Interference between enterovirus and reovirus as a limiting factor in environmental virus detection.
Faecal material from raw sewage or other sources lacking effective treatment sometimes contaminates water for human consumption. The relevant Italian regulations therefore call for testing drinking and recreational water for the presence of enterovirus. Traditional methods of analysis are based on revealing the typical cytopathic effects of enterovirus on cell cultures. However, the presence in environmental samples of different types of virus may cause interference phenomena that mask such cytopathic effects. The paper reports on an experimental test of this interference hypothesis. Buffalo Green Monkey cell cultures were co-infected via mixed suspensions of the polio type 3 virus and reovirus type 1. Cytopathic effects were then sought and the presence of enterovirus tested for via RT-PCR. The results obtained indicate that the normally high sensitivity of tests for the detection of enterovirus in samples is considerably decreased by the simultaneous presence of reovirus.


Environmental Biofilms from an Urban Community in Salvador, Brazil, Shelter Previously Uncharacterized Saprophytic Leptospira.
Biofilms are complex microecosystems with valuable ecological roles that can shelter a variety of microorganisms. Spirochetes from the genus Leptospira have been observed to form biofilms in vitro, in rural environments, and in the kidneys of reservoir rats. The genus Leptospira is composed of pathogenic and non-pathogenic species, and the description of new species is ongoing due to the advent of whole genome sequencing. Leptospires have increasingly been isolated from water and soil samples. To investigate the presence of Leptospira in environmental biofilms, we collected three distinct samples of biofilms formed in an urban setting with poor sanitation: Pau da Lima, in Salvador, Bahia, Brazil. All biofilm samples were negative for the presence of pathogenic leptospires via conventional PCR, but cultures containing saprophytic Leptospira were identified. Whole genomes were generated and analyzed for twenty isolates obtained from these biofilms. For species identification, we used digital DNA-DNA hybridization (dDDH) and average nucleotide identity (ANI) analysis. The obtained isolates were classified into seven presumptive species from the saprophytic S1 clade. ANI and dDDH analysis suggest that three of those seven species were new. Classical phenotypic tests confirmed the novel isolated bacteria as saprophytic Leptospira. The isolates presented typical morphology and ultrastructure according to scanning electron microscopy and formed biofilms under in vitro conditions. Our data indicate that a diversity of saprophytic Leptospira species survive in the Brazilian poorly sanitized urban environment, in a biofilm lifestyle. We believe our results contribute to a better understanding of Leptospira biology and ecology, considering biofilms as natural environmental reservoirs for leptospires.


Psychosocial aspects of upper extremity lymphedema in women treated for breast carcinoma.
Lymphedema of the upper extremity following breast carcinoma is highly distressing and disabling. A review is presented of the literature on psychosocial aspects of lymphedema. Studies have shown that women who develop lymphedema exhibit higher levels of psychological, social, sexual, and functional morbidity than women with breast carcinoma who do not develop this complication. Women who have poor social support, pain, lymphedema in the dominant hand, and/or a passive and avoidant coping style report the highest levels of disability. Due to the morbidity of lymphedema once it develops, prevention and information given early are extremely important. However, the recommendations made to women sometimes involve considerable changes in lifestyle but are not based on solid, prospective evidence. In addition, how to best impart and time information about lymphedema pre- and postoperatively require investigation. In this paper, the authors discuss the psychological and functional impact of lymphedema and strategies for intervention and research to help women prevent the condition or enhance coping with it once it develops.


Integrating Social Learning, Adaptive Capacity and Climate Adaptation for Regional Scale Analysis: A Conceptual Framework.
The impact of climate-related changes on northern Canada's renewable resource sectors makes bolstering adaptive capacity an urgent imperative throughout the region. Although social learning is a key ingredient of adaptive capacity, our understanding of the relationships among social learning, adaptive capacity, and climate change adaptation is limited. Building on previous conceptual and empirical studies, this paper develops a framework that clarifies the interactions among social learning, adaptive capacity and climate change adaptation pertinent to a regional scale of analysis. The framework is multi-layered and consists of different levels of governing variables, units of analysis, learning outcomes and climate change adaptations. It is also integrative in that it encompasses social learning motivations, context and process factors, and outcomes, along with key determinants of adaptive capacity. A post hoc assessment of two climate change disturbances in northern boreal resource systems reveals the applicability of the framework to a regional scale analysis.


Is Cardiac Diastolic Dysfunction a Part of Post-Menopausal Syndrome?
Post-menopausal women exhibit an exponential increase in the incidence of heart failure with preserved ejection fraction compared with men of the same age, which indicates a potential role of hormonal changes in subclinical and clinical diastolic dysfunction. This paper reviews the preclinical evidence that demonstrates the involvement of estrogen in many regulatory molecular pathways of cardiac diastolic function and the clinical data that investigates the effect of estrogen on diastolic function in post-menopausal women. Published reports show that estrogen deficiency influences both early diastolic relaxation via calcium homeostasis and the late diastolic compliance associated with cardiac hypertrophy and fibrosis. Because of the high risk of diastolic dysfunction and heart failure with preserved ejection fraction in post-menopausal women and the positive effects of estrogen on preserving cardiac function, further clinical studies are needed to clarify the role of endogenous estrogen or hormone replacement in mitigating the onset and progression of heart failure with preserved ejection fraction in women.


Structural evolution of lignin after selective oxidation of lignin-carbohydrate complex by chlorine dioxide.
Lignin-carbohydrate complexes (LCCs) are important from the perspective of the anti-depolymerization barrier of lignocellulosic biomass, as it limits the high-value utilization of lignocellulosic biomass resources. In this study, the unit structure of lignin in the LCC has been investigated in depth. Oxidation of a selective lignin unit by chlorine dioxide revealed that the LCC structures are enriched with xylanase-macroporous resins, and the structure that was not oxidized in LCC was also identified. At a chlorine dioxide concentration of 90.93 mg/L, 1 g of LCC lignin is oxidized by 0.7 g chlorine dioxide. The purified residual hemicellulose lignin was mainly H-type. The β-O-4' signal was the strongest for the bond between lignin and carbohydrates. Therefore, it is speculated that most of the residual lignin in bamboo-alkali hemicellulose exists in the form of non-phenolic structural units. This study provides a reference for further studies on the specific structures of LCC.


Corrigendum: Clinical characteristics, renal involvement, and therapeutic options of pediatric patients with Fabry disease.
[This corrects the article DOI: 10.3389/fped.2022.908657.].


Cryosurgical treatment of warts: dimethyl ether and propane versus liquid nitrogen - case report and review of the literature.
For years, dermatologists have relied on cryotherapy with liquid nitrogen as a safe and effective treatment for warts. More recently, several over-the-counter (OTC) wart-freezing therapies have become available. Manufacturers have substituted liquid nitrogen with dimethyl ether and propane (DMEP), and marketed these new preparations to be safe and effective alternatives to in-office cryotherapy with liquid nitrogen. However, data from in vitro studies and comparative studies in humans refute manufacturers' claims that these products reproduce in-office cryotherapy.


Stem cell biology for vascular regeneration.
The isolation of endothelial progenitor cells (EPCs) derived from bone marrow (BM) was one epoch-making event for the recognition of neovessel formation in adults occurring as physiological and pathological responses. The finding that EPCs home to sites of neovascularization and differentiate into endothelial cells (ECs) in situ is consistent with vasculogenesis, a critical paradigm that has been well described for embryonic neovascularization, but proposed recently in adults in which a reservoir of stem or progenitor cells contribute to vascular organogenesis. EPCs have also been considered as therapeutic agents to supply the potent origin of neovascularization under pathological conditions. This chapter highlights an update of EPC biology as well as its potential use for therapeutic regeneration.


Biological and immunological characterization of norovirus major capsid proteins from three different genotypes.
Noroviruses (NoVs) are the leading cause of non-bacterial acute gastroenteritis worldwide. Due to a lack of cell culture system and animal model, our understanding of NoVs has been lagging behind. In this study, NoV major capsid proteins (VP1) from three different genotypes (GI.2, GII.3 and GII.4) were expressed by using recombinant baculovirus expression system and which led to successful assembly of virus-like particles (VLPs). The receptor binding patterns of three kinds of VLPs were characterized by using synthetic and salivary HBGA-VLP binding assay. Cross-reactivity and cross-blocking activity of rabbit hyperimmune sera against these VLPs were determined by ELISA/Western blot analysis and saliva-VLP binding blockade assay, respectively. Expression of the major capsid proteins from three genotypes all led to smaller VLPs in dominance when sf9 cells were cultured in suspension, which was in consistence with our previous report. These smaller VLPs were used for in vitro synthetic and salivary HBGA-VLP binding and binding blockade assays. VLPs from GII.3 strain exhibited no binding to all synthetic HBGAs and saliva samples tested while VLPs from GI.2 and GII.4 strain showed similar binding pattern and bound to all salivary HBGAs tested. Rabbit anti-GII.3 VLPs hyperimmune serum didn't block the binding of GI.2 and GII.4 VLPs to salivary HBGAs while rabbit anti-GI.2 VLP hyperimmune serum blocked the binding of GII.4 VLPs to salivary HBGAs but not vice versa. Our results provide further evidence indirectly in support of presence of other factors involved in receptor binding other than HBGAs for NoVs, and demonstrate poor cross-blocking activities of antibodies against VLPs within or across genogroups.


Green synthesize of copper nanoparticles on the cotton fabric as a self-regenerating and high-efficient plasmonic solar evaporator.
Harvesting solar energy, as a clean and abundant resource, in the photothermal process, is the winning point of solar steam generation (SSG) systems. Herein, copper plasmonic nanoparticles were synthesized through a green method via red sanders extraction on the cotton fabric as the reducing matrix. The prepared fabrics were analyzed using FESEM, EDS, XRD, PL, Raman, and contact angle. The treated fabric on the stitched PU foam with cotton yarns with bio-inspired jellyfish structure was used for heat localization and water transmission, simultaneously. The evaporation rate, enhancement, and conversion efficiency of the plasmonic SSG were 1.73 kg m-2 h-1, 179%, and ~ 98%, under one sun irradiation, respectively. The quality of the collected water was investigated via induced coupled plasma which presents the proper solar desalination (> 99.83% for filtration of Na+ ion). Regenerating features of the treated fabric along with the simple and cost-effective preparation method promises viable aspects of our system for large-scale applications.


