A single amino acid change makes the peptide specificity of B*3910 unrelated to B*3901 and closer to a group of HLA-B proteins including the malaria-protecting allotype HLA-B53.
HLA-B*3910, which has only been found in African and African American individuals, differs from B*3901 by the single amino acid change of Cys67 to Tyr67. Sequence analysis of the B*3910-bound peptide pool and of several individual ligands revealed that this subtype has strong preference for peptides with Pro2. This is in contrast with the preference of B*3901 for peptides with basic residues (Arg and His) at this position, and indicates that the single amino acid substitution between B*3910 and B*3901 totally changes the repertoire of bound peptides. This is presumably due to the significant decrease in the size of the B pocket, and to its increased hydrophobicity, since Tyr67 takes part in this pocket. B*3910 is similar to various other class I proteins in its preference for peptides with Pro2 and nonpolar C-terminal residues, including HLA-B53, an antigen associated with protection against severe malaria. The role of these two motifs as major peptidic anchors suggests that B*3910 and HLA-B53 may bind common peptides.


Carbon-Encapsulated Magnetite Nanodoughnut as a NIR-II Responsive Nanozyme for Synergistic Chemodynamic-Photothermal Therapy.
Magnetite-based nanozymes have attracted great interest for catalytic cancer therapy enabled by catalyzing hydrogen peroxide (H2 O2 ) to produce highly toxic hydroxyl radicals (•OH) to kill tumor cells. However, their therapeutic efficacies remain low due to insufficient •OH. Here, a light-responsive carbon-encapsulated magnetite nanodoughnuts (CEMNDs) with dual-catalytic activities for photothermal-enhanced chemodynamic therapy (CDT) is reported. The CEMNDs can accumulate in tumor and get into tumor cells and effectively act as peroxidase to convert H2 O2 to •OH that causes tumor cell death. The CEMNDs also possess intrinsic glutathione oxidase-like activity that which catalyzes the oxidation of reduced glutathione and produce lipid peroxidase for enhanced catalytic therapy. Furthermore, the CEMNDs can absorb 1064 nm light to elevate local temperature and increase release of Fe ions for photothermal therapy and enhanced CDT respectively. The in vivo experiments in an aggressive and drug-resistant metastatic mouse model of triple negative breast cancer model demonstrate excellent synergistic anti-tumor function and no measurable systemic toxicity of CEMNDs.


Isothermal titration calorimetry and vesicle leakage assays highlight the differential behaviors of tau repeat segments upon interaction with anionic lipid membranes.
Tau misfolding has been implicated in a variety of tauopathies, including Alzheimer's disease. The microtubule binding domain of tau consists of four repeat segments (R1-R4), and aggregation of these segments leads to the formation of neurofibrillary tangles. Previous studies indicate that misfolded tau associates with anionic phospholipid membranes, invoking structural transformations that could play a role in aggregation. Here, we investigated the role of membrane surface charge on the binding affinity of individual tau repeat segments, and whether these segments exhibit lytic activity. We quantified the thermodynamics of this process in terms of the affinity (Kd), enthalpy (ΔH), entropy (ΔS), and change in specific heat capacity (ΔCp). While neutral membranes exhibited weak interactions with each tau repeat segment, segments R2 and R3 exhibited relatively strong binding with anionic membranes with favorable ΔS and a negative value of ΔCp. Calcein leakage assays show that each repeat segment displays lytic activity, but only upon the interaction with anionic membranes. Taken together, these results distinguish the relative selectivity for anionic membranes by each repeat segment and the degree of membrane disruption that results.


Exhaled breath condensate as bioanalyte: from collection considerations to biomarker sensing.
Since the SARS-CoV-2 pandemic, the potential of exhaled breath (EB) to provide valuable information and insight into the health status of a person has been revisited. Mass spectrometry (MS) has gained increasing attention as a powerful analytical tool for clinical diagnostics of exhaled breath aerosols (EBA) and exhaled breath condensates (EBC) due to its high sensitivity and specificity. Although MS will continue to play an important role in biomarker discovery in EB, its use in clinical setting is rather limited. EB analysis is moving toward online sampling with portable, room temperature operable, and inexpensive point-of-care devices capable of real-time measurements. This transition is happening due to the availability of highly performing biosensors and the use of wearable EB collection tools, mostly in the form of face masks. This feature article will outline the last developments in the field, notably the novel ways of EBA and EBC collection and the analytical aspects of the collected samples. The inherit non-invasive character of the sample collection approach might open new doors for efficient ways for a fast, non-invasive, and better diagnosis.


Umbilical artery catheterization in newborns. I. Thrombosis in relation to catheter type and position.
Seventy-one sick newborn infants, who had an umbilical artery catheterized, were randomized in one of four catheter groups: long end-hole-, short end-hole-, long side-hole- or short side-hole catheter. A long catheter means a high position of the catheter tip (Th6--11) and a short catheter a low position of the tip (L3--5). An angiography through the indwelling catheter in order to diagnose thrombosis was performed before the catheter was withdrawn. Dissection of the aorta and its brances was performed on infants who died. The total frequency of thromboses was 26%. There were no thromboses among infants with long end-hole catheters while infants with short end-hole catheters had thrombosis in 26%, long side-hole catheters in 33% and short side-hole catheters in 64%. Long end-hole catheters functioned better than the others. Only 6 of 16 infants with thrombosis had physical signs from the legs, while 12 infants without thrombosis had similar signs.


Effects of palytoxins extracted from Ostreopsis ovata on the oxidative stress and immune responses in Pacific white shrimp Litopenaeus vannamei.
Palytoxins (PLTXs) are a group of complex and poisonous marine natural products that are toxic to marine life and even human beings. In the present study, the oxidative stress and immune response in the hepatopancreas and gills of Litopenaeus vannamei were assessed for 72 h after injection with PLTX extracts. Chemical and physiological parameters, e.g., the respiratory burst (O2-), activities of antioxidant enzymes, oxidative damage to lipids, carbonylation of proteins, and immune gene mRNA expression levels, were analysed. The results showed that the PLTX extract was not fatal to the shrimp but could reduce their mobility. The O2- levels in the gills gradually increased after exposure to PLTX extracts and were significantly higher than those in the control from 6 to 72 h. The malondialdehyde content, lipid peroxidation, protein carbonyl levels, and total antioxidant capacity in the gills all peaked at 12 h. At the same time, the gills were loosely connected, there was a clear disintegration of the epithelial tissue, and the stratum corneum disappeared after 12 h. In addition, compared to those in the control group, the PLTX extract treatment increased the O2- content, malondialdehyde content, lipid peroxidation, and protein carbonyl levels from 12 to 72 h, 24-48 h, 12-24 h, and 12-72 h after injection in the hepatopancreas of the shrimp, respectively. Both the Crustin and Toll gene expression levels significantly increased in the hepatopancreas compared to those in the control 6-72 h after injection of the toxin. In parallel, the expression levels of the manganese superoxide dismutase gene gradually decreased from 6 to 48 h and returned to normal levels after 72 h. Interestingly, the total antioxidant capacity also significantly increased compared to that in the control from 6 to 72 h. Our results indicate that although PLTX extracts cause lipid peroxidation and carbonylation of proteins in hepatopancreatic cells, leading to their damage, they did not cause a decrease in the total antioxidant capacity of the hepatopancreas.


Non-invasive NMR stratigraphy of a multi-layered artefact: an ancient detached mural painting.
NMR stratigraphy was used to investigate in situ, non-destructively and non-invasively, the stratigraphy of hydrogen-rich layers of an ancient Nubian detached mural painting. Because of the detachment procedure, a complex multi-layered artefact was obtained, where, besides layers of the original mural painting, also the materials used during the procedure all became constitutive parts of the artefact. NMR measurements in situ enabled monitoring of the state of conservation of the artefact and planning of minimum representative sampling to validate results obtained in situ by solid-state NMR analysis of the samples. This analysis enabled chemical characterization of all organic materials. Use of reference compounds and prepared specimens assisted data interpretation.


Endothelium-dependent contractions to NG-nitro-L-arginine methyl ester in the porcine isolated splenic artery are sensitive to cyclooxygenase and lipoxygenase inhibitors.
The nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), produced large endothelium-dependent contractions in isolated segments of the porcine splenic artery, equivalent to approximately 30% of the maximum responses to 5-hydroxytryptamine (5-HT). These responses were inhibited by 1mM L-arginine, but not by either 1mM D-arginine or the superoxide anion scavenger, superoxide dismutase. However, L-NAME-induced contractions were markedly inhibited by the cyclooxygenase inhibitor, flurbiprofen, and the lipoxygenase inhibitor, 2,3,5-tri-methyl-6-(12-hydroxy-5,10-dodecadiynyl)1,4-benzoquinone (AA-861). The combined cyclooxygenase and lipoxygenase inhibitor 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW-755C) abolished L-NAME-induced contractions. These findings suggest that suppression of endothelial nitric oxide synthase in the porcine isolated splenic artery results in activation of arachidonic metabolism and production of vasoconstrictor eicosanoids.


Distraction Lengthening of the Apert Thumb.
The thumbs of patients with Apert syndrome are characteristically short and radially deviated, contributing to functional hand impairment. The authors report a two-staged technique for distraction lengthening of the Apert thumb using a robust cohort of pediatric patients. The authors retrospectively reviewed medical records of pediatric patients with Apert syndrome who underwent thumb distraction lengthening between 1999 and 2019. The technique was two-staged: (1) application of uniplanar distractor and phalangeal osteotomy, followed by (2) distractor removal, bone grafting, and fixation. Clinical records, preoperative and postoperative radiographs, and photographs were reviewed. Twenty-two patients (41 thumbs) with Apert syndrome were identified and treated (mean age at initial distraction, 11.5 years). A mean distraction gap of 31.3 mm was achieved over a median time of 40.0 days. The mean healing index was 26.3 days per centimeter. The thumbnail complex was lengthened a median length of 3.0 mm. The median follow-up time was 5.0 years, with complications occurring in 36.4 percent (eight out of 22) of patients. A delayed bone union occurred in one patient, and rotational malunion occurred in one patient. Although long-term outcomes data are needed, thumb distraction lengthening following syndactyly release in patients with Apert syndrome is safe and should be considered to augment the overall appearance and functionality of the hand. Therapeutic, IV.


