Principalis, oralis and interpolaris responses to whisker movements provoked by air jets in rats.
The present study was designed to compare the electrophysiological characteristics of the principalis, oralis and interpolaris nuclei of the trigeminal sensory complex under stimulation of the vibrissae by air puffs. This stimulus generates deflection profiles resembling those induced by contact with real objects in natural conditions. Three populations of neurons were identified in each nucleus according to their mean spiking frequency at rest. The three nuclei differed in terms of their mean spiking frequencies, the response latencies of their neurons and the proportions of each neuron population observed in single and multi-unit recordings. Findings suggest different information processing tasks for each nucleus.


Inflammation-relevant microbiome signature of the stroke brain, gut, spleen, and thymus and the impact of exercise.
Stroke remains a significant unmet need in the clinic with few therapeutic options. We, and others, have implicated the role of inflammatory microbiota in stroke secondary cell death. Elucidating this inflammation microbiome as a biomarker may improve stroke diagnosis and treatment. Here, adult Sprague-Dawley rats performed 30 minutes of exercise on a motorized treadmill for 3 consecutive days prior to transient middle cerebral artery occlusion (MCAO). Stroke animals that underwent exercise showed 1) robust behavioral improvements, 2) significantly smaller infarct sizes and increased peri-infarct cell survival and 3) decreasing trends of inflammatory microbiota BAC303, EREC482, and LAB158 coupled with significantly reduced levels of inflammatory markers ionized calcium binding adaptor molecule 1, tumor necrosis factor alpha, and mouse monoclonal MHC Class II RT1B in the brain, gut, spleen, and thymus compared to non-exercised stroke rats. These results suggest that a specific set of inflammatory microbiota exists in central and peripheral organs and can serve as a disease biomarker and a therapeutic target for stroke.


Cross-dehydrogenative coupling of α-C(sp(3))-H of ethers/alkanes with C(sp(2))-H of heteroarenes under metal-free conditions.
Here we have developed an effective metal-free dehydrogenative coupling method wherein α-oxyalkyl and alkyl radicals were generated from various ethers and alkanes to undergo coupling with a variety of electron-deficient heteroarenes such as un/substituted iso-quinolones, quinolines, pyridines, pyrazines and pyrimidines. The persulfate-acetone-water system was optimized for the dehydrogenative coupling with cyclic ethers which gave moderate to excellent yields of α-oxyalkyl containing heteroarenes. We have also optimized the conditions for coupling with cyclic alkanes and alicyclic ethers and demonstrated by conducting the reactions with a variety of electron-deficient heteroarenes. Further, the present method is also applicable to electron deficient arenes like naphthoquinones and moreover, it didn't require any external acid.


Antibiotics in the pathogenesis of diabetes and inflammatory diseases of the gastrointestinal tract.
Antibiotic use is increasing worldwide. However, the use of antibiotics is clearly associated with changes in gut microbiome composition and function, and perturbations have been identified as potential environmental risk factors for chronic inflammatory disorders of the gastrointestinal tract. In this Review, we examine the association between the use of antibiotics and the onset and development of both type 1 and type 2 diabetes, inflammatory bowel disease, including ulcerative colitis and Crohn's disease, as well as coeliac disease and eosinophilic oesophagitis. We discuss the key findings of epidemiological studies, provide mechanistic insights into the pathways by which the gut microbiota might contribute to these diseases, and assess clinical trials investigating the effects of antibiotics. Such studies indicate that antibiotic exposures, varying in type, timing and dosage, could explain differences in disease risk. There seems to be a critical window in early life in which perturbation of the microbiome has a substantial effect on disease development. Identifying the antibiotic-perturbed gut microbiota as a factor that contributes to the pathophysiology of these inflammatory disorders might stimulate new approaches to prevention, diagnosis and treatment.


Calcium Oxide Nanoparticles Have the Role of Alleviating Arsenic Toxicity of Barley.
Arsenic (As) contamination in agricultural soils has become a great threat to the sustainable development of agriculture and food safety. Although a lot of approaches have been proposed for dealing with soil As contamination, they are not practical in crop production due to high cost, time-taking, or operational complexity. The rapid development of nanotechnology appears to provide a novel solution to soil As contamination. This study investigated the roles of calcium oxide nanoparticles (CaO NPs) in alleviating As toxicity in two barley genotypes (LJZ and Pu-9) differing in As tolerance. The exposure of barley seedlings to As stress showed a significant reduction in plant growth, calcium and chlorophyll content (SPAD value), fluorescence efficiency (Fv/m), and a dramatic increase in the contents of reactive oxygen species (ROS), malondialdehyde (MDA) and As, with LJZ being more affected than Pu-9. The exogenous supply of CaO NPs notably alleviated the toxic effect caused by As in the two barley genotypes. Moreover, the expression of As transporter genes, that is, HvPHT1;1, HvPHT1;3, HvPHT1;4 and HvPHT1;6, was dramatically enhanced when barley seedlings were exposed to As stress and significantly reduced in the treatment of CaO NPs addition. It may be concluded that the roles of CaO NPs in alleviating As toxicity could be attributed to its enhancement of Ca uptake, ROS scavenging ability, and reduction of As uptake and transportation from roots to shoots.


Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C.
It is unclear whether hepatitis C virus (HCV) is eradicated in patients with chronic hepatitis C who achieved a sustained virologic response (SVR). In this long-term follow-up study, including chronic hepatitis C patients who achieved SVR after interferon-based therapy, the presence of residual HCV RNA in serum, liver, and peripheral blood mononuclear cells (PBMCs) was assessed, using transcription-mediated amplification (sensitivity, <9.6 IU/mL). The benefit of SVR on liver fibrosis was evaluated using the METAVIR score. A total of 344 patients were followed up for a median duration of 3.27 years (range, 0.50-18 y; interquartile range [IQR], 1.68-5.35 y). A total of 114 patients had a posttreatment liver tissue (median, 0.50 y; range, 0-14 y; IQR, 0-3.5 y) and a total of 156 had one PBMC (median, 3.0 y; range, 0.50-18 y; IQR, 1.25-5.50 y). Serum HCV RNA remained undetectable (1300 samples), indicating that none of the patients had a relapse. HCV RNA was detectable in 2 of 114 (1.7%) liver specimens, and in none of 156 PBMC specimens. Histologic analysis of 126 paired pretreatment and posttreatment liver biopsy specimens (median, 0.50 y; range, 0-14 y; IQR, 0-3.5 y) showed that fibrosis stage was improved in 56%, stable in 32%, deteriorated in 12%. Regression of cirrhosis was observed in 9 of 14 (64%) (95% confidence interval, 39-89) patients. No cirrhosis decompensation was observed, and 3 patients developed hepatocellular carcinoma. In this large cohort of chronic hepatitis C patients, SVR was durable up to 18 years after treatment cessation, in addition to fibrosis stability/improvement (88%) and cirrhosis regression (64%). The presence of residual HCV RNA was observed only in liver tissue (1.7%). This result strongly suggests that SVR may be considered to show eradication of HCV infection.


The epidemiology of Mycobacterium bovis in wild deer and feral pigs and their roles in the establishment and spread of bovine tuberculosis in New Zealand wildlife.
In New Zealand, wild deer and feral pigs are assumed to be spillover hosts for Mycobacterium bovis, and so are not targeted in efforts aimed at locally eradicating bovine tuberculosis (TB) from possums (Trichosurus vulpecula), the main wildlife host. Here we review the epidemiology of TB in deer and pigs, and assess whether New Zealand's TB management programme could be undermined if these species sometimes achieve maintenance host status. In New Zealand, TB prevalences of up to 47% have been recorded in wild deer sympatric with tuberculous possums. Patterns of lesion distribution, age-specific prevalences and behavioural observations suggest that deer become infected mainly through exposure to dead or moribund possums. TB can progress rapidly in some deer (<10%), but generalised disease is uncommon in wild deer; conversely some infected animals can survive for many years. Deer-to-deer transmission of M. bovis is rare, but transmission from tuberculous deer carcasses to scavengers, including possums, is likely. That creates a small spillback risk that could persist for a decade after transmission of new infection to wild deer has been halted. Tuberculosis prevalence in New Zealand feral pigs can reach 100%. Infections in lymph nodes of the head and alimentary tract predominate, indicating that TB is mostly acquired through scavenging tuberculous carrion, particularly possums. Infection is usually well contained, and transmission between pigs is rare. Large reductions in local possum density result in gradual declines (over 10 years) in TB prevalence among sympatric wild deer, and faster declines in feral pigs. Elimination of TB from possums (and livestock) therefore results in eventual disappearance of TB from feral pigs and wild deer. However, the risk of spillback infection from deer to possums substantially extends the time needed to locally eradicate TB from all wildlife (compared to that which would be required to eradicate disease from possums alone), while dispersal or translocation of pigs (e.g. by hunters) creates a risk of long-distance spread of disease. The high rate at which pigs acquire M. bovis infection from dead possums makes them useful as sentinels for detecting TB in wildlife. It is unlikely that wild deer and feral pigs act as maintenance hosts anywhere in New Zealand, because unrestricted year-round hunting keeps densities low, with far less aggregation than on New Zealand farms. We conclude that active management of wild deer or feral pigs is not required for local TB eradication in New Zealand.


Effect of aldosterone on BK channel expression in mammalian cortical collecting duct.
Apical large-conductance Ca(2+)-activated K(+) (BK) channels in the cortical collecting duct (CCD) mediate flow-stimulated K(+) secretion. Dietary K(+) loading for 10-14 days leads to an increase in BK channel mRNA abundance, enhanced flow-stimulated K(+) secretion in microperfused CCDs, and a redistribution of immunodetectable channels from an intracellular pool to the apical membrane (Najjar F, Zhou H, Morimoto T, Bruns JB, Li HS, Liu W, Kleyman TR, Satlin LM. Am J Physiol Renal Physiol 289: F922-F932, 2005). To test whether this adaptation was mediated by a K(+)-induced increase in aldosterone, New Zealand White rabbits were fed a low-Na(+) (LS) or high-Na(+) (HS) diet for 7-10 days to alter circulating levels of aldosterone but not serum K(+) concentration. Single CCDs were isolated for quantitation of BK channel subunit (total, alpha-splice variants, beta-isoforms) mRNA abundance by real-time PCR and measurement of net transepithelial Na(+) (J(Na)) and K(+) (J(K)) transport by microperfusion; kidneys were processed for immunolocalization of BK alpha-subunit by immunofluorescence microscopy. At the time of death, LS rabbits excreted no urinary Na(+) and had higher circulating levels of aldosterone than HS animals. The relative abundance of BK alpha-, beta(2)-, and beta(4)-subunit mRNA and localization of immunodetectable alpha-subunit were similar in CCDs from LS and HS animals. In response to an increase in tubular flow rate from approximately 1 to 5 nl.min(-1).mm(-1), the increase in J(Na) was greater in LS vs. HS rabbits, yet the flow-stimulated increase in J(K) was similar in both groups. These data suggest that aldosterone does not contribute to the regulation of BK channel expression/activity in response to dietary K(+) loading.


