Uncovering the Fate and Risks of Intravenously Injected Prussian Blue Nanoparticles in mice by an Integrated Methodology of Toxicology, Pharmacokinetics, Proteomics, and Metabolomics.
Prussian blue (PB) nanoparticles (NPs) have been intensively investigated for medical applications, but an in-depth toxicological investigation of PB NPs has not been implemented. In the present study, a comprehensive investigation of the fate and risks of PB NPs after intravenous administration was carried out by using a mouse model and an integrated methodology of pharmacokinetics, toxicology, proteomics, and metabolomics. General toxicological studies demonstrated that intravenous administration of PB NPs at 5 or 10 mg/kg could not induce obvious toxicity in mice, while mice treated with a relatively high dose of PB NPs at 20 mg/kg exhibited loss of appetite and weight decrease in the first two days postinjection. Pharmacokinetic studies revealed that intravenously administered PB NPs (20 mg/kg) underwent fast clearance from blood, highly accumulated in the liver and lungs of mice, and finally cleared from tissues. By further integrated proteomics and metabolomics analysis, we found that protein expression and metabolite levels changed significantly in the liver and lungs of mice due to the high accumulation of PB NPs, leading to slight inflammatory responses and intracellular oxidative stress. Collectively, our integrated experimental data imply that the high accumulation of PB NPs may cause potential risks to the liver and lungs of mice, which will provide detailed references and guidance for further clinical application of PB NPs in the future.


A tutorial review for employing enzymes for the construction of G-quadruplex-based sensing platforms.
With rapid advances in the field of DNA chemistry, nucleic acids and DNA-modifying enzymes have recently emerged as versatile components for the construction of oligonucleotide-based sensors. Meanwhile, the G-quadruplex motif has been widely employed for the development of DNA-based assays due to its diverse structural variety. In this tutorial, we introduce the principles of G-quadruplex-based sensing and the use of DNA-modifying enzymes for sensor platform development. We also highlight recent studies of the application of DNA-modifying enzymes for the development of G-quadruplex-based luminescent detection platforms with a view towards how those enzymes play an important role in sensitivity enhancement.


Clinical efficacy of IgM-enriched immunoglobulin as adjunctive therapy in neonatal and pediatric sepsis: a systematic review and meta-analysis.
Sepsis is a major cause of mortality and morbidity globally, with around one-quarter of all sepsis-related deaths occurring in children under the age of 5. We conducted a meta-analysis and systematic review of the literature to evaluate the clinical effectiveness of an IgM-enriched immunoglobulin preparation in pediatrics patients and neonates with sepsis. Systematic searches of PubMed, the Cochrane Library and Embase databases were performed in November 2022, with no date limitations, to identify studies in which IgM-enriched immunoglobulin was used as adjunctive therapy in neonatal and pediatric patients with sepsis. In total, 15 studies fulfilled the eligibility criteria, 13 neonatal studies and 2 pediatric studies. Pooled estimates from all studies indicated that mortality rates were significantly lower in patients who received treatment with the IgM-enriched immunoglobulin compared with controls (OR 0.41; 95% CI 0.32-0.55). Further analyses in neonatal studies, alone, showed a significant benefit with longer treatment durations (>3 days) vs. the recommended treatment duration (3 days) (OR 0.32; 95% CI 0.22-0.47) vs. (OR 0.61; 95% CI 0.41-0.92). Treatment with IgM-enriched immunoglobulin was associated with a lower mortality risk compared with controls in prospective studies vs. retrospective analyses (OR 0.37; 95% CI 0.27-0.51) vs. (OR 0.73; 95% CI 0.41-1.30). This systematic review suggests that adjunctive treatment with IgM-enriched immunoglobulin may reduce the risk of mortality in neonatal and pediatric populations. However, large randomized controlled trials are required to further substantiate and evaluate these findings.


Low Ca diet leads to increased Ca retention by changing the gut flora and ileal pH value in laying hens.
Osteoporosis is a common degenerative metabolic bone disease in caged laying hens. Intensive egg production mobilizing large amounts of Ca from bone for eggshell formation, consequently leading to Ca deficiency, has been recognized as a critical factor causing osteoporosis in commercial laying hens. The aim of this study was to examine the effect of Ca deficiency on the function of the gut microbiota-bone axis and related egg production traits and bone health in laying hens. Twenty-four 48-week-old laying hens were fed a control diet (Control, 3.72%) or a low Ca diet (LC, 2.04%) for 60 d (n = 12). Compared to the Control hens, the LC hens had higher levels of alkaline phosphatase and tartrate resistant acid phosphatase (P < 0.05) with lower bone strength, eggshell thickness, and eggshell strength (P < 0.05). In addition, the LC hens had higher plasma estradiol concentrations, while having lower concentrations of interleukin-1 (IL-1) and IL-6. The LC hens also had a lower pH value in the ileum with an increased Ca retention. The principal co-ordinates analysis showed significantly separate cecal microbiota populations between the Control and LC hens. The Prevotellaceae_UCG-001, Subdoligranulum, Peptococcus, and Eubacterium_hallii_group (P < 0.05) were higher, while the CHKC1001 and Sutterella (P < 0.05) were lower at the genus level in the LC hens. In addition, Prevotellaceae_UCG-001, Subdoligranulum and Eubacterium_hallii_group had a negative correlation, while Sutterella was positively correlated with ileal pH values. The transcriptome analysis revealed that the low Ca diet caused 20 and 31 genes to be significantly up- and down-regulated, respectively. The gene expressions of cystic fibrosis transmembrane conductance regulator, solute carrier family 26 member 3 of the anion exchangers, and mitogen-activated protein kinase 12 of pro-inflammatory factors were lower in the LC birds, which was correlated with the lower ileal pH values. These results suggest that the hens with low Ca diet-induced osteoporosis have an increased intestinal Ca retention with a decreased ileal pH value, correlated with the changes in Prevotellaceae_UCG-001, Subdoligranulum, and Eubacterium_hallii_group of beneficial genera. The results provide insights for further understanding and preventing osteoporosis in laying hens.


Solid State NMR Structure Analysis of the Antimicrobial Peptide Gramicidin S in Lipid Membranes: Concentration-Dependent Re-alignment and Self-Assembly as a β-Barrel.
Antimicrobial peptides can kill bacteria by permeabilizing their cell membrane, as these amphiphilicmolecules interact favourably with lipid bilayers. This mechanism of action is attributed eitherto the formation of a peptide "carpet" on the membrane surface, or to a transmembranepore. However, the structure of such a pore has not yet been resolved under relevant conditions.Gramicidin S is a symmetrical cyclic β-sheet decapeptide, which has been previouslyshown by solid state NMR to lie flat on the membrane surface at low peptide:lipid ratios (≤ 1:80).Using highly sensitive (19)F-NMR, supported by (15)N-labelling,we found that gramicidin S can flip into an upright transmembrane alignment at high peptide:lipidratios (≥ 1:40). Orientational NMR constraints suggest that the peptide may self-assembleas an oligomeric β-barrel pore, which is stabilized by intermolecular hydrogen bonds. Comparisonof different model membranes shows that the observed re-alignment is favoured in thin bilayers withshort-chain lipids, especially near the chain melting temperature, whereas long-chain lipids suppresspore formation. Based on the oligomeric structural model and the conditions of pore formation, guidelinesmay now be derived for rationally designing peptide analogues as antibiotics with improved selectivityand reduced side effects.


Disappearance of the Brugada-type electrocardiogram after surgical castration: a role for testosterone and an explanation for the male preponderance.
We describe two cases of asymptomatic Brugada syndrome that displayed a persistent ECG manifestation, but in which the typical ECG pattern disappeared following surgical castration for prostate cancer. These facts suggest a possible association between manifestation of the Brugada-type ECG pattern and testosterone.


The effect of in vitro aging on human lung fibroblast beta-adrenergic receptor density, coupling and response.
Age-related changes in regulation of receptor response have been observed in several tissues and include regulation of beta-adrenergic receptor (beta-receptor) responses. The role of cellular aging in age-related changes in receptor response is not clear. We have examined the effect of aging in vitro on human fibroblast beta-receptor function. MRC-5 (embryonic lung) fibroblasts were aged by replication to produce cells of early, middle and late stages corresponding to the following cumulative population doublings: 15-20, 35-45 and greater than 50, respectively. Fibroblast membrane beta-receptor responses to isoproterenol (ISO, 0.1 mM) did not differ between the three stages. Adenylate cyclase responses to prostaglandin E1 (PGE1, 1 microM), guanosine triphosphate (GTP, 0.1 mM) and 5'-guanylimidodiphosphate (Gpp(NH)p, 0.1 mM) were also similar between the stages. Beta-receptor density (Bmax) was unaffected by in vitro aging. Beta-receptor agonist affinity, an indication of the capacity for beta-receptor coupling to the nucleotide binding protein (NS), was also unaffected by cell aging. These findings suggest that cellular aging in fibroblasts alone is not accompanied by changes in beta-receptor function.


Decreased contraction to phenylephrine by ouabain in 2K-1C rat aorta is modulated by the endothelium.
The effects of ouabain were studied on the contraction stimulated with phenylephrine or KCl in intact endothelium and denuded aortic rings isolated from normotensive (2K) and renal hypertensive 2 kidney-1clip (2K-1C) rats. Ouabain did not change the basal tone of aortic rings. Ouabain (1 nmol/l) had no effect on the contraction to phenylephrine in all the artery groups studied. Ouabain (10 nmol/l) decreased the E(max) to phenylephrine in intact endothelium arteries from 2K-1C. By contrast, ouabain (10 nmol/l) had no effect on the contraction to KCl. Ouabain induced membrane depolarization measured by confocal image with Di-4-ANEPPS dye, that was greater in 2K than in 2K-1C rat aorta smooth muscle cells. In conclusion, ouabain (10 nmol/l) decreased the contractile responses to phenylephrine only in 2K-1C rat aortic rings with intact endothelium. Interestingly, 10 nmol/l ouabain depolarizes the smooth muscle cells but this depolarization level is not enough to alter the phenylephrine or KCl-induced contractions. Our results indicate that the endothelium modulates the vascular action of ouabain.


Mechanism of cisplatin resistance in gastric cancer and associated microRNAs.
Gastric cancer (GC) is a common malignant tumor with high morbidity and mortality rates that seriously affects human health worldwide. Although surgery is currently the preferred clinical treatment for GC, chemotherapy remains the first choice for perioperative treatment, adjuvant therapy, and palliative care for patients with advanced GC. Cisplatin (DDP) is an antineoplastic agent that has been used clinically for decades, and it is the first-line chemotherapy for many solid tumors. However, the therapeutic efficacy of DDP is often limited by resistance and the complexity of its resistance mechanisms, which involve multiple proteins and signaling pathways. It is well documented that a variety of microRNAs (miRNAs) differentially expressed in DDP-resistant GC cells play important roles in regulating or reversing DDP resistance via various pathways. In this review, we first provide an introduction to the cytotoxicity and major resistance mechanisms of DDP in GC and then discuss the role and mechanism of miRNAs in regulating the DDP resistance process in GC cells. This work demonstrates the potential of relevant miRNAs to become diagnostic and prognostic biomarkers for gastric cancer and targets of action to enhance chemosensitivity and provides directions for future research.