Lack of myocardial necrosis despite clinical and electrocardiographic criteria of acute transmural infarction.
The development of "pathologic" Q waves with ST segment elevation is considered diagnostic of transmural myocardial infarction. Previous reports have suggested that myocardial ischemia without infarction can result in electrocardiographic abnormalities simulating those of acute infarction. However, lack of infarction has been poorly documented in these reports. If real, this phenomenon could have an impact on the management of patients with apparent acute infarction. This study describes a patient with documented severe myocardial ischemia and electrocardiographic evidence of acute transmural myocardial infarction, in whom significant myocardial necrosis has been excluded definitively.


Do cosmetic surgeons consider estrogen-containing drugs to be of significant risk in the development of thromboembolism?
Well-documented evidence shows that estrogen increases the risk of deep vein thrombosis (DVT), and that the effects of DVT are compounded by the stress of surgery and an anesthetic. This study sought to determine the current views and practice of plastic surgeons regarding combined oral contraceptive and surgery. In the United Kingdom, 285 consultant plastic surgeons were identified, and postal questionnaires were distributed to each surgeon. Of 286 postal questionnaires distributed to consultant plastic surgeons, 53% were returned and analyzed. Most of the surgeons considered combined oral contraceptive and surgery to be a risk factor for DVT, although only 54% discontinued it before surgery. Approximately 50% believed hormone-replacement therapy (HRT) is a risk, but fewer than a one-fourth of surgeons stopped its use before surgery. There was a range of distribution for the length of time HRT was discontinued for surgery. The majority of consultants discontinue HRT use for 5 to 6 weeks before surgery and until full ambulation after surgery. Data retrieved were used to compare documented evidence relating to combined oral contraceptive and surgery and its association with DVT. This survey shows that the management of patients taking estrogen-containing medication before plastic surgery varies, and guidelines regarding this should be sought.


The roles of knitted mesh-reinforced collagen-chitosan hybrid scaffold in the one-step repair of full-thickness skin defects in rats.
Full-thickness skin defects represent a significant and urgent clinical problem. Dermal substitutes serving as a regenerative template to induce dermal reconstruction provide a promising method to treat serious skin defects. Although collagen-chitosan dermal scaffolds display good biocompatibility and a suitable porous structure for angiogenesis and tissue regeneration, their poor mechanical properties compromise their application. To develop a well-supported dermal substitute, a poly(l-lactide-co-glycolide) (PLGA) knitted mesh was fabricated and integrated with collagen-chitosan scaffold (CCS) to obtain a PLGA knitted mesh-reinforced CCS (PLGAm/CCS). The morphology of this PLGAm/CCS was investigated in vitro. To characterize the tissue response, specifically angiogenesis and tissue regeneration, the PLGAm/CCS was transplanted in combination with thin split-thickness autografts to repair full-thickness skin wounds using a one-step surgical procedure in Sprague-Dawley rats. These results were then compared with CCSs. At weeks 2, 4 and 8 after the operation, the healing wounds were imaged to analyse wound changes, and tissue specimens were harvested for histology, immunohistochemistry, real-time quantitative polymerase chain reaction and Western blot analysis. The results demonstrated that collagen-chitosan sponge in the PLGAm/CCS remained porous, interconnected and occupied the openings of PLGA mesh, and the incorporation of the PLGA knitted mesh into CCS improved the mechanical strength with little influence on its mean pore size and porosity. Following transplantation, PLGAm/CCS inhibited wound contraction, and effectively promoted neotissue formation and blood vessel ingrowth. In conclusion, the mechanical strength of the scaffolds plays an important role in the process of tissue regeneration and vascularization. The ability of PLGAm/CCS to promote angiogenesis and induce in situ tissue regeneration demonstrates its potential in skin tissue engineering.


Comparing clinical responses and the biomarkers of BDNF and cytokines between subthreshold bipolar disorder and bipolar II disorder.
Patients with subthreshold hypomania (SBP; subthreshold bipolar disorder) were indistinguishable from those with bipolar disorder (BP)-II on clinical bipolar validators, but their analyses lacked biological and pharmacological treatment data. Because inflammation and neuroprogression underlies BP, we hypothesized that cytokines and brain-derived neurotrophic factor (BDNF) are biomarkers for BP. We enrolled 41 drug-naïve patients with SBP and 48 with BP-II undergoing 12 weeks of pharmacological treatment (valproic acid, fluoxetine, risperidone, lorazepam). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical responses at baseline and at weeks 0, 1, 2, 4, 8, and 12. Inflammatory cytokines (tumour necrosis factor [TNF]-α, transforming growth factor [TGF]-β1, interleukin [IL]-6, IL-8 and IL-1β) and BDNF levels were also measured. Mixed models repeated measurement was used to examine the therapeutic effect and changes in BDNF and cytokine levels between the groups. HDRS and YMRS scores significantly (P < 0.001) declined in both groups, the SBP group had significantly lower levels of BDNF (P = 0.005) and TGF-β1 (P = 0.02). Patients with SBP and BP-II respond similarly to treatment, but SBP patients may have different neuroinflammation marker expression.


Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen.
Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities. Some mutant genes are expressed in the skin, whereas others are not, indicating systemic effects. One phenotype is affected by diet and several are incompletely penetrant. In-depth analysis of three mutants, Krt76, Myo5a (a model of human Griscelli syndrome) and Mysm1, provides validation of the screen. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community.


Cardiovascular component of the context signal memory in the crab Chasmagnathus.
Research on diverse models of memory in vertebrates demonstrates that behavioral, autonomic and endocrine responses occur together during fear conditioning. With invertebrates, no similar studies have been performed despite the extensive study of fear memory paradigms, as the context signal memory (CSM) of the crab Chasmagnathus granulatus, usually assessed by a behavioral parameter. Here, we study the crab's CSM, considering both the behavioral response and the concomitant neuroautonomic adjustments resulting in a heart rate alteration. Results show that upon the first presentation of the visual danger stimulus, a heart arrest followed by bradycardia is triggered together with a conspicuous escape response. The latter declines throughout training, while heart arrests become sporadic and bradycardia tends to deepen along the session. At test, 24 h after training, the outcome clearly contrasts with that shown at training, namely, stimulus presentation in the same context induces lower escape, no heart arrests and quick suppression of bradycardia. These results support the view that the same memory process brings about the changes in both responses. High escape, heart arrest and bradycardia are considered three parameters of the unconditioned response while minor escape, no heart arrests and bradycardia attenuation are three parameters of the learned response.


Expression of nitric oxide system in clinically evaluated cases of Alzheimer's disease.
The expression of neuronal nitric oxide (nNOS) and inducible nitric oxide (iNOS) as isoforms of the nitric oxide synthase (NOS) as well as nitrotyrosine as an end product of protein nitration was analyzed in sections of temporal cortex taken from postmortem brains of patients with Alzheimer's disease (AD). The patients were evaluated by the Clinical Dementia Rating scale (CDR0-CDR3) and studied in the Memory and Aging Project (MAP) of the Washington University Alzheimer Disease Research Center (ADCR). With the use of immunocytochemical procedures, neurons immunoreactive to nNOS were found to show large and small multipolar and pyramidal morphologies over the entire chronic AD evolution. The iNOS and nitrotyrosine immunoreactivities were also found in pyramidal-like cortical neurons and glial cells. Here, we speculate on the interaction among all specific neurodegenerative changes in AD and nitric oxide as an additional contribution to neuronal death in AD.


Comparison of induction of labor methods for unfavorable cervices in trial of labor after cesarean delivery.
To compare induction of labor methods in patients attempting a trial of labor after cesarean (TOLAC) with an unfavorable cervix. This is a retrospective cohort study from patients attempting TOLAC from 2009 to 2013. Patients with a simplified Bishop score of three or less where labor was initiated with either a Cook balloon or oxytocin were included. Our primary outcome was mode of delivery. Our secondary outcomes included duration of labor and multiple maternal and neonatal morbidities. Two-hundred and fourteen women met inclusion criteria: 150 received oxytocin and 64 had the Cook balloon placed. The vaginal birth after cesarean delivery rate was significantly higher in the oxytocin group at 70.7% versus 50.0% in the Cook balloon group (p = 0.004). In the multivariable analysis, odds for cesarean delivery were two times higher with the Cook balloon than with oxytocin (Adjusted OR = 2.09, 95% CI = 1.05-4.18, p = 0.036). The duration of labor was longer with the Cook balloon versus oxytocin (21.9 versus 16.3 hours, p = 0.0002). There were no significant differences in maternal and neonatal health outcomes. Oxytocin induction of labor was associated with a higher rate of vaginal delivery and a shorter duration of labor compared to the Cook balloon in women undergoing TOLAC with an unfavorable cervix.


Targeting the NCOA3-SP1-TERT axis for tumor growth in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) has a high mortality rate and lacks an effective therapeutic target. Elevated expression of human telomerase reverse transcriptase (TERT) is an important hallmark in cancers, but the mechanism by which TERT is activated differentially in cancers is poorly understood. Here, we have identified nuclear receptor coactivator-3 (NCOA3) as a new modulator of TERT expression and tumor growth in HCC. NACO3 specifically binds to the TERT promoter at the -234 to -144 region and transcriptionally activates TERT expression. NCOA3 promotes HCC cell growth and tumor progression in vitro and in vivo through upregulating the TERT signaling. Knockdown of NACO3 suppresses HCC cell viability and colony formation, whereas TERT overexpression rescues this suppression. NCOA3 interacts with and recruits SP1 binding on the TERT promoter. Knockdown of NCOA3 also inhibits the expression of the Wnt signaling-related genes but has no effect on the Notch signaling-targeting genes. Moreover, NCOA3 is positively correlated with TERT expression in HCC tumor tissues, and high expression of both NCOA3 and TERT predicts a poor prognosis in HCC patients. Our findings indicate that targeting the NCOA3-SP1-TERT signaling axis may benefit HCC patients.