Benign Fibromyxoid Lesion of the Breast: A Distinct Entity From Benign Spindle Cell Tumors of the Mammary Stroma?
Myxoid lesions of the breast can be diagnostically challenging entities. We report 4 cases of CD34+ fibromyxoid lesion that have been previously diagnosed as "benign myxoid lesion," "nodular mucinosis," or "mammary myofibroblastoma, myxoid type" on the basis of CD34-positivity. The lesions were microscopically well circumscribed and composed of a paucicellular spindle cell proliferation in a background of myxoid stroma. No epithelial component was identified. The spindle cells showed immunohistochemical reactivity for CD34 and smooth muscle actin. Based on morphologic and immunohistochemical similarities between these cases and myxoid myofibroblastoma, we compared 4 myxoid lesions with cases of typical myofibroblastoma, utilizing retinoblastoma (Rb) antibody and fluorescent in situ hybridization for 13q14 gene rearrangement (encoding the Rb gene). The myxoid lesions showed retention of Rb protein by immunohistochemistry, whereas Rb expression was lost in cases of myofibroblastoma. We identified loss of 13q14 in 3 of 4 cases of myofibroblastoma. Notably, 13q14 gene rearrangement was not observed in any of the myxoid lesions. Our data show that there is at least a subset of CD34+ fibromyxoid lesions that, despite overlapping morphologic and immunohistochemical phenotype and proposed common histogenesis with myofibroblastomas, is genetically distinct from the latter based on Rb analysis.


The role of fatty acids in insulin resistance.
Insulin resistance is a multi-faceted disruption of the communication between insulin and the interior of a target cell. The underlying cause of insulin appears to be inflammation that can either be increased or decreased by the fatty acid composition of the diet. However, the molecular basis for insulin resistance can be quite different in various organs. This review deals with various types of inflammatory inputs mediated by fatty acids, which affect the extent of insulin resistance in various organs.


Cause and effect.
The experimental tractability of biological systems makes it possible to explore the idea that causal relationships can be estimated from observational data.


[Study on Chemical Composition of Phyllanthus emblica].
To study the chemical constituents of Phyllanthus emblica. The chemical constituents were isolated and purified by silica gel, polyamide and Sephadex LH-20 chromatography. Their structures were elucidated by physicochemical proper- ties and spectral analysis. 13 compounds were isolated and identified as Triacontanol (1), Triacontanoic acid (2), β-Amyrin ke- tone (3), Betulonic acid (4), Daucosterol (5), Lupeol acetate (6), β-Amyrin-3-palmitate (7), Gallic acid (8), Betulinic acid (9), Ursolic acid (10), Oleanolic acid (11), Quercetin (12) and Rutin (13). Compounds 1,2,4,6,7,9,10 and 11 are obtained from Phyllanthus emblica for the first time.


Role of immune complexes in cerebral malaria.
To investigate the involvement of immune complexes in the pathogenesis of cerebral malaria, a comparative study between Plasmodium berghei infected Swiss albino mice and BALB/c mice was conducted. Rise in parasitemia was found to be same with differences in manifestation of disease and mortality, level of immune complexes and histopathology. Increased parasitized red cells with swelling of endothelial cells in the brain capillaries along with increased levels of circulating immune complexes were observed in the BALB/c mice.


Daily Step Count and All-Cause Mortality: A Dose-Response Meta-analysis of Prospective Cohort Studies.
Uncertainty remains about the optimum step count per day for health promotion. We aimed to investigate the association between step count per day and all-cause mortality risk. PubMed, Scopus, and ISI Web of Science were searched to January 2021 to find prospective cohort studies of the association between device-based step count per day and all-cause mortality risk in the general population. Two reviewers extracted data in duplicate and rated the certainty of evidence using the GRADE approach. Study-specific hazard ratios (HRs) were pooled using a random-effects model. Seven prospective cohort studies with 175,370 person-years and 2310 cases of all-cause mortality were included. The HR for each 1000 steps per day was 0.88 (95% CI 0.83-0.93; I2 = 79%, n = 7) in the overall analysis, 0.87 (95% CI 0.78-0.97; I2 = 59%, n = 3) in adults older than 70 years, and 0.92 (95% CI 0.89-0.95; I2 = 37%, n = 2) in studies controlled for step intensity. Dose-response meta-analysis indicated a strong inverse association, wherein the risk decreased linearly from 2700 to17,000 steps per day. The HR for 10,000 steps per day was 0.44 (95% CI 0.31-0.63). The certainty of evidence was rated strong due to upgrades for large effect size and dose-response gradient. Even a modest increase in steps per day may be associated with a lower risk of death. These results can be used to develop simple, efficient and easy-to-understand public health messages.


The thromboplastic activity of lung surfactant in amniotic fluid and its application to prenatal assessment of fetal lung maturity.
Based on the fact that both tissue thromboplastin and lung surfactant show lamellar structures under the electron microscope and belong chemically to lipoprotein, the thromboplastic activity of lung surfactant in amniotic fluid was studied by measuring plasma recalcification time. The results obtained were as follows (1) The surfactant fractions isolated from amniotic fluid and rabbit or pig lung showed the thromboplastic activity with dose response. (2) The thromboplastic activity of amniotic fluid increased with advancing gestational age. (3) It was found that the thromboplastic activity determined by plasma recalcification time was parallel with the surfactant concentration of amniotic fluid. (4) The shortening rate of plasma recalcification time in amniotic fluid could estimate well the risk of RDS, and the critical value for RDS was assumed to be about 33%.


Population Pharmacokinetics of Z-Endoxifen in Patients With Advanced Solid Tumors.
The purpose of this study was to develop and validate a population pharmacokinetic model for Z-endoxifen in patients with advanced solid tumors and to identify clinical variables that influence pharmacokinetic parameters. Z-endoxifen-HCl was administered orally once a day on a 28-day cycle (±3 days) over 11 dose levels ranging from 20 to 360 mg. A total of 1256 Z-endoxifen plasma concentration samples from 80 patients were analyzed using nonlinear mixed-effects modeling to develop a population pharmacokinetic model for Z-endoxifen. A 2-compartment model with oral depot and linear elimination adequately described the data. The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 4.89 L/h, 323 L, and 39.7 L, respectively, with weight-effect exponents of 0.75, 1, and 1, respectively. This model was used to explore the effects of clinical and demographic variables on Z-endoxifen pharmacokinetics. Weight, race on clearance, and aspartate aminotransferase on the absorption rate constant were identified as significant covariates in the final model. This novel population pharmacokinetic model provides insight regarding factors that may affect the pharmacokinetics of Z-endoxifen and may assist in the design of future clinical trials.


Likelihood and approximate likelihood analyses of genetic structure in a linear habitat: performance and robustness to model mis-specification.
We evaluate the performance of maximum likelihood (ML) analysis of allele frequency data in a linear array of populations. The parameters are a mutation rate and either the dispersal rate in a stepping stone model or a dispersal rate and a scale parameter in a geometric dispersal model. An approximate procedure known as maximum product of approximate conditional (PAC) likelihood is found to perform as well as ML. Mis-specification biases may occur because the importance sampling algorithm is formally defined in term of mutation and migration rates scaled by the total size of the population, and this size may differ widely in the statistical model and in reality. As could be expected, ML generally performs well when the statistical model is correctly specified. Otherwise, mutation rate estimates are much closer to mutation probability scaled by number of demes in the statistical model than scaled by number of demes in reality when mutation probability is high and dispersal is most limited. This mis-specification bias actually has practical benefits. However, opposite results are found in opposite conditions. Migration rate estimates show roughly similar trends, but they may not always be easily interpreted as low-bias estimates of dispersal rate under any scaling. Estimation of the dispersal scale parameter is also affected by mis-specification of the number of demes, and the different biases compensate each other in such a way that good estimation of the so-called neighborhood size (or more precisely the product of population density and mean-squared parent-offspring dispersal distance) is achieved. Results congruent with these findings are found in an application to a damselfly data set.


The recent rise in Palestinian fertility: permanent or transient?
The purpose of this paper is to describe trends in fertility and fertility change in the West Bank and Gaza Strip during the years 1968-1992, with a particular focus on the recent rise in fertility. The paper is based primarily on vital registration data. The findings show that the fertility transition has been well underway in the West Bank since 1985, with a lull during the Intifada period. No indication of a fertility transition in the Gaza Strip was found. An examination of the age pattern of fertility reveals that Palestinian fertility has been increasingly shifting toward younger ages, with a particular concentration in the age group 15-24 during the Intifada period. A decomposition analysis of the fertility rates shows that the recent rise in fertility is essentially due to changes in marital structure, but also to increased fertility within marriage among younger women. No evidence of increased fertility among older women is found. Some implications of the findings are discussed.


Dynamic interactions of neutrophils and biofilms.
The majority of microbial infections in humans are biofilm-associated and difficult to treat, as biofilms are highly resistant to antimicrobial agents and protect themselves from external threats in various ways. Biofilms are tenaciously attached to surfaces and impede the ability of host defense molecules and cells to penetrate them. On the other hand, some biofilms are beneficial for the host and contain protective microorganisms. Microbes in biofilms express pathogen-associated molecular patterns and epitopes that can be recognized by innate immune cells and opsonins, leading to activation of neutrophils and other leukocytes. Neutrophils are part of the first line of defense and have multiple antimicrobial strategies allowing them to attack pathogenic biofilms. In this paper, interaction modes of neutrophils with biofilms are reviewed. Antimicrobial strategies of neutrophils and the counteractions of the biofilm communities, with special attention to oral biofilms, are presented. Moreover, possible adverse effects of neutrophil activity and their biofilm-promoting side effects are discussed. Biofilms are partially, but not entirely, protected against neutrophil assault, which include the processes of phagocytosis, degranulation, and formation of neutrophil extracellular traps. However, virulence factors of microorganisms, microbial composition, and properties of the extracellular matrix determine whether a biofilm and subsequent microbial spread can be controlled by neutrophils and other host defense factors. Besides, neutrophils may inadvertently contribute to the physical and ecological stability of biofilms by promoting selection of more resistant strains. Moreover, neutrophil enzymes can degrade collagen and other proteins and, as a result, cause harm to the host tissues. These parameters could be crucial factors in the onset of periodontal inflammation and the subsequent tissue breakdown.


