Factor XIII: inherited and acquired deficiency.
Factor XIII (XIII), an enzyme found in plasma (present as a pro-enzyme), platelets and monocytes, is essential for normal haemostasis. It may also have a role to play in the processes of wound healing and tissue repair. Inherited XIII deficiency results in a life-long, severe bleeding diathesis which, if untreated, carries a very high risk of death in early life from intracranial bleeding. XIII is a zymogen requiring thrombin and calcium for activation. In plasma, XIII has two subunits: the 'a' subunit, which is the active enzyme, and the 'b' subunit which is a carrier protein. Activated XIII modifies the structure of clot by covalently crosslinking fibrin through an epsilon (gamma-glutamyl)lysine link. It also crosslinks other proteins, including fibronectin and alpha-2-plasmin inhibitor (alpha-2PI), into the clot through the same link. Clot modified by XIII is physically stronger, relatively more resistant to fibrinolysis and may be a more suitable medium for the ingrowth of fibroblasts. Inheritance of factor XIII is autosomal recessive. The majority of patients with the inherited defect show no XIII activity and absence of 'a' subunit protein in plasma, platelets and monocytes. At the molecular level, the defect is not a major gene rearrangement or deletion, but most likely a single point mutation which may be different in each family. Because of the severity of the bleeding diathesis, prophylaxis is desirable and has been shown to be very effective as the in vivo half-life of plasma XIII is long, and low plasma levels are sufficient for haemostasis. Acquired inhibitors have been reported in only two cases with inherited XIII deficiency. Acquired XIII deficiency has been described in a variety of diseases and bleeding has been controlled by therapy with large doses of XIII in such conditions as Henoch-Schönlein purpura, various forms of colitis, erosive gastritis and some forms of leukaemia. Large dose XIII therapy has also been used in an endeavour to promote wound healing after surgery and bone union in non-healing fractures. The use of XIII in these conditions remains controversial. Very rarely a bleeding diathesis results from the development of a specific inhibitor to XIII arising de novo, often as a complication in the course of a disease or in association with long-term drug therapy. The bleeding diathesis in these patients is difficult to treat.


Environmental behaviors of phoxim with two formulations in bamboo forest under soil surface mulching.
Phoxim (emulsifiable concentrate (EC) and granules (G)) has been widely used in bamboo forests. The persistence and magnitude of phoxim residues in the crop and soil must be investigated to ensure human and environmental safety. The environmental behaviors of the two formulations were investigated in a bamboo forest under soil surface mulching conditions (CP) and non-covered cultivation conditions (NCP). The half-lives of phoxim in soil under the two conditions in soil were 4.1-6.2days (EC) and 31.5-49.5days (G), respectively. Phoxim in EC could be leached from the topsoil into the subsoil. A minimized leaching effect was observed for G under NCP. Inversely, an enhanced leaching effect was observed for G under CP. The G formulation resulted in more parent compound (in bamboo shoots) and metabolite (in soil) residues of phoxim than in the case of EC, especially under CP conditions. In addition, the intensity and duration of the formulation effect on soil pH adjustment from G were more obvious than that from EC. Results showed that the environmental behaviors (distribution, degradation, residue) of phoxim in the bamboo forest were significantly influenced by the type of formulation. The prolongation effect from phoxim G might cause persistence and long-term environmental risk. However, bamboo shoot consumption could be considered relatively safe after applying the recommended dose of the two phoxim formulations.


Imaging of Childhood Vasculitis.
Pediatric vasculitides are rare conditions that can represent a diagnostic challenge because symptoms are usually aspecific and variable. Symptoms are related to the size of the involved vessel, extension of disease, and organs affected. The outcome is closely linked to an early diagnosis and proper treatment. Diagnostic imaging allows visualization of the involvement of large-size and medium-size vessels and assesses end-organ changes and response to therapy, thus playing a pivotal role in the diagnosis and treatment. This article explores the general features of pediatric vasculitis and discusses the imaging approach and the most common diagnostic findings.