When will video-assisted and robotic-assisted endoscopy replace almost all open surgeries?
This article traces the development of laparoscopy, and establishment resistance to its emergence as the technique to replace almost all laparotomies.


A cross-sectional study on stigma and discrimination confronted by HIV positive patients in the economic capital of India.
HIV/AIDS is a serious public health, economic and social problem. Stigma is a common human reaction to disease and discrimination follows stigma. Stigma and discrimination act as impediments to uptake of HIV testing, treatment, care and adherence to treatment. The aim of this study was to estimate the prevalence of the stigma and discrimination faced by HIV positive patients receiving antiretroviral therapy (ART). A cross-sectional, observational study conducted at ART center of a tertiary care hospital in an urban area. Participants were selected by simple random sampling among HIV positive patients. A predesigned, pretested and self-administered, semi-structured questionnaire in local language was used to assess stigma and discrimination. The data were entered in Microsoft Excel and analyzed with SPSS version 20 statistical software. Simple proportions, mean, standard deviation, median, range and inter-quartile range were calculated. Of 336 participants, 170 were male, whereas 166 were females. The mean age was 36.42 years. The total mean scores for Berger's HIV stigma scale experienced was 122.82, whereas for individual subscale Personalized stigma, Negative self-image, public attitudes and disclosure of HIV status were 38.31, 27.46, 33.09 and 23.97, respectively. The maximum participants expressed the stigma regarding disclosure concerns (58.63%) followed by negative self-image stigma (43.45%). Stigma hurdles the delivery of effective medical social care. People Living with HIV and AIDS (PLWHA) need to have greater involvement in their care, support and treatment. Support groups of PLWHA need to be established so that stigma and discrimination at various levels can be challenged collectively.


Intranasal Fentanyl and Quality of Pediatric Acute Care.
Changes in the manner in which medications can be delivered can have significant effects on the quality of care in the acute care setting. The objective of this study was to evaluate the change in three Institute of Medicine quality indicators (timeliness, safety, and effectiveness) in the pediatric emergency department (ED) after the introduction of the Mucosal Atomizer Device Nasal™ (MADn) for opioid analgesia. This was a retrospective review of patients receiving opioid analgesia for certain conditions over a 5-year period. We compared patients receiving intravenous opioid (IVO) to those receiving intranasal fentanyl (INF). Timeliness outcomes include time from medication order to administration, time from dose to discharge, overall time to analgesia, and ED length of stay. Effectiveness outcomes include change in pain score and frequency of repeat dosing. Safety outcomes were the frequency of reversal agent administration or a documented oxygen desaturation of < 90%. Sensitivity analyses were performed to evaluate the effect of moderate sedation on all three outcomes. During the study period, 1702 patients received opioid analgesia, 744 before and 958 after MADn introduction, of whom, 233 (24%) received INF. After MADn introduction, patients receiving INF had a shorter time to discharge from dose (109 vs. 203 min; p < 0.05) and shorter ED length of stay (168 vs. 267 min; p < 0.05). There was no difference in pain score reduction; however, repeat dosing was less frequent for patients receiving INF (16% vs. 27%). There was no use of reversal medication and no difference in the frequency of oxygen desaturations. When patients undergoing moderate sedation were removed from the analysis, there was no difference in the direction of findings for all three outcomes. INF is associated with improved timeliness and equivalent effectiveness and safety when compared to IVO in the setting of the pediatric ED.


Comparative analysis between self-collected and clinician-collected samples for HPV testing in public health facilities in Zimbabwe.
Cervical cancer screening programs that use visual inspection with acetic acid to identify women with pre-cancerous lesions in Zimbabwe have had limited success due to challenges with human resource constraints and patient acceptability. Nucleic acid amplification tests for human papillomavirus (HPV) have been endorsed by the World Health Organization for cervical cancer screening, along with self-collection of samples. As evidence shows self-collected sampling to be acceptable and preferable, Zimbabwe's Ministry of Health and Child Care (MOHCC) required a comparative analysis on the agreement between self- and clinician-collected samples for testing with Hologic Aptima HPV mRNA assay, to determine if self-collected samples could be used as another method to increase coverage of cervical cancer screening programs. In four public health facilities in Zimbabwe from July to August 2020, self- and clinician-collected HPV samples were obtained from HIV-positive women aged 30-49 years for HPV testing. A total of 280 self- and clinician-collected samples were tested and results were found to have good agreement (κ: 0.75, 95% CI: 0.66-0.82). HPV prevalence was 43.0% (95% CI: 37.0%-49.3%) for self-samples and 48.0% (95% CI: 41.0%-54.2%) for clinician-samples. Self-collected sampling had good agreement with clinician-collected and its inclusion in the national cervical cancer screening policy by Zimbabwe's MOHCC is expected to increase testing coverage, especially among underserved communities such as women living with HIV, as well as decentralize access to cervical cancer screening services for lower-level facilities and increase the geographical scope of where HPV testing can be offered through the country.


Glucocorticoids increase interleukin-6-dependent gene induction by interfering with the expression of the suppressor of cytokine signaling 3 feedback inhibitor.
Glucocorticoids are known to be potent regulators of inflammation and have been used pharmacologically against inflammatory, immune, and lymphoproliferative diseases for more than 50 years. Due to their possible and well-documented side effects, it is crucial to understand the molecular mechanisms and targets of glucocorticoid action in detail. Several modes of action have been discussed; nevertheless, none of them fully explain all the functions of glucocorticoids. Therefore, we analyzed the cross-talk between glucocorticoids and interleukin-6 (IL-6) in the liver. IL-6 exerts pro-inflammatory as well as anti-inflammatory properties and is a main inducer of the acute-phase response. The balance between the proinflammatory and anti-inflammatory activities of IL-6 is tightly regulated by suppressor of cytokine signaling 3 (SOCS3), a well-known feedback inhibitor of IL-6 signaling. Here, it is demonstrated that glucocorticoids enhance IL-6-dependent γ-fibrinogen expression. Studying of the underlying mechanism revealed prolonged activation of signal transducer and activator of transcription 3 (STAT3) caused by down-regulation of SOCS3 protein expression. Consequently, in SOCS3-deficient cells glucocorticoids do not affect IL-6-induced signal transduction. Moreover, in hepatocytes lacking the SOCS3 recruiting motif within gp130, IL-6-dependent γ-fibrinogen expression is not influenced by glucocorticoid treatment. Glucocorticoids interfere with IL-6-induced expression of the feedback inhibitor SOCS3, thereby leading to enhanced expression of acute-phase genes in hepatocytes. This mechanism contributes to the explanation of how glucocorticoids affect inflammation and acute-phase gene induction.


Metabolite damage and its repair or pre-emption.
It is increasingly evident that metabolites suffer various kinds of damage, that such damage happens in all organisms and that cells have dedicated systems for damage repair and containment. First, chemical biology is demonstrating that diverse metabolites are damaged by side reactions of 'promiscuous' enzymes or by spontaneous chemical reactions, that the products are useless or toxic and that the unchecked buildup of these products can be devastating. Second, genetic and genomic evidence from prokaryotes and eukaryotes is implicating a network of new, conserved enzymes that repair damaged metabolites or somehow pre-empt damage. Metabolite (that is, small-molecule) repair is analogous to macromolecule (DNA and protein) repair and seems from comparative genomic evidence to be equally widespread. Comparative genomics also implies that metabolite repair could be the function of many conserved protein families lacking known activities. How--and how well--cells deal with metabolite damage affects fields ranging from medical genetics to metabolic engineering.


Studies on prolonged acute regional ischemia. II. Implications of progression from dyskinesia to akinesia in the ischemic segment.
This study analyzed the pattern of regional wall motion in 58 dogs undergoing 4 to 6 hours of left anterior descending coronary artery occlusion. Regional wall motion was measured by ultrasonic crystals and ischemic muscle either remained dyskinetic (-40% of control systolic shortening, n = 26) or progressed toward akinesia (less than 20% of control systolic shortening or greater than 50% reduction in passive lengthening, n = 32). Ten dogs underwent unmodified blood reperfusion. Regional blood flow (radioactive microspheres), histochemical damage (triphenyltetrazolium chloride staining), and mitochondrial function were determined. Hearts showing persistent dyskinesia had more collateral flow (12 versus 2 ml/100 gm/min, p less than 0.05), less histochemical damage (26% versus 63% area at risk/area of nonstaining, p less than 0.05), and better retention of mitochondrial oxidative phosphorylation capacity (adenosine triphosphate, 622 versus 444 nmol/mg protein/min, p less than 0.05), and tended toward mitochondrial calcium accumulation (48 versus 64 nmol/mg protein). Unmodified blood reperfusion after 4 hours of ischemia produced prompt akinesia (-2% +/- 3% systolic shortening) and was associated with increased edema (82% water content), caused the low-reflow phenomenon (19% control subendocardial flow, 13 ml/100 gm/min), and increased histochemical damage (69% triphenyltetrazolium chloride nonstaining, p less than 0.05). These findings suggest that persistent dyskinesia during early ischemia (first 6 hours) may reflect a relatively optimistic sign, as regression to akinesia occurs in muscle with less collateral flow, more impaired mitochondrial function, worsened calcium homeostasis, and more severe histochemical and ultrastructural damage. These observations imply that careful evaluation of ischemic wall motion may provide a valuable insight into potential muscle salvage.


Correction to: Retrospective analysis of fractionated intensity-modulated radiotherapy (IMRT) in the interdisciplinary management of primary optic nerve sheath meningiomas.
An amendment to this paper has been published and can be accessed via the original article.