Interactions between mercury and dissolved organic matter--a review.
Dissolved organic matter (DOM) interacts very strongly with mercury, affecting its speciation, solubility, mobility, and toxicity in the aquatic environment. Strong binding of mercury by DOM is attributed to coordination of mercury at reduced sulfur sites within the organic matter, which are present at concentrations much higher than mercury concentrations found in most natural waters. The ability of organic matter to enhance the dissolution and inhibit the precipitation of mercuric sulfide, a highly insoluble solid, suggests that DOM competes with sulfide for mercury binding. This is confirmed by very high conditional stability constants for mercury-organic sulfur (RSHg+) complexes (10(25)-10(32)) recently reported in literature. DOM appears to play a key role in the photochemical reduction of ionic mercury to elemental mercury and subsequent reoxidation of elemental mercury to ionic mercury, thus affecting volatilization loss and bioavailability of mercury to organisms. DOM affects the production and bioaccumulation of methylmercury, the most bioaccumulative mercury species in fish.


Associations of MTHFR Polymorphisms and Cytosine Modifications with Early-Gestational Diabetes Mellitus in Chinese Pregnant Women.
Early-Gestational Diabetes Mellitus (Early-GDM) is a complex condition that may cause complications in infants of affected mothers. The aim of this case-control study was to analyze the effects of genetic-epigenetic interaction on Early-GDM and fetal development with respect to cytosine modifications (i.e., 5mC, 5-methylcytosines; and 5hmC, 5-hydroxymethylcytosines) and single nucleotide polymorphisms (SNPs) of MTHFR, a key gene involving cytosine modifications. Peripheral blood samples were collected from 92 women in their first or second trimester of pregnancy (Early-GDM, n = 14; Controls, n = 78). Global DNA 5mC and 5hmC were quantified by HPLC-MS/MS, and MTHFR SNPs (rs1801133 C > T and rs1801131 A > C) were determined by TaqMan-qPCR. Association analysis suggested that MTHFR rs1801133 TT genotype was a risk factor of Early-GDM (OR [odds ratio] = 4.00; 95% CI [confidence interval]: 1.24, 12.86; p = 0.02). The C allele of rs1801131 appeared to be a protective factor for the 2-h OGTT (oral glucose tolerance test) (OR = -0.79; 95% CI: -1.48, -0.10; p = 0.03). Patients with Early-GDM had higher global 5mC and lower global 5hmC. The reduction of global 5hmC and the TT genotype of rs1801133 were associated with higher level of the 1st-FBG (fasting blood glucose in the first trimester) (p < 0.05). Additionally, global 5mC showed a positive correlation with birth weight, body length and head circumference of newborns, while global 5hmC showed a negative correlation with birth weight. The current study implicated MTHFR SNPs and cytosine modifications in the development of Early-GDM and potential complications in their newborns.


Hsa_circ_0094606 promotes malignant progression of prostate cancer by inducing M2 polarization of macrophages through PRMT1-mediated arginine methylation of ILF3.
Circular RNA (circRNA), a type of noncoding RNAs, has been demonstrated to act vital roles in tumorigenesis and cancer deterioration. Although tumor-associated macrophages are involved in tumor malignancy, the interactions between circRNAs and tumor-associated macrophages in prostate cancer (PCa) remain unclear. In the present study, we found that hsa_circ_0094606 (subsequently named circ_0094606) could promote proliferation, epithelial-mesenchymal transition (EMT) as well as migration of PCa cells through cell viability and migration assays and the determination of EMT markers. Mass spectrometry analysis after RNA pull-down experiment identified that circ_0094606 bound to protein arginine methyltransferase 1 (PRMT1) in PCa cells, and further functional assays revealed that circ_0094606 promoted the malignant progression of PCa by binding to PRMT1. Moreover, co-immunoprecipitation (Co-IP), glutathione-S-transferase (GST) pull-down and immunofluorescence showed that PRMT1 mediated arginine methylation of ILF3 to stabilize the protein. Bioinformatics analysis combined with data from RNA-binding protein immunoprecipitation and RNA pull-down suggested that ILF3 could stabilize IL-8 mRNA, which promoted the M2 polarization in coculture study. Finally, in vivo experiments showed that circ_0094606 subserve PCa growth and promoted the M2 polarization of macrophages through the PRMT1/ILF3/IL-8 regulation pathway, supporting circ_0094606 as a potential novel effective target for PCa treatment.


Osteocytes autophagy mediated by mTORC2 activation controls osteoblasts differentiation and osteoclasts activities under mechanical loading.
Autophagy is an important mechanosensitive response for cellular homeostasis and survival in osteocytes. However, the mechanism and its effect on bone metabolism have not yet clarified. The objective of this study was to evaluate how compressive cyclic force (CCF) induced autophagic response in osteocytes and to determine the effect of mechanically induced-autophagy on bone cells including osteocytes, osteoblasts, and osteoclasts. Autophagic puncta observed in MLO-Y4 cells increased after exposure to CCF. The upregulated levels of the LC3-II isoform and the degradation of p62 further confirmed the increased autophagic flux. Additionally, ATP synthesis and release, osteocalcin (OCN) expression, and cell survival increased in osteocytes as well. The Murine osteoblasts MC3T3-E1 cells and RAW 264.7 macrophage cells were cultured in conditioned medium collected from MLO-Y4 cells subjected to CCF. The concentration of FGF23 increased and the concentrations of SOST and M-CSF and RANKL/OPG ratio decreased significantly in the conditioned medium. Moreover, the promotion of osteogenic differentiation in MC3T3-E1 cells and inhibition of osteoclastogenesis and function in RAW 264.7 cells were significantly attenuated when osteocytes autophagy was inhibited by siAtg7. Our findings suggested that CCF induced protective autophagy in osteocytes and subsequently enhanced osteocytes survival and osteoblasts differentiation and downregulated osteoclasts activities. Further study revealed that CCF induced autophagic response in osteocytes through mechanistic target of rapamycin complex 2 (mTORC2) activation. In conclusion, CCF-induced osteocytes autophagy upon mTORC2 activation promoted osteocytes survival and osteogenic response and decreased osteoclastic function. Thus, osteocytes autophagy will provide a promising target for better understanding of bone physiology and treatment of bone diseases.


Vitamin D deficiency in patients with either rheumatic diseases or inflammatory bowel diseases on biologic therapy.
Vitamin D deficiency has been reported in patients with chronic inflammatory conditions, such as rheumatic and inflammatory bowel diseases (IBD). We evaluated the role of biologic therapy on vitamin D, calcium and parathormone (PTH) levels. This cross-sectional study enrolled consecutive patients with either rheumatic diseases or IBD who underwent an ambulatory visit. Patients receiving vitamin D/calcium supplementation were excluded. Vitamin D deficiency or insufficiency was diagnosed when values were <20 ng/mL and 21-29 ng/ml, respectively. Patients were sub-grouped according to biologic therapy. A multivariate analysis was performed. Two-hundred patients, including 136 with a rheumatic disease (M/F 37/99; mean age 60.7 ± 12.9 years) and 64 with IBD (M/F 41/23; Mean age 49.6 ± 13.1 years) were enrolled. Vitamin D deficiency/insufficiency was detected in as many as 63.5 % patients, being 61.8 and 67.2 % in patients with either rheumatic diseases or IBD, respectively. The prevalence of vitamin D deficiency/insufficiency was higher in those receiving biologics than other therapies (78.3 vs 43.2 %; p < 0.0001), in either rheumatic diseases (78.7 vs 41 %; p < 0.0001) or IBD (75 vs 50 %; p = 0.03) group. At multivariate analysis, only biologic therapy was independently associated with vitamin D deficit (OR 4.61; p = 0.001). Patients with vitamin D deficiency/insufficiency had hypocalcemia more frequently than controls (22.8 vs 10.9 %; p = 0.03), while PTH values did not differ significantly. This study finds that the prevalence of vitamin D deficiency/insufficiency was very high in patients with either rheumatic diseases or IBD receiving a biologic therapy.


Comparison of an Atomic Model and Its Cryo-EM Image at the Central Axis of a Helix.
Cryo-electron microscopy (cryo-EM) is an important biophysical technique that produces three-dimensional (3D) density maps at different resolutions. Because more and more models are being produced from cryo-EM density maps, validation of the models is becoming important. We propose a method for measuring local agreement between a model and the density map using the central axis of the helix. This method was tested using 19 helices from cryo-EM density maps between 5.5 Å and 7.2 Å resolution and 94 helices from simulated density maps. This method distinguished most of the well-fitting helices, although challenges exist for shorter helices.


What causes internalising traits and autistic traits to co-occur in adolescence? A community-based twin study.
Autism shows a high degree of comorbidity with anxiety disorders. Adolescence is a time of increased stress and vulnerability to internalising problems. This study addresses for the first time the degree of genetic and environmental overlap between autistic traits (total measure and subscales) and internalising traits in a community-based adolescent twin sample. Parents of 12-14-year-old twins (N = 3,232 pairs; 3,460 males, 3,004 females) reported on the twins' internalising and autistic traits. Autistic trait subscales were created using principal component analysis. Bivariate twin model-fitting was conducted. Autistic and internalising traits correlated moderately (r = 0.30). Genetic influences on individual traits were substantial but genetic overlap between traits was moderate (genetic correlation: males = 0.30, females = 0.12). Shared environmental influences were low for internalising traits and moderate for autistic traits, and showed considerable overlap (shared environmental correlation: males = 0.53, females = 1). Nonshared environmental influences were moderate for internalising traits and low for autistic traits and showed low overlap. A multiple component solution was found for autistic traits and of the derived subscales, autistic-like 'Social Unease' showed the most phenotypic and genetic overlap with internalising traits.


Effects of (-)-epigallocatechin gallate on the development of morphine-induced physical dependence.
Among the various nervous systems and signaling components involved in the development of morphine withdrawal symptoms, sensitization of the brain dopaminergic nervous system and an increase in the cAMP levels in the locus coeruleus are believed to be the most important cellular events. This study tested the effects of (-)-epigallocatechin gallate (EGCG), a major compound of green tea, on the development of morphine-induced withdrawal symptoms. All the naloxone-precipitated withdrawal symptoms in morphine-dependent animals were inhibited by an EGCG pretreatment in a dose-dependent manner, being forepaw tremor, rearing, teeth chattering, urination, and wet dog shake were more sensitive than jumping and ptosis. In addition, EGCG showed moderate inhibitory effects on the morphine-induced increase in the cAMP levels in the locus coeruleus at 100 mg/kg and the signaling of the dopamine D2 receptor at 100 microM. Effects of EGCG on the sequestration of D2 receptor were inconclusive. These results suggest that EGCG has strong pharmacological activity against the development of morphine dependence, which can be partly explained by its inhibitory effects on the morphine-induced increase in the cAMP levels in the locus coeruleus and the signaling of the dopamine D2 receptor.