DNA methylation dataset of bovine embryonic fibroblast cells treated with epigenetic modifiers and divergent energy supply.
Fetal programming is established early in life, likely through epigenetic mechanisms that control gene expression. Micronutrients can act as epigenetic modifiers (EM) by modulating the genome through mechanisms that include DNA methylation and post-translational modification of chromatin. Among the EM, methionine, choline, folate, and vitamin B12 have been suggested as key players of DNA methylation. However, the effects of supplementing these four EM, involved in the methionine folate cycle on DNA methylation, are still under investigation. This manuscript provides the genome-wide DNA methylation dataset (GSE180362) of bovine embryonic fibroblast cells exposed to different supplementation levels of glucose and methionine, choline, folate, and vitamin B12 (collectively named as Epigenetic Modifiers - EM). The DNA methylation was measured using MSP-I digestion and Reduced Representation Bisulfite Sequencing. Bioinformatics analyses included data quality control, read mapping, methylation calling, and differential methylation analyses. Supplementary file S1 and data analysis codes are within this article. To our knowledge, this is the first dataset investigating the effects of four EM in bovine embryonic fibroblast DNA methylation profiles. Furthermore, this data and its findings provide information on putative candidate genes responsive to DNA methylation due to EM supplementation.


Stochastic simulation algorithm for isotope-based dynamic flux analysis.
Carbon isotope labeling method is a standard metabolic engineering tool for flux quantification in living cells. To cope with the high dimensionality of isotope labeling systems, diverse algorithms have been developed to reduce the number of variables or operations in metabolic flux analysis (MFA), but lacks generalizability to non-stationary metabolic conditions. In this study, we present a stochastic simulation algorithm (SSA) derived from the chemical master equation of the isotope labeling system. This algorithm allows to compute the time evolution of isotopomer concentrations in non-stationary conditions, with the valuable property that computational time does not scale with the number of isotopomers. The efficiency and limitations of the algorithm is benchmarked for the forward and inverse problems of 13C-DMFA in the pentose phosphate pathways, and is compared with EMU-based methods for NMFA and MFA including the central carbon metabolism. Overall, SSA constitutes an alternative class to deterministic approaches for metabolic flux analysis that is well adapted to comprehensive dataset including parallel labeling experiments, and whose limitations associated to the sampling size can be overcome by using Monte Carlo sampling approaches.


Nintedanib administration after the onset of acute exacerbation of interstitial lung disease in the real world.
Nintedanib reduces the decline in forced vital capacity and extends the time to the first acute exacerbation of interstitial lung disease (AE-ILD). However, the effect of additional nintedanib administration after AE-ILD onset is unknown. This study aimed to investigate the efficacy and safety of nintedanib administration after AE-ILD development. We retrospectively collected the data of 33 patients who developed AE-ILD between April 2014 and January 2022. Eleven patients who received nintedanib after AE-ILD development and the remaining who did not were classified into the N and No-N groups, respectively. The survival time in the N group tended to be longer than that in the No-N group. The generalized Wilcoxson test revealed that the cumulative mortality at 90 days from AE-ILD onset was significantly lower in the N group. The time to subsequent AE-ILD development was significantly longer in the N group than that in the No-N group. The incidence of adverse gastrointestinal effects and liver dysfunction in the N group was 9-18%. Treatment without nintedanib after AE-ILD development and the ratio of arterial oxygen partial pressure to fractional inspired oxygen were significant independent prognostic factors in the multivariate analysis. Thus, nintedanib administration may be a treatment option for AE-ILD.


A new strategy for the synthesis of oligodeoxynucleotides in the phosphoramidite method without base protection via phosphite intermediates.
Deoxyadenosine and deoxycytidine have highly nucleophilic amino groups. Therefore, without base protection, the undesired N-phosphitylations of these amino groups occur in the previous phosphoramidite methods. Now, we report that these N-phosphitylations were considerably suppressed in our new coupling strategy using HOBt as a promoter capable of formation of phosphite-type intermediates.


"You're a 'high-risk' customer": A qualitative study of women's experiences of receiving information from health professionals regarding health problems or complications in pregnancy.
Experiencing complications in pregnancy is stressful for women and can impact on fetal and maternal outcomes. Supportive encounters with health professionals can reduce the worry women experience. Further research is needed to understand women's perspectives on communicating with their healthcare providers about their concerns. This study explored women's experiences of receiving information about pregnancy complications from healthcare providers and their interactions with multiple professionals and services during pregnancy. This was a qualitative interpretive study. Semi-structured interviews were conducted with 20 women experiencing pregnancy complications recruited from antenatal services at two hospitals in Sydney. Inductive thematic analysis was used to analyse the data. Women had a range of reactions to their diagnoses, including concern for their baby, for themselves and for their labour. Most women reported that communication with healthcare providers was distressing, they were not listened to and staff used insensitive, abrupt language. Women were also distressed by delays in education, receiving contradictory information and having to repeatedly share their stories with different health professionals. In some cases, this damaged the therapeutic relationship and reduced trust towards healthcare providers. Midwives were generally preferred over doctors because they had a more woman-centred approach. To improve women's experiences of care for pregnancy complications, it is critical to improve the communication skills of maternity service providers. Women's need for information, resources and support can best be provided by continuity of care with a named health professional, for example, a midwife working within an integrated multidisciplinary antenatal service model.


