermoneutral exercise intervention (TNE, 19 °C, 45% RH; n = 9), work-matched to EHA, was also included to determine thermoregulatory adaptations to daily exercise in temperate conditions. An exercise-heat-stress-test was performed before and after three and six intervention days and involved a 40-min treadmill-run and time-to-exhaustion (TTE) at 65% V̇O2peak in the heat (33 °C, 40% RH). ANCOVA, using baseline values as the covariate, revealed no interaction effects but significant group effects demonstrated that compared to EHA, HWI elicited larger reductions in resting rectal temperature (Tre; p = 0.021), Tre at sweating onset (p = 0.011), and end-exercise Tre during exercise-heat-stress (-0.47 °C; p = 0.042). Despite a similar endogenous thermal stimulus to HWI, EHA elicited a modest reduction in end-exercise Tre (-0.26 °C), which was not different from TNE (-0.25 °C, p = 1.000). There were no main effects or interaction effects for end-exercise Tsk, heart rate, physiological strain index, RPE, thermal sensation, plasma volume, or TTE (all p ≥ 0.154). Compared with conventional short-term exercise heat acclimation, short-term post-exercise hot water immersion elicited larger thermal adaptations.


Experimental studies on vertical infection of mice with Japanese encephalitis virus. I. Effect of mouse strain on placental and fetal infection.
An experiment was carried out with mice to study the effect of the mouse strain on the establishment of experimental vertical infection with Japanese encephalitis virus. Mice of various inbred strains were inoculated with a field strain of virus on the 7th day of pregnancy. An attempt was made on them to recover the virus from the placenta and fetuses. As a result, there were differences in the rate of placental and fetal infection among the mouse strains used. It was clarified that vertical infection could be established experimentally in some selected mouse strains. There was not always a parallel relationship between the rate of placental and fetal infection and the severity of viremia or visceral infection in the dam.


Chemopreventive mechanisms of amentoflavone: recent trends and advancements.
In parallel to the continuous rise of new cancer cases all over the world, the interest of scientific community in natural anticancer agents has steadily been increased. In the past decades, numerous phytochemicals have been shown to possess a strong anticancer potential in preclinical conditions. One of such interesting compounds, derived from different plants such as ginkgo, hinoki, and St. John`s wort, is amentoflavone. In this review article, a wide range of anticancer properties of this natural biflavone are described, revealing its ability to suppress the malignant growth and lead tumor cells to apoptotic death, besides impeding also angiogenic and metastatic processes. Therefore, amentoflavone can be considered a potential lead compound for the development of novel anticancer drug candidates, definitely deserving further in vivo studies and also initiation of clinical trials. It is expected that this plant biflavone might be important, either alone or in combination with the current standard chemotherapeutics, in providing some alleviation for the continuous rise of global cancer burden.


Study on the new dynamics and driving factors of soil pH in the red soil, hilly region of South China.
Soil acidification has always been a substantial eco-environmental problem restricting agricultural development in the red soil region of southern China. It is necessary to determine the dynamic change in soil pH in this area to formulate regional agricultural and environmental management measures. Yujiang County, a typical county with red soil acidification in southern China, was selected as the study area. Based on soil data from 1982, 2007, and 2018, the spatiotemporal variation characteristics and the latest changes in soil pH in the county were analyzed. The results show that the soil pH in Yujiang County decreased from 5.66 to 4.74 and then increased to 4.96 from 1982 to 2018, showing a trend of first decreasing and then increasing. According to the spatial distribution characteristics of soil pH, the low soil pH values in the three periods were mainly distributed in the northern mountainous areas with more forestland and dry land area and some southern hilly areas, while the paddy soil pH values in the middle low hilly areas were relatively higher. The soil pH decreased rapidly from 1982 to 2007, showing a large area of acidification. In 2007, the proportions of acidic (4.5 < pH < 5.5) and strongly acidic (pH < 4.5) soils increased by 67.37% and 10.6%, respectively, compared with that in 1982. However, from 2007 to 2018, the soil pH of the whole county increased, and the acidification trend was alleviated, which is of great significance to the regional red soil ecological environment. Through the analysis of the main factors affecting the change in soil pH, it was found that the sharp decline in soil pH in Yujiang County during 1982-2007 was mainly caused by acid rain and excessive nitrogen application. From 2007 to 2018, no significant reduction in nitrogen fertilizer in this area occurred, and although the increase in soil organic matter contributed to alleviating soil acidification, the analysis showed that the decrease in acid rain was the main reason for the rise in soil pH in Yujiang County. At the same time, notably, there is a large area of soil in the area that is still acidic, and effective control of soil acidification is still an important ecological and environmental issue in this area. In order to further improve the pH value of soil in red soil region, it is suggested that on the basis of continuous improvement of acid rain, in addition to increasing soil organic matter by returning straw to field and other measures, appropriate amount of lime or alkaline biochar can be applied to better improve the soil ecological environment in red soil hilly region.