SARS-CoV-2 serology in pediatrics: Seroprevalence studies in unvaccinated children and humoral antibody response post vaccination.
Humoral response against SARS-CoV-2 is increasingly accepted as the central correlate of immune protection. Recent pediatric seroprevalence data are extremely limited. Significant knowledge gaps also exist in immune response to mRNA SARS-CoV-2 vaccination in children. As children demonstrate distinct response to naïve infection relative to adults, it is essential to investigate age-specific differences in seroprevalence and antibody response to SARS-CoV-2 vaccination. Seroprevalence was assessed through two cross-sectional serosurveys prior to COVID-19 vaccination approval in children <5 years using residual patient specimens (n = 2902). To assess antibody response post-vaccination, 842 participants (580 children, 262 adults) were prospectively recruited with informed consent. Participation required completion of a health questionnaire and blood donation. Samples were collected at varying times post-vaccination and assayed using the Abbott AdviseDx SARS-CoV-2 IgG II and DiaSorin LIAISON SARS-CoV-2 TrimericS IgG assays. Significant increases in seroprevalence were observed between the first and second serosurveys in unvaccinated children <6 months to 5 years (38-75%). In the prospective vaccination cohort, serokinetic response decreased with time post-dose of an mRNA vaccine. Measured IgG titres were significantly higher in children relative to adults across all time points. This is the largest evaluation of quantitative SARS-CoV-2 antibody assays in a cohort of Canadian children, adolescents, and adults. Findings suggest high rates of SARS-CoV-2 exposure among unvaccinated young children in the Toronto community. Additional data supports children have higher antibody titres relative to adults post-vaccination.


The influence of city development on urban pedodiversity.
The aim of this study was to use a pedodiversity index (PI) to assess changes in the spatial structure of soil cover in Inowrocław, Poland during the twentieth and twenty-first centuries. An original cartographic approach based on landscape metrics was implemented using GIS techniques and statistical calculations. Based on maps of urban soil complexes and pedodiversity, it was revealed that land and soil cover changes in two studied periods (1934-1978 and 1978-2016) significantly affected pedodiversity in the city. In general, the spatio-temporal increase of the pedodiversity index was observed. The percentage of highest values of the PI ranged from 15.9% in 1934, 17.3% in 1978 to 20.9% in 2016. We revealed that pedodiversity index (PI) values are highly spatially and temporally variable and are associated with urban development and changes in the city's internal structure. The applied approach allowed for the identification of both spatial patterns of changes in soil cover that closely reflect the successive stages of the city's development, and problem areas that require revitalization and the implementation of the principles of sustainable development. Therefore, the proposed method can be recommended for landscape monitoring and in determining ecosystem services in urban and landscape planning, and environmental management.


Pelvic floor sex steroid hormone receptors, distribution and expression in pre- and postmenopausal stress urinary incontinent women.
Hormonal influence on stress urinary incontinence (SUI) is under debate. Sex steroid hormonal activity is mediated by nuclear receptor proteins. The aim of this study is to identify receptor isoforms and their genetic expression in the pelvic floor extra cellular matrix (ECM), and to compare women with and without SUI before and after menopause. Sub-mucosal para-urethral biopsies from 4 pre-menopausal and 8 postmenopausal patients with SUI were analysed immunohistochemically regarding estrogen receptors (ER) alpha and beta, the progesterone receptor (PR) (A+B) and B, and the androgen receptor (AR). Six pre-menopausal and 5 postmenopausal women served as controls. All receptors were scored manually. Additionally, ER-alpha and ER-beta were quantified by image analysis. Biopsies from 7 pre-menopausal and 7 postmenopausal women suffering from SUI were studied by real-time RT-PCR for expression of ER-alpha, ER-beta, PR and AR. The control group consisted of 5 pre-menopausal and 5 postmenopausal women. Immunohistochemistry revealed receptor-positive cells for all isoforms in all groups. Higher ER-beta scores were seen in the pre-menopausal SUI group compared to controls. Lower PR-B scores were found after menopause in both groups. The image analysis confirmed that ER-beta was significantly increased in the pre-menopausal SUI group compared to controls (p=0.02). By real-time RT-PCR, no difference of mRNA expression regarding any receptor was detected between any SUI and control group. ER-beta mRNA levels were low or undetectable. There was a significant down-regulation of PR among postmenopausal women (p=0.001). The para-urethral ECM is a target for sex steroid hormones mediated by the respective receptor. The significant higher expression of ER-beta protein in the pre-menopausal SUI-group was not reflected by a corresponding up-regulation of mRNA which was poorly expressed in all groups.


MRI-Guided stereotactic laser ablation for epilepsy surgery: Promising preliminary results for cognitive outcome.
Cognitive outcome data are reviewed with respect to the use of magnetic-resonance guided stereotactic laser ablation (SLA) as an epilepsy surgical procedure, with comparisons drawn to traditional open resection procedures. Cognitive outcome with stereotactic laser amygdalohippocampotomy (SLAH) appears better than open resection for several functions dependent on extra-mesial temporal lobe (TL) structures, including category-related naming, verbal fluency, and object/familiar person recognition. Preliminary data suggests episodic, declarative verbal memory can decline following SLAH in the language dominant hemisphere, although early findings suggest comparable or even superior outcomes compared with open resection. The hippocampus has long been considered a central structure supporting episodic, declarative memory, with epilepsy surgical teams attempting to spare it whenever possible. However, ample data from animal and human neuroscience research suggests declarative memory deficits are greater following broader mesial TL lesions that include parahippocampal gyrus and lateral TL inputs. Therefore, employing a neurosurgical technique that restricts the surgical lesion zone holds promise for achieving a better cognitive outcome. Focal SLA lesions outside of the amygdalohippocampal complex may impair select cognitive functions, although few data have been published in such patients to date. SLA is being effectively employed with adults and children with TL or lesional epilepsies across several U.S. epilepsy centers, which may simultaneously optimize cognitive outcome while providing a curative treatment for seizures.


[Characteristics of thermograms of the skin of the anterior surface of the trunk in persons with various tonus of the sympathetic and parasympathetic nervous system].
Vegetative regulation is shown to affect the heat pattern of the trunk skin. Two types of thermograms are found in men: "monotonous" and "spotted", the first thermogram being characterized by prevalence of the parasympathetic and the second one-by sympathetic tonus. In women "spotted" thermograms and sympathicotonic direction of the vegetative regulation are registered.


Volumetric MR-HIFU ablation of uterine fibroids: role of treatment cell size in the improvement of energy efficiency.
To evaluate the energy efficiency of differently sized volumetric ablations in MR-guided high-intensity focused ultrasound (MR-HIFU) treatment of uterine fibroids. This study was approved by the institutional review board and informed consent was obtained from all participants. Ten symptomatic uterine fibroids (mean diameter 8.9 cm) in 10 women (mean age 42.2) were treated by volumetric MR-HIFU ablation under binary feedback control. The energy efficiency (mm3/J) of each sonication was calculated as the volume of lethal thermal dose (240 equivalent minutes at 43 °C) per unit acoustic energy applied. Operator-controllable parameters and signal intensity ratio of uterine fibroid to skeletal muscle on T2-weighted MR images were tested with univariate and multivariate analyses to discern which parameters significantly correlated with the ablation energy efficiency. We analyzed a total of 236 sonications. The energy efficiency of the ablations was 0.42±0.25 mm3/J (range 0.004-1.18) with energy efficiency improving with the treatment cell size (4 mm, 0.06±0.06 mm3/J; 8 mm, 0.29±0.12 mm3/J; 12 mm, 0.58±0.18 mm3/J; 16 mm, 0.91±0.17 mm3/J). Treatment cell size (r=0.814, p<0.001), distance of ultrasound propagation (r=-0.151, p=0.020), sonication frequency (1.2 or 1.45 MHz; p<0.001), and signal intensity ratio (r=-0.205, p=0.002) proved to be significant by univariate analysis, while multivariate analysis revealed treatment cell size (B=0.075, p<0.001), US propagation distance (B=-6.928, p<0.001), and signal intensity ratio (B=-0.024, p=0.001) to be independently significant. Energy efficiency in volumetric MR-HIFU ablation of uterine fibroids improves with increased treatment cell size, independent of other significant contributors such as distance of ultrasound propagation or signal intensity of the tumor on T2-weighted MR imaging.


Morphology and molecular taxonomy of Evlachovaea-like fungi, and the status of this unusual conidial genus.
The entomopathogenic anamorphic genus Evlachovaea was described to differ from other fungi in forming its conidia obliquely to the axis of the conidiogenous cell and with successive conidia having alternate orientations with a zipper- or chevron-like arrangement resulting in flat, ribbon-like chains. Morphological and molecular studies of six Evlachovaea-like isolates baited from Central Brazilian soils using Triatoma infestans (a vector of Chagas disease) and of other entomopathogens with Evlachovaea-like conidiogenesis led to a re-evaluation of the status of this little known fungal genus. The Brazilian isolates formed two distinct groups based on gene sequences for both the internal transcribed spacer (ITS) and translation elongation factor (EF-1α) genes, morphology, and growth patterns; both groups also differed from the type species, Evlachovaea kintrischica. More detailed studies of these fungi indicated that the alternatingly oblique orientations of forming conidia are neither a stable nor invariant character (even on single phialides). Furthermore, the molecular cladistic analysis unambiguously placed the Evlachovaea isolates firmly within the genus Isaria (Hypocreales: Cordycipitaceae). The ITS sequences of E. kintrischica were very similar or even identical to those of Isaria amoenerosea and Isaria cateniobliqua, thereby suggesting that E. kintrischica is a synonym of one of these species, and that the genus Evlachovaea must be treated as a later synonym of Isaria, which must now be recognized to include several highly divergent modes of conidiogenesis. These taxonomic findings are discussed in the context of dramatic changes recently imposed on the nomenclatural standards used to determine the correct names of all pleomorphic fungi.


The affinity of atropine for muscarine receptors in human sphincter pupillae.
Concentration-dependent contractions in response to carbachol were determined on isolated pieces of human iris. Atropine competivtively antagonized the effect of carbachol. An apparent dissociation equilibrium constant of 0.4--0.7 nM was estimated for the muscarine receptor-atropine complex.


Long-term neuro-endocrine sequelae after treatment for childhood medulloblastoma.
The occurrence of neuro-endocrine deficiencies following craniospinal irradiation for medulloblastoma is well known, but data concerning the spectrum and prevalence of endocrine abnormalities in adulthood are scarce. We studied endocrine function in 20 (median age 25 years) adult subjects, 8-25 years (median 16 years) after therapy. The radiation dose to the whole cranium and spinal axis was 35 +/- 2.6 Gray (mean +/- standard deviation) with a boost to the posterior fossa of 18 +/- 3.7 Gray. 13 subjects had received additional chemotherapy. In 15 of 20 (75%) subjects, endocrine abnormalities were observed. In 14 (70%), growth hormone (GH) secretion was impaired; 7 (35%) subjects had an absolute GH deficiency, while 7 (35%) showed subnormal responses to insulin-induced hypoglycaemia. In contrast, only 20% (4) of these subjects showed impairment of the hypothalamus-pituitary-thyroid (HPT) axis, while 15% (3) showed central impairment of hypothalamus-pituitary-gonadal (HPG) function. Central impairment of the HPG axis was associated with impaired GH secretion in all cases. Central adrenal insufficiency was not observed. Basal levels of prolactin were normal in all subjects. Young age at treatment was a determinant of GH deficiency in adulthood (P = 0.014). Neither post-treatment interval, nor the use of chemotherapy were determinants of central endocrine impairment in adulthood. In long-term survivors of medulloblastoma, GH deficiency has a high prevalence. In contrast, impairment of the HPG and HPT axis is less common, while central adrenal insufficiency was not observed.