Phenomenon of formation of giant fat-containing cells in human bone marrow cultures induced by human serum factor: normal and leukemic patterns.
Normal human sera induce the formation of fat-containing cells (FCC) in human bone marrow cultures. A nearly complete monolayer of FCC is formed after 7-14 days of cultivation with 20% human sera in the medium. FCC-inducing activity (FCCIA) is nondialyzable through 14,900-dalton cutoff membrane and is stable at 56 degrees C for 30 min. Abundant FCCIA was found in 83% of normal human sera but in only 20% of sera from untreated patients with different hemopoietic disorders and in 32% of treated leukemic patients. It is suggested that FCCIA may be involved in regulation of the bone marrow microenvironment an that it varies in normal individuals and in patients with different diseases.


A diagnostic dilemma of a pulmonary nodule of a patient who suffered advanced ovarian cancer: A case report and a hypothesis.
This report presents a case of lung cancer which can be easily misdiagnosed as distant metastasis. Along with a literature review on the morphological, pathological and prognostic characteristics of lung cancer associated with cystic airspaces (LCCA), it would help to improve our understanding of the dynamic evolution of LCCA, to avoid its delayed diagnosis and treatment. We also propose here a hypothesis on the etiology of LCCA. A patient with advanced ovarian cancer who presented with elevated serum CA125 at time of admission and had undergone TAHBSO at first, and second operation of sigmoid colon resection was performed due to her locoregional recurrence of ovarian cancer. After her second operation, patient showed further increment of serum CA125 and CECT scan indicated an airspace-related pulmonary nodule in the right middle lobe of her lungs. It was suspected that distant metastases of ovarian cancer had reoccurred postoperatively. After comparing the characteristic of metastatic ovarian cancer with LCCA, we diagnosed the pulmonary nodule as primary lung cancer. Surgery eventually confirmed the pulmonary nodule as second primary lung cancer associated with cystic airspaces. The rare occurrence of LCCA should merit special attention from clinicians and radiologists so as to avoid missed or delayed diagnosis. We propose here a hypothesis that LCCA is related to spreading of tumour cells during surgical procedures in lung cancer surgery. Should our hypothesis be substantiated in further studies, this would affect the operation procedures for surgeons in the future.


Exposure to environmental tobacco smoke in Chaves after the implementation of the law 37/2007. A cross-sectional study in two healthcare settings.
Environmental tobacco smoke (ETS) is currently the main indoor pollutant and causes a high morbility and mortality. A partial restriction came into force in Portugal, in 2008, law 37/2007, trying to control, define and regulate smoke-free environments. To assess exposure and perceived impact of the law 37/2007 on exposure to ETS among adults attending to the two health care facilities of Chaves (Portugal). A cross-sectional survey on tobacco consumption and exposure to ETS was undertaken in Chaves (Northern Portugal) between November 2009 and February 2010. All the patients, over 17, attending to any of the Chaves Primary Care Facilities were interviewed. Patient enrolment was done on a rolling basis covering all days of the week. A face to face interview was carried out and a carbon monoxide was measured. Prevalence and means are shown with 95% confidence intervals. 287 patients participated in the survey, 56% were males and the mean age was 54 years. Smoking prevalence was 23,6%, significantly higher in males (31% vs 17%). 46,2% reported exposure tobacco smoke elsewhere (53% in males vs. 40% in females). Smokers declared to be more exposed to ETS than non-smokers. 16.2% of the population declared to be exposed at home, 14% at work and 33% at leisure places. The highest decrease in perception of passive exposure was found for restaurants (95%). In nightclubs 68% of the participants stated that exposure has remained unchanged. The tobacco control law offered protection against tobacco smoke in several closed public spaces. However, a significant proportion of the population remains exposed. This study highlights the ineffectiveness of a partial ban. A comprehensive law is, therefore, required in Portugal.