Dissociation of renin and aldosterone during dehydration: studies in a case of diabetes insipidus and adipsia.
The regulation of aldosterone was studied in a child with diabetes insipidus and adipsia, associated with holoprosencephaly. Plasma ADH was low and unresponsive to dehydration. Plasma renin concentration ranged from 52 to 1350 ng ml-1 h-1 at various degrees of hydration, and plasma aldosterone ranged from 4.7 to 104 ng/100 ml. Despite these wide ranges, the levels of the two hormones were not correlated. The aldosterone-renin ratio (log.) was inversely related to the plasma sodium concentration, while the plasma renin concentration (log.) was directly related to plasma sodium. Reduced values of both extracellular fluid volume (radiosulphate and sodium spaces) and total exchangeable sodium were measured when plasma sodium was elevated. Sodium depletion at the time when the patient was in a dehydrated state appeared to be caused, at least partly, by defective renal sodium conservation. Thus, in the dehydrated state, the patient showed the following unusual combination of abnormalities: hypernatraemia, sodium depletion, hyperreninaemia, and low to normal plasma aldosterone. The abnormal aldosterone-renin ratio was probably not caused by an intrinsic adrenal abnormality, since high levels of aldosterone were measured as long as a certain degree of hydration had been achieved with or without exogenous ADH, and since plasma cortisol was normal and responsive to exogenous ACTH. The results suggest that the responsiveness of the adrenal cortex to angiotensin may vary with extracellular sodium concentration. The direction of this effect, that is, suppression of aldosterone with increased sodium concentration, is not different from what is observed under experimental conditions, when extra-cellular sodium concentration is raised by infusions of hyperosmolar saline.


Study of thermal behavior of vitamin D3 by pyrolysis-GC-MS in combination with boiling point-retention time correlation.
The thermal behavior of vitamin D3 was studied based on pyrolysis-GC-MS technique. It was pyrolyzed at 600 degrees C, 750 degrees C, 900 degrees C, respectively. The pyrolysis product were separated With an HP-5 column and identified by the NIST mass spectral search program in combination with the correlation of boiling point and retention time (BP-RT). There are totally 50 components, including mono aromatics and polycyclic aromatic hydrocarbons (PAHs), were determined. It is shown that the contents of the PAHs are increasing with the increasing of the pyrolysis temperature. The contents of the determined components vary from 0.04% to 37.08%.


Vascular and cardiac overexpression of endothelin-1 gene in one-kidney, one clip Goldblatt hypertensive rats but only in the late phase of two-kidney one clip Goldblatt hypertension.
To investigate a model of experimental hypertension that exhibits severe hypertrophy of small blood vessels but in which deoxycorticosterone acetate (DOCA) and salt are absent: the one-kidney, one clip model of Goldblatt renovascular hypertension, which is non-renin-dependent, and compare it with the renin-dependent two-kidney, one clip Goldblatt hypertensive rat, in which additionally vascular hypertrophy is less severe. Endothelin-1 gene expression in blood vessels and in the heart was examined by Northern blot analysis. After 2 or 4 weeks of application of the silver clip to unilaterally nephrectomized rats, the aorta and mesenteric arteries exhibited a significant increase in the intensity of the 2.3 kb band corresponding to hybridization with endothelin-1 messenger RNA (mRNA) in comparison with results obtained in control unilaterally nephrectomized rats. No increase was noted in the blood vessels of the two-kidney, one clip hypertensive rat at 2 or 4 weeks, but significant increases were found at 8 weeks in aorta, but not in mesenteric arteries. Cardiac abundance of endothelin-1 mRNA was also increased in ventricles and in the left atria of one-kidney, one clip hypertensive rats, but only in the late phase (at 8 weeks) in two-kidney, one clip hypertensive rats. Because one-kidney, one clip hypertensive rats presented severe vascular hypertrophy whereas two-kidney, one clip hypertensive rats only did so in the late phase of hypertension, these results lend further support to there being a relationship between vascular hypertrophy and endothelin-1 vascular overexpression in experimental models of hypertension. They also demonstrate that enhancement of the expression of endothelin-1 gene in blood vessels and in the heart of hypertensive rats may occur in the absence of exposure to DOCA and salt, and that endothelin-1 gene overexpression in experimental hypertension occurs early in non-renin-dependent, volume-expanded models such as the one-kidney, one clip or the DOCA-salt hypertensive rat, but only in the progressively non-renin-dependent late phase of the initially renin-dependent volume-contracted two-kidney, one clip hypertensive rat.


A Brown Mesoporous TiO2-x /MCF Composite with an Extremely High Quantum Yield of Solar Energy Photocatalysis for H2 Evolution.
A brown mesoporous TiO2-x /MCF composite with a high fluorine dopant concentration (8.01 at%) is synthesized by a vacuum activation method. It exhibits an excellent solar absorption and a record-breaking quantum yield (Φ = 46%) and a high photon-hydrogen energy conversion efficiency (η = 34%,) for solar photocatalytic H2 production, which are all higher than that of the black hydrogen-doped TiO2 (Φ = 35%, η = 24%). The MCFs serve to improve the adsorption of F atoms onto the TiO2 /MCF composite surface, which after the formation of oxygen vacancies by vacuum activation, facilitate the abundant substitution of these vacancies with F atoms. The decrease of recombination sites induced by high-concentration F doping and the synergistic effect between lattice Ti(3+)-F and surface Ti(3+)-F are responsible for the enhanced lifetime of electrons, the observed excellent absorption of solar light, and the photocatalytic production of H2 for these catalysts. The as-prepared F-doped composite is an ideal solar light-driven photocatalyst with great potential for applications ranging from the remediation of environmental pollution to the harnessing of solar energy for H2 production.


An examination of the lateralized abstractive/form specific model using MiXeD-CaSe primes.
CaSe AlTeRnAtIoN effects on the two cerebral hemispheres were studied in a lateralized visual lexical decision task with 32 right-handed participants. The study aimed to compare two well-known lateralization theories, the two processing modes and the abstractive/form-specific theories, that differ in the predictions regarding case alternation effects on the hemispheres. The experiment employed the masked priming paradigm, where prime and target words were presented in mixed case. The results of the experiment demonstrated no hemispheric differences in priming size when prime and target were similar in (mixed) case, thus were in line with the two modes theory. However, a new interpretation to the abstractive/form-specific model may also account for the results.


Support for lowering cervical cancer screening age to 25 for women living with HIV: retrospective cross-sectional programmatic data from Botswana.
Women living with human immunodeficiency virus (HIV) tend to develop cervical cancer at a younger age than women without HIV. The World Health Organization's (WHO) 2021 guidelines for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention include a conditional recommendation for initiating screening at age 25 for women living with HIV (WLWH). This recommendation is based on low-certainty evidence, and WHO calls for additional data. We describe the association of age and HIV status with visual inspection with acetic acid (VIA) positivity and cervical intraepithelial neoplasia grade two or higher (CIN2+) in Botswana. This was a retrospective cross-sectional study of 5714 participants aged 25 to 49 years who underwent VIA screening in a clinic mainly serving WLWH. VIA-positive women received cryotherapy if eligible or were referred for colposcopy and excisional treatment. Known cervical cancer risk factors, screening outcome, and histological results were extracted from the program database. We compared the proportions and association of VIA positivity and CIN2+ by age and HIV status. The median age was 35 years [IQR 31-39], and 18% of the women were aged 25-29. Ninety percent were WLWH; median CD4 count was 250 cells/µL [IQR 150-428], and 34.2% were on anti-retroviral treatment (ART). VIA-positivity was associated with younger age (OR 1.48, CI 1.28, 1.72 for 25-29 years vs. 30-49 years), and HIV-positivity (OR 1.85, CI 1.51, 2.28). CIN2+ was only associated with HIV-positivity (OR 6.12, CI 3.39, 11.10), and proportions of CIN2+ were similar for both age groups in WLWH (69.1% vs. 68.3%). Younger WLWH in Botswana had a significant burden of CIN2+. This finding further supports lowering the screening age for WLWH from 30 to 25.


Treatment of rat fibrosarcoma by radiotherapy plus immune adjuvant.
Combined radiotherapy and nonspecific adjuvant C. parvum or Piromen treatment of rat tumors show improvement over radiotherapy alone. The most effective protocol, resulting in complete remission in 6 of 6 rats was obtained with C. parvum given i.p. in three doses 1 day prior to tumor X-irradiation of three doses of 1500 R each given on days 1, 4, and 8. Animals receiving the same dose schedule without adjuvant had only partial regression of their tumor. Without adjuvant, increasing the dose to 6000 R also resulted in tumor regression, but at the expense of marked necrosis to the leg. One mechanism for the observed results may be stimulation of the reticulo-endothelial system to produce macrophages activated against the tumor. It is also possible that C. parvum causes increased rate of clearance of soluble antigens released as a result of radiation destruction of the tumor, as suggested by Proctor et al (3).


A Pilot Evaluation of the Possible Association of Metronidazole With Neurodevelopmental Outcomes in Premature Neonates.
Metronidazole is recommended as a first-line treatment of necrotizing enterocolitis (NEC) in neonates. Metronidazole-associated neurotoxicity has been reported, but long-term neurodevelopmental effects in neonates have not been explored. The primary objective was to evaluate the relationship of cumulative metronidazole dose with each Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) composite score in neonates with NEC. Secondary objectives included comparison of seizure rates, mean Bayley-III scores, and neurodevelopmental impairment defined as 2 of 3 Bayley-III composite scores ≤ 79 or 1 score ≤ 70 between the metronidazole exposed and non-exposed groups. This multisite, retrospective cohort study compared infants with a birth weight < 1500 grams between January 1, 2011, and December 31, 2016, who developed stage 2 or greater NEC or spontaneous intestinal perforation and were followed up at a developmental clinic visit at approximately 1 year of age. Patients were excluded if admitted >72 hours of life, had congenital neurodevelopmental anomalies, hypoxic ischemic encephalopathy, grade III or IV intraventricular hemorrhage, or seizures prior to treatment of NEC. Included patients were stratified into 2 groups based on metronidazole exposure versus no metronidazole. Data were assessed using descriptive and inferential statistical techniques, using SAS 9.4. Forty-one patients were included. Seven patients received metronidazole and 34 patients were in the non-metronidazole group. The only statistical difference noted between groups was for gestational age, with the non-exposed group being more premature. There was no statistical difference in Bayley-III scores, seizure rates, or neurodevelopmental impairment between groups. No differences in neurodevelopmental outcomes were found between those with and without metronidazole exposure. Further studies are needed to validate our results.