Combination of cytochrome b heteroduplex-assay and sequencing for identification of triatomine blood meals.
The identification of blood meals in vectors contributes greatly to the understanding of interactions between vectors, microorganisms and hosts. The aim of the current work was to complement the validation of cytochrome b (Cytb) heteroduplex assay (HDA) previously described, and to add the sequencing of the Cytb gene of some samples for the identification of blood meals in triatomines. Experimental feedings of reared triatomines helped to clarify the sensitivity of the HDA. Moreover, the sequencing coupled with the HDA, allowed the assessment of the technique's taxonomic level of discrimination. The primers used to produce DNA fragments of Cytb genes for HDA had a very high sensitivity for vertebrate DNAs, rather similar for mammals, birds and reptiles. However, the formation of heteroduplex depended on blood meal's quality rather than its quantity; a correlation was observed between blood meals' color and the positivity of HDA. HDA electrophoresis profiles were reproducible, and allowed the discrimination of blood origins at the species level. However, in some cases, intraspecific variability of Cytb gene generated different HDA profiles. The HDA based on comparison of electrophoresis profiles is a very useful tool for screening large samples to determine blood origins; the subsequent sequencing of PCR products of Cytb corresponding to different HDA profiles allowed the identification of species whatever the biotope in which the vectors were captured.


"Doughnut" Amniotic Membrane Transplantation With Penetrating Keratoplasty for Vernal Keratoconjunctivitis With Limbal Stem Cell Disease.
Severe vernal keratoconjunctivitis (VKC) can cause ocular surface disease including partial or complete limbal stem cell deficiency (LSCD), especially in early-onset and severe limbal form of VKC. We report a novel technique of doughnut amniotic membrane transplantation (AMT) along with penetrating keratoplasty (PK) for management of partial LSCD and corneal scarring in a case of severe VKC. Case report. A 17-year-old boy, with onset of disease at 8 years of age, and development of partial LSCD and corneal scarring over a period of 9 years despite therapy, presented with profound visual loss due to dense bilateral corneal scarring. After the active allergy subsided, he underwent modified AMT (doughnut AMT) with simultaneous PK in his left eye. Histopathology of the excised button revealed conjunctival phenotype and dense corneal scarring up to the posterior stroma. At 1-year follow up, his best spectacle-corrected visual acuity was maintained at 20/30 in the operated eye, the graft was clear, and the ocular surface was stable. Severe VKC can cause ocular surface disease including LSCD with corneal scarring, especially in early-onset limbal form of VKC. The modified technique of AMT (doughnut AMT) along with PK can successfully visually rehabilitate and address partial LSCD in such patients.


Long-term suppression of EAE relapses by pharmacological impairment of epitope spreading.
Immune events sustaining dendritic cell (DC)-dependent epitope spreading (ES) are of key relevance to the development of relapses during multiple sclerosis (MS). Although no drugs are currently available to target ES, its inhibition would represent a major advancement in MS therapy. Inhibitors of the enzyme PARP-1 afford protection in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). These drugs epigenetically impair antigen presentation by DCs, but whether these drugs affect ES is unknown. Here, we investigated whether short-term treatments with these compounds would impair ES, thereby preventing EAE relapses. We used a model of relapsing EAE in SJL mice and also adopted in vivo and ex vivo models of DC-dependent T-cell polarization. The effect of PARP-1 inhibitors on ES was evaluated at the humoral and cellular level. Short-term treatments with PARP-1 inhibitors during the acute phase of relapsing EAE of mice induced, at later times, more tolerogenic DCs, increased numbers of Treg cells and impairment of ES at the humoral and cellular level. These effects are followed by long-lasting reduction of relapse severity and incidence, although drug treatment had been discontinued for several weeks. PARP-1 inhibitors also induced tolerogenic DCs and increased Treg cells number and function in a model of ovalbumin immunization. Our data emphasize the therapeutic potential of PARP-1 inhibitors in the treatment of relapsing-remitting MS and additional ES-driven autoimmune disorders.


Cytokine network imbalance in children with B-cell acute lymphoblastic leukemia at diagnosis.
Immune imbalance has been proved to be involved in the pathogenesis of hematologic neoplasm. However, little research has been reported altered cytokine network in childhood B-cell acute lymphoblastic leukemia (B-ALL) at diagnosis. Our study aimed to evaluate the cytokine network in peripheral blood of newly diagnosed pediatric patients with B-ALL. Serum levels of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), interferon (IFN)-γ, and IL-17A in 45 children with B-ALL and 37 healthy control children were measured by cytometric bead array, while the level of transforming growth factor-β1 (TGF-β1) in the serum was measured by enzyme-linked immunosorbent assay. Patients showed a significant increase in IL-6 (p < 0.001), IL-10 (p < 0.001), IFN-γ (p = 0.023) and a significant reduction in TGF-β1 (p = 0.001). The levels of IL-2, IL-4, TNF and IL-17A were similar in the two groups. Higher concentrations of pro-inflammatory cytokines were associated with febrile in patients without apparent infection by using unsupervised machine learning algorithms. In conclusion, our results indicated a critical role for aberrant cytokine expression profiles in the progression of childhood B-ALL. Distinct cytokine subgroups with different clinical features and immune response have been identified in patients with B-ALL at the time of diagnosis.


Dependence on the lipophilicity of maleimide derivatives in their inhibitory action upon chemotaxis in neutrophils.
Modification of polymorphonuclear neutrophils by a series of maleimide derivatives with various degrees of lipophilicity and hydrophilicity indicated that hydrophilic reagents had little effect on chemotaxis, whereas the degree of the inhibitory effect of lipophilic reagents on the chemotaxis was parallel to the degree of their lipophilicity.


The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage.
Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for mammalian antiviral immunity, and its intracellular localization determines induction of type I interferons; however, the mechanism terminating TLR3 signaling remains obscure. Here, we show that the E3 ubiquitin ligase ZNRF1 controls TLR3 sorting into multivesicular bodies/lysosomes to terminate signaling and type I interferon production. Mechanistically, c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation. ZNRF1-deficient mice and cells are resistant to infection by encephalomyocarditis virus and SARS-CoV-2 because of enhanced type I interferon production. However, Znrf1-/- mice have exacerbated lung barrier damage triggered by antiviral immunity, leading to enhanced susceptibility to respiratory bacterial superinfections. Our study highlights the c-Src-ZNRF1 axis as a negative feedback mechanism controlling TLR3 trafficking and the termination of TLR3 signaling.


Predictive models for first-onset and persistence of depression and anxiety among university students.
Depression and anxiety are both prevalent among university students. They frequently co-occur and share risk factors. Yet few studies have focused on identifying students at highest risk of first-onset and persistence of either of these conditions. Multicenter cohort study among Spanish first-year university students. At baseline, students were assessed for lifetime and 12-month Major Depressive Episode and/or Generalized Anxiety Disorder (MDE-GAD), other mental disorders, childhood-adolescent adversities, stressful life events, social support, socio-demographics, and psychological factors using web-based surveys; 12-month MDE-GAD was again assessed at 12-month follow-up. A total of 1253 students participated in both surveys (59.2% of baseline respondents; mean age = 18.7 (SD = 1.3); 56.0% female). First-onset of MDE-GAD at follow-up was 13.3%. Also 46.7% of those with baseline MDE-GAD showed persistence at follow-up. Childhood/Adolescence emotional abuse or neglect (OR= 4.33), prior bipolar spectrum disorder (OR= 4.34), prior suicidal ideation (OR=4.85) and prior lifetime symptoms of MDE (ORs=2.33-3.63) and GAD (ORs=2.15-3.75) were strongest predictors of first-onset MDE-GAD. Prior suicidal ideation (OR=3.17) and prior lifetime GAD symptoms (ORs=2.38-4.02) were strongest predictors of MDE-GAD persistence. Multivariable predictions from baseline showed AUCs of 0.76 for first-onset and 0.81 for persistence. 74.9% of first-onset MDE-GAD cases occurred among 30% students with highest predicted risk at baseline. Self-report data were used; external validation of the multivariable prediction models is needed. MDE-GAD among university students is frequent, suggesting the need to implement web-based screening at university entrance that identify those students with highest risk.


Fcγ receptors enable anticancer action of proapoptotic and immune-modulatory antibodies.
Antibodies have important roles in controlling cellular immunity through interaction with activating or inhibitory Fcγ receptors (FcγRs). FcγR engagement can facilitate receptor cross-linking on target cells, or induce retrograde FcγR signals to stimulate or suppress antibody-dependent, cell-mediated depletion of antigen-bearing target cells. Recent studies uncover unexpectedly important roles for FcγRs in the anticancer action of antibodies designed to trigger tumor cell apoptosis or enhance antitumor immunity. Here, we outline a conceptual framework for understanding these findings and discuss their mechanistic and translational implications.


Astragaloside IV ameliorates preeclampsia-induced oxidative stress through the Nrf2/HO-1 pathway in a rat model.
Preeclampsia (PE) can cause serious health problems for pregnant women and their infants. Astragaloside IV has been shown to exert cardioprotective, anti-inflammatory, and antioxidative effects on various disorders. We aimed to study the effects of Astragaloside IV on PE symptoms using an NG-nitro-l-arginine methyl ester (l-NAME)-induced rat model of PE. The pregnant rats' physiological features, including blood pressure, urine protein, serum soluble fms-like tyrosine kinase-1(sFlt-1)/placental growth factor (PlGF) ratio, and weight of placenta, as well as the weight, length, and survival of pups, were documented. The expression levels of target genes were analyzed by Western blot and qRT-PCR assays. The levels of target secreted proteins were determined by ELISA. We demonstrated that the administration of Astragaloside IV might exert a multitude of beneficial effects on attenuated PE symptoms in a rat model of PE. We further revealed that the effects of Astragaloside IV on PE rats were achieved, at least partially, through elimination of oxidative stress and stimulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Our study indicated that Astragaloside IV may serve as a promising candidate for the development of new therapeutic methods for patients with PE.