Glucose-induced O₂ consumption activates hypoxia inducible factors 1 and 2 in rat insulin-secreting pancreatic beta-cells.
Glucose increases the expression of glycolytic enzymes and other hypoxia-response genes in pancreatic beta-cells. Here, we tested whether this effect results from the activation of Hypoxia-Inducible-factors (HIF) 1 and 2 in a hypoxia-dependent manner. Isolated rat islets and insulin-secreting INS-1E cells were stimulated with nutrients at various pO₂ values or treated with the HIF activator CoCl₂. HIF-target gene mRNA levels and HIF subunit protein levels were measured by real-time RT-PCR, Western Blot and immunohistochemistry. The formation of pimonidazole-protein adducts was used as an indicator of hypoxia. In INS-1E and islet beta-cells, glucose concentration-dependently stimulated formation of pimonidazole-protein adducts, HIF1 and HIF2 nuclear expression and HIF-target gene mRNA levels to a lesser extent than CoCl₂ or a four-fold reduction in pO₂. Islets also showed signs of HIF activation in diabetic Lepr(db/db) but not non-diabetic Lepr(db/+) mice. In vitro, these glucose effects were reproduced by nutrient secretagogues that bypass glycolysis, and were inhibited by a three-fold increase in pO₂ or by inhibitors of Ca²⁺ influx and insulin secretion. In INS-1E cells, small interfering RNA-mediated knockdown of Hif1α and Hif2α, alone or in combination, indicated that the stimulation of glycolytic enzyme mRNA levels depended on both HIF isoforms while the vasodilating peptide adrenomedullin was a HIF2-specific target gene. Glucose-induced O₂ consumption creates an intracellular hypoxia that activates HIF1 and HIF2 in rat beta-cells, and this glucose effect contributes, together with the activation of other transcription factors, to the glucose stimulation of expression of some glycolytic enzymes and other hypoxia response genes.


A novel splicing mutation of ANK1 is associated with phenotypic heterogeneity of hereditary spherocytosis in a Chinese family.
Hereditary spherocytosis (HS) is a common hematological genetic disorder that results in anemia, jaundice and splenomegaly. It is caused by mutations in the ANK1, SPTA, SPTB, SLC4A1 and EPB42 genes, which encode red blood cell membrane and skeletal proteins. Patients show high heterogeneity in phenotype and genotype and the genotype-phenotype correlation still requires clarification. Here, a novel splicing mutation (ANK1: c.4391-2 A>C) was identified by whole-exome sequencing (WES) and Sanger sequencing in a Chinese boy who exhibited a moderately severe HS phenotype. However, his father exhibited a mild phenotype, despite carrying the same HS-causing mutation. The function of the mutant ANK1 protein was analyzed by both bioinformatics and experimental analysis. The mutant protein (p.N1463Kfs*4) showed a different 3D-structure and altered subcellular localization, when compared with the wild-type ANK1 protein. These changes disrupted the normal cell membrane structure and resulted in spheroidized red blood cells. Amplification of cDNA from the son and his father revealed a difference in expression of the abnormal transcript produced by the splicing mutation. We proposed that the lower expression of the mutant allele may have contributed to the relatively mild symptoms of the father. Our study verified ANK1 c. c.4391-2 A>C as a novel pathogenic mutation that causes HS. We have also provided new insights into the interpretation of phenotypic variability within families, which could greatly improve the clinical diagnosis and genetic counseling of HS.


The metabolic syndrome, atherosclerosis and cognitive functioning in a non-demented population: the Hoorn Study.
The metabolic syndrome (MetS) is associated with cognitive deficits and atherosclerotic vascular disease. We examined whether the relation between the MetS and cognitive dysfunction is mediated by measures of atherosclerosis or the presence of clinically manifest cardiovascular disease. In 380 individuals (153 with MetS; 60-87 years) from the population based Hoorn Study, measures of atherosclerosis including carotid intima-media thickness (c-IMT), flow mediated dilation (FMD), ankle-brachial index and the presence of clinically manifest cardiovascular disease were assessed at baseline and 7 later years at follow-up. Cognitive functioning (information processing speed, memory, and attention and executive functioning) was assessed at follow-up. The relation between the MetS, atherosclerosis and cognitive functioning was assessed with linear regression analysis. Individuals with MetS showed worse performance on information processing speed (adjusted mean difference z-score ± SE: -0.22 ± 0.6; p = 0.01) and attention and executive functioning (-0.32 ± 0.07; p < 0.001), but not on the domain memory. The affected cognitive domains were also associated with measures of atherosclerosis (standardised B (95%CI) c-IMT: -0.14 (-0.24; -0.05); p < 0.01; FMD: 0.13 (0.02; 0.24), p < 0.05) and a history of clinically manifest cardiovascular disease: (-0.29 (-0.47; -0.11); p < 0.01). However, the relation between the MetS and cognitive functioning did not change after adjustment for c-IMT, FMD or a history of clinically manifest cardiovascular disease (p > 0.05). In this population based cohort, the relation between the MetS and cognitive dysfunction was not mediated by atherosclerosis or a history of cardiovascular disease. These findings should stimulate future studies to elucidate alternative mechanisms underlying cognitive deficits in individuals with MetS.