Imperatorin as a Promising Chemotherapeutic Agent Against Human Larynx Cancer and Rhabdomyosarcoma Cells.
Naturally occurring coumarins are bioactive compounds widely used in Asian traditional medicine. They have been shown to inhibit proliferation, induce apoptosis, and/or enhance the cytotoxicity of currently used drugs against a variety of cancer cell types. The aim of our study was to examine the antiproliferative activity of different linear furanocoumarins on human rhabdomyosarcoma, lung, and larynx cancer cell lines, and dissolve their cellular mechanism of action. The coumarins were isolated from fruits of Angelica archangelica L. or Pastinaca sativa L., and separated using high-performance counter-current chromatography (HPCCC). The identity and purity of isolated compounds were confirmed by HPLC-DAD and NMR analyses. Cell viability and toxicity assessments were performed by means of methylthiazolyldiphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, respectively. Induction of apoptosis and cell cycle progression were measured using flow cytometry analysis. qPCR method was applied to detect changes in gene expression. Linear furanocoumarins in a dose-dependent manner inhibited proliferation of cancer cells with diverse activity regarding compounds and cancer cell type specificity. Imperatorin (IMP) exhibited the most potent growth inhibitory effects against human rhabdomyosarcoma and larynx cancer cell lines owing to inhibition of the cell cycle progression connected with specific changes in gene expression, including CDKN1A. As there are no specific chemotherapy treatments dedicated to laryngeal squamous cell carcinoma and rhabdomyosarcoma, and IMP seems to be non-toxic for normal cells, our results could open a new direction in the search for effective anti-cancer agents.


Isolated recurrence of ovarian serous adenocarcinoma to adrenal gland.
The purpose of this report was to present the diagnosis and management of an unusual case of a woman with ovarian carcinoma who developed an isolated recurrence to the adrenal gland six years after initial diagnosis. A 79-year-old woman was diagnosed with stage IVa high-grade serous carcinoma of the ovary with malignant pleural effusion in January 2014. She received six cycles of carboplatin and paclitaxel and underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and optimal tumor debulking in May 2014. After developing new liver implants in August 2015 and peritoneal carcinomatosis in April 2016, she received 5 cycles of carboplatin and paclitaxel and 6 cycles of doxorubicin, respectively, after which she had no evidence of disease. In March 2020, a surveillance computed tomography (CT) scan showed a 1-cm interval thickening of the left adrenal gland suspicious for metastasis. Positron emission tomography (PET) scan revealed an adrenal mass that was intensely fluorodeoxyglucose (FDG) avid with subsequent fine-needle aspiration (FNA) consistent with metastatic serous carcinoma. She was treated with laparoscopic left adrenalectomy in October 2020 and underwent 4 cycles of adjuvant carboplatin and paclitaxel. Follow-up CT imaging revealed stable post-adrenalectomy status with no interval thickening of the gland and post-operative Ca-125 level of 11.2 from 26.1 pre-operatively. Interval adrenal thickening detected on surveillance CT was the most important initial indicator of adrenal metastasis in this case of ovarian carcinoma. The adrenal mass was further evaluated using PET CT and FNA for pathology diagnosis. As this new recurrence occurred in a patient with no evidence of disease, we suggested an aggressive management approach consisting of surgical excision in combination with chemotherapy to eliminate visible disease and optimize survival.


A new perspective of S-antigen from immunochemical analysis.
Elucidation of the amino acid sequences of retinal S-antigens from several species has allowed the fine dissection of T cell and antibody epitopes using synthetic peptides. S-antigen, isolated from retinal rod photoreceptor cells, elicits experimental autoimmune uveoretinitis (EAU), a predominantly CD4+ T-cell mediated autoimmune disease of the retina and uveal tract of the eye and pineal gland. Three uveitogenic T cell lines, R9, R17 and R208, prepared against native bovine S-antigen, human S-antigen and cyanogen bromide peptide CB123, respectively, were used to identify the T cell recognition sites responsible for uveitogenic and proliferative responses. T cell epitopes were found to be clustered into 6 regions, some of which were species-specific. The two synthetic peptides known to actively induce EAU, residues 286-297 and 303-314 of bovine S-antigen, were unable to induce significant proliferative responses in any of the three T cell lines. However, both of these sites were adjacent to synthetic peptides, residues 273-292 and 317-328, respectively, which were unable to actively induce EAU, but elicited proliferative responses from the T cell lines. We also report the presence of a new pathogenic site, also associated with an adjacent proliferative site, together in residues 343-362 of bovine S-Ag. Our results indicate that spatially separate and distinct T cell epitopes are present in S-antigen which are responsible for the active induction of EAU, lymphocyte proliferation, and adoptive transfer of EAU.


E3 ubiquitin ligases SINA4 and SINA11 regulate anthocyanin biosynthesis by targeting the IAA29-ARF5-1-ERF3 module in apple.
Auxin/indole-3-acetic acid (AUX/IAA) and auxin response factor (ARF) proteins are important components of the auxin signalling pathway, but their ubiquitination modification and the mechanism of auxin-mediated anthocyanin biosynthesis remain elusive. Here, the ARF MdARF5-1 was identified as a negative regulator of anthocyanin biosynthesis in apple, and it integrates auxin and ethylene signals by inhibiting the expression of the ethylene response factor MdERF3. The auxin repressor MdIAA29 decreased the inhibitory effect of MdARF5-1 on anthocyanin biosynthesis by attenuating the transcriptional inhibition of MdERF3 by MdARF5-1. In addition, the E3 ubiquitin ligases MdSINA4 and MdSINA11 played negative and positive regulatory roles in anthocyanin biosynthesis by targeting MdIAA29 and MdARF5-1 for ubiquitination degradation, respectively. MdSINA4 destabilized MdSINA11 to regulate anthocyanin accumulation in response to auxin signalling. In sum, our data revealed the crosstalk between auxin and ethylene signals mediated by the IAA29-ARF5-1-ERF3 module and provide new insights into the ubiquitination modification of the auxin signalling pathway.


Immunosuppressive anti-immunoglobulin autoantibodies: specificity, gene structure and function in health and disease.
Anti-immunoglobulin autoantibodies (anti-Ig auto-Abs) are part of the physiological immune repertoire. Herein we focus on Abs directed against the F(ab')2 region of the Ig molecule. The vast majority of previously described anti-F(ab')2 auto-Abs were antiidiotypes. The antibodies we studied recognize epitopes located in the hinge region of IgG and in other conserved domains of F(ab')2. Gene structure analyses revealed germline gene identity of VL chains and 88% homology with the closest germline gene of VH chains. We present evidence for a B cell suppressive role of anti-Ig Abs and discuss the mechanism of suppression. Moreover, the role of anti-Ig auto-Abs in immunoregulation as well as in the pathogenesis of autoimmune and other diseases is discussed. There is substantial evidence indicating that anti-Ig auto-Abs are important immunoregulatory molecules.


Multifractal structure of the harmonic measure of diffusion-limited aggregates.
The method of iterated conformal maps allows one to study the harmonic measure of diffusion-limited aggregates with unprecedented accuracy. We employ this method to explore the multifractal properties of the measure, including the scaling of the measure in the deepest fjords that were hitherto screened away from any numerical probing. We resolve probabilities as small as 10(-35), and present an accurate determination of the generalized dimensions and the spectrum of singularities. We show that the generalized dimensions D(q) are infinite for q<q*, where q* is of the order of -0.2. In the language of f(alpha) this means that alpha(max) is finite. The f(alpha) curve loses analyticity (the phenomenon of "phase transition") at alpha(max) and a finite value of f(alpha(max)). We consider the geometric structure of the regions that support the lowest parts of the harmonic measure, and thus offer an explanation for the phase transition, rationalizing the value of q* and f(alpha(max)). We thus offer a satisfactory physical picture of the scaling properties of this multifractal measure.


Lignin-Biosynthetic Study: Reactivity of Quinone Methides in the Diastereopreferential Formation of p-Hydroxyphenyl- and Guaiacyl-Type β- O-4 Structures.
p-Quinone methides are involved in lignin biosynthesis as transient intermediates, and the aromatization step has a great impact on the chemical structure of the resulting lignin. A series of quinone methides (QMs) were synthesized and allowed to react with water in pH 3-7 buffers at 25 °C to mimic the formation of p-hydroxyphenyl- and guaiacyl-type (H- and G-type, respectively) β- O-4 structures in gymnosperm-plant cell walls. Water addition occurred in 3-methoxy-substituted QMs (G-type QMs) with half-lives of 1.4-15 min. In contrast, nonsubstituted QMs (H-type QMs) were very labile; they were aromatized to β- O-4 products with half-lives of only 10-40 s. The rapid aromatization in H-type QMs may provide an advantage over G-type species for efficiently driving the lignin-polymerization cycle, which possibly contributes to the development of highly lignified compression wood. In the water-addition reaction, the threo isomers of the β- O-4 products were stereopreferentially formed more than the erythro isomers from both G- and H-type QMs ( erythro/ threo ratios of 24:76 and 50:50, respectively). The proportion of erythro isomers was higher at lower-pH conditions. This pH-dependent trend agrees with findings from a previous study on 3,5-dimethoxy-substituted (syringyl-type, S-type) QMs; thus, this pH-dependent trend is common in H-, G-, and S-type lignin-related QMs. Higher threo-selectivity was obtained by changing the β-etherified aromatic rings from G- to H-type. A similar but weaker effect was also observed by changing the QM moiety from G- to H-type.


Caloric Restriction Mimetic 2-Deoxyglucose Alleviated Inflammatory Lung Injury via Suppressing Nuclear Pyruvate Kinase M2-Signal Transducer and Activator of Transcription 3 Pathway.
Inflammation is an energy-intensive process, and caloric restriction (CR) could provide anti-inflammatory benefits. CR mimetics (CRM), such as the glycolytic inhibitor 2-deoxyglucose (2-DG), mimic the beneficial effects of CR without inducing CR-related physiologic disturbance. This study investigated the potential anti-inflammatory benefits of 2-DG and the underlying mechanisms in mice with lipopolysaccharide (LPS)-induced lethal endotoxemia. The results indicated that pretreatment with 2-DG suppressed LPS-induced elevation of tumor necrosis factor alpha and interleukin 6. It also suppressed the upregulation of myeloperoxidase, attenuated Evans blue leakage, alleviated histological abnormalities in the lung, and improved the survival of LPS-challenged mice. Treatment with 2-DG had no obvious effects on the total level of pyruvate kinase M2 (PKM2), but it significantly suppressed LPS-induced elevation of PKM2 in the nuclei. Prevention of PKM2 nuclear accumulation by ML265 mimicked the anti-inflammatory benefits of 2-DG. In addition, treatment with 2-DG or ML265 suppressed the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3). Inhibition of STAT3 by stattic suppressed LPS-induced inflammatory injury. Interestingly, posttreatment with 2-DG at the early stage post-LPS challenge also improved the survival of the experimental animals. This study found that treatment with 2-DG, a representative CRM, provided anti-inflammatory benefits in lethal inflammation. The underlying mechanisms included suppressed nuclear PKM2-STAT3 pathway. These data suggest that 2-DG might have potential value in the early intervention of lethal inflammation.