A cognitive behavioral therapy program for overweight children.
To assess the 1-year results of a multidisciplinary, cognitive behavioral therapy treatment program for overweight and obese children. Children (n = 73; 8 to 15 years old) participated in a prospective study aimed at reduction of the body mass index-standard deviation score (BMI-SDS), adapting a healthy lifestyle and creating a positive self-image and higher self-esteem, by use of a group approach and parental involvement. Reduction in BMI-SDS and percent overweight were measured and analyzed by use of MIXED modeling. The participants achieved a 0.6 BMI-SDS reduction, comparable to a weight loss of 18.7% after 1 year (P < .0001). The proportion of dropouts was 33%. Compared with the follow-up group, dropouts were older, increased in BMI-SDS before start of treatment, and were less successful in BMI-SDS reduction during treatment. This treatment program had a positive effect on BMI-SDS in overweight and obese children at 1-year follow-up. Differences between the characteristics of the dropout and follow-up group may reflect predictor variables for treatment outcome.


Pharmacological dissociation of the b-wave and pattern electroretinogram.
Electroretinographic responses to modulation of either luminance (focal ERG) or spatial contrast (pattern ERG) were recorded from the pigeon eye before and after intravitreal injection of glutamate analogues DL alpha amino adipic acid (DL alpha AA) and 2-amino-4 phosphonobutyric acid (APB). Both toxins reversibly abolished the b-wave. The pattern ERG was still present, however, when the b-wave had been abolished by the toxins. This result demonstrates that the b-wave and the pattern ERG can be pharmacologically dissociated and suggests the possibility that in pigeons the b-wave and pattern ERG reflect the activity of different generators.


High-sensitivity C-reactive protein and ankle brachial index in a finnish cardiovascular risk population.
High-sensitivity C-reactive protein (hsCRP) has been previously linked to different forms of vascular disease. However, some studies have not found any relationship between hsCRP and atherosclerosis. Also, studies investigating correlation between hsCRP and ankle brachial index (ABI) are scarce. We studied hsCRP in a cardiovascular risk population with a special interest in correlation between hsCRP and ABI. All men and women aged 45 to 70 years from a rural town Harjavalta, Finland were invited to participate in a population survey. Diabetics and people with known vascular disease were excluded. Seventy-three percent (n = 2085) of the invited persons participated and 70% of the respondents (n = 1496) had at least one risk factor to cardiovascular diseases. These subjects were invited to further examinations. From them we measured ABI, hsCRP, leukocyte count, glucose tolerance, systemic coronary risk evaluation (SCORE), body mass index (BMI), and waist circumference. Mean hsCRP was 1.9 mg/L. Smokers had higher hsCRP (mean 2.2 mg/L) than nonsmokers (mean 1.8 mL/L). hsCRP in women was higher than in men (mean 2.0 mg/L versus 1.8 mg/L). Mean ABI was 1.10, and the prevalence of peripheral arterial disease was 3.1%. ABI correlated weakly with hsCRP (r = -0.077, p = 0.014), leukocyte count (r = -0.107, p = 0.001), and SCORE (r = -0.116, p = 0.001). It did not have correlation between age, weight, BMI, or waist circumference. hsCRP correlated with BMI (r = 0.208, p < 0.0001) and waist circumference (r = 0.325, p < 0.0001). When we excluded subjects with hsCRP >10 mg/L, ABI no longer correlated with hsCRP. In a cardiovascular risk population, hsCRP has only a weak correlation with ABI, and this correlation disappeared when we excluded subject with hsCRP >10 mg/L. Instead, hsCRP was correlated to the measures of obesity (waist circumference and BMI), indicating its role as a marker of adipose tissue-driven inflammation. hsCRP does not seem to be a suitable screening method for peripheral arterial disease.


GNAQ mutations drive port wine birthmark-associated Sturge-Weber syndrome: A review of pathobiology, therapies, and current models.
Port-wine birthmarks (PWBs) are caused by somatic, mosaic mutations in the G protein guanine nucleotide binding protein alpha subunit q (GNAQ) and are characterized by the formation of dilated, dysfunctional blood vessels in the dermis, eyes, and/or brain. Cutaneous PWBs can be treated by current dermatologic therapy, like laser intervention, to lighten the lesions and diminish nodules that occur in the lesion. Involvement of the eyes and/or brain can result in serious complications and this variation is termed Sturge-Weber syndrome (SWS). Some of the biggest hurdles preventing development of new therapeutics are unanswered questions regarding disease biology and lack of models for drug screening. In this review, we discuss the current understanding of GNAQ signaling, the standard of care for patients, overlap with other GNAQ-associated or phenotypically similar diseases, as well as deficiencies in current in vivo and in vitro vascular malformation models.


A liquid perfluorochemical decreases the in vitro production of reactive oxygen species by alveolar macrophages.
To determine whether reactive oxygen metabolite production by alveolar macrophages is affected by liquid perfluorochemical exposure. Controlled, animal laboratory investigation of alveolar macrophage function in vitro. Animal research facility of a health sciences university. Six adult male New Zealand white rabbits and six young piglets. Alveolar macrophages were obtained after sacrifice from both species by total lung lavage. Macrophages were divided into control and experimental groups. Macrophages in the experimental groups were exposed to perfluorooctylbromide. To determine production of reactive oxygen metabolites, hydrogen peroxide production and chemiluminescence were measured in both experimental and control groups after chemical stimulation. Perfluorooctylbromide-exposed alveolar macrophages produced significantly less hydrogen peroxide (1.4 +/- 1.5 vs. 2.4 +/- 1.6 nmol/10(6) cells; p = .002). Perfluorooctylbromide-exposed alveolar macrophages demonstrated significantly less chemiluminescence activity compared with nonexposed cells (0.70 +/- 0.2 vs. 1.5 +/- 0.2 mV of relative activity per 3.5 x 10(5) cells; p = .005). Exposure of alveolar macrophages to perfluorooctylbromide in vitro decreases the responsiveness of macrophages to potent stimuli. This finding may partially explain the decrease in pulmonary inflammation seen in animals treated with partial liquid ventilation during experimentally induced lung injury.


Daily foraging schedule of field colonies of the eastern tent caterpillar Malacosoma americanum.
The daily foraging patterns of seven colonies of the eastern tent caterpillar, Malacosoma americanum, were monitored photoelectronically during the last three larval stadia to provide the first detailed record of the foraging behavior of a gregarious caterpillar under field conditions. Colonies were active an average of 49.3% of each day. Three bouts of foraging, centered about 0600 h, 1500 h and 2000 h (EST), occurred daily during the fourth and fifth stadia. Although ambient temperatures were less favorable for foraging and food processing than at other times of the day, the caterpillars were most active at dusk and dawn, and spent comparatively little time away from the tent during the daylight hours. In the last (sixth) stadium, the caterpillars foraged only under the cover of darkness. A lack of relationship between the rate at which the caterpillars processed food and the spacing of their feeding bouts, indicates that this species follows a schedule of feeding and growth shaped by factors other than those directly related to feeding efficiency and ambient temperature. Colony foraging patterns may reduce caterpillar mortality by minimizing contact between larvae and day-active predators and parasitiods.


Effects on the periodontium of vertical bone cutting for segmental osteotomy.
The periodontal response to vertical osteotomy was evaluated in seven males and ten females, aged 14-45 years (mean 26.8), who were scheduled for maxillary and/or mandibular segmental osteotomies. Plaque and gingival indices, pocket depth, clinical attachment level, width of attached gingiva, and osseous support were recorded from teeth adjacent to each osteotomy site prior to and from six months to three years after surgery. In each patient teeth numbers 3, 9, 13, 19, 25, and 29 were used as controls. There was no significant (P less than or equal to 0.05) difference between experimental and control teeth with respect to plaque, gingivitis, pocket depth, or clinical attachment level. Slightly decreased osseous support and width of attached gingiva were found adjacent to osteotomy sites. However, although these decreases were statistically significant (P = 0.005), they were not clinically very large. It was concluded that segmental osteotomies, in general, may be performed without producing significant changes in the periodontal structures.


'What research was carried out on this vaginal mesh?' Health-related concerns in women following mesh-augmented prolapse surgery: a thematic analysis.
To understand health-related issues in women following mesh-augmented prolapse surgery. Inductive thematic analysis of free-text comments from participants in a cross-sectional study of laparoscopic mesh sacrohysteropexy. Tertiary urogynaecology centres, United Kingdom. Women who underwent laparoscopic mesh sacrohysteropexy by surgeons based at two tertiary urogynaecology centres between 2010 and 2018. A total of 1766 potential participants were contacted by post and invited to complete paper, online or telephone questionnaires containing a free-text comments section. Of 1121 participants (response proportion 63.5%), 752 (67.1%) provided such comments. These were analysed with a six-stage inductive thematic analysis, using NVivo 11® software. Themes developed from free-text comments. Following familiarisation, 29 codes and 189 sub-codes were identified. These defined six themes: pelvic floor symptoms, health status, treatment success, mesh, pain and care received. The majority of comments centred on the first of these six themes. There were concerns about mesh use and a desire for more information. A range of pain symptoms were mentioned, often associated with pelvic floor symptoms, prolapse surgery or mesh. Despite the mesh controversy, pelvic floor symptoms and their impact on quality of life remain the principle concern of women following mesh-augmented prolapse surgery. There is a need for quality, accessible and evidence-based information sources for those women with concerns, and for those considering such surgery in the future, particularly regarding mesh safety and postoperative recovery. The relationships between pain, prolapse, mesh and pelvic floor surgery require further study. Following mesh-augmented prolapse surgery, pelvic floor symptoms remain women's main focus; pain deserves further research.