Chromium(VI) removal by mechanochemically sulfidated zero valent iron and its effect on dechlorination of trichloroethene as a co-contaminant.
Mechanochemically sulfidated microscale zero valent iron (S-mZVIbm) is a promising groundwater remediation material as it has been proven to be not only efficient in dechlorinating chlorinated compounds but also amenable to up-scaling. Yet, its efficiency in treating metal contaminants remains barely studied. In this study, we investigated the mechanism and efficiencies of Cr(VI) removal by S-mZVIbm and its effect on TCE dechlorination as a co-contaminant. The Cr(VI) removal by S-mZVIbm was mainly a chemisorption process and its kinetics was well fitted by a pseudo-second-order model. Alkaline pH inhibited Cr(VI) removal while dissolved oxygen slightly depressed the Cr(VI) removal. The Cr(VI) removal rapidly formed a non-conductive layer on S-mZVIbm surface to hinder further electron transfer from Fe0 core before H+ was able to accept any electrons to produce H2, which resulted in 100% electron efficiencies of Cr(VI) removal but <1% of Fe0 utilization efficiency. The presence of Cr(VI) also dramatically inhibited the dechlorination of TCE and its electron efficiency as a co-contaminant by passivating the FeS surface. Therefore, Cr(VI) is likely to be an electron sink if present for remediation of other contaminants in groundwater.


Diffusion properties of NAA in human corpus callosum as studied with diffusion tensor spectroscopy.
In diffusion tensor imaging (DTI) the anisotropic movement of water is exploited to characterize microstructure. One confounding issue of DTI is the presence of intra- and extracellular components contributing to the measured diffusivity. This causes an ambiguity in determining the underlying cause of diffusion properties, particularly the fractional anisotropy (FA). In this study an intracellular constituent, N-acetyl aspartate (NAA), was used to probe intracellular diffusion, while water molecules were used to probe the combined intra- and extracellular diffusion. NAA and water diffusion measurements were made in anterior and medial corpus callosum (CC) regions, which are referred to as R1 and R2, respectively. FA(NAA) was found to be greater than FA(Water) in both CC regions, thus indicating a higher degree of anisotropy within the intracellular space in comparison to the combined intra- and extracellular spaces. A decreasing trend in the FA of NAA and water was observed between R1 and R2, while the radial diffusivity (RD) for both molecules increased. The increase in RD(NAA) is particularly significant, thus explaining the more significant decrease in FA(NAA) between the two regions. It is suggested that diffusion tensor spectroscopy of NAA can potentially be used to further characterize microscopic anatomic organization in white matter.


Early Supplementation of d-Cysteine or l-Cysteine Prevents Hypertension and Kidney Damage in Spontaneously Hypertensive Rats Exposed to High-Salt Intake.
We investigate whether early supplementation of precursors of hydrogen sulfide (H2 S), d- or l-cysteine can prevent hypertension and kidney damage in spontaneously hypertensive rats (SHR) treated with high-salt. We examine 12-week-old male SHRs from four groups: SHR, high salt SHR (SHRs received 1% NaCl in drinking water for 8 weeks), high salt SHR+d (SHRs received high salt and d-cysteine), and high salt SHR+l (SHRs received high salt and l-cysteine). d- or l-cysteine was supplemented at 8 mmol kg-1 body weight/day between 4 and 6 weeks of ages. High salt intake exacerbate hypertension and kidney damage in SHRs, which is prevented by d- or l-cysteine supplementation. d- or l-Cysteine supplementation reduce the degree of high salt-induced oxidative stress damage. Renal 3-mercaptopyruvate sulphurtransferase (3MST) protein levels and activity are reduced by d- or l-cysteine supplementation. Additionally, d- or l-Cysteine supplementation reduce renal angiotensin I and angiotensin II concentrations, decrease mRNA expression of Ren, and increase protein levels of type 2 angiotensin II receptor. Early supplementation of d- or l-cysteine before hypertension becomes evident and may protect against hypertension and kidney damage in adult SHRs exposed to high salt consumption via regulation of oxidative stress, renin-angiotensin system, and H2 S-generating pathways.


Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function.
This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL(CR)s) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL(CR)s of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL(CR)s of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC(τ)) was computed as dose/CL. The probability of achieving an AUC(τ)/MIC ratio of ≥ 219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC(τ)/MIC ratio of ≥ 219 for MIC values as high as 2 mg/liter. For patients with CL(CR)s of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC₀₋₂₄ (AUC from 0 to 24 h) and AUC₂₄₋₄₈ intervals for MICs of ≤ 1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC₀₋₂₄ and AUC₂₄₋₄₈ intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate.


Cross-species transcriptomics reveals bifurcation point during the arterial-to-hemogenic transition.
Hemogenic endothelium (HE) with hematopoietic stem cell (HSC)-forming potential emerge from specialized arterial endothelial cells (AECs) undergoing the endothelial-to-hematopoietic transition (EHT) in the aorta-gonad-mesonephros (AGM) region. Characterization of this AECs subpopulation and whether this phenomenon is conserved across species remains unclear. Here we introduce HomologySeeker, a cross-species method that leverages refined mouse information to explore under-studied human EHT. Utilizing single-cell transcriptomic ensembles of EHT, HomologySeeker reveals a parallel developmental relationship between these two species, with minimal pre-HSC signals observed in human cells. The pre-HE stage contains a conserved bifurcation point between the two species, where cells progress towards HE or late AECs. By harnessing human spatial transcriptomics, we identify ligand modules that contribute to the bifurcation choice and validate CXCL12 in promoting hemogenic choice using a human in vitro differentiation system. Our findings advance human arterial-to-hemogenic transition understanding and offer valuable insights for manipulating HSC generation using in vitro models.


Immunogenic variants obtained by mutagenesis of mouse Lewis lung carcinoma. Recognition of variant-specific antigens by cytolytic T lymphocytes.
By mutagenesis of a cell line derived from Lewis lung carcinoma (3LL), it is possible to obtain at high frequency stable tumor cell variants (tum-) that are rejected by syngeneic mice. The possibility of obtaining a cytolytic T cell (CTL) response directed specifically against these tum- variants was examined. With the four variants that were analysed, a significant cytolytic activity was obtained with peritoneal cells from immune mice collected shortly after an intraperitoneal boost and also with spleen cells after a secondary stimulation in vitro. The CTL populations preferentially lysed the immunizing tum- variant, while also showing a cross-reactive lysis against the other variants and the original 3LL cells. Highly active CTL clones could be isolated from limiting dilution microcultures of these CTL populations. The clonal analysis clearly showed the existence of two distinct CTL populations, one directed exclusively against the immunizing variant and another that lysed all 3LL targets equally. This CTL specificity analysis therefore demonstrates directly the presence of new antigens on the 3LL tum- cell variants.


Biodegradation of Reactive Yellow-145 azo dye using bacterial consortium: A deterministic analysis based on degradable Metabolite, phytotoxicity and genotoxicity study.
Azo dyes are used at larger-scale as coloring agent in the textile industry. It generates a huge amount of dye containing wastewater and its toxicity threatens all kinds of life and also impacts human beings. At present, more impetus is being given to the biological treatment of dye effluent because of its azoreductase enzyme action to break down azo bond which leads to decolorization and degradation of dye. Bacterial consortium of E. asburiae and E. cloacae (1:1 ratio) was used for degradation and decolorization of Reactive Yellow-145 (RY-145) dye. The optimization of dye concentration, temperature, pH, and media has been carried out to determine the conditions required for maximum degradation and decolorization. The mixed consortium (10%) has shown 98.78% decolorization of RY-145 dye under static condition at 500 mgL-1 concentration, 35 °C and pH 7.0 at 12 h contact period. FTIR analysis showed formation of new functional groups in the treated dye, such as O-H stretch at 1361 cm-1, C-H stretch at 890 cm-1, N-H stretch at 1598 cm-1 and aromatic C-H at 671 cm-1 revealing degradation of dye. Biodegraded metabolites of RY-145 dye were identified through GC-MS analysis that includes 2-Cyclohexen-1-ol, 5-Nitroso-2, 4, 6-triaminopyrimidine, Octahydroquinoline-9-hydroxyperoxide, Tetramethyl-2-hexadecen-1-ol, 9-Octadecanoic acid, methyl ester and Hexadecanoic acid, methyl ester, respectively which have industrial applications. Cyclohexane was used in gasoline and adhesive while Octahydroquinoline-9-hydroxyperoxide and 5-Nitroso-2, 4, 6-triaminopyrimidine were used in manufacturing drugs. Tetramethyl-2-hexadecen-1-ol, 9-Octadecanoic acid, methyl ester and Hexadecanoic acid, methyl ester are antimicrobial and antioxidant. Phytotoxicity test also showed non-toxic effects of treated dye on germination of Cicer arietinum and Vigna radiata seeds. Similarly, genotoxicity study indicated less toxic effects of biodegraded dye products on Mitotic index (MI) and cell division of Allium cepa.


[Replantations: indications and operative technique (author's transl)].
Replantation is indicated without exception in amputations of the thumb, in children, and upon loss of several fingers. Other factors include the type of injury, the interval between injury and vascular anastomoses, the condition and preoperative treatment of the amputated part as well as age, occupation, and general condition of the patient. The operative technique is described with the sequence of repair of the anatomical structures: bone, flexor tendons, arteries, extensor tendons, veines, nerves, and skin; possible complications are mentioned.


Laparoscopic management of an obstructed obturator hernia: should laparoscopic assessment be the default option?
An obturator hernia is a rare diagnosis that is frequently missed. Patients present with few clinical signs to identify the cause, apart from symptoms of intestinal obstruction. Therefore, obturator hernias are often diagnosed at exploratory laparotomy. The use of computed tomography (CT) has increased the chance of definitive preoperative diagnosis. However, despite these advances, patients who present acutely will frequently undergo an open procedure rather than laparoscopy. We present a case of an acute obstructed obturator hernia diagnosed in a 62-year-old female that was successfully managed laparoscopically.


New aspects of cerebrospinal fluid dynamics in humans investigated by sequential gamma camera cisternography, with data evaluation by the digital multichannel analyzer. Part 4: A unifying criterion of the development of hydrocephalic syndrome. Its dynamic basis.
In the final part of this series we present all of the clinical material, and the patients are classified by different cisternographic syndromes on the dynamic basis offered for our method: dynamic disconnection between ventricular system and basal cisterns, brain atrophy, initial dynamic decompensation or prehydrocephalus, communicating hydrocephalus with and without epicortical fluid circulation. A nomogram method for clinical estimation of CSF production based on the mathematical properties of our analysis of the ventricular reflux is proposed. The different normal and pathological characteristics of fluid movements in the spinal canal are given, and their importance as signs of turbulence in the posterior fossa are emphasized. Different aspects of the dynamics of CSF production are shown and discussed, and an evolving conception of hydrocephalus development is presented.