Relationship between the expression of RASSF1A protein and promoter hypermethylation of RASSF1A gene in bladder tumor.
To investigate the relationship between the expression of RASSF1A protein and promoter hypermethylation of RASSF1A gene, RASSF1A protein expression was measured by Western blotting in 10 specimens of normal bladder tissues and 23 specimens of bladder transitional cell carcinoma (BTCC). The promoter methylation in BTCC and normal bladder tissues was detected by methylation-specific PCR (MSP). The results showed that the expression level of RASSF1A protein was significantly lower in BTCC tissues than that in normal bladder tissues. However, it was not correlated with its clinical stages and pathological grades. The frequency of promoter methylation of RASSF1A gene was higher in BTCC tissues than that in normal bladder tissues. In 14 patients with the aberrant promoter methylation, 13 showed loss or low expression of RASSF1A protein. It is concluded that RASSF1A gene promoter methylation may contribute to the low level or loss of RASSF1A protein expression, the inactivation of RASSF1A gene and the genesis of BTCC. But, it may bear no correlation with its clinical stages and pathological grades.


Prevalence of Ureaplasma urealyticum, Chlamydia trachomatis, and Neisseria gonorrhoeae in gynecological outpatients, Taizhou, China.
Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), and Neisseria gonorrhoeae (NG) are highly prevalent worldwide and may lead to some genital diseases. The objective of this large-scale study was to estimate the prevalence characteristics of UU, CT, and NG among women in Taizhou, Zhejiang Province, China. A total of 13 303 women who visited the gynecologic outpatient service of Taizhou First People's Hospital in Taizhou from 2013 to 2018 were analyzed. The testing of UU, CT, and NG was performed on the collected vaginal swabs using real-time fluorescence quantitative polymerase chain reaction (RT-PCR) method. The overall infection rates of UU, CT, and NG were 62.04%, 10.20%, and 4.09% in the Taizhou-based population, respectively. The age-specific prevalence showed that younger women (age <25 years) were the preferred period for the positive detection of UU or CT, while elder women (age ≥40 years) had the highest prevalence of NG. In addition, the UU-CT co-infection pattern (7.32%) predominated in the study population, and CT was significantly associated with UU and NG. Our novel data demonstrated that UU, CT, and NG infection are prevalent among women in Taizhou, and comprehensive UU, CT, and NG screening guidelines and treatment policies for this population are warranted.


[Novel biomarkers in renal cell carcinoma. Identification and functional characterization].
Due to advanced imaging techniques, renal cell carcinoma (RCC) is now identified earlier, often in localized stages. As a result, nephron-sparing surgical resection is possible in most cases. The development of new targeted therapies has changed the way metastatic RCC is treated. Despite this positive trend with improved survival rates and expanding treatment options, reliable biomarkers for better predicting disease course are lacking. These are urgently needed to enable personalized therapy based on the treatment-associated risks, the presence of comorbidities, and molecular tumor characteristics. We were able to show that proteins with a regulatory influence on apoptotic signal cascades represent not only promising prognostic markers, but also interesting targets for new therapeutic approaches. Furthermore, our data demonstrate that molecular tests are necessary to correctly classify a RCC with Xp11.2 translocation, since in addition to translocation, amplification can also result in TFE3 activation. Translational research with RCC biomarker identification and establishment, as well as molecular characterization and subtyping of RCCs is required to guide therapeutic decisions and enable personalized medicine in RCC patients.


Life-threatening complications of cardiac operations and occurrence of myocardial catecholamine bombs.
Myocardial catecholamine bombs (huge local intra-axonal accumulations of catecholamine, mainly norepinephrine, within cardiac tissue) were observed in (right auricular) myocardial biopsy specimens in 16 of 65 adult patients selected randomly from a series of elective cardiac operations. The occurrence of catecholamine bombs was in highly significant correlation (p less than 0.001) with the occurrence of life-threatening complications of cardiac operations (life-threatening arrhythmias [ventricular tachycardias, ventricular fibrillation, asystole], clinically evident perioperative myocardial infarction/postoperative low-output syndrome, death). There was a very close correlation between the occurrence of catecholamine bombs and life-threatening arrhythmias. Life-threatening arrhythmias occurred in 13 patients. Eight of them belonged to the group of 16 patients with catecholamine bombs and five belonged to the group of 49 patients with no bombs; the difference (8/16 versus 5/49) is very clear (p less than 0.001). It was our experience that dangerous arrhythmias related to catecholamine bombs may occur as late as during the second postoperative week. We believe our observations are of considerable clinical importance, because catecholamine bombs are easily identified by fluorescence microscopic examination of right auricular myocardial specimens retrieved intraoperatively, and patients at high risk can then be selected (during the operation) for more extensive and prolonged surveillance and possibly prophylactic treatment.


Up-regulation of ribophorin I after yellow head virus (YHV) challenge in black tiger shrimp Penaeus monodon.
This work constitutes the second report from a continuing investigation of shrimp genes that may be involved in apoptosis associated death resulting from yellow head virus (YHV) infection. Here, we describe from the black tiger shrimp Penaeus monodon, a ribophorin I-like gene that is probably a subunit of the oligosaccharyltransferase complex (OST), a key enzyme in N-linked glycosylation that occurs in the endoplasmic reticulum. The OST complex also contains DAD1 (defender against apoptotic death 1) that has been reported to control apoptosis and that we have previously reported from P. monodon. The full length ribophorin I of P. monodon comprised 2157 bp with the ORF of 1806 bp corresponding to 601 deduced amino acids and three putative N-linked glycosylation sites. Analysis revealed hydrophobic properties implying that it could be a membrane protein. Tissue distribution analysis using real-time RT-PCR with SYBR Green revealed that ribophorin I was endogenously expressed in all examined tissues of normal shrimp. However, unlike DAD1 that was down-regulated after YHV challenge, ribophorin I expression was up-regulated and remained high until the moribund stage.


How 24-month-olds form and transfer knowledge about tools: the role of perceptual, functional, causal, and feedback information.
This study investigated cognitive processes underlying tool use and knowledge transfer in 24-month-olds (N=123). Following a demonstration, participants chose a tool to reach a reward in a training transfer paradigm. Differing from previous research, various aspects considered to be relevant for children's performance were integrated within the same study design, and performance was examined on a trial-by-trial basis. More specifically, we analyzed how the following aspects affected toddlers' learning and transfer performance: causal information, degree of conflict between perceptually salient and functionally relevant information, and feedback information. Children with access to causal information outperformed children without corresponding information during the training and transfer phases. Perceptual conflict had a negative impact on transfer performance. However, children were quickly able to correct their choices based on feedback. Results are discussed in the light of recent accounts on tool use understanding.


Effects of oxygen levels and a Lactobacillus plantarum strain on mortality and immune response of chickens at high altitude.
Chickens reared in high altitude regions suffer from a high mortality, possibly due to poor immune responses induced by hypoxia. This experiment was conducted to evaluate whether increasing the oxygen level or administration of a probiotic could improve mortality and immune response of chickens at high altitude (2,986 m above the sea level). One-d-old chickens were randomly allocated to 1 of 6 treatments in a 2 × 3 factorial arrangement. The first factor was the oxygen level (low and high), while the second factor was the diet (basal diet, basal diet containing aureomycin, and basal diet plus L. plantarum). Increasing the oxygen level significantly reduced the mortality and improved immune responses. The levels of IgA, IgG, IL-10 and anti-BSA antibodies were significantly higher, while IL-1β, LITAF were significantly lower in chickens reared in the high-oxygen room. In the low-oxygen room, L. plantarum significantly decreased the mortality of chickens compared with the other 2 groups. Moreover, L. plantarum significantly increased the levels of IgA, anti-BSA antibodies, IL-10 and decreased IL-1β, LITAF compared with the control group. These results demonstrated that increasing oxygen level or administration of L. plantarum can improve health status of chickens in high altitude regions.


Induction of differentiation in neuro-2A cells by the monoterpene perillyl alcohol.
The monoterpenes limonene and perillyl alcohol have been shown to induce the complete regression of rat mammary carcinomas by what appears to be a cytostatic and differentiation process. In order to evaluate the differentiating effects of the monoterpenes we tested the ability of perillyl alcohol to induce differentiation in a well-characterized neuroblastoma cell model. Perillyl alcohol was found to be a potent inducer of the neuroblastoma-derived cell line Neuro-2A. Several cellular effects of monoterpenes were ruled out as contributing to Neuro-2A differentiation including its cytostatic effect and its ability to inhibit ubiquinone (CoQ) syntheses.


Monitoring urban growth by using segmentation-classification of multispectral Landsat images in Izmit, Turkey.
Assessing the spatial land use and land cover (LULC) information is essential for decision making and management of landscapes. In fact, LULC information has been changed dramatically in fast-growing cities. This results in wrong land use problems due to unplanned and uncontrolled urbanization. The planning and evaluating of limited natural resources under the pressure of a growing population can be possible when a precise land use management plan is established. Therefore, it is imperative to monitor continuous LULC changes for future planning. Remote sensing (RS) technique is used for determining changes in LULC in urban areas. In this study, we have focused on Izmit, which is one of a growing number of metropolitan cities where the impact of the spatial growing period on LULC has been assessed over the past 30 years by using RS data. We have utilized the segmentation process and supervised classification of Landsat satellite images for four different dates (1985, 1995, 2005, and 2015). The outcome of this research can be summarized by significant changes in the shares of urban areas and farmland LULC classes. The overall observed increase in urban area class is up to 2177 ha between 1985 and 2015 period and this dramatic change has resulted in the decline of 1211 ha of farmland. Another conclusion is that the new residential areas have been created to the north, south and east of Izmit during this period.


Mevastatin accelerates loss of synaptic proteins and neurite degeneration in aging cortical neurons in a heme-independent manner.
The therapeutic use of statins in reducing cholesterol requires careful assessment of potential neuroprotective and/or neurotoxic mechanisms. Chronic treatment with mevastatin (MV) exerts effects on cortical neuron morphology, protein expression and synaptic function in primary culture. MV impaired expression of synaptic proteins, reduced N-methyl-d-aspartate receptor (NMDAR) currents and accelerated neurodegeneration associated with aging. The down-regulating effect of MV on neuronal protein expression was additive with aging-associated decline in culture. Induction of Heme oxygenase-1 (HMOX1) by MV was superimposed on age-related up-regulation. Comparison of MV-treated and heme-deficient neurons showed that inhibition of heme synthesis (by succinyl acetone) had similar damaging effect on neurite integrity and MNDAR expression and function but not on expression of the receptor for neuropeptide Y1 (NPY1R). Replacement of heme in heme-deficient cultures restored protein expression but had no effect in those cultures co-treated with MV. Despite the dramatic induction of HMOX1, intracellular heme remained sufficient in MV-treated cultures, consistent with a heme-independent mechanism of MV-induced neurotoxicity and this was confirmed by analysing neurons with lentiviral over-expression of HMOX1. We conclude that MV exerts a neurotoxic effect in cultured neurons in a heme-independent manner.