TRPV1-lineage neurons are required for thermal sensation.
The ion-channel TRPV1 is believed to be a major sensor of noxious heat, but surprisingly animals lacking TRPV1 still display marked responses to elevated temperature. In this study, we explored the role of TRPV1-expressing neurons in somatosensation by generating mice wherein this lineage of cells was selectively labelled or ablated. Our data show that TRPV1 is an embryonic marker of many nociceptors including all TRPV1- and TRPM8-neurons as well as many Mrg-expressing neurons. Mutant mice lacking these cells are completely insensitive to hot or cold but in marked contrast retain normal touch and mechanical pain sensation. These animals also exhibit defective body temperature control and lose both itch and pain reactions to potent chemical mediators. Together with previous cell ablation studies, our results define and delimit the roles of TRPV1- and TRPM8-neurons in thermosensation, thermoregulation and nociception, thus significantly extending the concept of labelled lines in somatosensory coding.


Copper and Diabetes: Current Research and Prospect.
Copper is an essential trace metal for normal cellular functions; a lack of copper is reported to impair the function of important copper-binding enzymes, while excess copper could lead to cell death. Numerous studies have shown an association between dietary copper consumption or plasma copper levels and the incidence of diabetes/diabetes complications. And experimental studies have revealed multiple signaling pathways that are triggered by copper shortages or copper overload in diabetic conditions. Moreover, studies show that treated with copper chelators improve vascular function, maintain copper homeostasis, inhibit cuproptosis, and reduce cell toxicity, thereby alleviating diabetic neuropathy, retinopathy, nephropathy, and cardiomyopathy. However, the mechanisms reported in these studies are inconsistent or even contradictory. This review summarizes the precise and tight regulation of copper homeostasis processes, and discusses the latest progress in the association of diabetes and dietary copper/plasma copper. Further, the study pays close attention to the therapeutic potential of copper chelators and copper in diabetes and its complications, and hopes to provide new insight for the treatment of diabetes.


Neuroendocrine control of egg-laying behavior in the nudibranch, Archidoris montereyensis.
We describe a group of neurons with egg-laying bioactivity in the cerebral ganglia of an opisthobranch mollusc, the nudibranch Archidoris montereyensis. These cells, the intercerebral white cells (IWCs), share morphological, biochemical, and electrophysiological characteristics with the egg-laying neuroendocrine cells of two other molluscs, Aplysia californica (bag cells) and Lymnaea stagnalis (caudodorsal cells). The IWCs, comprising two superficial clusters of about 100 neurons each, were located immediately posterior to the intercerebral commissure in the cerebral ganglia. The somata of these cells were small (< 20 microns) and possessed varicose, bifurcating unipolar processes that collectively formed a loop within the commissure and bilateral extensions into the cerebral ganglia. The IWC clusters and commissural processes were enveloped by a large ganglionic vascular sinus, forming a potential neurohemal release site. Homogenates of whole cerebral ganglia or isolated IWC clusters induced egg-laying behavior within hours of injection into the hemocoel of quiescent animals. The IWCs were immunoreactive for alpha bag-cell peptide, one of the neuropeptide transmitters encoded by the egg-laying hormone gene of Aplysia. Electrophysiologically, the IWCs were silent neurons with large resting potentials and appeared to be highly refractory to electrical stimulation. The similarities of the IWCs to the egg-laying neuroendocrine cells in Aplysia and Lymnaea suggest that they are members of a homologous group of neurons controlling egg-laying behavior in gastropod molluscs.


Ultrasound enhanced bioprocesses: cholesterol oxidation by Rhodococcus erythropolis.
Cholesterol oxidation to cholestenone by resting cells of Rhodococcus erythropolis ATCC25544 was investigated under a computer-controlled ultrasonic irradiation at a frequency of 20 kHz. The optimization of the ultrasound intensity and its mode of application to a stirred bioreactor was first established at a level which preserved the structural integrity of the cells and enabled their metabolic activity. A significant enhancement in the kinetic rates of the biotransformation was observed in microbial slurries of 1.0 and 2.5 g/L cholesterol when sonicated for 5 s every 10 min with a power output of 2.2 W/cm(2). In contrast, ultrasound had no effect on the enzymatic oxidation of cholesterol (2.5 g/L) by cholesterol oxidase. A high loading of cholesterol (5.0 g/L) in sonicated microbial systems had, however, an adverse effect. The ultrasound enhancement is discussed in terms of an increased dissolution rate of the sustrate crystals and more importantly, in terms of the uniquely ultrasound-induced enhancement of mass transfer inside and outside a cell.


Dexmedetomidine versus remifentanil for sedation during awake intubation using a Shikani optical stylet: a randomized, double-blinded, controlled trial.
The purpose of this study was to compare the efficacy and safety of dexmedetomidine versus remifentanil for sedation during awake intubation using a Shikani optical stylet (SOS). Sixty-eight patients with cervical trauma or severe cervical spondylosis undergoing cervical spinal surgery were enrolled in this prospective study. They were randomly assigned to receive dexmedetomidine (Group D) or remifentanil (Group R). In Group D, the patients received an intravenous loading dose of dexmedetomidine 1 μg · kg(-1) over 10 min followed by a continuous infusion of 0.7 μg · kg(-1) · h(-1). In Group R, a target-controlled infusion of remifentanil was administered to achieve a plasma concentration of 2.5 ng · ml(-1), increased to 3 ng · ml(-1) 10 min later. An endotracheal tube was inserted using a SOS under dexmedetomidine or remifentanil sedation after topical anesthesia to the airway. Midazolam was given as rescue sedation. We recorded the first attempt intubation success rate, the dose of midazolam, duration of intubation, Ramsay Sedation Scale (RSS) score, tracheal tube tolerance score, duration of drug infusion, adverse events and patient satisfaction score. The RSS score was significantly higher in Group D than in Group R. First attempt success rate, rescue midazolam dose and the duration of intubation did not differ between the groups. Patients in Group R were significantly more tolerant of the tracheal tube. The incidence of hypoxia was significantly higher in Group R than Group D, but there was no significant difference in the incidence of other adverse events between the groups. The hemodynamic responses of the two groups were similar, but more patients in Group R were able to recall airway instrumentation. Both dexmedetomidine and remifentanil are effective sedatives for awake intubation using an SOS. Although the first attempt success rates were similar, patients sedated with remifentanil tolerated the tracheal tube better after intubation with moderately increased risk of desaturation. www.chictr.org.cn ; ChiCTR-TRC-13003052 (February 4th, 2013).


Clinical Outcomes of Children With COVID-19 by SARS-CoV-2 Strain: A Cohort Study.
We sought to investigate the disease outcomes and predictors of severe outcomes among children infected with the Delta variant of SARS-CoV-2 compared with pre-Delta strains. Single-center retrospective cohort study in an emergency department located within an urban academic children's hospital. Patients included children (0-18 years) who tested positive for SARS-CoV-2. Main outcomes measured include need for hospital admission or COVID-directed therapies. There was a trend toward decreased hospital admission and no significant difference in the severity of outcomes in the Delta cohort relative to the pre-Delta cohort. The Delta cohort had lower odds of hospital admission (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.51-1.23), but the result was not statistically significant. Logistic regression analyses showed that overall, age 1 to 4 years (OR, 2.35; 95% CI, 1.23-4.57) and public insurance (OR, 1.80, 95% CI, 1.08-3.01) were predictors of hospital admission. Within the Delta cohort, the presence of any comorbidity increased the odds of admission (OR, 2.52; 95% CI, 1.09-6.04). Black children had lower odds of admission than white children (overall OR, 0.53; 95% CI, 0.31-0.90; pre-Delta OR, 0.50; 95% CI, 0.26-0.95). The severity of measured disease outcomes was similar in pediatric patients when comparing children infected with the pre-Delta and Delta variants of SARS-CoV-2, even among children with comorbidities once adjusting for acuity.Ongoing research is essential to determine disease severity and risk for children with comorbidities because SARS-CoV-2 continues to mutate, including with Omicron subvariants.


Autoimmune polyglandular syndrome type 2, alopecia universalis and Crohn's disease.
Autoimmune polyglandular syndromes are defined as a spectrum of association between 2 or more organ specific endocrinopaties and non-endocrine autoimmune diseases. Autoimmune polyglandular syndromes type 2 is characterized by the coexistence of adrenal failure with autoimmune thyroid disease and diabetes mellitus type 1. Inflammatory bowel diseases are rarely associated with these autoimmune disorders. Here, we report about a case of 33 years old male with known history of Crohn's colitis diagnosed in childhood. In 2003 the patient experienced sudden loss of hair, eyebrows, eyelashes, beard and body hair - alopecia universalis was diagnosed. At the age of 28, the patient was hospitalized with severe dehydration and clinical signs of ketoacidosis. Increased blood glucose (40 mmol/L), ketonuria and metabolic acidosis indicated diabetes mellitus type 1. In 2005, he had severe relapse of Crohn's disease and was treated with systemic corticosteroid. Although patient responded well to the induction therapy, fatigue, hypotension, bradycardia called for further investigations: free thyroxine - 6.99 pmol/L, thyroid-stimulating hormone >75 U/ml, anti-thyroid peroxidase antibodies >1000 U/mL, so diagnosis of Haschimoto thyroiditis was confirmed. Persistent hypotension and fatigue, recurrent hypoglycemic crises indicated a possible presence of hypo-function of adrenal glands. After complete withdrawal of corticosteroid therapy, low cortisol levels (69.4 nmol/L) and positive tetracosactide stimulation test proved adrenal cortex failure. Regardless of the intensive treatment for diabetes, hypothyroidism, adrenal insufficiency and Crohn's disease, it was extremely difficult to achieve and maintain control of all four diseases.


Kinins as vasoactive peptides.
During the past year, a number of significant publications have provided data that clearly establish the basis for the important role of the tissue kallikrein-kinin system in cardiovascular control and renal function. These publications include a report of advances in techniques for system component measurement, reports of the localization of central bradykinin receptors and an alteration in the sensitivity of the central bradykinin system in hypertension, and a description of the effects of new kinin receptor antagonists on our understanding of endogenous and exogenous kinin-induced vasorelaxation and its possible alteration in hypertension. Several significant reports describe the potentiation of endogenous kinin action by kininase inhibitors and establish the important interaction between kininase activity and kinin control of blood pressure.