The plasma kallikrein-kinin system and risk of cardiovascular disease in men.
The plasma kallikrein-kinin system (PKKS) has been implicated in cardiovascular disease, but activation of the PKKS has not been directly probed in individuals at risk of coronary heart disease (CHD) or stroke. To determine the involvement of the PKKS, including factor XI, in cardiovascular disease occurring in a nested case-control study from the Second Northwick Park Heart Study (NPHS-II). After a median follow-up of 10.7 years, 287 cases of CHD and stroke had been recorded and 542 age-matched controls were selected. When FXIIa-C1 esterase inhibitor (C1-inhibitor) concentrations were divided into tertiles (lowest tertile as reference), the odds ratios (ORs) at 95% CIs for CHD were 0.52 (0.34-0.80) in the middle tertile and 0.73 (0.49-1.09) in the highest tertile (P = 0.01 for the overall difference; P = 0.01 for CHD and stroke combined). For kallikrein-C1-inhibitor complexes, the ORs for stroke were 0.29 (0.12-0.72) and 0.67 (0.30-1.52) in the middle and high tertiles, respectively (P = 0.02). FXIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes were negatively related to smoking and fibrinogen (P < 0.005). FXIa-inhibitor complexes correlated strongly with FXIIa-inhibitor complexes. Lower levels of inhibitory complexes of the PKKS enzymes and particularly of FXIIa contribute to the risk of CHD and stroke in middle-aged men. This observation supports the involvement of the PKKS in atherothrombosis.


Fine structure of the developing oocytes in adult Argas (Persicargas) arboreus (Ixodoidea: Argasidae).
The structure of the developing oocytes in the ovary of unfed and fed female Argas (Persicargas) arboreus is described as seen by scanning (SEM) and transmission (TEM) electron microscopy. The unfed female ovary contains small oocytes protruding onto the surface and its epithelium consists of interstitial cells, oogonia and young oocytes. Feeding initiates oocyte growth through the previtellogenic and vitellogenic phases of development. These phases can be observed by SEM in the same ovary. The surface of isolated, growing oocytes is covered by microvilli which closely contact the basal lamina investing the ovarian epithelium and contains a shallow, circular area with cytoplasmic projections and a deep pit, or micropyle, at the epithelium side. In more advanced oocytes the shell is deposited between microvilli and later completely covers the surface. Transmission EM of growing oocytes in the previtellogenic phase reveals nuclear and nucleolar activity in the emission of dense granules passing into the cytoplasm and the formation of surface microvilli. The cell cytoplasm is rich in free ribosomes and polysomes and contains several dictyosomes associated with dense vesicles and mitochondria which undergo morphogenic changes as growth proceeds. Membrane-limited multivesiculate bodies, probably originating from modified mitochondria, dictyosomes and ribosomal aggregates, are also observed. Rough endoplasmic reticulum is in the form of annulate lamellae. During vitellogenesis, proteinaceous yolk bodies are formed by both endogenous and exogenous sources. The former is involved in the formation of multivesicular bodies which become primary yolk bodies, whereas the latter process involves internalization from the haemolymph through micropinocytosis in pits, vesicles and reservoirs. These fuse with the primary yolk bodies forming large yolk spheres. Glycogen and lipid inclusions are found in the cytoplasm between the yolk spheres.


Stabilization and adiabatic control of antiferromagnetically coupled skyrmions without the topological Hall effect.
Synthetic antiferromagnetically coupled (SAF) multilayers provide different physics of stabilizing skyrmions while eliminating the topological Hall effect (THE), enabling efficient and stable control. The effects of material parameters, external current drive, and a magnetic field on the skyrmion equilibrium and propagation characteristics are largely unresolved. Here, we present a computational and theoretical demonstration of the large window of material parameters that stabilize SAF skyrmions determined by saturation magnetization, uniaxial anisotropy, and Dzyaloshinskii-Moriya interaction. Current-driven SAF skyrmion velocities reach ∼200 m s-1 without the THE. The SAF velocities are about 3-10 times greater than the typical ferromagnetic skyrmion velocities. The current densities needed for driving SAF skyrmions could be reduced to 108 A m-2, while 1011 A m-2 or above is needed for ferromagnetic skyrmions. By reducing the SAF skyrmion drive current by 3 orders, Joule heating is reduced by 6 orders of magnitude. These results pave the way for new SAF interfaces with improved equilibrium, dynamics, and power savings in THE-free skyrmionics.


The transcriptional profile of adipose-derived stromal cells (ASC) mirrors the whitening of adipose tissue with age.
Multipotent stem cells persist within the stromal vascular fraction (SVF) of adipose tissue during adulthood. These cells, commonly referred to as adipose-derived stromal cells (ASC), have been extensively investigated over the past years as a promising therapeutic tool based on their regenerative and immunomodulatory properties. However, how ASC might mirror the age-related alteration of the fat they reside in remains unclear. Herein, we show that inguinal adipose tissue in mice turns from brown/beige- to white-like with age and resident ASC readily mirror these changes both at mRNA and microRNA transcriptional level. Mechanistically, our data suggest that these brown/age-related changes in ASC transcription rely on changes in the activity of E2F1 and NFkB transcription factors.


Ethnic differences in outcomes of diabetes care and the role of self-management behavior.
Ethnic differences in outcomes of outpatient diabetic care and the role of self-management behavior and its determinants in explaining observed differences. Face-to-face interviews were held with 102 Turkish or Moroccan, and 102 native Dutch diabetic patients to measure self-management behavior and determinants of self-management (as derived from the Attitudes-Social support self-Efficacy model, and Personal Models and Barriers). A medical record review was conducted to measure ethnic differences in outcomes of diabetes care. Data were analyzed using multiple linear regression. Outcomes differed significantly with ethnic minorities having higher levels of lipids (risk difference=RD=0.7%; CI: 0.3-1.2) and HbA1c (RD=0.9%; CI: 0.4-1.4) than native Dutch patients. Differences in self-management could not explain the ethnic differences in outcomes. Self-efficacy explained 18% of the ethnic differences in HbA1c. Beliefs about seriousness of diabetes and social support regarding diabetes management together explained 47% of the ethnic differences in lipids. This study provides evidence for ethnic differences in outcomes of diabetes care. Self-efficacy is the most important determinant in explaining the differences in HbA1c. For diabetes practice this suggests that strengthening patients' self-efficacy may improve the control of HbA1c and may result in a decrease of ethnic differences. The relationship between behavioral determinants like seriousness and social support and outcomes of diabetes care was differential by ethnic group, implying that caution is required when applying behavioral models to different ethnic groups.


New biologic agents for the treatment of gynecologic cancers.
The discovery of new biologic targeted agents and appropriately matching them to specific gynecologic tumor types either based on histology or the genetic make-up of the cancer is an exciting new chapter in the treatment of gynecologic malignancies. Therapeutic targets of multiple pathways are currently in study, and combinations with chemotherapy as well as combinations of pathway inhibitors are currently in development.


Prediction of outcome by historical, clinical and biological variables in schizoaffective disorder, depressed type.
The usefulness of several historical, clinical and biological variables as possible predictors of outcome was tested in a sample of patients with a cross-sectional diagnosis of schizoaffective disorder, depressed type. Four historical items were found to be successful: a family history of chronic schizophrenia, the occurrence of schizophrenic symptoms at some stage of the illness in the absence of depression and an onset of the index episode as exacerbation of previous symptoms (all associated with a relatively poor outcome), and a personal history of previous manic episodes (associated with a relatively good outcome). The various aspects of the clinical picture during the index episode, as well as the response on dexamethasone suppression test, were not found to have any predictive value. These findings confirm that, in patients with a cross-sectional diagnosis of schizodepressive disorder, the previous course of the illness is of crucial importance for prognosis, and support the usefulness of a multiaxial classification of schizoaffective states, taking into account not only cross-sectional symptomatology but also course.


Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients.
The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit.


Intraocular lens calculation accuracy limits in normal eyes.
To quantify the current accuracy limits, analyze the residual errors, and propose the next steps for prediction accuracy improvements. Eye hospitals in Germany, Denmark, and Austria. Numerical ray tracing using manufacturer's intraocular lens (IOL) data (vertex radii, central thickness, refractive index) was used for all calculations. Postoperative lens position was predicted by a simple scaling model based on measurements in 1 patient collective. The model was compared with 2 other approaches in 2 patient collectives at 2 hospitals (1121 eyes with 13 IOL models; 936 eyes with 2 models). Axial lengths were measured optically (IOLMaster, Zeiss). No parameter adjustments or individualization of IOL types or of surgeons/localizations were done. The prediction errors and measures of systematic bias for short or long eyes were used to quantify the outcome. The mean prediction errors in the 2 collectives were +0.13 diopter (D) and -0.13 D and the mean absolute errors were 0.44 D and 0.50 D without bias for long or short eyes, but depending on the IOL position model approach. The differences in the mean prediction errors for the IOL types were below the allowed manufacturing tolerances and below human recognition thresholds. The need to individualize and fudge parameters decreases with better physical models of the pseudophakic eye. Further improvements are possible by individual topography to extract corneal asphericity and measured pupil size to calculate the best focus, by improved position predictions based on individual measurements of the crystalline lens and by smaller tolerances for IOL manufacturing.


Ring chromosomes in chronic myelogenous leukemia: an ominous finding.
Two cases of Philadelphia chromosome positive chronic myelogenous leukemia (CML) demonstrated ring chromosomes. The appearance of the ring coincided with evolution from the stable to the aggressive phase. A literature search yielded six other cases of ring chromosomes in CML; all were in or were entering the aggressive phase of the disease. Thus, as is the case with acute nonlymphocytic leukemia, in CML the finding of an acquired ring chromosome is associated with a poor prognosis.


STAGA recruits Mediator to the MYC oncoprotein to stimulate transcription and cell proliferation.
Activation of eukaryotic gene transcription involves the recruitment by DNA-binding activators of multiprotein histone acetyltransferase (HAT) and Mediator complexes. How these coactivator complexes functionally cooperate and the roles of the different subunits/modules remain unclear. Here we report physical interactions between the human HAT complex STAGA (SPT3-TAF9-GCN5-acetylase) and a "core" form of the Mediator complex during transcription activation by the MYC oncoprotein. Knockdown of the STAF65gamma component of STAGA in human cells prevents the stable association of TRRAP and GCN5 with the SPT3 and TAF9 subunits; impairs transcription of MYC-dependent genes, including MYC transactivation of the telomerase reverse transcriptase (TERT) promoter; and inhibits proliferation of MYC-dependent cells. STAF65gamma is required for SPT3/STAGA interaction with core Mediator and for MYC recruitment of SPT3, TAF9, and core Mediator components to the TERT promoter but is dispensable for MYC recruitment of TRRAP, GCN5, and p300 and for acetylation of nucleosomes and loading of TFIID and RNA polymerase II on the promoter. These results suggest a novel STAF65gamma-dependent function of STAGA-type complexes in cell proliferation and transcription activation by MYC postloading of TFIID and RNA polymerase II that involves direct recruitment of core Mediator.