Identification of new NY-ESO-1 epitopes recognized by CD4+ T cells and presented by HLA-DQ B1 03011.
NY-ESO-1 is one of the most immunogenic cancer antigens eliciting strong humoral and cellular immune responses in patients with NY-ESO-1-expressing malignancies. Since CD4+ T cells play a critical role in generating and maintaining antigen-specific cellular and humoral immune responses, we searched for new NY-ESO-1 epitopes presented by MHC class II molecules. CD4+ T cells of patients with NY-ESO-1-expressing cancer were presensitized with 18-mer overlapping synthetic peptides spanning the entire sequence of NY-ESO-1. Two partly overlapping NY-ESO-1 epitopes p49-66 and p55-72 were identified as targets for NY-ESO-1-specific CD4+ T cells. Peptide-specific CD4+ T-cell clones were generated by repetitive stimulation with NY-ESO-1 p49-66 and p55-72. Further experiments confirmed distinct specificities for the CD4+ T-cell clones indicating that at least 2 different CD4+ T-cell epitopes are located in the region p49-72 of the NY-ESO-1 sequence. Using a set of partially histocompatible EBV-B cell lines and MHC class II-specific antibodies, we found that both CD4+ T-cell epitopes were presented in the context of HLA-DQ B1 03011(DQ7). Natural processing and presentation of these epitopes was demonstrated by recognition of an HLA-DQ B1 03011- and NY-ESO-1-expressing lymphoma cell line and by recognition of dendritic cells (DC) exogenously loaded with NY-ESO-1 protein or infected with recombinant NY-ESO-1 adenoviral constructs. The specific production of IFN-gamma and TNF-alpha suggests that the NY-ESO-1-specific CD4+ T-cell clones belong to the Th1 subtype. The characterization of the new HLA-DQ B1 03011-restricted NY-ESO-1 peptides broadens the repertoire of epitopes that can be used to monitor NY-ESO-1-specific spontaneous and vaccine-induced T-cell responses in cancer patients.


Review on the environmental impact of emissions from space launches: a case study for areas affected by the Russian space programme.
In this paper, we summarised the main field-based approaches and a large volume of data on the territories affected by the Russian space programme conducted at Plesetsk, Baikonur, and Vostochny cosmodromes. Influence of space transportation on the ozone layer depletion, as well as on environmental and human health, is negligible. The environmental consequences of rocket and space activities within launch pads and the terrestrial drop zones of jettisoned first stages of launch vehicles are allowable. Moreover, it is negligible in the second stage drop zones. Unsymmetrical dimethylhydrazine pollution is local and does not result in the formation of ecological disaster zones because ecosystems restore by themselves. Influence of rocket launches on the mesospheric cloud formation is short-time or/and insignificant. The environmental impact of space transportation by the Russian space programme on the terrestrial ecosystems is well-studied. To approve or to disprove these findings similar researches should be carried out in other terrestrial and aquatic drop zones affected due to the space programmes of other countries.


An electrochemical biosensor to distinguish between normal and cancer cells based on monitoring their acidosis using gold-coated silicon Nano-roughened electrode.
One of the most interesting fields of research in cancer diagnosis is tracing the relation between extracellular media and cancer progression. Detecting the secreting contents of the cells and translating these molecular identifications into label-free recognizable patterns would open new opportunities in cancer research. Electrochemical responses are in the range of most attractive sensing mechanisms especially in biochemical approaches. Perturbed ionic exchanges as a known biochemical function of cancer cells presented a strong correlation with the pH of the tumor microenvironment. Different ionic activities detected by an electrochemical bio-sensing system in the malignant and normal cells in the presence of acidic ambient were our main results presented in this research. Herein, silicon Nano-roughened substrate as a well-known electrochemical interface was applied in the construction of the biosensor. Viability rate as well as apoptotic factors involving in cancer progression were assessed by biochemical assays in normal (MCF10A) and cancer (MCF7 and MDA-MB468) breast cells. Our findings demonstrated that pH-based electrochemical responses were matched with the results obtained from the biological analyses of both normal and malignant cells. Induction of acidosis in the cells followed by monitoring their electrochemical responses would be a new trend in microenvironment based cancer investigation.


Multiple uptake of 99mTc-MDP in chest due to breast implant rupture in a patient with lung adenocarcinoma.
A 57-year-old woman was diagnosed as lung adenocarcinoma. 99mTc-MDP bone scan showed multiple radioactivity concentrated lesions on bilateral chest wall, which were confirmed as calcification foci after breast implant rupture by SPECT/CT. SPECT/CT could be used for differential diagnosis of breast implant rupture and malignant lesions.


The human impact of commercial delivery cycling injuries: a pilot retrospective cohort study.
Commercial delivery cyclists represent a uniquely vulnerable and poorly understood road user. The primary aim of this study was to pilot whether cycling injuries could be categorised as either commercial or non-commercial using documentation entered into routine hospital medical records, in order to determine the feasibility of conducting a large cohort study of commercial cycling injuries in the future. A secondary aim was to determine which key demographic, incident and injury characteristics were associated with commercial versus non-commercial cycling injuries in emergency. Pilot retrospective cohort study of adults presenting to an acute public hospital emergency department between May 2019 and April 2020 after sustaining a cycling-related injury. Multinomial logistic regression was used to examine the demographic, incident and injury characteristics associated with commercial compared to non-commercial cycling. Of the 368 people presenting to the emergency department with a cycling-related injury, we were able to categorise 43 (11.7%) as commercial delivery cyclists, 153 (41.6%) as non-commercial cyclists and the working status of 172 (46.7%) was unable to be confirmed. Both commercial and unconfirmed cyclists were more likely to be younger than non-commercial cyclists. Compared to non-commercial cyclists, commercial cyclists were 11 times more likely to speak a language other than English (AOR 11.3; 95% CI 4.07-31.30; p<0.001), less likely to be injured from non-collision incidents than vehicle collisions (AOR 0.36; 95% CI 0.15-0.91; p=0.030) and were over 13 times more likely to present to the emergency department between 8.00pm and 12.00am compared to the early morning hours (12.00 to 8.00am) (AOR 13.43; 95% CI 2.20-82.10; p=0.005). The growth of commercial cycling, particularly through online food delivery services, has raised concern regarding commercial cyclist safety. Improvements in the recording of cycling injury commercial status is required to enable ongoing surveillance of commercial cyclist injuries and establish the extent and risk factors associated with commercial cycling.


Exposure assessment of Bisphenol A intake from polymeric baby bottles in formula-fed infants aged less than one year.
BisphenolA (BPA) or 2,2-bis(4-hydroxyphenyl)propanepresent in polycarbonate baby bottles may have harmful effects for formula-fed infants. This study evaluated the risks associated with exposure to BPA among Iranian formula-fed infants in an urban society in Isfahan. New and used baby bottles (n = 7 and 8, respectively) as well as BPA-free marked bottles (n = 2) were collected from a retail outlet, and leaching of BPA was examined by conducting a migration test. Concentrations of BPA released from the new and used baby bottles were in the range of 0.49⿿8.58 and 0.63⿿2.47 μg/l, respectively. Next, probabilistic exposure estimation was performed. In all, 200 mothers registered with 11 health centres in Isfahan were interviewed. Data on feeding pattern, washing and sterilization practices, bottles types and manufacturers as well as the sex and weight of the infants were collected using a questionnaire. The results showed that majority of the surveyed infants were exposed to 0.1⿿0.3 μg/kg body weight (bw)/d of BPA, which corresponded to approximately 2⿿7.5% of the defined t-TDI (4 μg/kgbw/d). These results suggested that the risk of the adverse effects caused by exposure to BPA was very low in formula-fed Iranian infants even in the worst-case scenario.


Manuifolin Q, an unusual 4-aryl-substituted isoflavan from Maackia tenuifolia.
Manuifolin Q (1), an unusual 4-aryl-substituted isoflavan, was isolated from the roots of Maackia tenuifolia. Its absolute configuration was determined as (3R,4R)-3,4-trans-7,2'-dihydroxy-4'-methoxy-4-[(2,4-dihydroxy-5-(1,1-dimethyl-2-propenyl)]-phenyl-isoflavan, on the basis of spectroscopic analysis.


Research Advances in the Plant-Nematode Interaction.
Nematodes, which are highly important and abundant animals in the animal kingdom, demonstrate remarkable adaptability to various environments [...].


Operative management of external auditory canal cholesteatoma: case series and literature review.
To describe the clinical features of external auditory canal cholesteatoma, and to assess the outcome following bony meatoplasty with tragal cartilage and perichondrium graft repair. A retrospective review was carried out, comprising all patients with external auditory canal who presented between January 2007 and December 2011. Patients underwent pre-operative audiometry and computed tomography imaging of the temporal bones, before undergoing bony meatoplasty via a postauricular incision. Pre- and post-operative comparisons were made of patients' otological symptoms and the otoscopic appearance of the external ear canal. Eight patients were included in the analyses. The median age of patients was 46.5 years (range 14–68 years), with a male to female ratio of 1:1. The median length of follow up was 16 months. The most common presenting features were unilateral otalgia and purulent otorrhoea. All patients had relatively advanced disease at presentation, with erosion of the temporal bone. All patients underwent bony meatoplasty via a postauricular approach to eradicate the disease. Bony meatoplasty was successful in the definitive management of external ear canal cholesteatoma.


Diagnostic investigations of DKK-1 and PDCD5 expression levels as independent prognostic markers of human chondrosarcoma.
In this study, we investigated the expression levels of Dickkopf-1 (DKK-1) and programmed cell death 5 (PDCD5) by using quantitative real-time PCR and immunohistochemistry in patients with chondrosarcoma. The DKK-1 mRNA levels were significantly higher in chondrosarcoma when compared with the corresponding nontumor tissues (mean ± SD: 4.23 ± 1.54; 1.54 ± 0.87; P = 0.001). PDCD5 mRNA levels were remarkably deceased in tumor tissues when compared with corresponding nontumor tissues (mean ± SD: 1.94 ± 0.73; 5.42 ± 1.73; P = 0.001). The high and moderate DKK-1 expressions were observed for 60% of chondrosarcoma samples in comparison with 27.5% of corresponding nontumor tissues (P = 0.001). Moreover, low expression of PDCD5 was found in 67.5% of the tumor tissues when compared with the nontumor tissues (32.5%; P = 0.002). The results of this study showed that high DKK-1 expression levels were strongly related to MSTS stage (P = 0.011) and the advancement of histological grade (P < 0.001). Furthermore, the PDCD5 expression levels were correlated with histological grade (P < 0.001), MSTS stage (P = 0.016), and distant metastasis (P = 0.001). Kaplan-Meier survival and log-rank survival showed that patients with high DKK-1 levels and low PDCD5 levels were correlated with shorter overall survival (log-rank test P < 0.001). PDCD5 levels, histological grade, and tumor stage were independent predictors of overall survival. In conclusion, DKK-1 and PDCD5 can be independent predictors of overall survival in patients suffering from chondrosarcoma. © 2016 IUBMB Life, 68(7):597-601, 2016.