Blood flow reduction in local pulmonary microvessels during acute hypoxia imposed on a small fraction of the lung.
Hypoxia was induced in a small fraction (less than 0.2%) of the whole lung by introducing pure nitrogen into a small gas chamber placed on the exposed lung surface of bullfrogs. This method of gas application exposed only the several alveoli encircled by the chamber to hypoxia. Thus it produced changes in the microcirculation within a small localized test area. Blood flow velocity and vessel diameter were measured by means of a laser Doppler microscope with a scaled ocular lens on a lateral viewer. Mean blood flow velocity in arterioles and capillaries within the test area decreased by 21.7 +/- 8.0% and 12.1 +/- 4.5%, respectively, during hypoxia. Arteriolar vessel diameters decreased by 15.3 +/- 7.0%. Therefore, the computed blood flow through the observed arterioles leading into the capillary bed within the test area decreased to 59% of its control value. This large decrement in arteriolar flow rate should result in a large reduction of the flow velocity in the capillaries, in contrast to the actually observed small reduction in capillary flow velocity. The efficiency of the hypoxic regulation of blood flow distribution in pulmonary capillary bed is probably reduced when hypoxia is imposed on a very small fraction of the frog lung.


Acceptability of remote prescribing and postal delivery services for contraceptive pills and treatment of uncomplicated Chlamydia trachomatis.
The digitalisation of sexual and reproductive health (SRH) services offers valuable opportunities to deliver contraceptive pills and chlamydia treatment by post. We aimed to examine the acceptability of remote prescribing and 'medication-by-post' in SRH. An online survey assessing attitudes towards remote management was distributed in three UK SRH clinics and via an integrated sexually transmitted infection (STI) postal self-sampling service. Logistic regressions were performed to identify potential correlates. There were 1281 participants (74% female and 49% <25 years old). Some 8% of participants reported having received medication via post and 83% were willing to receive chlamydia treatment and contraceptive pills by post. Lower acceptability was observed among participants who were: >45 years old (OR 0.43 (95% CI 0.23-0.81)), screened for STIs less than once annually (OR 0.63 (0.42-0.93)), concerned about confidentiality (OR 0.21 (0.90-0.50)), concerned about absence during delivery (OR 0.09 (0.02-0.32)) or unwilling to provide blood pressure readings (OR 0.22 (0.04-0.97)). Higher acceptability was observed among participants who reported: previously receiving medication by post (OR 4.63 (1.44-14.8)), preference for home delivery over clinic collection (OR 24.1 (11.1-51.9)), preference for home STI testing (OR 10.3 (6.16-17.4)), ability to communicate with health advisors (OR 4.01 (1.03-15.6)) and willingness to: register their real name (OR 3.09 (1.43-10.6)), complete online health questionnaires (OR 3.09 (1.43-10.6)) and use generic contraceptive pills (OR 2.88 (1.21-6.83)). Postal treatment and entering information online to allow remote prescribing were acceptable methods for SRH services and should be considered alongside medication collection in pharmacies. These methods could be particularly useful for patients facing barriers in accessing SRH. The cost-effectiveness and implementation of these novel methods of service delivery should be further investigated.


LINC00943 regulates miR-1252-5p/YWHAH axis to promote tumor proliferation and metastasis in lung adenocarcinoma.
Lung cancer is the most common malignant tumor worldwide. In recent years, the incidence of lung adenocarcinoma (LAD) has increased significantly, with an unfavorable 5-year survival rate. Long non-coding RNAs (lncRNAs) have been shown to play a significant role in the emergence, growth, and metastasis of tumors. However, the functional role and mechanism of LINC00943 in LAD progression have not yet been investigated. Aberrant expressions of LINC00943, miR-1252-5p, and YWHAH were determined by RT-qPCR and Western blot analyses. The binding relationship between miR-1252-5p and LINC00943 or YWHAH was examined by Pearson's correlation analysis, RNA pull-down, and dual-luciferase reporter assays. MTT assay was conducted to measure cell viability and colony formation assay was performed to evaluate cell proliferation potential. Transwell assay was used to investigate cell migration and invasion and flow cytometry was applied to evaluate cell apoptosis. We found that LINC00943 was highly expressed in LAD tissue samples and cell lines and was a reliable biomarker with high sensitivity, and specificity (P < 0.0001; AUC: 0.8966) for LAD detection. LINC00943 was mainly localized in the cytoplasm. In vitro, LINC00943 promoted LAD cell proliferation, migration, and invasion; however, silencing LINC00943 inhibited LAD tumor metastasis. Mechanistically, LINC00943 was competitively bound with miR-1252-5p to enhance YWHAH expression. Moreover, LINC00943 silencing sponged miR-1252-5p to inhibit YWHAH, thereby retraining LAD cell malignant behaviors. In summary, LINC00943 facilitates LAD cell malignancy through sponging miR-1252-5p to upregulate YWHAH. LINC00943 is a novel lncRNA that serves as an oncogene and might be used as a prognostic biomarker for LAD.


Engagement and availability in shaping nurses' management of postoperative pain: a qualitative study.
Studies reporting inadequate nursing care for patients indicate that nurses are negatively affected in such situations, and research is needed to study nursing care in postoperative situations. To describe situations of postoperative pain management in a surgical ward in Thailand. A qualitative approach using the Critical Incident Technique was chosen to investigate situations of postoperative pain management from the perspective of surgical nurses in Thailand. Data were collected through multiple semi-structured interviews with nine nurses over a five-week period. The situations of surgical nurses described three elements that heavily influenced the quality of postoperative pain management: engagement in a trustful nurse-patient relationship, availability of pain medication and nursing care when needed, and imbalance between meeting the patient's needs and completing routine nursing duties. The results help to expand our understanding of how Thai nurses manage pain in postoperative situations and indicate areas that could be improved in terms of how nurses respond to patients' pain. Nurses challenge existing guidelines and facilitate development of new nursing guidelines and/or policies in pain management.


Comparison of the effect of ranibizumab and dexamethasone implant on serous retinal detachment in diabetic macular edema.
To compare the efficacy of intravitreal ranibizumab (IVR) and intravitreal dexamethasone implant (IDI) on neurosensory retinal detachment (SRD) associated with diabetic macular edema (DME) in the early treatment period. This was a retrospective, interventional, case-control study. After three monthly loading doses of IVR or an initial IDI injection, the changes in best-corrected visual acuity (BCVA), central macular thickness (CMT) on OCT, and presence and height of SRD were evaluated. The IVR and IDI groups consisted of 101 and 35 eyes, respectively. The mean changes in CMT in the IVR and IDI groups were 204.4±176.6 and 311.4±163, respectively (P<0.001). The mean changes in SRD height in the IVR and IDI groups were 133.6±92.1 and 168.6±103.9μm, respectively. The decrease in SRD height was significantly greater in the IDI group than in the IVR group (P=0.002). The SRD resolved completely in 72.2% and 71.4% of the patients in the IVR and IDI groups, respectively (P=0.9). The mean reduction in CMT and SRD height was greater in the IDI group than in the IVR group. There was a negative correlation between baseline best-corrected visual acuity (BCVA) and SRD height and also between BCVA and CMT.


[Alzheimer's disease: from morphology to pathogenic hypotheses].
Main changes of Alzheimer's disease (neuronal degeneration and death, neurofibrillary tangles, senile plaques, granulo-vacuolar degenerations) are described. Recent hypotheses concerning their causes, origin and development and their relationship with the mental changes are given.


Burden of healthcare-associated infections in China: results of the 2015 point prevalence survey in Dong Guan City.
Healthcare-associated infections (HCAIs) are a major health threat. There are few data about HCAI and antibiotic use in the People's Republic of China in the English literature. To describe and discuss the prevalence of HCAI and antibiotic use from the 2015 point prevalence survey (PPS) in Dong Guan City. In 2015, the Dong Guan (City) Nosocomial Infection Control and Quality Improvement Centre organized its yearly PPS in the secondary and tertiary care hospitals of Dong Guan City. The survey was performed on one single calendar day. Thirty-seven secondary and 14 tertiary care hospitals assessed 9679 and 11,641 patients, respectively. A total of 616 patients had 681 HCAIs. The pooled HCAI prevalence (95% confidence interval) in secondary care, tertiary care, and all hospitals together was 2.3% (2.0-2.6), 3.4% (3.0-3.7), and 2.9% (2.6-3.1), respectively. Lower respiratory tract infection (LRTI), urinary tract infection (UTI), surgical site infection (SSI), and bloodstream infection together accounted for 73.1% of HCAIs. LRTI was the most frequently diagnosed HCAI (35.5%), followed by UTI (17.0%), and SSI (15.1%). Gram-negative bacteria were most frequently isolated (68.1%), followed by Gram-positive bacteria (19.3%), and fungi (10.9%). Escherichia coli was the most frequent pathogen (14.8%), and Acinetobacter baumannii accounted for 10.9%. A total of 34.8% of the patients received one or more antimicrobials. The pooled prevalence is in the range of other recent Chinese studies, but lower compared to previous reports in Europe, and the USA. The use of antimicrobials for therapeutic purposes is similar to that in Europe, but lower than previous Chinese reports, and lower than in the USA.


Agitated Geriatric Patients and Violence in the Workplace.
Older adults may suddenly exhibit behaviors that are viewed as noncompliant, noncooperative, and threatening. They may even lash out verbally and physically causing injury to health care staff. In addition to taking actions that prevent harm to the staff and the patient, determining what caused this behavior (dementia vs delirium or other cases) will be critical, as well as debriefing the staff after the incident.