A stochastic formulation of the gompertzian growth model for in vitro bactericidal kinetics: parameter estimation and extinction probability.
Time-kill curves have frequently been employed to study the antimicrobial effects of antibiotics. The relevance of pharmacodynamic modeling to these investigations has been emphasized in many studies of bactericidal kinetics. Stochastic models are needed that take into account the randomness of the mechanisms of both bacterial growth and bacteria-drug interactions. However, most of the models currently used to describe antibiotic activity against microorganisms are deterministic. In this paper we examine a stochastic differential equation representing a stochastic version of a pharmacodynamic model of bacterial growth undergoing random fluctuations, and derive its solution, mean value and covariance structure. An explicit likelihood function is obtained both when the process is observed continuously over a period of time and when data is sampled at time points, as is the custom in these experimental conditions. Some asymptotic properties of the maximum likelihood estimators for the model parameters are discussed. The model is applied to analyze in vitro time-kill data and to estimate model parameters; the probability of the bacterial population size dropping below some critical threshold is also evaluated. Finally, the relationship between bacterial extinction probability and the pharmacodynamic parameters estimated is discussed.


The Role of Telecytology in the Primary Diagnosis of Thyroid Fine-Needle Aspiration Specimens.
The Acibadem Health Group (AHG) has been using telepathology/digital pathology stations since 2006. In 2013, the system was changed from videoconferencing to digital pathology (whole-slide imaging) utilizing 3DHISTECH scanners and software. In 2017, digital cytology started to be used for routine cytopathologic diagnosis for thyroid fine-needle aspiration (FNA) cases. Two hundred and twenty-seven thyroid cases were received for analysis using telecytology (TC) during the period from November 2017 to May 2018. Rapid on-site evaluation was performed at the Atakent Hospital of the AHG by a cytotechnologist and scanned on the same day. For every case, there were Diff-Quik- and Papanicolaou-stained FNA smears. Each glass slide was digitized with a 3DHISTECH whole-slide scanner in 1 focal Z-plane at ×40 magnification. Two hundred and twenty-seven thyroid FNA specimens were retrieved, of which 25 had histologic follow-up. Samples were classified as nondiagnostic in 3%, benign in 74%, atypia of undetermined significance/follicular lesion of undetermined significance in 13%, suspicious for follicular neoplasia/follicular neoplasia in 3%, suspicious for malignancy in 4%, and malignant in 3%. When only the "suspicious for malignancy" and "malignancy" categories were considered positive tests, cytology sensitivity and specificity using TC for diagnosis was 100%. Our data demonstrate that TC is suitable to provide a primary diagnosis in daily routine cytology practice. Despite the promising results, there were some challenges stemming from the novelty of using TC for the primary diagnosis. The study also addresses both advantages and disadvantages of TC in daily practice to increase the efficiency of the technique in primary diagnosis.


Azygous lobe presenting as a posterior mediastinal mass in a 2-year-old boy.
Posterior mediastinal masses encompass a varied group of surgical lesions that include malignant diseases as well as the anatomic malformations of four organ systems. The authors report on a 2-year-old child with a posterior mediastinal mass who was found at thoracotomy to have a chronically infected "hepatized" azygous lobe of the right lung. The authors review current literature on this topic as well as the embryogenesis of azygous lobes.


Technetium99m-sestamibi scanning before initial neck exploration in patients with primary hyperparathyroidism.
Technetium99m (Tc) sestamibi(mibi) has been proposed as an alternative to the standard radionuclide imaging technique of thallium 201 chloride-99mTc pertechnetate subtraction scan (TTS) in patients with primary hyperparathyroidism. In the present study, mibi was evaluated as an alternative to TTS in 37 patients who had either mibi-99mTc pertechnetate subtraction scans, mibi-iodine123 (I) subtraction scans or mibi single isotope washout scans. There were 30 females and 7 males with an average age of 57 years (range, 27-78 years). Parathyroid adenomas were found in 35 patients and hyperplasia in 2. Twenty-eight mibi scans were positive and 25 of these correctly localized the parathyroid abnormality for a sensitivity of 68% (25 of 37) and a positive predictive value of 89% (25 of 28). There were 3 false-positives (8%) and 9 false-negatives (25%). The scan was not helpful in either patient with parathyroid gland hyperplasia. Mibi-123I subtraction was the most accurate scan and was diagnostic clinically in all 7 patients studied. Mibi scans were significantly more likely to identify inferior rather than superior adenomas (P = 0.01). Twenty-seven of the 37 patients also had a TTS which was correct in only 37% of cases while the mibi scan was correct in 68% (P = 0.02). However, routine use of nuclear scanning with mibi was still not supported by these data. Further clinical evaluation of various techniques may improve accuracy. Since mibi was significantly more accurate than TTS, it should be considered preferentially when radionuclide imaging is used in patients with recurrent hyperparathyroidism.


Persistent slow inward calcium current in voltage-clamped hippocampal neurones of the guinea-pig.
CA1 and CA3 neurones in transverse slices of guinea-pig hippocampus were voltage clamped through a single micro-electrode, and perfused with Krebs solution containing 0.5 microM-tetrodotoxin and 10 mM-tetraethylammonium at (normally) 24-26 degrees C. Slow inward currents of less than or equal to 0.5 nA were recorded during depolarizing voltage commands to membrane potentials positive to between -40 and -30 mV. These currents peaked at 100-300 msec after the onset of the depolarizing command, then subsequently declined during continuing depolarization. This decline could be ascribed to a developing outward current since repolarizing inward current tails showed no diminution up to 700 msec. No clear evidence for time-dependent inactivation of the inward current could be obtained. A persistent component of inward current could be detected when the membrane potential was maintained above the inward current threshold, such that small hyperpolarizing commands induced an outward relaxation and large hyperpolarizations produced an inward tail current. The inward current was depressed by removing external Ca, or by adding 0.2-0.5 mM-Cd, or 0.1 mM-verapamil, and was increased by adding 1 mM-Ba. A possible role for this persistent inward current in generating the slow membrane depolarization underlying burst discharges in these neurones is discussed. In some neurones (primarily CA1), an additional fast spike-like current was recorded, which was blocked by Cd or Mn and depressed by a depolarizing pre-pulse. It is suggested that this was a manifestation of the previously-reported dendritic Ca spike.


Group B streptococcal endocarditis in a neonate.
This is a case of bacterial endocarditis and dissecting aneurysm of the ascending aorta secondary to group B streptococcal (GBS) septicemia in a one-mouth-old infant girl who presented with meningitis. A large aortic vegetation and a large dissecting aneurysm of the root of the aorta were detected by two-dimensional (2D) echocardiography. Apparently the infant did not have any preexisting cardiac anomaly. She received intravenous ampicillin for six weeks. She also underwent successful surgery for the replacement of the ascending aorta with an aortic homograft. This occurrence reemphasizes the value of 2D echocardiography in detecting vegetations for endocarditis.


Interaction of Platinum-based Drugs with Proteins: An Overview of Representative Crystallographic Studies.
Pt-based drugs are widely used in clinics for the treatment of cancer. The mechanism of action of these molecules relies on their interaction with DNA. However, the recognition of these metal compounds by proteins plays an important role in defining pharmacokinetics, side effects and their overall pharmacological profiles. Single crystal X-ray diffraction studies provided important information on the molecular mechanisms at the basis of this process. Here, the molecular structures of representative adducts obtained upon reaction with proteins of selected Pt-based drugs, including cisplatin, carboplatin and oxaliplatin, are briefly described and comparatively examined. Data indicate that metal ligands play a significant role in driving the reaction of Pt compounds with proteins; non-covalent interactions that occur in the early steps of Pt compound/protein recognition process play a crucial role in defining the structure of the final Pt-protein adduct. In the metallated protein structures, Pt centers coordinate few protein side chains, such as His, Met, Cys, Asp, Glu and Lys residues upon releasing labile ligands.


Campylobacter hyointestinalis associated with human gastrointestinal disease in the United States.
Campylobacter hyointestinalis was isolated from stool specimens of four persons, all of whom were experiencing nonbloody, watery diarrhea. The youngest (8 months of age) and the oldest (79 years of age) individuals were females, and the other two were homosexual men. C. hyointestinalis was the only clinically significant pathogen isolated from stool specimens for three of the individuals. In case 3 (involving a 37-year-old homosexual man), Entamoeba histolytica and Shigella sonnei were also present in the stool. The identification of all C. hyointestinalis strains was made biochemically and confirmed by DNA hybridization. This study documented the isolation of C. hyointestinalis from four patients with diarrhea, and our findings suggest that the clinical significance of Campylobacter species must be expanded to include C. hyointestinalis as a potential cause of human gastrointestinal disease.


Immortalization and characterization of bovine peritoneal macrophages transfected with SV40 plasmid DNA.
A transformed bovine peritoneal macrophage cell line was developed and characterized. Primary peritoneal macrophages were transformed by calcium-phosphate transfection with SV40 plasmid DNA. The transformed cell line retained the morphology of resident peritoneal macrophages as determined by light microscopy and histochemical analysis showed non-specific esterase activity. In addition, immunohistochemical staining of transformed peritoneal macrophages for lysozyme activity was positive. Transformed cells phagocytized Staphylococcus aureus, lysed chicken red blood cell (RBC) targets with and without opsonization and produced hydrogen peroxide radicals and interleukin-6 upon stimulation with opsonized zymosan and lipopolysaccharide, respectively. Transformed cells were also able to ingest and kill Mycobacterium paratuberculosis, an acid-fast bacillus. These results suggest that this cell line should be useful to study interactions between the bovine and intracellular pathogens.