HapCUT2: A Method for Phasing Genomes Using Experimental Sequence Data.
Rapid advances in high-throughput DNA sequencing technologies have enabled variant discovery from whole-genome sequencing (WGS) datasets; however linking variants on a chromosome together into haplotypes, also known as haplotype phasing, remains difficult. Human genomes are diploid and haplotype phasing is crucial for the complete interpretation and analysis of genetic variation.Hapcut2 ( https://github.com/vibansal/HapCUT2 ) is an open-source software for phasing diploid genomes using sequence data generated using different sequencing technologies and experimental methods. In this article, we give an overview of the algorithm used by Hapcut2 and describe how to use Hapcut2 for haplotype phasing of individual genomes using different types of sequence data.


Concussive head injury exacerbates neuropathology of sleep deprivation: Superior neuroprotection by co-administration of TiO2-nanowired cerebrolysin, alpha-melanocyte-stimulating hormone, and mesenchymal stem cells.
Sleep deprivation (SD) is common in military personnel engaged in combat operations leading to brain dysfunction. Military personnel during acute or chronic SD often prone to traumatic brain injury (TBI) indicating the possibility of further exacerbating brain pathology. Several lines of evidence suggest that in both TBI and SD alpha-melanocyte-stimulating hormone (α-MSH) and brain-derived neurotrophic factor (BDNF) levels decreases in plasma and brain. Thus, a possibility exists that exogenous supplement of α-MSH and/or BDNF induces neuroprotection in SD compounded with TBI. In addition, mesenchymal stem cells (MSCs) are very portent in inducing neuroprotection in TBI. We examined the effects of concussive head injury (CHI) in SD on brain pathology. Furthermore, possible neuroprotective effects of α-MSH, MSCs and neurotrophic factors treatment were explored in a rat model of SD and CHI. Rats subjected to 48h SD with CHI exhibited higher leakage of BBB to Evans blue and radioiodine compared to identical SD or CHI alone. Brain pathology was also exacerbated in SD with CHI group as compared to SD or CHI alone together with a significant reduction in α-MSH and BDNF levels in plasma and brain and enhanced level of tumor necrosis factor-alpha (TNF-α). Exogenous administration of α-MSH (250μg/kg) together with MSCs (1×106) and cerebrolysin (a balanced composition of several neurotrophic factors and active peptide fragments) (5mL/kg) significantly induced neuroprotection in SD with CHI. Interestingly, TiO2 nanowired delivery of α-MSH (100μg), MSCs, and cerebrolysin (2.5mL/kg) induced enhanced neuroprotection with higher levels of α-MSH and BDNF and decreased the TNF-α in SD with CHI. These observations are the first to show that TiO2 nanowired administration of α-MSH, MSCs and cerebrolysin induces superior neuroprotection following SD in CHI, not reported earlier. The clinical significance of our findings in light of the current literature is discussed.


Dietary uptake of Salvia macilenta extract improves Nrf2 antioxidant signaling pathway and diminishes inflammation and apoptosis in amyloid beta-induced rats.
Studies showed the protective role of Salvia in traditional medicine against neurodegenerative diseases. Salvia macilenta is one of the potent antioxidant herbs among Salvia species against oxidative stress. In the current study, the effect of oral administration of S. macilenta in the antioxidant, anti-inflammatory activities of Aβ-injected male albino Wistar rats was determined. Rats were received S. macilenta (50 mg/kg/day) orally, for ten successive days and then some of them received Aβ (10 ng/µl) in their hippocampus (CA1 region). Proteins involved in antioxidant defense system and inflammatory signaling pathways in the hippocampus and prefrontal cortex were evaluated using Western blotting technique. To study apoptosis, Western blotting technique and histological staining were used. Catalase activity, glutathione peroxidase (GSH) and nitric oxide levels were measured. Results demonstrated that S. macilenta increased Nrf2 protein level and decreased TNFα and IL-6 protein level in Aβ-injected rats compared to the Aβ-injected group in the hippocampus and prefrontal cortex. Histological analysis showed pretreatment with S. macilenta decreased apoptosis levels in the hippocampus and prefrontal cortex, about 41 and 42%, compared to Aβ-injected rats, respectively. This study showed that catalase activity was changed in the S. macilenta + Aβ group compared to the Aβ-injected rats. Also, GSH level was increased in the S. macilenta + Aβ group compared to the Aβ-injected rat. Orally treatment of S. macilenta extract in Aβ-injected rats could ameliorate protective pathways and, so, it can be one of the proposed dietary supplements for the prevention of Alzheimer's disease and dementia.


Evaluation of preoperative prediction of intestinal invasion in patients with ovarian cancer.
To optimize prediction for intestinal invasion of epithelial ovarian cancer. It is important to achieve debulking surgery to improve prognosis in ovarian cancer; intestinal resection is adopted if the cancer is invaded and resectable, but the preoperative evaluation method of intestinal invasion is still controversial. Patients (n = 174) who underwent primary debulking surgery for epithelial ovarian cancer were recruited for retrospective study; 28 and 146 patients were classified into the invasion and non-invasion groups, whether they needed intestinal resection or not. We collected clinical data including evaluation of computed tomography (CT), magnetic resonance imaging (MRI), and barium contrast radiography, and analyzed their accuracy. The sensitivity and specificity for intestinal invasion were 33.3% and 98.6%, 42.9% and 98.6%, and 66.7% and 93.9% in CT, MRI, and barium contrast radiography, respectively. CT and MRI combined showed a sensitivity of 58.3% and specificity of 96.9%; all three methods combined was the most sensitive combination, showing a sensitivity of 79.2% and specificity of 90.8%. Combination of CT, MRI, and barium contrast radiography predicts intestinal invasion with the highest sensitivity. These three modalities, however, could not predict all intestinal invasion. Patients should be informed of the possibility of unexpected extensive resection.


Comparison of the learning curve of intraoral scanning with two different intraoral scanners based on scanning time.
The appearance of intraoral scanners (IOSs) in dental offices was an important milestones for the digital innovations in dentistry. Knowing the learning curve for intraoral scanning is crucial, because it can serve as a guideline for clinicians before buying a new IOS. The aim of the present in vivo study was to determine the learning curve required by dental students for intraoral scanning with the 3Shape Trios 4 IOS and the CEREC Primescan IOS, based on scanning time. A total of 20 dental students with no previous experience in intraoral scanning participated in the present study. 10 students scanned with Trios 4® IOS (TRI) and 10 students took digital impressions with Primescan® IOS (CER). Every student created 15 digital impressions from patients. Prior to taking the impressions, theoretical and practical education was provided. The total scanning time included the upper and lower arches as well as bite registration, for which average values were calculated. Statistical analysis was performed using the Stata package with a mixed-effects generalized least squares regression models. The average total scanning times were the following: TRI - 205 s for the 1st impression, 133.6 s for the 15th, CER - 289.8 s for the 1st impression, 147 s for the 15th. The model-based estimate of the difference between the two in case of TRI was 57.5 s, and in CER was 144.2 s which is a highly significant improvement in both cases (P < 0.0001). The slope of the scanning time vs. learning phase curve gradually approached flatness, and maintained a plateau: TRI - from the 11th measurement and CER - from the 14th measurement onward. Given the limitations of the present study, we found difference between the learning curve of scanner types which are operate various principle of imaging. In case of the TRI fewer digital impressions (11 repeating) were sufficient to reach the average scanning time of an experienced user than using CER (14 repeating). The permission for this study was given by the University Ethics Committee of Semmelweis University (SE RKEB number: 184/2022).


Cholecystokinin antagonism by anthramycin, a benzodiazepine antibiotic, in the central nervous system in mice.
Anthramycin (ATM) which is a product of some streptomyces micro-organisms was shown to antagonize the central effects of cholecystokinin (CCK) such as antinociception and satiety and to displace CCK bound to the slices from the brains of mice. Sulfated octapeptide CCK (CCK8) was administered intracisternally to mice at doses of 1 microgram/mouse for inducing antinociception and 200 ng/mouse for satiety. ATM was administered intraperitoneally to mice at doses such as 0.3 and 0.5 mg/kg. CCK8-induced antinociception and satiety were significantly reversed by ATM in those doses. [125I]CCK8 binding to the brain slices was observed autoradiographically. The autoradiograms from the slices were converted to false color images by using a microcomputer. The radioactivity in the autoradiograms was expressed by color spectra in the false color images. Comparison of the binding of [125I]CCK8 to the brain slices in the presence and the absence of ATM revealed that ATM (10(-6) M) clearly displaced the CCK8 binding in the various regions, especially in the cortex, of the brain. These findings suggest that ATM acts as an potent antagonist of CCK in the central nervous system in mice.


Maternal communication of circadian phase to the developing mammal.
In rodents, an entrainable circadian clock begins oscillating prenatally in the hypothalamic suprachiasmatic nuclei (SCN). The maternal circadian system coordinates (entrains) the timing of the developing clock to the prevailing light-dark cycle during both late fetal and early neonatal life. This maternal communication of circadian phase ensures that the developing animal is coordinated to the outside world until maturation of the normal pathway of light-dark entrainment in adults, the retinohypothalamic pathway, permits direct photic entrainment through the neonatal eye. The mechanism of maternal communication of circadian phase remains to be determined, but the necessity of the maternal SCN in this communication has been demonstrated. Indirect lines of evidence suggest that a similar scheme occurs for the development of circadian rhythms in humans.


Functional Mapping for Glioma Surgery, Part 2: Intraoperative Mapping Tools.
Intraoperative functional mapping of tumor and peri-tumor tissue is a well-established technique for avoiding permanent neurologic deficits and maximizing extent of resection. Motor, language, and other cognitive domains may be assessed with intraoperative tasks. This article describes techniques used for motor and language mapping including awake mapping considerations in addition to less traditional intraoperative testing paradigms for cognition. It also discusses complications associated with mapping and insights into complication avoidance.