Disability-a chronic omission in health equity that must be central to Canada's post-pandemic recovery.
As Canada begins to recover and learn from the COVID-19 pandemic, health equity and public health policies must be a central tenet of reform. Recent work has begun to provide guidance on an equitable pandemic recovery in Canada, which highlights many important groups that require specific consideration in recovery policies.1 There is a key omission in many of these guidelines and, in fact, most health equity efforts-people with disabilities.


Self-nanoemulsifying drug-delivery systems improve oral absorption and antischistosomal activity of epiisopiloturine.
To develop a self-nanoemulsifying drug-delivery system (SNEDDS) able to improve oral absorption of epiisopiloturine (EPI), and test the antischistosomal activity in a mice model. SNEDDS had a nanoscopic size and was able to enhance EPI bioavailability after oral administration, and SNEDDS-EPI (40 mg.kg-1) improved the in vivo antischistosomal activity of EPI, demonstrating that SNEDDS was able to improve the pharmacokinetics of EPI, and to maintain the pharmacodynamic activity against Schistosoma mansoni in vivo. Taken together, these results indicate that SNEDDS-EPI is efficient in reducing worm burden in comparison to treatment with the free version of EPI. [Formula: see text].


Building a BioChemformatics database.
The structural registration of chemically modified macromolecules is vital for the development of biopharmaceuticals. However, registration and search of such complex molecules has so far posed formidable challenges performance-wise, since today's chemistry-oriented databases do not scale well to macromolecules. As a practical consequence, macromolecules tend to be stored in protein databases with a focus on protein sequence only, and salient chemistry details are therefore lost. This article describes protein format extensions and the use of pseudoatoms for representing natural amino acids in chemical structures to allow high-performance registration and retrieval of large macromolecules. The representations include exact chemical modifications and enable lossless conversion between chemistry and sequence formats. Registration is done in parallel in both sequence and chemistry formats, and users can register and retrieve molecules in either format as they choose, resulting in what we call a BioChemformatics database. Having both sequence and chemistry formats available on-demand allows for the construction of protein SAR tables with mixed sequence and chemistry information. Likewise, searching may combine sequence and chemistry terms and be performed in standard vendor applications like MDL's ISIS/Base or in-house applications using standard SQL queries.


Surface/interface effects on the effective propagation constants of coherent waves in composites with random parallel nanofibers.
The effective propagation constants of elastic waves in an inhomogeneous medium with randomly distributed parallel cylindrical nanofibers are studied. First, the surface energy theory proposed by Huang and Wang (Handbook of Micromechanics and Nanomechanics, 2013) is used to derive the nontraditional boundary conditions on the surfaces of the nanoholes and the interfaces between the nanofibers and the host. Then, the scattering matrix of individual scatterer (cylindrical hole or nanofiber) is derived from the nontraditional boundary condition. The total wave field is obtained by considering the multiple scattering processes among the dispersive scatterers. The configuration average of the total wave field results in the coherent waves or the averaged waves. By using the corrected Linton-Martin formula, the effective propagation constants (effective speed and effective attenuation) of the coherent waves are estimated. The in-plane waves (P and SV waves) and the anti-plane waves (SH wave) are considered, respectively, and the numerical results are shown graphically. Apart from the effects of surface elasticity, the effects of inertia of surface/interface and the effects of residual surface tension (which are often ignored in the previous literature) are also considered. Moreover, the influences of the nonsymmetric parts of in-plane surface stress and the out-of-plane parts of the surface stress are both discussed first based on the numerical examples. These investigations show the underestimation and overestimation of effective propagation constants caused by various simplifications.


The effects of short-term administration of two low doses versus the standard GH replacement dose on insulin sensitivity and fasting glucose levels in young healthy adults.
GH has both diabetogenic and insulin-like actions. Supraphysiological GH doses are known to reduce insulin sensitivity (S(I)), but lower doses are less well studied. We therefore compared the effects of two physiological GH doses (intermediate, 0.0033 mg/kg x d; low, 0.0017 mg/kg x d) with the standard adult GH deficiency replacement dose (standard, 0.008 mg/kg x d) on S(I), beta-cell function, IGF-I, and IGF binding proteins (IGFBPs)-1 and -3 in healthy adults. Eleven healthy nonobese volunteers (4 males and 7 females, aged 21-38 yr) received 7 daily injections of the standard and intermediate GH doses, and 10 (5 males and 5 females, aged 21-38 yr) received the low dose. Fasting blood samples were collected daily (days 1-8). S(I) and beta-cell function were calculated using the Homeostasis model assessment. All GH doses increased IGF-I and IGFBP-3 levels, with the standard dose inducing the greatest rise (P < 0.001). At day 2 vs. baseline, all three doses increased the IGF-I/IGFBP-3 ratio, but only the standard dose lowered IGFBP-1 levels (P = 0.03). The standard dose reduced S(I) (P = 0.01), whereas the intermediate dose increased S(I) (P < 0.005) and lowered fasting insulin levels (P < 0.01). The low dose did not modify S(I), but reduced fasting glucose levels (P < 0.0001) and increased beta-cell function (P = 0.001). Males demonstrated higher IGF-I and IGFBP-3 responsiveness to the standard dose than females. Males also showed greater increase in S(I) and decrease in fasting glucose levels on both intermediate and low doses. In conclusion, the metabolic effects of GH are dose- and gender-dependent. The standard adult GH deficiency replacement dose induced insulin resistance, whereas lower doses improved S(I), especially in males. The low GH dose lowered fasting glucose levels and could represent the optimal dose to stimulate beta-cell function without compromising S(I) in insulin-resistant GH-deficient adults.


The Effect of Sharrows, Painted Bicycle Lanes and Physically Protected Paths on the Severity of Bicycle Injuries Caused by Motor Vehicles.
We conducted individual and ecologic analyses of prospectively collected data from 839 injured bicyclists who collided with motorized vehicles and presented to Bellevue Hospital, an urban Level-1 trauma center in New York City, from December 2008 to August 2014. Variables included demographics, scene information, rider behaviors, bicycle route availability, and whether the collision occurred before the road segment was converted to a bicycle route. We used negative binomial modeling to assess the risk of injury occurrence following bicycle path or lane implementation. We dichotomized U.S. National Trauma Data Bank Injury Severity Scores (ISS) into none/mild (0-8) versus moderate, severe, or critical (>8) and used adjusted multivariable logistic regression to model the association of ISS with collision proximity to sharrows (i.e., bicycle lanes designated for sharing with cars), painted bicycle lanes, or physically protected paths. Negative binomial modeling of monthly counts, while adjusting for pedestrian activity, revealed that physically protected paths were associated with 23% fewer injuries. Painted bicycle lanes reduced injury risk by nearly 90% (IDR 0.09, 95% CI 0.02-0.33). Holding all else equal, compared to no bicycle route, a bicycle injury nearby sharrows was nearly twice as likely to be moderate, severe, or critical (adjusted odds ratio 1.94; 95% confidence interval (CI) 0.91-4.15). Painted bicycle lanes and physically protected paths were 1.52 (95% CI 0.85-2.71) and 1.66 (95% CI 0.85-3.22) times as likely to be associated with more than mild injury respectively.


Amniotic membrane transplantation for pseudomonal keratitis with impending perforation.
To determine whether amniotic membrane transplantation (AMT) can be used as adjunctive therapy to promote wound healing and prevent perforation in bacterial keratitis caused by Pseudomonas aeruginosa. We report on 6 eyes from 6 patients with bacterial keratitis caused by Pseudomonas aeruginosa associated with prominent stromal melting and extensive stromal loss. AMT was performed after treatment with fortified antibiotics for at least 1 week. The mean follow-up period was 12.8+/-2.5 months. The lesion became sterile in all but 1 case for which AMT was performed. Rapid reepithelialization and decreased inflammation was observed in 5 cases, with complete reepithelialization occurred at 9.4+/-2.1 days postoperatively. The amniotic membrane dissolved in the remaining case with active, extensive corneal infection and persistent epithelial defect; this case finally received evisceration due to intractable glaucoma. In all other cases, after AMT treatment, lesions did not extend, stromal loss was limited, and considerable stromal thickness was preserved. AMT may be considered an alternative method for treating pseudomonal keratitis, especially when stromal melting and loss are extensive, and the infection has been controlled.


The effect of gender on planning: An fMRI study using the Tower of London task.
Since the introduction of brain mapping, evidences of functional gender differences have been corroborating previous behavioral and neuropsychological results showing a sex-specific brain organization. We investigated gender differences in brain activation during the performance of the Tower of London (TOL) task which is a standardized test to assess executive functions. Eighteen healthy subjects (9 females and 9 males) underwent fMRI scanning while solving a series of TOL problems with different levels of difficulty. Data were analyzed by modeling both genders and difficulty task load. Task-elicited brain activations comprised a bilateral fronto-parietal network, common to both genders; within this network, females activated more than males in dorsolateral prefrontal cortex (DLPFC) and right parietal cortex, whereas males showed higher activity in precuneus. A prominent parietal activity was found at low level of difficulty while, with heavier task demand, several frontal regions and subcortical structures were recruited. Our results suggest peculiar gender strategies, with males relying more on visuospatial abilities and females on executive processing.


HIF-1 α as a Key Factor in Bile Duct Ligation-Induced Liver Fibrosis in Rats.
Although several studies suggested hypoxia as an important microenvironmental factor contributing to inflammation and fibrosis in chronic liver diseases, the mechanism of this process is not fully understood. We considered hypoxia inducible factor (HIF-1α) as a key transcription factor in liver fibrosis. The aim of the study was to evaluate the mechanisms of signaling pathway during bile duct ligation (BDL)-induced liver fibrosis in rats. BDL animal model of liver fibrosis was used in the study. Male Wistar rats were divided randomly into two experimental groups: sham group (n = 15), BDL group (n = 30). Hydroxyproline (Hyp) content as a marker of collagen accumulation in liver of rats subjected to BDL was evaluated according to the method described by Gerling B et al. Expression of signaling proteins [integrin β1 receptor, HIF-1α, nuclear factor kappa B (NF-κB), and transforming growth factor (TGF-β)] was evaluated applying Western-immunoblot analysis. In all experiments, the mean values for six assays ± standard deviations (SD) were calculated. The results were submitted to the statistical analysis using the Student's "t" test, accepting p < 0.05 as significant. Ligation of bile ducts was found to increase Hyp content in rat liver, accompanied by increase of HIF-1α expression during 10 weeks after BDL. The Hyp level was time dependent. There was not such a difference in control group (p < 0.001). Simultaneously expression of NF-κB, TGF-β, β1-integrin receptor was significantly elevated starting from sixth week after ligation. Activity of metalloproteinases 2 and 9 in the livers were increased 1 week after surgery and remained increased until the end of the experiment. The mechanism of development of liver fibrosis involves activation of Matrix metalloproteinase-2 (MMP-2) and Matrix metalloproteinase-9 (MMP-9), upregulation of HIF-1α transcriptional activity and its related factors, NF-κB and TGF-β. It suggests that they may represent targets for the treatment of the disease.