Deep-Stacked Convolutional Neural Networks for Brain Abnormality Classification Based on MRI Images.
An automated diagnosis system is crucial for helping radiologists identify brain abnormalities efficiently. The convolutional neural network (CNN) algorithm of deep learning has the advantage of automated feature extraction beneficial for an automated diagnosis system. However, several challenges in the CNN-based classifiers of medical images, such as a lack of labeled data and class imbalance problems, can significantly hinder the performance. Meanwhile, the expertise of multiple clinicians may be required to achieve accurate diagnoses, which can be reflected in the use of multiple algorithms. In this paper, we present Deep-Stacked CNN, a deep heterogeneous model based on stacked generalization to harness the advantages of different CNN-based classifiers. The model aims to improve robustness in the task of multi-class brain disease classification when we have no opportunity to train single CNNs on sufficient data. We propose two levels of learning processes to obtain the desired model. At the first level, different pre-trained CNNs fine-tuned via transfer learning will be selected as the base classifiers through several procedures. Each base classifier has a unique expert-like character, which provides diversity to the diagnosis outcomes. At the second level, the base classifiers are stacked together through neural network, representing the meta-learner that best combines their outputs and generates the final prediction. The proposed Deep-Stacked CNN obtained an accuracy of 99.14% when evaluated on the untouched dataset. This model shows its superiority over existing methods in the same domain. It also requires fewer parameters and computations while maintaining outstanding performance.


Impact on staff of providing non-invasive advanced respiratory support during the COVID-19 pandemic: a qualitative study in an acute hospital.
To explore the experiences of healthcare workers providing non-invasive advanced respiratory support (NARS) to critically unwell patients with COVID-19. A qualitative study drawing on a social constructionist perspective using thematic analysis of semistructured interviews. A single acute UK National Health Service Trust across two hospital sites. Multidisciplinary team members in acute, respiratory and palliative medicine. 21 nurses, doctors (juniors and consultants) and physiotherapists described the provision of NARS to critically unwell COVID-19 patients as extremely challenging. The main themes were of feeling ill prepared and unsupported, a need to balance complex moral actions and a sense of duty to patients and their families. The impact on staff was profound and findings are discussed via a lens of moral injury. Injurious events included staff feeling they had acted in a way that caused harm, failed to prevent harm or had been let down by seniors or the Trust. Participants identified factors that mitigated adverse impact. Although many of the issues described by participants are likely immutable components of healthcare in a pandemic, there were several important protective factors that emerged from the data. Experience, debriefing and breaks from COVID-19 wards were valuable to participants and successfully achieving a peaceful death for the patient was often viewed as compensation for a difficult journey. These protective factors may provide modelling for future education and support services to help prevent moral injury or aide in its recovery. Registered on the Open Science Framework, DOI 10.17605/OSF.IO/TB5QJ.


Staphylococcal endogenous endophthalmitis in association with pyogenic vertebral osteomyelitis.
PURPOSE To describe pyogenic vertebral osteomyelitis as a rare infection associated with endogenous endophthalmitis.METHODS A retrospective review of three patients with endogenous endophthalmitis and sepsis due to underlying Staphylococcal vertebral osteomyelitis presenting during a 21-month time period. The ophthalmic and systemic features and management and outcomes are presented.RESULTS One patient developed unilateral endophthalmitis with cervical spine osteomyelitis, Staphylococcus aureus being isolated from blood cultures. The second presented with bilateral endophthalmitis with disseminated Methicillin-resistant S. aureus (MRSA) infection, with thoracic and lumbar discitis and para-spinal abscesses. MRSA was cultured from vitreous, blood, and synovial fluid. Both patients received prolonged courses of intravenous antibiotics. Intravitreal antibiotic therapy was used in the second patient. Excellent visual and systemic outcomes were achieved in both cases with no ocular complications. The third patient developed lumbar osteomyelitis following spinal surgery and presented with disseminated S. aureus sepsis including unilateral endogenous endophthalmitis. Despite systemic antibiotics and intensive care the patient died.CONCLUSIONS Endogenous endophthalmitis should be suspected in septic patients developing eye symptoms. Endogenous endophthalmitis with staphylococcal bone infection is a rare but serious condition. Osteomyelitis should be considered as an infective source in any such patient reporting bone pain or reduced spinal mobility. Prompt investigation and treatment can achieve favourable visual and systemic outcomes.


Parental History of Diabetes, Positive Affect, and Diabetes Risk in Adults: Findings from MIDUS.
Family history of diabetes is one of the major risk factors for diabetes, but significant variability in this association remains unexplained, suggesting the presence of important effect modifiers. To our knowledge, no previous work has examined whether psychological factors moderate the degree to which family history of diabetes increases diabetes risk. We investigated the relationships among parental history of diabetes, affective states (positive affect, negative affect, and depressed affect), and diabetes in 978 adults from the MIDUS 2 national sample. As expected, parental history of diabetes was associated with an almost threefold increase in diabetes risk. We found a significant interaction between positive affect and parental history of diabetes on diabetes (p = .009): higher positive affect was associated with a statistically significant lower relative risk for diabetes in participants who reported having a parental history of diabetes (RR = .66 per unit increase in positive affect; 95 % CI = .47; .93), but it did not influence diabetes risk for participants who reported no parental history of diabetes (p = .34). This pattern persisted after adjusting for an extensive set of health and sociodemographic covariates and was independent of negative and depressed affect. These results suggest that psychological well-being may protect individuals at increased risk from developing diabetes. Understanding such interactions between non-modifiable risk factors and modifiable psychological resources is important for delineating biopsychosocial pathways to diabetes and informing theory-based, patient-centered interventions to prevent the development of diabetes.


Cost analysis of vestibular schwannoma screening with contrast-enhanced magnetic resonance imaging in patients with asymmetrical hearing loss.
Vestibular schwannomas are a rare cause of asymmetrical hearing loss, and routine screening with magnetic resonance imaging can be costly. This paper reports results on vestibular schwannoma screening at our institution and compares the cost of screening to a utility of hearing benefit. All screening examinations with magnetic resonance imaging performed for asymmetrical hearing loss between 2006 and 2011 were retrospectively reviewed. The cost per new vestibular schwannoma diagnosis was calculated. The cost per patient for those who benefitted from intervention was estimated based on rates of hearing preservation reported in the literature. Forty-five (4.3 per cent) of 1050 screening examinations with magnetic resonance imaging performed for asymmetrical hearing loss were positive for vestibular schwannoma, and the cost per new diagnosis was $11,436. The estimated screening cost per patient for those who benefitted from surgery or radiation was $147,030, while US federal compensation for unilateral hearing loss was $44,888. Although we achieved a lower screening cost per new diagnosis than reported in the current literature, there remains disparity between the screening cost per benefitted patient and the 'benefit' of hearing.


ZFAT expression in B and T lymphocytes and identification of ZFAT-regulated genes.
The human ZFAT gene encodes a 1243-amino-acid protein containing one AT hook and 18 C2H2 zinc finger domains, which are highly conserved among ZFAT orthologues from fish to mammalian species. Consistent with the presence of multiple predicted nuclear localization signals, endogenous ZFAT protein was found to be localized to the nucleus. In the mouse tissues examined by Western blotting, ZFAT was found to be expressed in thymus, spleen, and lymph nodes, but not in other tissues, including bone marrow. Furthermore, ZFAT protein was found to be up-regulated during the transition from CD4(-)CD8(-) to CD4(+)CD8(+) thymocytes and to be expressed only in B and T lymphocytes in peripheral lymphoid tissues. Expression array analyses demonstrated that genes that are down-regulated upon ZFAT overexpression in mouse Ba/F3 cells are significantly enriched for those functionally related to immune responses. These results suggest that ZFAT functions as a critical transcriptional regulator in B and T lymphocytes.


Diet and hypertension: critical concepts and controversies.
Diet, alcohol consumption and physical activity stand out as the major influences on blood pressure levels and hypertension. Many studies on the effects of different nutrients on blood pressure have been confounded by methodological problems, but a careful appraisal of these problems leads to new concepts in interpreting the literature, and allows some interesting conclusions to be drawn.


Intake and excretion of disodium monomethylarsonate in horses: a speciation study.
Capillary electrophoresis coupled to inductively coupled plasma mass spectrometry was used in a speciation study on disodium monomethylarsonate (DS-MMA(V)) and its metabolites in horses, to which the drug was administered by intramuscular injection on five consecutive days at a single arsenic dosage of 270 mg day(-1). Samples of urine, whole blood, plasma, and mane hair were analyzed before, during, and after drug administration. The data show that blood clearing and urinary excretion of MMA is a fast process following first-order kinetics with biological half-lives of about 38 h and 44 h for urine and plasma, respectively. In the time period of 9 days studied, the only metabolite detected in urine was dimethylarsinic acid (DMA(V)), which 4 days after the last drug administration accounted for up to 75% of the total excreted arsenic species. This shows, for the first time, that biomethylation of MMA(V) to DMA(V) is the principal metabolic pathway of this drug in horses. Although DS-MMA(V) was administered only during a short 5-day period, an up to six fold increase of arsenic could be measured in the newly grown mane hair.


Diarrhetic shellfish poisoning by okadaic acid esters from Brown crabs (Cancer pagurus) in Norway.
In 2002 several hundred people were taken ill after eating self-harvested brown crabs (Cancer pagurus) in the southern part of Norway. The symptoms were similar to diarrhetic shellfish poisoning (DSP) although with a somewhat delayed onset. This happened at the same time as an unusual early bloom of Dinophysis acuta had lead to high amounts of DSP toxins in blue mussels (Mytilus edulis) in the same area. The proposed cause of the intoxication was that crabs had accumulated toxins by eating blue mussels. Analyses of crab material from the area revealed very little free toxin in the form of okadaic acid (OA). However, after alkaline hydrolysis of the material, the amounts of OA found in the crabs were above the toxic level. MS/MS analysis of a sample from one intoxication episode indicated presence of the 14:0, 16:1, 16:0 and 18:1 fatty acid esters of okadaic acid. Esterified OA constituted more than 90% of total identified DSP toxins in crabs, indicating that not only esterified toxin from mussels was accumulated, but also that appreciable transfer of OA to OA-esters occurred in the crabs.