Risk factors associated with prevalent vertebral fractures in Duchenne muscular dystrophy.
Patients with Duchenne muscular dystrophy (DMD) have a high fracture burden due to progressive myopathy and steroid-induced osteoporosis. This study in males with DMD showed that markers of systemic glucocorticoid exposure including shorter stature, greater bone age delay, and lower lumbar spine bone mineral density were associated with spine fragility. Fragility fractures are frequent in DMD. The purpose of this study was to identify clinical factors associated with prevalent vertebral fractures (VF) in boys, teens/young adults with Duchenne muscular dystrophy (DMD). This was a cross-sectional study of males aged 4-25 years with DMD. VF were evaluated using the modified Genant semi-quantitative method on T4-L4 lateral spine radiographs. Areal bone mineral density (aBMD) was measured at the lumbar spine (LS) and used to estimate volumetric BMD (vBMD). Clinical factors were analyzed for their association with the Spinal Deformity Index (SDI, the sum of the Genant grades). Sixty participants were enrolled (mean age 11.5 years, range 5.4-19.5). Nineteen participants (32%) had a total of 67 VF; 23/67 VF (34%) were moderate or severe. Participants with VF were shorter (mean height Z-score ± standard deviation: - 3.1 ± 1.4 vs. - 1.8 ± 1.4, p = 0.001), had longer glucocorticoid exposure (mean duration 6.0 ± 3.3 vs. 3.9 ± 3.3 years, p = 0.027), greater bone age (BA) delay (mean BA to chronological age difference - 3.2 ± 3.4 vs. - 1.3 ± 1.2 years, p = 0.035), and lower LSaBMD Z-scores (mean - 3.0 ± 1.0 vs. - 2.2 ± 1.2, p = 0.023). There was no difference in LSvBMD Z-scores. Multivariable Poisson regression showed that every 0.1 mg/kg/day increment in average glucocorticoid daily dose was associated with a 1.4-fold SDI increase (95% confidence interval: 1.1-1.7, p = 0.013). Greater BA delay (p < 0.001), higher weight Z-score (p = 0.004), decreased height Z-score (p = 0.025), and lower LSvBMD Z-score (p = 0.025) were also associated with SDI increase. Readily measurable clinical variables were associated with prevalent VF in males with glucocorticoid-treated DMD. These variables may be useful to identify candidates for primary osteoporosis prevention after glucocorticoid initiation.


Agents Which Inhibit NF-κB Signaling Block Spontaneous Contractile Activity and Negatively Influence Survival of Developing Myotubes.
Inhibiting the NF-κB signaling pathway provides morphological and functional benefits for the mdx mouse, a model for Duchenne muscular dystrophy characterized by chronic elevations in the nuclear expression of p65, the transactivating component of the NF-κB complex. The purpose of this study was to examine p65 expression in nondystrophic and mdx myotubes using confocal immunofluorescence, and determine whether inhibitors of the NF-κB pathway alter myotube development. Primary cultures of nondystrophic and mdx myotubes had identical levels of nuclear and cytosolic p65 expression and exhibited equivalent responses to TNF-α, thus excluding the hypothesis that the lack of dystrophin is sufficient to induce increases in NF-κB signaling. The NF-κB inhibitors pyrrolidine dithiocarbamate (PDTC) and sulfasalazine decreased spontaneous contractile activity and reduced myotube viability in a dose- and time-dependent manner. Similarly, a vivo-morpholino designed to block translation of murine p65 (m-p65tb-vivomorph1) rapidly abolished spontaneous contractile activity, reduced p65 expression measured by confocal immunofluorescence, and induced cell death in primary cultures of nondystrophic and mdx myotubes. Similar effects on p65 immunofluorescence and cell viability were observed following m-p65tb-vivomorph1 exposure to spontaneously inactive C2C12 myotubes, while exposure to a control scrambled vivo morpholino had no effect. These results indicate a direct role of the NF-κB pathway in myotube development and identify a potential therapeutic limitation to the use of NF-κB inhibitors in treating Duchenne and related muscular dystrophies. J. Cell. Physiol. 231: 788-797, 2016. © 2015 Wiley Periodicals, Inc.


N-terminomics - its past and recent advancements.
N-terminomics is a rapidly evolving branch of proteomics that encompasses the study of protein N-terminal sequence. A proteome-wide collection of such sequences has been widely used to understand the proteolytic cascades and in annotating the genome. Over the last two decades, various N-terminomic strategies have been developed for achieving high sensitivity, greater depth of coverage, and high-throughputness. We, in this review, cover how the field of N-terminomics has evolved to date, including discussion on various sample preparation and N-terminal peptide enrichment strategies. We also compare different N-terminomic methods and highlight their relative benefits and shortcomings in their implementation. In addition, an overview of the currently available bioinformatics tools and data analysis pipelines for the annotation of N-terminomic datasets is also included. SIGNIFICANCE: It has been recognized that proteins undergo several post-translational modifications (PTM), and a number of perturbed biological pathways are directly associated with modifications at the terminal sites of a protein. In this regard, N-terminomics can be applied to generate a proteome-wide landscape of mature N-terminal sequences, annotate their source of generation, and recognize their significance in the biological pathways. Besides, a system-wide study can be used to study complicated proteolytic machinery and protease cleavage patterns for potential therapeutic targets. Moreover, due to unprecedented improvements in the analytical methods and mass spectrometry instrumentation in recent times, the N-terminomic methodologies now offers an unparalleled ability to study proteoforms and their implications in clinical conditions. Such approaches can further be applied for the detection of low abundant proteoforms, annotation of non-canonical protein coding sites, identification of candidate disease biomarkers, and, last but not least, the discovery of novel drug targets.


Structural and immunological studies of hetero polysaccharide isolated from the alkaline extract of Tricholoma crassum (Berk.) Sacc.
An immunoenhancing water-soluble hetero polysaccharide was isolated from an alkaline extract of the fruit bodies of an ectomycorrhizal edible mushroom, Tricholoma crassum (Berk.) Sacc. The structure of the molecule was investigated using acid hydrolysis, methylation analysis; periodate oxidation study, and NMR spectroscopy techniques ((1)H, (13)C, DEPT-135, DQF-COSY, TOCSY, NOESY, ROESY, HSQC, and HMBC). On the basis of the above-mentioned experiments the structure of the repeating unit of the polysaccharide was established as: This polysaccharide exhibited splenocyte, thymocyte as well as macrophage activations.


Corrigendum: Impaired Glymphatic Transport Kinetics Following Induced Acute Ischemic Brain Edema in a Mouse pMCAO Model.
[This corrects the article DOI: 10.3389/fneur.2022.860255.].


Use of sugarcane filter cake and nitrogen, phosphorus and potassium fertilization in the process of bioremediation of soil contaminated with diesel.
This study evaluated the use of sugarcane filter cake and nitrogen, phosphorus and potassium (NPK) fertilization in the bioremediation of a soil contaminated with diesel fuel using a completely randomized design. Five treatments (uncontaminated soil, T1; soil contaminated with diesel, T2; soil contaminated with diesel and treated with 15 % (wt) filter cake, T3; soil contaminated with diesel and treated with NPK fertilizer, T4; and soil contaminated with diesel and treated with 15 % (wt) filter cake and NPK fertilizer, T5) and four evaluation periods (1, 60, 120, and 180 days after the beginning of the experiment) were used according to a 4 × 5 factorial design to analyze CO2 release. The variables total organic carbon (TOC) and total petroleum hydrocarbons (TPH) remaining in the soil were analyzed using a 5 × 2 factorial design, with the same treatments described above and two evaluation periods (1 and 180 days after the beginning of the experiment). In T3 and T5, CO2 release was significantly higher, compared with the other treatments. Significant TPH removal was observed on day 180, when percent removal values were 61.9, 70.1, 68.2, and 75.9 in treatments T2, T3, T4, and T5, respectively, compared with the initial value (T1).


A recurrent model of transformation invariance by association.
This paper describes an investigation of a recurrent artificial neural network which uses association to build transform-invariant representations. The simulation implements the analytic model of Parga and Rolls [(1998). Transform-invariant recognition by association in a recurrent network. Neural Computation 10(6), 1507-1525.] which defines multiple (e.g. "view") patterns to be within the basin of attraction of a shared (e.g. "object") representation. First, it was shown that the network could store and correctly retrieve an "object" representation from any one of the views which define that object, with capacity as predicted analytically. Second, new results extended the analysis by showing that correct object retrieval could occur where retrieval cues were distorted; where there was some association between the views of different objects; and where connectivity was diluted, even when this dilution was asymmetric. The simulations also extended the analysis by showing that the system could work well with sparse patterns; and showing how pattern sparseness interacts with the number of views of each object (as a result of the statistical properties of the pattern coding) to give predictable object retrieval performance. The results thus usefully extend a recurrent model of invariant pattern recognition.


Predictors of Human Milk Feeding and Direct Breastfeeding for Infants with Single Ventricle Congenital Heart Disease: Machine Learning Analysis of the National Pediatric Cardiology Quality Improvement Collaborative Registry.
To identify factors that support or limit human milk (HM) feeding and direct breastfeeding (BF) for infants with single ventricle congenital heart disease at neonatal stage 1 palliation (S1P) discharge and at stage 2 palliation (S2P) (∼4-6 months old). Analysis of the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) registry (2016-2021; 67 sites). Primary outcomes were any HM, exclusive HM, and any direct BF at S1P discharge and at S2P. The main analysis involved multiple phases of elastic net logistic regression on imputed data to identify important predictors. For 1944 infants, the strongest predictor domain areas included preoperative feeding, demographics/social determinants of health, feeding route, clinical course, and site. Significant findings included: preoperative BF was associated with any HM at S1P discharge (OR = 2.02, 95% CI = 1.74-3.44) and any BF at S2P (OR = 2.29, 95% CI = 1.38-3.80); private/self-insurance was associated with any HM at S1P discharge (OR = 1.91, 95% CI = 1.58-2.47); and Black/African-American infants had lower odds of any HM at S1P discharge (OR = 0.54, 95% CI = 0.38-0.65) and at S2P (0.57, 0.30-0.86). Adjusted odds of HM/BF practices varied among NPC-QIC sites. Preoperative feeding practices predict later HM and BF for infants with single ventricle congenital heart disease; therefore, family-centered interventions focused on HM/BF during the S1P preoperative time are needed. These interventions should include evidence-based strategies to address implicit bias and seek to minimize disparities related to social determinants of health. Future research is needed to identify supportive practices common to high-performing NPC-QIC sites.


Diagnostic accuracy of three-dimensional contrast-enhanced MR angiography at 3-T for acute pulmonary embolism detection: comparison with multidetector CT angiography.
Three-dimensional contrast-enhanced MR pulmonary angiography (MRPA) is a suitable option for pulmonary embolism (PE) detection. However, there have been few reports on the diagnostic accuracy of MRPA for PE detection in a 3-T MR system. The purpose of this study was to evaluate the accuracy of MRPA in a 3-T MR system to detect acute PE with multidetector CT pulmonary angiography (CTPA) as reference standard. Twenty-seven patients (18 males and 9 females, mean age 38.9±14.4 years) underwent both MRPA and CTPA within 3 days (range, 0-3 days) for evaluating PE. Pulmonary emboli in MRPA were independently analyzed on a per-patient and per-lobe basis by two radiologists. CTPA was regarded as reference standard, which was evaluated by another two radiologists in consensus. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for PE detection were calculated. Weighted κ values were calculated to evaluate agreement between readers. Twenty-four patients had PE in 55 lung lobes in CTPA, while 3 patients had no PE detected. Readers 1 and 2 correctly detected 47 and 46 lung lobes having clots in 24 and 23 patients, corresponding to sensitivities, specificities, PPV, NPV, and accuracies of 100%, 100%, 100%, 100%, 100%; 100%, 66.7%, 96.0%, 100%, 96.4% on a per-patient basis and 85.5%, 100%, 100%, 90.9%, 94.1%; 83.6%, 93.7%, 90.2%, 89.2%, 89.6% on a per-lobe basis; respectively. Excellent inter-reader agreement (κ values=1.00 and 0.934; both P<0.001) were found for detecting PE on a per-patient and per-lobe analysis. Three-dimensional contrast-enhanced MRPA with a 3-T MR system is a suitable alternative modality to CTPA to detect PE on a per-patient basis based on this small cohort study.