Prominent atrial fibrosis and its correlation with atrial tachyarrhythmia and dilated atrium long after classic Fontan surgery.
The progression of atrial fibrosis long after Fontan surgery is unclear. This study aimed to evaluate the degree of atrial fibrosis long after the classic Fontan procedure and to investigate the factors associated with atrial fibrosis. We obtained atrial free wall specimens resected at Fontan conversion from 43 patients (Fontan group) and studied the degree of atrial fibrosis, along with its association with atrial tachycardia/fibrillation (AT/AF) and other clinical parameters, compared with those of the control group without heart disease (n=6). The time after the initial Fontan procedure was 19.9 (15.9-25.3) years. Atrial fibrosis (%) was more common in the Fontan group than in the control group [24.3 (20.9-35.0)% vs. 6.2 (5.6-7.5)%, p<0.001]. The severity of atrial fibrosis was mild in 16% (n=7), moderate in 54% (n=23), and severe in 30% (n=13) of cases. Atrial fibrosis (%) was more common in the persistent/permanent AT/AF group than in the no AT/AF (p<0.001) and paroxysmal AT/AF (p<0.001) groups. The maximum atrial diameter on computed tomography (CT) (mm) significantly correlated with atrial fibrosis (%) (r=0.52, p<0.001). The maximum diameter of the right atrium (≥75 mm) on CT was a significant risk factor for severe atrial fibrosis on multivariate logistic analysis (hazard ratio=10.22, 95% confidence interval=1.04-254.8, p=0.04). Atrial fibrosis was prominent long after classic Fontan surgery, especially in patients with non-paroxysmal AT/AF and dilated right atrium.


Temporal patterning of neural progenitors in Drosophila.
Drosophila has recently become a powerful model system to understand the mechanisms of temporal patterning of neural progenitors called neuroblasts (NBs). Two different temporal sequences of transcription factors (TFs) have been found to be sequentially expressed in NBs of two different systems: the Hunchback, Krüppel, Pdm1/Pdm2, Castor, and Grainyhead sequence in the Drosophila ventral nerve cord; and the Homothorax, Klumpfuss, Eyeless, Sloppy-paired, Dichaete, and Tailless sequence that patterns medulla NBs. In addition, the intermediate neural progenitors of type II NB lineages are patterned by a different sequence: Dichaete, Grainyhead, and Eyeless. These three examples suggest that temporal patterning of neural precursors by sequences of TFs is a common theme to generate neural diversity. Cross-regulations, including negative feedback regulation and positive feedforward regulation among the temporal factors, can facilitate the progression of the sequence. However, there are many remaining questions to understand the mechanism of temporal transitions. The temporal sequence progression is intimately linked to the progressive restriction of NB competence, and eventually determines the end of neurogenesis. Temporal identity has to be integrated with spatial identity information, as well as with the Notch-dependent binary fate choices, in order to generate specific neuron fates.


Predictive value of surveillance cultures for systemic infection due to Candida species.
Weekly fungal surveillance cultures (1,542 cultures) of urine (475), stool (520) and oropharyngeal (547) specimens from 111 patients on the bone marrow transplant and hematologic malignancy services were analyzed. Forty-three percent of the patients were colonized by Candida albicans and 10.8% by Candida tropicalis. There were 22 proven systemic fungal infections, ten due to Candida albicans, eight to Candida tropicalis, one each to Candida pseudotropicalis and Torulopsis glabrata, and two to Aspergillus species. Positive surveillance cultures for Candida tropicalis were highly predictive of systemic infection. The finding of two or more positive cultures yielded high positive predictive values (100%) as a function of body site. Positive surveillance cultures for Candida albicans were not predictive of disease but negative cultures for Candida albicans and Candida tropicalis had a high negative predictive value (95-99%). Surveillance culture data for specific Candida species may aid in diagnostic and therapeutic decision making.


Evaluation of factors associated with medical male circumcision in South Africa: A case-control study.
The World Health Organization recommends medical male circumcision (MMC) to prevent human immunodeficiency virus (HIV). More research is needed in South Africa on factors influencing the uptake of MMC. To evaluate factors associated with uptake of MMC. Diepsloot, Johannesburg, South Africa. An observational case-control study. Cases (men attending a private general practice (GP) offering free MMC) were compared to controls (uncircumcised men attending a local shopping mall) for a variety of demographic, sociocultural and financial factors. Factors were analysed using bivariate and multiple-variable binary forward logistic regression with the Statistical Package for Social Sciences. There were 350 cases and 350 controls. Four factors were associated with the uptake of MMC: being a student (adjusted odds ratio [AOR]: 6.29, 95% confidence interval [CI]: 2.29-17.26), attending a mainline Christian denomination (AOR 2.85, 95% CI: 1.39-5.78), speaking an African language other than Zulu (range of AORs: 2.5-6.8, p 0.05) and being South African (AOR: 2.50, 95% CI: 1.58-3.96). MMC was associated with feeling susceptible to HIV, seeing it as a serious health problem and being encouraged by partners. Men who were sterilised, not sexually active and without symptoms of a sexually transmitted infection felt less susceptible. Other barriers included the pain of the procedure, indirect costs, anticipated impact on sexual activity, lack of information, cultural beliefs, embarrassment and access to health services.


Cytotoxicity of three novel fluoropyrimidines in cultured L1210 murine lymphocytic leukemia cells.
Cultured L1210 murine lymphocytic leukemia cells were used to compare metabolic activation and cytotoxicity of 5-fluorouracil (FU), Ftorafur (FT), and three novel FU-sulfur analogues. These analogues, 1-(2'-tetrahydrothienyl)-5-fluorouracil (FUS), 1-(2'-tetrahydrothienyl)-5- fluorouracil-1'-oxide (FUSO), and 1-(2'-tetrahydrothienyl)-5-fluorouracil-1'-1'-dioxide (FUSO2), have yet to be fully evaluated for potential therapeutic value based on in vitro cytotoxicity. The role of these FU analogues as prodrugs was evaluated by comparing metabolism of normal pyrimidine pathways and activation by hepatic mixed function oxidases (MFO). Significant differences in biochemical activity and cytotoxicity were measured between FU and FU analogues. FU and FU analogues were cytotoxic to L1210 cells (63-92% growth inhibition of 100 microM concentrations after 72 hr of incubation). However, at equimolar concentration cytotoxicity of the FU analogues after MFO activation (56-66% growth inhibition) was greater than FU (47% growth inhibition). Hypoxanthine, a purine precursor, did not significantly alter fluoropyrimidine cytotoxicity with or without MFO. Thymidine and uridine, pyrimidine precursors, reduced FT and FUS cytotoxicities in the presence (27, 40%) and absence (25, 15%) of MFO but did not modify FU, FUSO, or FUSO2 cytotoxicities.


A genetic basis for the interrelation of coagulation factors.
Evidence found in the literature for a strong correlation between coagulation factors suggests that single genes might influence the plasma concentrations of multiple coagulation factors (i.e. pleiotropically acting genes). To determine whether there is a genetic basis for the correlation among coagulation factors by assessing the heritability of interrelated coagulation factors. We performed principal components analysis, and subsequently variance components analysis, to estimate the heritability of principal components of coagulation factors in family members of a large French-Canadian kindred. Four clusters were identified by principal components analysis in 200 family members who did not carry the protein C 3363C mutation. Cluster 1 consisted of prothrombin, factor VII (FVII), FIX, FX and protein S; cluster 2 consisted of FV, FIX, protein C and tissue factor pathway inhibitor; cluster 3 consisted of FVIII and von Willebrand factor; and cluster 4 consisted of antithrombin, protein C and FVII. The heritability of the principal components estimated by variance components analysis was, respectively, 37%, 100%, 37%, and 37%. Our findings support the hypothesis that genes can influence plasma levels of interrelated coagulation factors.


Relationship between procalcitonin levels and presence of vesicoureteral reflux during first febrile urinary tract infection in children.
To investigate the association between the procalcitonin (PCT) level during the first febrile urinary tract infection (UTI) in children and the presence of vesicoureteral reflux (VUR). VUR-associated UTI is among the primary causes of chronic renal failure in Turkey. From March 2008 to November 2009, patients admitted with their first febrile UTI were included in the present prospective hospital-based study. The serum concentrations of C-reactive protein, complete blood count, and PCT were measured. All patients underwent renal ultrasonography and voiding cystourethrography. Of the 66 patients who were diagnosed with UTI, 18 had VUR. The geometric mean of the PCT levels was significantly greater in the children with VUR than in those without (P = .006). After logistic regression adjustment, the association between the PCT levels and the presence of VUR remained significant (odds ratio 5.08, 95% confidence interval [CI] 1.43-18.02). A PCT level >0.56 ng/mL had 66.7% sensitivity (95% CI 41-86.6) and 77.1% specificity (95% CI 62.7-88) for diagnosing VUR. The area under the receiver operating characteristic curve for PCT was 0.715 (95% CI, 0.56-0.86, P = .007), and the area under the curve for C-reactive protein was 0.723 (95% CI 0.58-0.86, P = .006). A PCT-guided strategy could help in detecting patients with VUR. Large cohort studies are needed to define an accurate cutoff value for children who are at risk of VUR, which increases the risk of renal damage and subsequent scarring.


Association of ambient PM10 and PM2.5 with coronary stenosis measured using selective coronary angiography.
Long-term ambient particulate matter (PM) exposure exerts detrimental effects on cardiovascular health. Evidence on the relation of chronically exposed ambient PM10 and PM2.5 with coronary stenosis remains lacking. Our aim was to investigate the association of PM10 and PM2.5 with coronary stenosis in patients undergoing coronary angiography. We performed a retrospective cohort study consisting of 7513 individuals who underwent coronary angiography in Fujian Province, China, from January 2019 to December 2021. We calculated a modified Gensini score (GS) to represent the degree of stenosis in coronary arteries by selective coronary angiography. We fitted linear regressions and logistic models to assess the association of PM10 and PM2.5 with coronary stenosis. We employed restricted cubic splines to describe the exposure-response curves. We performed mediation analyses to assess the potential mediators. Long-term ambient PM10 and PM2.5 (prior three years average) exposure was significantly associated with the GS, with a breakpoint concentration of 47.5 μg/m3 and 25.8 μg/m3 for PM10 and PM2.5, respectively, above which we found a linear positive exposure-response relationship of ambient PM with GS. Each 10 µg /m3 increase in PM10 exposure (β: 4.81, 95 % CI: 0.44-9.19) and PM2.5 exposure [β: 10.50, 95 % CI: 3.14-17.86] were positively related to the GS. The adjusted odds ratio (OR) for each 10 µg/m3 increment in PM10 exposure on severe coronary stenosis was 1.33 (95 % CI: 1.04-1.76). Correspondingly, the adjusted OR for PM2.5 was 1.87 (95 % CI: 1.24-2.99). The mediation analysis indicated that the effect of PM10 on coronary stenosis may be partially mediated through total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, serum creatinine and blood urea nitrogen, and the effect of PM2.5 may be mediated in part by hemoglobin A1c. Our study provides the first evidence that chronic ambient PM10 and PM2.5 exposure was associated with coronary stenosis assessed by GS in patients with suspected coronary artery disease and reveals its potential mediators.