Arundic Acid (ONO-2506) Attenuates Neuroinflammation and Prevents Motor Impairment in Rats with Intracerebral Hemorrhage.
Intracerebral hemorrhage (ICH) is a severe stroke subtype caused by the rupture of blood vessels within the brain. Increased levels of S100B protein may contribute to neuroinflammation after ICH through activation of astrocytes and resident microglia, with the consequent production of proinflammatory cytokines and reactive oxygen species (ROS). Inhibition of astrocytic synthesis of S100B by arundic acid (AA) has shown beneficial effects in experimental central nervous system disorders. In present study, we administered AA in a collagenase-induced ICH rodent model in order to evaluate its effects on neurological deficits, S100B levels, astrocytic activation, inflammatory, and oxidative parameters. Rats underwent stereotactic surgery for injection of collagenase in the left striatum and AA (2 μg/μl; weight × 0.005) or vehicle in the left lateral ventricle. Neurological deficits were evaluated by the Ladder rung walking and Grip strength tests. Striatal S100B, astrogliosis, and microglial activation were assessed by immunofluorescence analysis. Striatal levels of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) were measured by ELISA, and the ROS production was analyzed by dichlorofluorescein (DCF) oxidation. AA treatment prevented motor dysfunction, reduced S100B levels, astrogliosis, and microglial activation in the damaged striatum, thus decreasing the release of proinflammatory cytokines IL-1β and TNF-α, as well as ROS production. Taken together, present results suggest that AA could be a pharmacological tool to prevent the harmful effects of increased S100B, attenuating neuroinflammation and secondary brain damage after ICH.


Is there a requirement for axillary lymph node dissection following identification of micro-metastasis or isolated tumour cells at sentinel node biopsy for breast cancer?
Recent decades have seen a significant shift towards conservative management of the axilla. Increasingly, immunohistochemical analysis of sentinel nodes leads to the detection of small tumour deposits, the significance of which remains uncertain. The aims of this study are to examine patients whose sentinel lymph nodes are positive for macro-metastasis, micro-metastasis or isolated tumour cells (ITCs) and to determine the rate of further nodal disease after axillary lymph node dissection (ALND). A retrospective analysis of all patients undergoing a sentinel lymph node biopsy (SLNB) between January 2007 and December 2010 in a tertiary referral breast unit was performed. Patients who underwent an axillary lymph node dissection for macro-metastasis, micro-metastasis or ITCs were identified. Demographics, histological data and the rate of further axillary disease were examined. In total, 664 breast cancer patients attended the symptomatic breast unit during the study period, 360 of whom underwent a SLNB. Seventy patients had a SLNB positive for macro-metastasis. All of these patients underwent ALND. A positive SLNB with either micro-metastasis or ITCs was identified in 58 patients. Only 41 of the 58 patients went on to have an ALND, due primarily to variations in surgeons' preferences. Nineteen patients with micro-metastasis underwent an ALND. Four patients had further axillary disease (21%). Twenty-two patients had ITCs identified, of whom only one had further disease (4.5%). No statistically significant difference was found between the two groups in terms of tumour size, grade, lymphovascular invasion or oestrogen receptor status. ALND should be considered in patients with micro-metastasis at SLNB. It should rarely be employed in the setting of SLNB positive for ITCs.


Detection of alkylating agents by the analysis of amino acid residues in hemoglobin and urine. 1. The in vivo and in vitro effects of ethyl methanesulfonate, methyl methanesulfonate, hycanthone methanesulfonate, and naltrexone.
The effect of alkylating agents on the amino acid composition of rat and human hemoglobin has been examined. Because the amino acid compositions of these proteins are well established, the changes in the molar ratios of specific amino acids could be monitored in purified hemoglobin samples. Ratios of histidine, which is readily attacked by alkylating agents, to proline, which is not, were consistent in hemoglobin purified from untreated blood samples from 14 rats and 25 human subjects. Treatment of hemoglobin in vitro or in vivo with methyl methanesulfonate, ethyl methanesulfonate, or hycanthone methanesulfonate resulted in a loss of histidine residues relative to proline or phenylalanine. The decrease in histidine content increased with treatment dose and time and reached a maximum at about 15% of total histidine. Treatment of rats with methyl methanesulfonate or hycanthone methanesulfonate resulted in increased urinary excretion of methyl histidines.


Survival after combined resection and ablation is not inferior to that after resection alone, in patients with four or more colorectal liver metastases.
Colorectal liver metastases (CRLM) are the predominant factor limiting survival in patients with colorectal cancer. Multimodal treatment strategies are frequently necessary to achieve total tumor elimination. This study examines the efficacy of liver resection combined with local ablative therapy in comparison to liver resection only, in the treatment of patients with ≥ 4 CRLM. This retrospective cohort study was conducted at the University Hospital RWTH Aachen, Germany. Patients with ≥ 4 CRLM in preoperative imaging, who underwent curative resection between 2010-2021, were included. Recurrent resections and deaths in the early postoperative phase were excluded. Ablation modalities included radiofrequency or microwave ablation, and irreversible electroporation. Differences in overall- (OS) and recurrence-free-survival (RFS) between patients undergoing combined resection-ablation vs. resection only, were examined. Of 178 included patients, 46 (27%) underwent combined resection-ablation and 132 (73%) resection only. Apart from increased rates of adjuvant chemotherapy in the first group (44% vs. 25%, p = 0.014), there were no differences in perioperative systemic therapy. Kaplan-Meier and log-rank test analyses showed no statistically significant differences in median OS (36 months for both, p = 0.638) or RFS (9 months for combined resection-ablation vs. 8 months, p = 0.921). Cox regression analysis showed a hazard ratio of 0.891 (p = 0.642) for OS and 0.981 (p = 0.924) for RFS, for patients undergoing resection only. For patients with ≥ 4 CRLM, combined resection-ablation is a viable option in terms of OS and RFS. Therefore, combined resection-ablation should be considered for complete tumor clearance, in patients with multifocal disease.


A bioactive microparticle-loaded osteogenically enhanced bioprinted scaffold that permits sustained release of BMP-2.
Extrusion-based bioprinting technology is widely used for tissue regeneration and reconstruction. However, the method that uses only hydrogel as the bioink base material exhibits limited biofunctional properties and needs improvement to achieve the desired tissue regeneration. In this study, we present a three-dimensionally printed bioactive microparticle-loaded scaffold for use in bone regeneration applications. The unique structure of the microparticles provided sustained release of growth factor for > 4 weeks without the use of toxic or harmful substances. Before and after printing, the optimal particle ratio in the bioink for cell viability demonstrated a survival rate of ≥ 85% over 7 days. Notably, osteogenic differentiation and mineralization-mediated by human periosteum-derived cells in scaffolds with bioactive microparticles-increased over a 2-week interval. Here, we present an alternative bioprinting strategy that uses the sustained release of bioactive microparticles to improve biofunctional properties in a manner that is acceptable for clinical bone regeneration applications.


Delayed-onset radiculopathy caused by a retropulsed bone fragment after percutaneous kyphoplasty: report of four cases and literature review.
Vertebral compression fractures caused by osteoporosis are common in elderly patients and are often encountered by clinical physicians. Percutaneous balloon kyphoplasty (PKP) is widely accepted as a minimally invasive procedure for effectively relieving pain and correcting deformities, but complications may occur. Radiculopathy with a delayed onset caused by a retropulsed bone fragment has not been adequately described in the literature. Thus, this article presents a case report of four cases of retropulsed bone fragment-related radiculopathy after PKP. In this article, we reported that four out of 251 patients developed radiculopathy after PKP between January 2012 and January 2019 despite experiencing substantial improvements in back pain. All patients with radiculopathy were female and diagnosed with osteoporosis, and their ages ranged from 68 to 89 years. Radiculopathy occurred from 2 to 16 weeks after PKP. All four patients underwent another operation (posterior decompression and instrumentation). Three patients recovered completely, and one died of postoperative intracranial haemorrhage. A detailed imaging study with pre- and postoperative magnetic resonance imaging (MRI) revealed that retropulsed bone fragments that impinged on the corresponding root after PKP were responsible for this complication, and all four patients developed a disrupted posterior vertebral rim preoperatively. No leakage of cement or pedicle track violations were observed. Although PKP is a safe and effective treatment for painful osteoporotic vertebral compression fractures, a risk of catastrophic neurological injury remains. Radiculopathy with delayed onset caused by a retropulsed bone fragment after kyphoplasty is rare and challenging to treat, and the integrity of the posterior vertebral cortex should be carefully evaluated preoperatively to prevent this complication.


Novel ATM mutations with ataxia-telangiectasia.
Ataxia telangiectasia is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia with onset in childhood, oculocutaneous telangiectasia, increased serum alpha-fetoprotein, immunodeficiency, chromosomal instability, and radiation hypersensitivity. Ataxia-telangiectasia mutated gene (ATM) is one of the known genes to be associated with ataxia telangiectasia. We reported the clinical and genetic findings of three early-onset Chinese patients who demonstrated ataxia, oculomotor apraxia, choreoathetosis, myoclonus and telangiectasia of eyes. Sequence analysis of ATM revealed two known nonsense mutations c.8287C>T and c.9139C>T in the siblings. Though the siblings carried the same mutations, they showed different clinical features involving strephenopodia, exotropia, torsion dystonia, myoclonus and extrapyramidal impairments. The other patient was compound heterozygotes for ATM: c.8911C>T and c.7141_7151delAATGGAAAAAT, both of which were not reported previously and not found in 200 control chromosomes. This study widens the spectrum of mutations and phenotypes in ataxia telangiectasia.


Temporal dynamics of perisylvian activation during language processing in children and adults.
The perisylvian region of the human cortex is known to play a major role in language processing. Especially the superior temporal cortex (STC) and the inferior frontal cortex (IFC) have been investigated with respect to their particular involvement in language comprehension. In the present research, the timing of recruitment of these language-related brain areas in both hemispheres was examined as a function of age using functional imaging data of 6-year-old children and adults with a special focus on blood oxygenation level dependent (BOLD) response time courses. The results show that children's activation time courses differ from that of adults. First, children show an overall later peak of BOLD responses. Second, children's IFC responds much later than their STC, while in adults the difference between both regions is less pronounced. Within the STC, both groups show similar regionally U-shaped activation patterns with fastest peaks in voxels at the STC's mid-portion around Heschl's gyrus and longer latencies in anterior and posterior directions, suggesting a coarsely similar information flow in adults and children in the temporal region. Finally, children in contrast to adults, display a temporal primacy of right over left hemispheric activation. The observed overall latency differences between children and adults are in line with the assumption of ongoing maturation in perisylvian brain regions and the connections between them. A functional perspective on BOLD timing argues for a developmental change from higher processing costs in children compared to adults due to slower and less automatic language processes, in particular those located in the IFC. The observed hemispheric differences are discussed in the context of developmental models assuming a high reliance on right-hemisphere-based suprasegmental information processing during language comprehension in childhood.