Preschool children health impacts from indoor exposure to PM2.5 and metals.
To better understand the relation between children health and indoor air quality, we measured the concentrations of fine particulate matter (PM2.5) and 11 metals (arsenic, cadmium, chromium, copper, iron, manganese, nickel, lead, antimony, selenium, and zinc) from air samples taken during both winter and spring, and focused on urban and rural area kindergartens of the Upper Silesia Region, Poland, typified by the use of fossil fuels for power and heat purposes. We combined related inhalation intake estimates for children and health effects using separate dose-response approaches for PM2.5 and metals. Results show that impacts on children from exposure to PM2.5 was 7.5 min/yr, corresponding to 14 μDALY/yr (DALY: disability-adjusted life years) with 95% confidence interval (CI): 0.3-164 min/yr, which is approximately 10 times lower than cumulative impacts from exposure to the metal components in the PM2.5 fraction of indoor air (median 76 min/yr; CI: 0.2-4.5 × 103 min/yr). Highest metal-related health impacts were caused by exposure to hexavalent chromium. The average combined cancer and non-cancer effects for hexavalent chromium were 55 min/yr, corresponding to 104 μDALY/yr, with CI: 0.5 to 8.0 × 104 min/yr. Health impacts on children varied by season and across urban and rural sites, both as functions of varying PM2.5 metal compositions influenced by indoor and outdoor emission sources. Our study demonstrates the need to consider indoor environments for evaluating health impacts of children, and can assist decision makers to focus on relevant impact reduction and indoor air quality improvement.


The impact of birthweight on the development of cerebral palsy: A population-based matched case-control study.
Cerebral palsy (CP) is a common cause of physical impairment in children, especially in newborns who are small for gestational age (SGA). The aim of our study was to investigate the association between birth weight and the risk of developing CP, controlling for gestational age and plurality. This retrospective, observational, case-control study was based on Slovenian Registry of Cerebral Palsy (SRCP) and Slovenian National Perinatal Information System (NPIS) data for the period 2002 to 2010. For each pregnancy that resulted in the birth of the newborn(s) who later developed CP (n = 254), three pregnancies with newborns who did not develop CP (n = 762) were selected and matched for gestational age and plurality. Diagnosis of CP was made at age 5 years or older by a developmental pediatrician trained in child neurology or a child neurologist using standard measures. Risk of CP increased progressively as birth weight percentiles fell below the 50th centile, with children in the lowest percentiles at greatest risk. Birth weight percentiles traditionally classified as SGA were an independent risk factor for developing CP, with an odds ratio of 2.43 (95% confidence interval 1.57, 3.73). The results of this study suggest that the risk for developing CP is inversely related to birth weight, even at birth weights that do not meet the standard definitions of SGA. Does birth weight represent a potential risk factor for the development of cerebral palsy (CP) when controlling for gestational age and plurality? Newborns who are small for gestational age (SGA) are at higher risk of developing CP according to published studies. However, different definitions of SGA (birth weight below the 10th, 5th, or 3rd percentile for gestational age) have been used by researchers and clinicians, making it difficult to compare studies. This study suggests that the risk of developing CP is inversely related to birth weight, even at birth weights that do not meet standard definitions of SGA.


Changes in body size and fatness of Australian schoolchildren 1911-1976.
Data have been analysed from surveys of Queensland schoolchildren done in 1911, 1950 and 1976. Over this period there has been a marked increase in both height-for-age and weight-for-age in boys and girls. However, in boys, this increases growth has been associated with minimal increase in fatness. In girls there has probably been a real increase in body fatness, particularly since 1950. Raw data from past growth studies would make the analysis for secular changes in status more meaningful and accurate. We suggest that a central data bank for Australian growth studies be set up.


Quantitative multi-slice computed tomography assessment of the mitral valvular complex for transcatheter mitral valve interventions part 1: systematic measurement methodology and inter-observer variability.
Transcatheter mitral valve replacement (TMVR) is an emerging technology with the potential to treat patients with severe mitral regurgitation at excessive risk for surgical mitral valve surgery. Multimodality imaging of the mitral valvular complex and surrounding structures will be an important component for patient selection for TMVR. Our aim was to describe and evaluate a systematic multi-slice computed tomography (MSCT) image analysis methodology that provides measurements relevant for transcatheter mitral valve replacement. A systematic step-by-step measurement methodology is described for structures of the mitral valvular complex including: the mitral valve annulus, left ventricle, left atrium, papillary muscles and left ventricular outflow tract. To evaluate reproducibility, two observers applied this methodology to a retrospective series of 49 cardiac MSCT scans in patients with heart failure and significant mitral regurgitation. For each of 25 geometrical metrics, we evaluated inter-observer difference and intra-class correlation. The inter-observer difference was below 10% and the intra-class correlation was above 0.81 for measurements of critical importance in the sizing of TMVR devices: the mitral valve annulus diameters, area, perimeter, the inter-trigone distance, and the aorto-mitral angle. MSCT can provide measurements that are important for patient selection and sizing of TMVR devices. These measurements have excellent inter-observer reproducibility in patients with functional mitral regurgitation.


An improved method for estimating the activity of a mouse with the photoswitch.
A new method for estimating the activity of a mouse by means of the photoswitch is contrived. This device can follow the activity with high fidelity and notable sensitivity, as compared with the conventional method.


Reduction of conjugated dienes in lung transplantation: effect of BN 52021.
Oxygen-derived free radicals have been identified as the mediators of tissue injury during reperfusion in organ transplantation. Lipid peroxidation of cell membrane polyunsaturated fatty acids, generating conjugated dienes (CD), is a toxicity of oxygen-derived free radicals. The CD structure in fatty acyl moieties was measured by high-pressure liquid chromatography in samples of inferior pulmonary venous blood and pulmonary tissue to assess reperfusion injury and oxygen-derived free radical-mediated damage in a canine model of left lung allotransplantation. The cold ischemic preservation interval was 6 hours and the posttransplantation monitoring period was 6 hours. Twenty-eight size- and weight-matched adult male dogs underwent left lung allotransplantation and were randomized to receive pulmonary artery flush of modified Euro-Collins (EC) (40 mL/kg) or University of Wisconsin (UW) (40 mL/kg) solutions alone or with the addition of the platelet-activating factor antagonist BN 52021 (10 mg/kg). When employed, BN 52021 was administered to donors 30 minutes before harvest and recipients 30 minutes before reperfusion. Left and right inferior pulmonary venous blood samples were obtained at baseline before transplantation and at 1, 2, 4, and 6 hours after transplantation; tissue samples were obtained after euthanasia. Serum and tissue CD levels are expressed as mean fraction of the total hydroperoxide sample +/- standard error of the mean. At 6 hours after transplantation, the EC group's (n = 7) CD fraction was 0.28 +/- 0.03, whereas that of the EC + BN 52021 group (n = 7) was 0.12 +/- 0.03 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Correction of uneven illumination (vignetting) in digital microscopy images.
Many digital microscopy images suffer from poor illumination at the peripheries (vignetting), often attributable to factors related to the light path between the camera and the microscope. A commonly used method for correcting this has been to use the illumination of an empty field as a correction filter (white shading correction). To develop an alternative shading correction method that does not require this additional image. / This report outlines an alternative shading correction method that is based upon the intrinsic properties of the image, which are revealed through Gaussian smoothing. The technique can be implemented within Adobe Photoshop or other graphics editing software and works well with both haematoxylin and eosin and immunohistochemical images. This technique provides an effective means of optimising digital microscopy image appearances for printing, image analysis, or telepathology.


Correlations Between Pitch and Phoneme Perception in Cochlear Implant Users and Their Normal Hearing Peers.
This study examined correlations between pitch and phoneme perception for nine cochlear implant users and nine normal hearing listeners. Pure tone frequency discrimination thresholds were measured for frequencies of 500, 1000, and 2000 Hz. Complex tone fundamental frequency (F0) discrimination thresholds were measured for F0s of 110, 220, and 440 Hz. The effects of amplitude and frequency roving were measured under the rationale that individuals who are robust to such perturbations would perform better on phoneme perception measures. Phoneme identification was measured using consonant and vowel materials in quiet, in stationary speech-shaped noise (SSN), in spectrally notched SSN, and in temporally gated SSN. Cochlear implant pure tone frequency discrimination thresholds ranged between 1.5 and 9.9 %, while cochlear implant complex tone F0 discrimination thresholds ranged between 2.6 and 28.5 %. On average, cochlear implant users had 5.3 dB of masking release for consonants and 8.4 dB of masking release for vowels when measured in temporally gated SSN compared to stationary SSN. Correlations with phoneme identification measures were generally higher for complex tone discrimination measures than for pure tone discrimination measures. Correlations with phoneme identification measures were also generally higher for pitch perception measures that included amplitude and frequency roving. The strongest correlations were observed for measures of complex tone F0 discrimination with phoneme identification in temporally gated SSN. The results of this study suggest that musical training or signal processing strategies that improve F0 discrimination should improve consonant identification in fluctuating noise.