[Incidence of disorders of heart rhythm and conduction in idiopathic mitral valve prolapse].
Out of 99 examinees, 78 patients had mitral valve prolapse of various degree. The control group included 21 individuals without the prolapse who had the same clinical signs. All the patients underwent Holter monitoring and bicycle ergometry; diagnostic transesophageal atrial pacing was performed in 26 examinees. Rhythm and conduction disturbances were shown to occur as frequently in patients with mitral valve prolapse as in the controls. For diagnosing extrasystolic arrhythmias, it was recommended to apply Holter monitoring to detect paroxysmal supraventricular tachyarrhythmias and to employ transesophageal cardiac pacing to find accessory pathways.


Trending Cardiovascular Nutrition Controversies.
The potential cardiovascular benefits of several trending foods and dietary patterns are still incompletely understood, and nutritional science continues to evolve. However, in the meantime, a number of controversial dietary patterns, foods, and nutrients have received significant media exposure and are mired by hype. This review addresses some of the more popular foods and dietary patterns that are promoted for cardiovascular health to provide clinicians with accurate information for patient discussions in the clinical setting.


Morphogenesis of Drosophila ovarian ring canals.
We analyzed the structure of cytoplasmic bridges called ring canals in Drosophila egg chambers. Two mutations, hu-li tai shao (hts) and kelch, disrupt normal ring canal development. We raised antibodies against the carboxy-terminal tail of hts and found that they recognize a protein that localizes specifically to ring canals very early in ring canal assembly. Accumulation of filamentous actin on ring canals coincides with the appearance of the hts protein. kelch, which is localized to the ring canals hours after hts and actin, is necessary for maintaining a highly ordered ring canal rim since kelch mutant egg chambers have ring canals that are obstructed by disordered actin and hts. Anti-phosphotyrosine antibodies immunostain ring canals beginning early in the germarium before hts and actin and throughout egg chamber development. The use of antibody reagents to analyze the structure of wild-type and mutant ring canals has shown that ring canal development is a dynamic process of cytoskeletal protein assembly, possibly regulated by tyrosine phosphorylation of some ring canal components.


In search of a course design and teaching methods to improve critical thinking skills.
This article describes a unique course design to teach critical thinking skills to students in formal academic degree programs preparing to become healthcare administrators. The course and its experimental design were motivated by several factors. First, intelligent and competent problem solving and decision making, most would agree, are directly dependent on critical thinking proficiency. Therefore, elevating students' critical-thinking competence will inherently improve their problem-solving and decision-making ability. Second, problem solving and decision making consumes the majority of an administrator's time. And finally, a review of AUPHA's catalog descriptions of healthcare graduate curriculums listrelatively few critical-thinking courses compared to the time administrators devote to it.


The importance of age and high degree, in protein-protein interaction networks.
Here we present an in-depth analysis of the protein age patterns found in the edge and triangle subgraphs of the yeast protein-protein interaction network (PIN). We assess their statistical significance both according to what would be expected by chance given the node frequencies found in the yeast PIN, and also, for the case of triangles, given the age frequencies observed in the currently available pairwise data. We find that pairwise interactions between Old proteins are over-represented even when controlling for high degree, and triangle interactions between Old proteins are over-represented even when controlling for pairwise interaction frequencies. There is evidence for negative selection of interactions between Middle-aged and Old proteins within triangles, despite pairwise Middle-Old interactions being common. Most triangles consist solely of vertices with high degree. Our findings point towards an architecture of the yeast PIN that is highly heterogeneous, having connected clumps which contain a large number of interacting Old proteins along with selective age-dependent interaction patterns. Supplementary Material is available online (www.liebertonline.com/cmb).


[Renal urodilatin secretion is associated with diuresis and natriuresis after spontaneous, supraventricular tachycardia].
Patients with paroxysmal supraventricular tachycardia (SVT) may have a polyuria after termination of tachycardia. There is increasing evidence that the renal peptide urodilatin (ANP (95-126))--and not plasma ANP (ANP (99-126))--is the member of the natriuretic peptide family mediating natriuresis and diuresis in man. In patients with SVT we, therefore, analyzed the relationship between diuresis, natriuresis, plasma ANP, urinary urodilatin excretion and renal excretion of cyclic GMP, the second messenger in the ANP system. During and after clinical presentation with spontaneously occurring SVT, two patients with AV-nodal and one patient with atrioventricular reentry tachycardia (heart rate 160 to 200 bpm) were studied. Urinary urodilatin excretion was correlated to diuresis (r = 0.73) and natriuresis (r = 0.93); similarly urinary cyclic GMP excretion was related to diuresis (r = 0.80) and natriuresis (r = 0.87; p < 0.001, respectively). In contrast, there was no significant correlation between plasma ANP concentrations and diuresis (r = 0.28, n.s.) or natriuresis (r = 0.11, n.s.). As an explorative analysis, stepwise multiple linear regression identified urinary urodilatin as the most important contributor to diuresis and natriuresis after SVT. These data on polyuria after spontaneous SVT further support the view that in man urodilatin is the member of the natriuretic peptide family participating in kidney physiology.


Maternal uniparental isodisomy 10 and mosaicism for an additional marker chromosome derived from the paternal chromosome 10 in a fetus.
We report a case of maternal isodisomy 10 combined with mosaic partial trisomy 10 (p12.31-q11.1). Chromosome examinations from a CVS sample showed a karyotype 47,XX,+mar/46,XX [corrected]. The additional marker chromosome which was present in 6/25 interphase nuclei was shown by fluorescence in situ hybridization (FISH) to have been derived from a pericentromeric segment of chromosome 10. DNA analysis was performed from umbilical cord blood from the fetus after termination of the pregnancy at 18 weeks. The results showed that the two structurally normal chromosomes 10 were both of maternal origin, whereas the marker chromosome derived from the father. Autopsy of the fetus revealed hypoplasia of heart, liver, kidneys and suprarenal glands, but, apart from a right bifid ureter, no structural organ abnormalities. This fetus represents the second reported instance of a maternal uniparental disomy (UPD) 10.


Comparison of an enzyme-linked immunoassay and a quantitative indirect fluorescent-antibody test with the conventional indirect fluorescent-antibody test for detecting antibodies to Toxoplasma gondii.
Two new methods for the detection of antibodies to Toxoplasma gondii, an enzyme-linked immunosorbent assay and a quantitative immunofluorescence assay, were evaluated and compared with the conventional indirect fluorescent-antibody slide test. Each of 100 human sera was assayed twice by the three procedures. Both the enzyme-linked immunosorbent assay and the quantitative immunofluorescence assay correlated well with serologically positive (indirect fluorescent-antibody titer greater than or equal to 1:32) and negative sera. The enzyme-linked immunosorbent assay was more specific, but less sensitive, than the quantitative immunofluorescence assay. However, the quantitative immunofluorescence assay was more reproducible and more rapid than the enzyme-linked immunosorbent assay.


Field cancerization in breast cancer.
Breast cancer affects one in seven women worldwide during their lifetime. Widespread mammographic screening programs and education campaigns allow for early detection of the disease, often during its asymptomatic phase. Current practice in treatment and recurrence monitoring is based primarily on pathological evaluations but can also encompass genomic evaluations, both of which focus on the primary tumor. Although breast cancer is one of the most studied cancers, patients still recur at a rate of up to 15% within the first 10 years post-surgery. Local recurrence was originally attributed to tumor cells contaminating histologically normal (HN) tissues beyond the surgical margin, but advances in technology have allowed for the identification of distinct aberrations that exist in the peri-tumoral tissues themselves. One leading theory to explain this phenomenon is the field cancerization theory. Under this hypothesis, tumors arise from a field of molecularly altered cells that create a permissive environment for malignant evolution, which can occur with or without morphological changes. The traditional histopathology paradigm dictates that molecular alterations are reflected in the tissue phenotype. However, the spectrum of inter-patient variability of normal breast tissue may obfuscate recognition of a cancerized field during routine diagnostics. In this review, we explore the concept of field cancerization focusing on HN peri-tumoral tissues: we present the pathological and molecular features of field cancerization within these tissues and discuss how the use of peri-tumoral tissues can affect research. Our observations suggest that pathological and molecular evaluations could be used synergistically to assess risk and guide the therapeutic management of patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Thyrotoxicosis leading to adrenal crises reveals primary bilateral adrenal lymphoma.
Primary adrenal lymphoma is a rare malignancy. It frequently presents bilaterally and with symptoms of adrenal insufficiency. Amiodarone may induce secondary organ dysfunction, and thyrotoxicosis develops in 15% of cases. The symptomatology of both conditions is nonspecific, especially in the elderly, and a high suspicion index is necessary for appropriate diagnosis. A 78-year-old female presented to the emergency department with confusion, nausea and vomiting. She had recently been to the emergency department with urinary tract infection, vomiting and acute hypochloremic hyponatremia. Upon re-evaluation, the leukocyturia persisted and because of TSH 0.01 µU/mL and free-T4 68 (10-18) pmol/L, she was admitted to the Endocrinology ward. Further evaluation supported amiodarone-induced thyroiditis type 2. Sepsis ensued, in the setting of nosocomial pneumonia. Hemodynamic instability, hyponatremia, hypoglycemia and vomiting raised the suspicion of adrenocortical insufficiency. Fluid resuscitation and hydrocortisone led to clinical improvement, and adrenal insufficiency was admitted. The thoracoabdominal tomography suggested an endobronchic primary lesion with hepatic and adrenal secondary deposits (6.6 and 7 cm), but this was confirmed neither on pleural effusion nor on bronchofibroscopic fluid analyses. The adrenals were not accessible for biopsy. Despite high-dose hydrocortisone maintenance, the patient died before definite diagnosis. The autopsy confirmed primary non-Hodgkin lymphoma. Primary adrenal lymphoma is a rare cause of adrenal insufficiency, but progression can be fast and fatal.Hyperpigmentation is frequently absent.The presenting symptoms are nonspecific and might mimic infection. Disproportion of the general state with signs of specific organ symptomatology is a diagnostic clue.Infection may precipitate adrenal crisis and worsen thyroid function with further adrenal insufficiency exacerbation.In the context of thyrotoxicosis, there may be little clinical response to a therapeutic trial with standard dose glucocorticoids.High-dose glucocorticoid substitution may be required to achieve clinical stability in thyrotoxic patients.