Proposal and Validation of New Diagnostic Criteria for Diagnostic Weights of Endoultrasonographic Findings for Early Chronic Pancreatitis.
[Background and study aim] A commonly applied method for diagnosing chronic pancreatitis (CP) uses endoscopic ultrasonography (EUS), assigning weights to each EUS diagnostic finding. It is the Rosemont classification (RC). In 2019, to improve EUS diagnostic specificity, Japanese diagnostic criteria for early chronic pancreatitis (ECP) were revised. Nevertheless, the criteria use no weighting of EUS diagnostic findings, as the RC does. This study was undertaken to propose diagnostic criteria that would weight each EUS finding of ECP and that would be more specific than the RC. [Methods] By EUS of the pancreas, 773 patients underwent detailed observation from January 2018 to March 2019 at our institution. An expert finalized all cases when patients were diagnosed. Using data from the medical records, 97 consecutive patients with EUS diagnostic findings of ECP based on the Japanese diagnostic criteria of ECP2009 (JDCECP2009) were selected. The definition under the RC of "Indeterminate for CP" was equivalent to ECP. Each case was diagnosed using (1) JDCECP2009 and (2) the Japanese diagnostic criteria of ECP2019 (JDCECP2019). Moreover, the four diagnostic EUS findings in JDCECP2019 were applied to the RC, weighted (modified-JDCECP2019), and subsequently compared with the earlier diagnostic criteria. As Modified-JDCECP2019, we suggested (3) RC-A-the current four items scored related to the RC, and (4) RC-B-the five items scored by dividing lobularity with and without honeycombing. [Results] Diagnoses produced based on each criterion were normal: ECP = (1) 20:77, (2) 46:51, (3) 52:42, and (4) 60:35. [Conclusions] Modified-JDCECP2019 may provide EUS diagnoses for ECP with higher specificity.


Respiratory effects of 5'-ethylcarboxamidoadenosine, an analog of adenosine, following microinjections into the nucleus tractus solitarius of rats.
Microinjections of 5'-ethylcarboxamidoadenosine (NECA), an adenosine analog, were made into respiratory-related regions of the nucleus tractus solitarius (NTS) of spontaneously breathing rats and cardiorespiratory parameters were recorded during a 60-min test period. Microinjections of NECA, in the dose range of 0.35-350 picomol per rat, produced significant dose-related reductions in respiratory rate which were accompanied by correlative increases in tidal volume. At the end of the 60-min test period following the administration of NECA, the respiratory rate remained profoundly depressed, whereas blood pressure and heart rate were not significantly affected compared to preinjection control values. The data from this study suggest that adenosine may exert modulatory influences in brainstem respiratory control regions.


NRASQ61K melanoma tumor formation is reduced by p38-MAPK14 activation in zebrafish models and NRAS-mutated human melanoma cells.
Oncogenic BRAF and NRAS mutations drive human melanoma initiation. We used transgenic zebrafish to model NRAS-mutant melanoma, and the rapid tumor onset allowed us to study candidate tumor suppressors. We identified P38α-MAPK14 as a potential tumor suppressor in The Cancer Genome Atlas melanoma cohort of NRAS-mutant melanomas, and overexpression significantly increased the time to tumor onset in transgenic zebrafish with NRAS-driven melanoma. Pharmacological activation of P38α-MAPK14 using anisomycin reduced in vitro viability of melanoma cultures, which we confirmed by stable overexpression of p38α. We observed that the viability of MEK inhibitor resistant melanoma cells could be reduced by combined treatment of anisomycin and MEK inhibition. Our study demonstrates that activating the p38α-MAPK14 pathway in the presence of oncogenic NRAS abrogates melanoma in vitro and in vivo. SIGNIFICANCE: The significance of our study is in the accountability of NRAS mutations in melanoma. We demonstrate here that activation of p38α-MAPK14 pathway can abrogate NRAS-mutant melanoma which is contrary to the previously published role of p38α-MAPK14 pathway in BRAF mutant melanoma. These results implicate that BRAF and NRAS-mutant melanoma may not be identical biologically. We also demonstrate the translational benefit of our study by using a small molecule compound-anisomycin (already in use for other diseases in clinical trials) to activate p38α-MAPK14 pathway.


Omalizumab inhibits acceleration of FcεRI-mediated responsiveness of immature human mast cells by immunoglobulin E.
A large body of evidence has demonstrated that treatment with omalizumab is clinically effective for the management of moderate to severe allergic asthma, emphasizing the importance of IgE in the pathogenesis of allergic asthma. We hypothesized that IgE accelerates FcεRI-mediated responsiveness of "immature" human mast cells (MCs) and that omalizumab downregulates the acceleration. To examine when MC progenitors acquired the ability to degranulate following FcεRI aggregation, whether IgE accelerates the responsiveness of immature MCs following FcεRI aggregation, and whether omalizumab regulates such an acceleration. Gene expression was examined using a microarray and quantitative reverse transcription polymerase chain reaction. Protein expression was investigated using FACS. Histamine release was examined using an EIA. The time-course analysis of the mRNA expression of MC-related genes, including FcεRI, in Kit(+) sorted cells during the differentiation and histamine experiments revealed that the expression level of FcεRI in 5 week (w)-cultured MCs was not sufficient to induce degranulation following FcεRI aggregation but that 5 w-cultured MCs were fully responsive to calcium ionophore. By addition of IgE in culture medium FcεRI expression level and FcεRI-mediated histamine release of 5 w-cultured MCs were significantly increased compared with those without addition of IgE, whereas the expression level of tryptase and number of MCs was not affected. Omalizumab significantly inhibited IgE-dependent enhancement of FcεRI expression level and FcεRI-mediated histamine release. High levels of IgE in the microenvironment in vivo may upregulate the responsiveness of immature MCs to allergens. Omalizumab may inhibit the IgE-mediated responsiveness of not only mature MCs, but also immature MCs.


Activation of miR-34a impairs autophagic flux and promotes cochlear cell death via repressing ATG9A: implications for age-related hearing loss.
Age-related hearing loss is a major unresolved public health problem. We have previously elucidated that the activation of cochlear miR-34a is correlated with age-related hearing loss in C57BL/6 mice. A growing body of evidence points that aberrant autophagy promotes cell death during the development of multiple age-related diseases. The aim of this study was to investigate the role of miR-34a-involved disorder of autophagy in the pathogenesis of age-related hearing loss. Our results showed that miR-34a expression was markedly upregulated in the aging cochlea accompanied with impairment of autophagic flux. In the inner ear HEI-OC1 cell line, miR-34a overexpression resulted in an accumulation of phagophores and impaired autophagosome-lysosome fusion, and led to cell death subsequently. Notably, autophagy-related protein 9A (ATG9A), an autophagy protein, was significantly decreased after miR-34a overexpression. Knockdown of ATG9A inhibited autophagy flux, which is similar to the effects of miR-34a overexpression. Moreover, ursodeoxycholic acid significantly rescued miR-34a-induced HEI-OC1 cell death by restoring autophagy activity. Collectively, these findings increase our understanding of the biological effects of miR-34a in the development of age-related hearing loss and highlight miR-34a as a promising therapeutic target for its treatment.


Alteration of bile acid metabolism and vitamin-B12-absorption in diabetics on biguanides.
Since vitamin B12malabsorption has been described in diabetics on biguanides and inhibition of bile acid absorption found in rat ileum the effect of treatment with different biguanides (phenformin, buformin, metformin) on bile acid metabolism and vitamin B12 absorption was assessed in maturity onset diabetics. Biguanides did not alter faecal weight or faecal fat excretion, but they decreased faecal bile acid excretion. All biguanides tested increased deconjugation of glycocholic acid, as determined by a simple breath test technique. Vitamin B12 malabsorption was most prominent in patients on metformin. Discontinuation of biguanide treatment, or administration of antibiotics, normalized or improved the increased deconjugation of bile acids and the Schilling test. Decreased faecal bile acid excretion, positive 14C-glycocholate breath tests, pathological Schilling tests and the reversal of pathological tests by antibiotic treatment suggest that small intestinal bacterial overgrowth, leading to binding of the intrinsic-factor-vitamin B12-complex to bacteria, is responsible for the previously observed pathological Schilling tests in diabetics on biguanides. Bile acid malabsorption, possibly responsible for the cholesterol-lowering effect of biguanides, does not occur in diabetics on biguanides. Whether qualitative changes in small intestinal bile acid composition might affect cholesterol metabolism remains to be determined.


Iron deficiency and susceptibility to infections: evaluation of the clinical evidence.
Iron is a fundamental nutrient for human and microbial life. We sought to examine the association of iron deficiency versus normal iron status with the susceptibility to infections. A systematic search in the PubMed and Scopus databases was performed to identify relevant clinical studies. Six studies (including a total of 1,422 participants) met the inclusion criteria: four prospective cohort (859 participants), one retrospective case-control (115 participants), and one retrospective cohort study (448 participants). Intensive care unit (ICU)-acquired and postoperative infections were more common in patients with iron deficiency than among those with normal iron status in two studies, while no difference was reported in another study. In one study examining pregnant women with normal mean iron values, higher soluble transferrin receptor values independently predicted vaginosis-like microflora. Iron deficiency anemia was an independent predictor of respiratory tract infections in one study, and postoperative urinary tract infections were more common in patients with iron deficiency anemia in another. The limited available evidence suggests that individuals with iron deficiency and those with iron deficiency anemia may be more susceptible to infections than patients with normal iron status. Future studies should elucidate further these findings.


Do upper respiratory viruses contribute to racial and ethnic disparities in emergency department visits for asthma?
There are marked disparities in asthma-related emergency department (ED) visit rates among children by race and ethnicity. Following the implementation of coronavirus disease 2019 (COVID-19) prevention measures, asthma-related ED visits rates declined substantially. The decline has been attributed to the reduced circulation of upper respiratory viruses, a common trigger of asthma exacerbations in children. To better understand the contribution of respiratory viruses to racial and ethnic disparities in ED visit rates, we investigated whether the reduction in ED visit rates affected Black, Latinx, and White children with asthma equally. Asthma-related ED visits were extracted from electronic medical records at Dell Children's Medical Center in Travis County, Texas. ED visit rates among children with asthma were derived by race/ethnicity. Incidence rate ratios (IRRs) and 95% CIs were estimated by year (2019-2021) and season. In spring 2019, the ED visit IRRs comparing Black children with White children and Latinx children with White children were 6.67 (95% CI = 4.92-9.05) and 2.10 (95% CI = 1.57-2.80), respectively. In spring 2020, when infection prevention measures were implemented, the corresponding IRRs decreased to 1.73 (95% CI = 0.90-3.32) and 0.68 (95% CI = 0.38-1.23), respectively. The striking reduction of disparities in ED visits suggests that during nonpandemic periods, respiratory viruses contribute to the excess burden of asthma-related ED visits among Black and Latinx children with asthma. Although further investigation is needed to test this hypothesis, our findings raise the question of whether Black and Latinx children with asthma are more vulnerable to upper respiratory viral infections.