Effects of acute ischemic mitral regurgitation on three-dimensional mitral leaflet edge geometry.
Improved quantitative understanding of in vivo leaflet geometry in ischemic mitral regurgitation (IMR) is needed to improve reparative techniques, yet few data are available due to current imaging limitations. Using marker technology we tested the hypotheses that IMR (1) occurs chiefly during early systole; (2) affects primarily the valve region contiguous with the myocardial ischemic insult; and (3) results in systolic leaflet edge restriction. Eleven sheep had radiopaque markers sutured as five opposing pairs along the anterior (A(1)-E(1)) and posterior (A(2)-E(2)) mitral leaflet free edges from the anterior commissure (A(1)-A(2)) to the posterior commissure (E(1)-E(2)). Immediately postoperatively, biplane videofluoroscopy was used to obtain 4D marker coordinates before and during acute proximal left circumflex artery occlusion. Regional mitral orifice area (MOA) was calculated in the anterior (Ant-MOA), middle (Mid-MOA), and posterior (Post-MOA) mitral orifice segments during early systole (EarlyS), mid systole (MidS), and end systole (EndS). MOA was normalized to zero (minimum orifice opening) at baseline EndS. Tenting height was the distance of the midpoint of paired markers to the mitral annular plane at EndS. Acute ischemia increased echocardiographic MR grade (0.5+/-0.3 vs 2.3+/-0.7, p<0.01) and MOA in all regions at EarlyS, MidS, and EndS: Ant-MOA (7+/-10 vs 22+/-19 mm(2), 1+/-2 vs 18+/-16 mm(2), 0 vs 17+/-15 mm(2)); Mid-MOA (9+/-13 vs 25+/-17 mm(2), 3+/-6 vs 21+/-19 mm(2), 0 vs 25+/-17 mm(2)); and Post-MOA (8+/-10 vs 25+/-16, 2+/-4 vs 22+/-13 mm(2), 0 vs 23+/-13 mm(2)), all p<0.05. There was no change in MOA throughout systole (EarlyS vs MidS vs EndS) during baseline conditions or ischemia. Tenting height increased with ischemia near the central and the anterior commissure leaflet edges (B(1)-B(2): 7.1+/-1.8mm vs 7.9+/-1.7 mm, C(1)-C(2): 6.9+/-1.3mm vs 8.0+/-1.5mm, both p<0.05). MOA during ischemia was larger throughout systole, indicating that acute IMR in this setting is a holosystolic phenomenon. Despite discrete postero-lateral myocardial ischemia, Post-MOA was not disproportionately larger. Acute ovine IMR was associated with leaflet restriction near the central and the anterior commissure leaflet edges. This entire constellation of annular, valvular, and subvalvular ischemic alterations should be considered in the approach to mitral repair for IMR.


An unconventional career path for an oral pathologist: Sharing personal insights from experience as a part of medical publishing industry.
Oral pathologists or dentists in general opting for alternate career paths are very common nowadays. Financial security, lesser availability of jobs and work satisfaction are the most commonly observed reasons for this openness to switch career. While there is a multitude of alternate career options available such as medical writing and pharmacovigilance in this review, we aim to give an insight specifically on opportunities available in the medical journals aspect of the publishing industry. Oral pathologists can opt to take this field as a full-time engagement and attain a constant growth in terms of finances, knowledge and personal development. One of the authors has opted for this career path and has provided personal opinions about the scope, opportunities and perks of working in this industry.


Adenoma of the iris-pigment epithelium.
An 11-year-old boy was noted to have a multinodular tumor involving the peripheral iris and trabecular meshwork in his left eye. During the next 12 years, the lesion slowly enlarged and produced pigmentary dispersion in the anterior chamber and glaucomatous changes in the optic disc. Histopathologic examination of the tumor after its removal by iridocyclectomy revealed features consistent with the diagnosis of adenoma of the iris-pigment epithelium. A correlation between the clinical and histopathologic features is presented. Clinical features that can be helpful in differentiating an adenoma of the iris-pigment epithelium from a malignant melanoma are discussed.


NT-proBNP in heart failure: therapy decisions and monitoring.
With increasing cardiac dysfunction, a complex neurohormonal response results in increasing circulating levels of an array of plasma hormones. Increments in plasma levels of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) and their amino-terminal congeners are more closely related to cardiac structure and function and to cardiovascular prognosis than changes in other plasma neurohormones. Reports suggest that changes in plasma BNP levels in the course of treatment of acutely decompensated heart failure provide a more powerful prognostic indicator of the likelihood of survival or recurrent decompensation than symptomatic assessment. This observation requires a randomised controlled trial in which changes in peptide levels determine aggression and duration of in-patient therapy in order to establish whether this indicator can improve results from management of acute in-patient heart failure. Plasma BNP or NT-proBNP is a powerful independent predictor of mortality and morbidity in long-term follow-up of heart failure cohorts. In addition, it appears likely to be a good predictor of beneficial response to the addition of beta blockade to anti-heart failure pharmacotherapy. Finally, adjustment of therapy for heart failure according to serial measurements of NT-proBNP promises to improve outcomes in comparison with adjusting therapy according to unassisted clinical acumen.


Moxifloxacin: Clinically compatible contrast agent for multiphoton imaging.
Multiphoton microscopy (MPM) is a nonlinear fluorescence microscopic technique widely used for cellular imaging of thick tissues and live animals in biological studies. However, MPM application to human tissues is limited by weak endogenous fluorescence in tissue and cytotoxicity of exogenous probes. Herein, we describe the applications of moxifloxacin, an FDA-approved antibiotic, as a cell-labeling agent for MPM. Moxifloxacin has bright intrinsic multiphoton fluorescence, good tissue penetration and high intracellular concentration. MPM with moxifloxacin was demonstrated in various cell lines, and animal tissues of cornea, skin, small intestine and bladder. Clinical application is promising since imaging based on moxifloxacin labeling could be 10 times faster than imaging based on endogenous fluorescence.


Control of actin turnover by a salmonella invasion protein.
Salmonella force their way into nonphagocytic host intestinal cells to initiate infection. Uptake is triggered by delivery into the target cell of bacterial effector proteins that stimulate cytoskeletal rearrangements and membrane ruffling. The Salmonella invasion protein A (SipA) effector is an actin binding protein that enhances uptake efficiency by promoting actin polymerization. SipA-bound actin filaments (F-actin) are also resistant to artificial disassembly in vitro. Using biochemical assays of actin dynamics and actin-based motility models, we demonstrate that SipA directly arrests cellular mechanisms of actin turnover. SipA inhibits ADF/cofilin-directed depolymerization both by preventing binding of ADF and cofilin and by displacing them from F-actin. SipA also protects F-actin from gelsolin-directed severing and reanneals gelsolin-severed F-actin fragments. These data suggest that SipA focuses host cytoskeletal reorganization by locally inhibiting both ADF/cofilin- and gelsolin-directed actin disassembly, while simultaneously stimulating pathogen-induced actin polymerization.


Alarming Internal Carotid Artery Aneurysm Eroding the Sphenoid Sinus.
In rare instances, extradural internal carotid artery aneurysms can present with massive epistaxis, which is often a fatal event. We present the case of a young female with an aneurysm eroding through the sphenoid sinus and whose timely diagnosis resulted in treatment of the aneurysm with coil embolization and satisfactory outcome.


Sex differences in the experience of COVID-19 post-traumatic stress symptoms by adults in South Africa.
The COVID-19 pandemic has created multiple mental health challenges. Many residents in South Africa face pre-existing elevated levels of stress and the pandemic may have had varying impacts on sub-populations. The aims of this study were to determine: 1) the factors associated with post-traumatic stress symptoms (PTSS) and 2) sex differences in the factors associated with PTSS in adults residing in South Africa during the COVID-19 pandemic. Study participants aged 18 years and above, were recruited for this cross-sectional study through an online survey implemented from June 29, 2020 to December 31, 2020. The outcome variable was PTSS; explanatory variables were sex at birth, COVID-19 status, social isolation and access to emotional support. Confounders considered were age, education level completed and current work status. Logistic regressions were used to determine the association between the outcome and explanatory variables after adjusting for confounders. There were 489 respondents. Among all respondents, those who were older (AOR: 0.97; 95% CI: 0.95 - 0.99) and had access to emotional support from family and relatives (AOR: 0.27; 95% CI: 0.14 - 0.53) had significantly lower odds of PTSS. Respondents who felt socially isolated had higher odds of PTSS (AOR: 1.17; 95% CI: 1.08 - 1.27). Females had higher PTSS scores and higher odds of PTSS compared to males (AOR: 2.18; 95% CI: 1.41-3.39). Females (AOR: 0.27; 95% CI: 0.08 - 0.95) and males (AOR: 0.26; 95% CI: 0.11, 0.59) who had access to emotional support had significantly lower odds of PTSS than those who had no support. Females (AOR: 1.15; 95% CI: 1.04 -1.27) and males (AOR: 1.19; 95% CI: 0.11, 0.59) who felt socially isolated had higher odds of PTSS compared to those who did not feel socially isolated. Compared to males, females had higher scores and higher odds of reporting PTSS during the COVID-19 pandemic. Access to emotional support ameliorated the odds of having PTSS for both sexes, while feeling socially isolated worsened the odds for both sexes.


Synthesis of High-Entropy-Alloy Nanoparticles by a Step-Alloying Strategy as a Superior Multifunctional Electrocatalyst.
High-entropy-alloy nanoparticles (HEA-NPs) have attracted great attention because of their unique complex compositions and tailorable properties. Further expanding the compositional space is of great significance for enriching the material library. Here, a step-alloying strategy is developed to synthesis HEA-NPs containing a range of strongly repellent elements (e.g., Bi-W) by using the rich-Pt cores formed during the first liquid phase reaction as the seed of the second thermal diffusion. Remarkably, the representative HEA-NPs-(14) with up to 14 elements exhibits extremely excellent multifunctional electrocatalytic performance for pH-universal hydrogen evolution reaction (HER), alkaline methanol oxidation reaction (MOR), and oxygen reduction reaction (ORR). Briefly, HEA-NPs-(14) only requires the ultralow overpotentials of 11 and 18 mV to deliver 10 mA cm-2 and exhibits ultralong durability for 400 and 264 h under 100 mA cm-2 in 0.5 m H2 SO4 and 1 m KOH, respectively, which surpasses most advanced pH-universal HER catalysts. Moreover, HEA-NPs-(14) also exhibits an impressive peak current density of 12.6 A mg-1 Pt in 1 m KOH + 1 m MeOH and a half-wave potential of 0.86 V (vs RHE.) in 0.1 m KOH. The work further expands the spectrum of possible metal alloys, which is important for the broad compositional space and future data-driven material discovery.


Single-stage anterior debridement and fusion with autografting and internal fixation for pyogenic lumbar spondylodiscitis.
Patients with pyogenic lumbar spondylodiscitis can be successfully treated by non-operative methods. However, the typical operation for this condition includes debridement of the infected site, bone grafting and internal fixation to stabilize the spine. Single-stage anterior debridement and fusion with autografting and internal fixation of one spinal segment were performed on nine patients with pyogenic lumbar spondylodiscitis. This operative procedure is rarely documented for pyogenic lumbar spondylodiscitis. To evaluate the safety and effectiveness of single-stage anterior debridement, autografting and internal fixation of one spinal segment for pyogenic lumbar spondylodiscitis. At the final follow-up, seven out of the nine patients were pain free. Two patients had mild, intermittent back pain (Visual Analogue Scale rating of 1-2), which represented an improvement from their preoperative pain. All nine patients had no clinical, laboratory or radiological evidence of recurrence of infection. Moreover, all the patients showed solid bony fusion. Based on the limited population studied, it suggested that this technique may be a safe and effective operative procedure for appropriate pyogenic lumbar spondylodiscitis in patients.