Characterization of Structurally Diverse 18F-Labeled d-TCO Derivatives as a PET Probe for Bioorthogonal Pretargeted Imaging.
Background: The pretargeted imaging strategy using inverse electron demand Diels-Alder (IEDDA) cycloaddition between a trans-cyclooctene (TCO) and tetrazine (Tz) has emerged and rapidly grown as a promising concept to improve radionuclide imaging and therapy in oncology. This strategy has mostly relied on the use of radiolabeled Tz together with TCO-modified targeting vectors leading to a rapid growth of the number of available radiolabeled tetrazines, while only a few radiolabeled TCOs are currently reported. Here, we aim to develop novel and structurally diverse 18F-labeled cis-dioxolane-fused TCO (d-TCO) derivatives to further expand the bioorthogonal toolbox for in vivo ligation and evaluate their potential for positron emission tomography (PET) pretargeted imaging. Results: A small series of d-TCO derivatives were synthesized and tested for their reactivity against tetrazines, with all compounds showing fast reaction kinetics with tetrazines. A fluorescence-based pretargeted blocking study was developed to investigate the in vivo ligation of these compounds without labor-intensive prior radiochemical development. Two compounds showed excellent in vivo ligation results with blocking efficiencies of 95 and 97%. Two novel 18F-labeled d-TCO radiotracers were developed, from which [18F]MICA-214 showed good in vitro stability, favorable pharmacokinetics, and moderate in vivo stability. Micro-PET pretargeted imaging with [18F]MICA-214 in mice bearing LS174T tumors treated with tetrazine-modified CC49 monoclonal antibody (mAb) (CC49-Tz) showed significantly higher uptake in tumor tissue in the pretargeted group (CC49-Tz 2.16 ± 0.08% ID/mL) when compared to the control group with nonmodified mAb (CC49 1.34 ± 0.07% ID/mL). Conclusions: A diverse series of fast-reacting fluorinated d-TCOs were synthesized. A pretargeted blocking approach in tumor-bearing mice allowed the choice of a lead compound with fast reaction kinetics with Tz. A novel 18F-labeled d-TCO tracer was developed and used in a pretargeted PET imaging approach, allowing specific tumor visualization in a mouse model of colorectal cancer. Although further optimization of the radiotracer is needed to enhance the tumor-to-background ratios for pretargeted imaging, we anticipate that the 18F-labeled d-TCO will find use in studies where increased hydrophilicity and fast bioconjugation are required.


The Influence of Different Surface Cleansing Agents on Shear Bond Strength of Contaminated Lithium Disilicate Ceramic: An In Vitro Study.
Seventy LDS specimens were randomly divided into seven groups. The first group was noncontaminated surface (PC). The six other groups were contaminated with the saliva and silicone disclosing medium and treated with no surface cleansing agent (NC); phosphoric acid (PO); Ivoclean (IV); sodium hydroxide solution (NA); Restorative Cleansing Agent (RC); and hydrofluoric acid (HF). Then, LDS specimens were cementated with Panavia V5 to resin composite rod. Each specimen was subjected to an SBS test. The modes of failure was inspected under light microscope. The surface element of each group was examined by SEM-EDS. The results were analyzed with one-way ANOVA and Tamhane's T2. The mean SBS value of NC was significantly lower than others (p < 0.05), and HF was significantly higher than others (p < 0.05). However, PC, PO, IV, NA, and RC were not significantly different from each other (p > 0.05). The mode of failure was mostly adhesive failure in every group. The surface showed similar amount of elements in every group. The SBS of LDS was reduced by saliva and silicone disclosing medium contamination which can be restored using acid- and alkaline-based surface cleansing agents before the cementation procedure.


Ab initio study of phosphorus donors acting as quantum bits in silicon nanowires.
A phosphorus (P) donor has been extensively studied in bulk Si to realize the concept of Kane quantum computers. In most cases the quantum bit was realized as an entanglement between the donor electron spin and the nonzero nuclei spin of the donor impurity mediated by the hyperfine coupling between them. The donor ionization energies and the spin-lattice relaxation time limited the temperatures to a few kelvin in these experiments. Here, we demonstrate by means of ab initio density functional theory calculations that quantum confinement in thin Si nanowires (SiNWs) results in (i) larger excitation energies of donor impurity and (ii) a sensitive manipulation of the hyperfine coupling by external electric field. We propose that these features may allow to realize the quantum bit (qubit) experiments at elevated temperatures with a strength of electric fields applicable in current field-effect transistor technology. We also show that the strength of quantum confinement and the presence of strain induced by the surface termination may significantly affect the ground and excited states of the donors in thin SiNWs, possibly allowing an optical read-out of the electron spin.


Associations between birth weight, early childhood weight gain and adult lung function.
Low birth weight is associated with lower values for spirometry in adults but it is not known if birth weight influences other measures of pulmonary function. It is also unclear whether postnatal growth affects adult lung function. The associations between birth weight, postnatal growth and adult lung function were assessed in an unselected birth cohort of 1037 children. Birth weight, weight gain between birth and age 3 years, and lung function at age 32 years were measured. Analyses were adjusted for adult height and sex and further adjusted for multiple other potential confounding factors. Birth weight was positively correlated with spirometric (forced expiratory volume in 1 s and forced vital capacity) and plethysmographic (total lung capacity and functional residual capacity) lung function and with lung diffusing capacity. These associations persisted after adjustment for confounding factors including adult weight, exposure to cigarette smoke in utero and during childhood, personal smoking, socioeconomic status, asthma and gestational age. Weight gain between birth and age 3 years was also positively associated with lung diffusing capacity, and with higher values of lung volumes in men after adjustment for covariates. Neither birth weight nor postnatal weight gain was associated with airflow obstruction. Low birth weight and lower weight gain in early childhood are associated with modest reductions in adult lung function across a broad range of measures of lung volumes and with lower diffusing capacity. These findings are independent of a number of potential confounding factors and support the hypothesis that fetal and infant growth is a determinant of adult lung function.


Developmental profiles of glutamate receptors and synaptic transmission at a single synapse in the mouse auditory brainstem.
Using whole-cell recordings from presynaptic terminals and postsynaptic principal neurons in the mouse medial nucleus of the trapezoid body (MNTB), we have characterized properties of the calyx of Held synapse during the first three postnatal weeks. We observed that evoked excitatory postsynaptic currents (EPSCs) mediated by NMDA receptors (NMDAR) increased until postnatal day 11/12 (P11/12) after which they declined to very low or undetectable levels at P16. Meanwhile, EPSCs mediated by AMPA receptors (AMPAR) showed an approximate three-fold increase in amplitude. These changes were paralleled by NMDAR and AMPAR currents evoked by exogenous NMDA and kainate to MNTB neurons except that whole-cell kainate currents remained constant after P7/8 while AMPAR-EPSCs continued to increase. We found that the decay time constant tau for NMDAR-EPSCs and AMPAR-EPSCs declined by about 30 % and 70 %, respectively. Analyses of NMDAR-EPSCs with subunit-specific pharmacological agents including ifenprodil, N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), zinc and Mg(2+) revealed subtle developmental changes in subunit composition. As maturation progressed, this synapse displayed a reduction in the number of presynaptic spike failures and the extent of synaptic depression in response to trains of stimuli (50-300 Hz) while the recovery rate from depression accelerated. These results demonstrate profound changes in the size and kinetics of postsynaptic glutamate receptors and in the spike-firing capability of presynaptic terminals at the calyx of Held-MNTB synapse during early development. We suggest that these concurrent presynaptic and postsynaptic adaptations represent important steps for synapse consolidation and refinement and ultimately for the development of fast high-fidelity transmission at this synapse.


Animal models of traumatic brain injury.
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity both in civilian life and on the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs that were identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies.


Dihydropteridine reductase deficiency: levodopa's long-term effectiveness without dyskinesia.
We report an adult patient lacking endogenous synthesis of monoamines (dopamine, serotonin, and catecholamines) due to a severe dihydropteridine reductase (DHPR) deficiency. With levodopa and 5-hydroxytryptophan (5HTP) supplementation, the patient exhibited moderate mental retardation, acute episodes of parkinsonism, and episodes of depression. Despite the use of levodopa from age 3 months, he exhibited no dyskinesia or dopaminergic cell loss as suggested by normal PET imaging of the dopamine transporter.


Bilateral kidney matrix stones: a rare case.
Kedney matrix stones are a rare form of calculi. Flank pain and urinary tract infections (UTI) are the most common presentations of matrix calculi. The diagnosis is usually made at surgery, but some preoperative radiographic findings might be suggestive. Open surgery was the method of choice for treatment. However, combination of ureterorenoscopy and percutaneous nephrolithotomy (PCNL) was found to be safe and effective. We report a rare case of renal and ureteral matrix stones that were diagnosed and treated by open surgery. We also describe its clinical, radiological and therapeutic features through a review of the literature.


OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY STUDY OF CHOROIDAL NEOVASCULARIZATION ASSOCIATED WITH EARLY-ONSET DRUSEN.
To report three middle-aged cases with choroidal neovascularization (CNV) associated with early-onset drusen documented with optical coherence tomography angiography (OCTA). Three patients with bilateral early-onset drusen were referred to our hospital. Fundus examination, fluorescein angiography, indocyanine green angiography, OCTA, and other multimodal imaging were performed. Case 1 involved a 47-year-old woman who presented with sudden unilateral anorthopia. She had no previous systemic pathologies. Funduscopic examination and fluorescein angiography revealed bilateral large colloid drusen accompanied by unilateral mild subretinal hemorrhage. Indocyanine green angiography revealed CNV, although it was unclear in fluorescein angiography. Optical coherence tomography angiography also showed interconnecting CNV beneath the retinal pigment epithelium. Case 2 involved a 40-year-old woman with membranoproliferative glomerulonephritis Type 3 who presented with unilateral anorthopia. On fluorescein angiography, cuticular drusen secondary to membranoproliferative glomerulonephritis were seen in both eyes. An interconnecting vascular network was revealed with OCTA and indocyanine green angiography indicating Type 1 CNV in the affected eye. Case 3 involved a 47-year-old man without any medical or family history. Predominant large colloid drusen associated with cuticular drusen were seen in both eyes. Unilateral mild serosanguinous changes were accompanied in the macula, where Type 1 CNV was detected with OCTA. All our cases with early-onset drusen showed Type 1 CNV that was detected by indocyanine green angiography or OCTA. Optical coherence tomography angiography has a potential to help noninvasively diagnose CNV in the cases of EOD.