Clinical outcomes of parenchymal-sparing versus anatomic resection for colorectal liver metastases: a systematic review and meta-analysis.
The advantages of parenchymal-sparing resection (PSR) over anatomic resection (AR) of colorectal liver metastases (CRLM) remain controversial. Here, we aim to evaluate their safety and efficacy. A systematic review and meta-analysis of short-term perioperative outcomes and long-term oncological outcomes for PSR and AR were performed by searching Pubmed, Embase, the Cochrane Library and Web of Science databases. Twenty-two studies were considered eligible (totally 7228 patients: AR, n = 3154 (43.6%) vs. PSR, n = 4074 (56.4%)). Overall survival (OS, HR = 1.08, 95% CI: 0.95-1.22, P = 0.245) and disease-free survival (DFS, HR = 1.09, 95% CI: 0.94-1.28, P = 0.259) were comparable between the two groups. There were no significant differences in 3-year OS, 5-year OS, 3-year DFS, 5-year DFS, 3-year liver recurrence-free survival (liver-RFS) and 5-year liver-RFS. In terms of perioperative outcome, patients undergoing AR surgery were associated with prolonged operation time (WMD = 51.48 min, 95% CI: 29.03-73.93, P < 0.001), higher amount of blood loss (WMD = 189.92 ml, 95% CI: 21.39-358.45, P = 0.027), increased intraoperative blood transfusion rate (RR = 2.24, 95% CI: 1.54-3.26, P < 0.001), prolonged hospital stay (WMD = 1.00 day, 95% CI: 0.34-1.67, P = 0.003), postoperative complications (RR = 2.28, 95% CI: 1.88-2.77, P < 0.001), and 90-day mortality (RR = 3.08, 95% CI: 1.88-5.03, P < 0.001). While PSR surgery was associated with positive resection margins (RR = 0.77, 95% CI: 0.61-0.97, P = 0.024), intrahepatic recurrence (RR = 0.90, 95% CI: 0.82-0.98, P = 0.021) and repeat hepatectomy (RR = 0.64, 95% CI: 0.55-0.76, P < 0.001). Considering relatively acceptable heterogeneity, PSR had better perioperative outcomes without compromising oncological long-term outcomes. However, these findings must be carefully interpreted, requiring more supporting evidence. PROSPERO registration number: CRD42023445332.


Bibliometric analysis of the African Health Sciences' research indexed in Web of Science and Scopus.
The Journal of African Health Sciences (AHS) is an internationally refereed journal in the field of health sciences with vast research contributions in the world and Africa region. The study aimed to document the scientific production and explore the AHS research bibliometric characteristics since its first issue. A comprehensive retrospective bibliometric analysis was performed on AHS published documents indexed in Web of Science (WoS) and Scopus since the journal's first issue. The analysis was done using SPSS v. 22.0, Bibliometrix Package in R, and VOSviewer v.1.6.15. A total of 1649 and 1879 documents indexed in Web of Science (WoS) and Scopus were retrieved. The annual number of publications showed a significant increase in both databases. The most contributing countries (in WoS vs. Scopus) were; Nigeria (n = 393 vs. 276), Uganda (215 vs. 220) and South Africa (143 vs. 101).The most productive authors were "Tumwine JK", "Mayanja-Kizza H", and "Ocama P". Makerere University, The University of Ibadan, and University of Nigeria were the most contributive institutions. International agencies mainly from the USA were the main funders of AHS documents. Analysis of keywords revealed the dominance of research topics with keywords such as HIV/AIDS, Tuberculosis, Malaria, Obesity, Hypertension, risk factors, infection, mortality, amongst others. This analysis has revealed the progress in the development and growth of scientific research from AHS. Moreover, top-cited documents-analysis has reflected its focus on health issues relevant to Africa. This analysis would help in evidence-based descriptions of AHS research output.


The association between serum uric acid and hypertriglyceridemia: evidence from the national health and nutrition examination survey (2007-2018).
Accumulating evidence suggests that elevated serum uric acid (SUA) may be a risk factor for hypertriglyceridemia (HTG). However, the epidemiological evidence for the association between SUA and HTG is limited. This article aimed to use the data from National Health and Nutrition Examination Survey (NHANES) (2007-2018) database to bridge the research gap. This cross-sectional study used data from 10027 adults involved in NHANES from 2007-2018. We designed the exposure variable as SUA and the outcome variable as HTG. The covariates included demographics, questionnaires, laboratory, and examination information. Weighted logistic regression and subgroup analysis were used to explore the independent association between SUA and HTG. Furthermore, interaction tests were also carried out to evaluate the strata differences. Generalized additive models (GAM), smooth curve fittings, and threshold effect analysis were applied to examine the non-linear relationship. A total of 10027 participants were included, of which 3864 were HTG participants and 6163 were non-HTG participants. After fully adjusting for confounders, weighted multiple logistic regression models revealed a 77% increase in the risk of HTG when each unit of log2-SUA increased. There was also a positive association between elevated log2-SUA and developed risk of HTG in the quartile (Q) groups (Q1 OR: 1.00; Q2 OR: 1.17 [95%CI: 0.95,1.45]; Q3 OR: 1.43 [95%CI: 1.16,1.78]; Q4 OR: 1.68 [95%CI: 1.36,2.08]. The subgroup analysis results remained consistent across strata, with a strong positive correlation between SUA and HTG. Interaction tests showed no dependence on physical activity (PA), gender, BMI, smoking status, alcohol intake, hypertension, and diabetes for this positive association between log2-SUA and HTG (all p for interaction >0.05). The participants' age may impact the strength of the association between SUA and HTG (p for interaction <0.05). There is a positive association between SUA and HTG in US adults. Considering that SUA may be a risk factor for HTG, individuals diagnosed with HTG should prioritize the daily management of SUA as part of their comprehensive care.


The Acceptability and Usefulness of Positive Behaviour Support Education for Family Carers of People With Frontotemporal Dementia: A Pilot Study.
This pilot study investigated the acceptability and usefulness of 4 weekly Positive Behaviour Support (PBS) education sessions (delivered face-to-face and online) for family carers of individuals diagnosed with behavioural-variant frontotemporal dementia (bvFTD). These sessions were adapted from the Family-directed Approach to Brain injury (FAB)-PBS program to the FTD population. A pre-test post-test mixed-methods design was utilized. Primary outcome measures included a Carer Confidence questionnaire and post-intervention Feedback Questionnaire. Assessments were conducted prior to the 4-week education program, immediately following the final session and a 3 months follow-up. Ten family carers completed the 4 PBS education sessions and indicated that the program was helpful in providing behaviour support. No significant changes in confidence ratings were found before and following the education sessions. A majority of participants, however, reported positive changes to their approach in providing behaviour support, with key themes including 'recognising the function of behaviour', 'changing their own behaviour' and 'promoting a calmer approach'. The FAB-PBS education sessions demonstrate to be an acceptable approach to increasing the capability of family carers in providing behaviour support to individuals with FTD, which will need to be confirmed in a larger feasibility study.


Adhesion molecules on peripheral blood-derived CD34+ cells: effects of cryopreservation and short-term ex vivo incubation with serum and cytokines.
The homing of hematopoietic precursor cells (HPC) within the bone marrow is most likely to be mediated by specific adhesion via surface receptors to cellular and extracellular matrix (ECM) components and to be regulated by cytokines. We investigated the effects of serum and cytokines on the expression of adhesion molecules on cryopreserved and fresh peripheral blood-derived progenitor cells (PBPC) and on the adhesion of PBPC to various ECM proteins. PBPC were collected from patients by leukapheresis during G-CSF-supported recovery from conventional cancer chemotherapy. Freezing markedly reduced the fraction of CD34+ cells with L-selectin (CD62L) expression from 62 to 11% and also diminished the fluorescence intensity for the integrin subunits CD29 and CD49d on CD34+ cells. A 14 h incubation of thawed PBPC with serum induced re-expression of adhesion molecules. The addition of the cytokine cocktails (G-CSF + SCF + IL-3 + IL-11 or IL-4 + IL-1beta + IFN-gamma) or MGDF, however, exerted no effects in addition to serum alone. Furthermore, when compared to serum alone, the addition of cytokine cocktails or MGDF did not alter the fraction of fresh PB-CD34+ cells adhering to collagen I, collagen IV, fibronectin, laminin or vitronectin. HPC adhesion to ECM components might be refractory to short-term alterations of the cytokine environment. Alternatively, longer incubation times or other cytokines may be necessary to modulate the expression of adhesion molecules on hematopoietic progenitor cells or adhesion itself under ex vivo conditions.


Targeting intracellular oncoproteins with antibody therapy or vaccination.
Antibody-based therapies have better specificity and thus improved efficacy over standard chemotherapy regimens, which result in extended survival and improved quality of life for cancer patients. Because antibodies are viewed as too large to access intracellular locations, antibody therapy has traditionally targeted extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are found within the cell (such as intracellular phosphatases/kinases and transcription factors) and have therefore not been pursued for antibody therapies. Here, we explored the possibility of antibody therapy or vaccination against intracellular proteins. As proofs of concept, we selected three representative intracellular proteins as immunogens for tumor vaccine studies: PRL-3 (phosphatase of regenerating liver 3), a cancer-associated phosphatase; EGFP (enhanced green fluorescent protein), a general reporter; and mT (polyomavirus middle T), the polyomavirus middle T oncoprotein. A variety of tumors that expressed these intracellular proteins were clearly inhibited by their respective exogenous antibodies or by antigen-induced host antibodies (vaccination). These anticancer activities were reproducibly observed in hundreds of C57BL/6 tumor-bearing mice and MMTV-PymT transgenic breast tumor mice. Our in vivo data suggest that immunotherapies can target not only extracellular but also intracellular oncoproteins.


Estimation of absolute bioavailability assuming steady state apparent volume of distribution remains constant.
The limitations of using estimates of extent of bioavailability (F) based on the assumption that either clearance (CL) or Varea remain, constant are discussed in relation to the situation where CL changes between doses. When estimates of F assume CL to remain constant, the extent of the error is the same for all drugs where the percentage change in CL is the same. Assuming Varea to remain constant, the error in F will vary between drugs for similar percentage changes in CL and is related to the extent to which the kinetics of the disposition process deviate from a one compartment body model. A noncompartmental method is described where, provided the reference dose is given intravenously, F can be estimated based on the assumption that Vss remains constant between doses. This method is more accurate than those based on the assumption that either CL or Varea remain, constant when CL changes between doses, but is subject to error when the terminal log-linear slope of Cp vs. time better reflects the process of absorption rather than elimination.