Non-redox protein interactions in the thioredoxin activation of chloroplast enzymes.
Thioredoxin derivatives lacking SH groups such as S,S'-dicarboxymethyl-, dicarboxamidomethyl-thioredoxin and cysteine----serine mutant protein are capable of activating chloroplast NADP malate dehydrogenase and fructose-bisphosphatase when added to enzyme assays together with suboptimal amounts of native thioredoxin. The modified thioredoxins alone are inactive. These findings indicate that protein-protein interactions play a significant role in addition to disulfide/thiol exchange reactions in the light-driven regulation of plant enzymes by the various plant thioredoxins.


Influence of microstructure and chemistry on the fracture toughness of dental ceramics.
the primary aim of this research was to measure fracture toughness for several groups of dental ceramics, and determine how this property is affected by chemistry and microstructure. Fracture toughness (KIc) values were obtained using Single Edge Precracked Beam (SEPB) and Single Edge V-Notch Beam (SEVNB) methods. Dynamic Young's modulus, which often scales with strength and has been used in explaining the microstructure/toughness relationship on a theoretical basis, was also obtained for the three groups of materials comprising this study. The first group, consisting of micaceous glass ceramics, included model materials that varied systematically in microstructure but not in chemistry. The second group, the feldspathic porcelains, varied significantly in microstructure, but little in chemistry. The ceramics comprising the third group were significantly different in both chemistry and microstructure. Upper toughness limits for the micaceous glass-ceramics and feldspathic porcelains were significantly raised compared to the base glasses, but remained under 2 MPa m(1/2). The highest toughnesses were associated with high percent crystallinity, large grains and high aspect ratios. The third group KIc values were 2.8 MPa m(1/2) for a lithium disilicate glass-ceramic, 3.1 MPa m(1/2) for a glass-infused alumina, and 4.9 MPa m(1/2) for zirconia. the correlations between microstructural characteristics and measured properties supports theoretical predictions in the literature. From a practical standpoint, microstructural effects were found to be important, but only within a limited range; the chemistry apparently defined a band of achievable property values. This suggests very large increases in fracture toughness are unlikely to be attained by changes in microstructure alone. A functional relationship determined for the micaceous glass-ceramics enables quantitative predictions of fracture toughness based on the microstructure.


Case Control Study to Compare Serum Vascular Endothelial Growth Factor (VEGF) Level in Women with Recurrent Pregnancy Loss (RPL) Compared to Women with Term Pregnancy.
Recurrent pregnancy loss (RPL) is defined as three or more spontaneous pregnancy losses before the 20th week of gestation or fetal weight of < 500 gm from the last menstrual period. Vascular endothelial growth factor (VEGF) is essential for implantation, development of embryo and placental angiogenesis. Women with low VEGF level are believed to be at higher risk of RPL. To measure the level of VEGF in women with RPL and compare it with women with 1 or more successful pregnancies. This is a Case control study carried out in King George Medical University, Lucknow from August 2015 to 2016. Participants sample size was 60 women. Thirty women with 3 or more spontaneous abortions were included as cases, and 30 women with at least 1 successful term pregnancy were controls. Serum VEGF level was analyzed using ELISA kit. Main outcome measured: 1. Serum VEGF level in the two groups. 2. Serum VEGF level in different underlying etiologies in women with RPL. Mean VEGF level was 105.3 pg/mL in RPL cases, while it was 156.8 pg/mL in fertile controls. (p = 0.01). VEGF level was 86.2 pg/mL in patients with anatomical defects, 109 pg/mL in APLA syndrome, 85.1 pg/mL in hypothyroidism and 122.2 pg/mL in unexplained RPL. The mean serum VEGF level was significantly lower in women with recurrent pregnancy loss compared with women with successful term pregnancy, implicating its role in maintaining pregnancy.


Short-term complications after surgically induced abortions: a register-based study of 56 117 abortions.
Performing an induced abortion is a rather simple medical procedure which is frequently done and side-effects will have public health implications unless they are very rare. We estimated the incidence of side-effects detected during the stay at the hospital and 2 weeks after the discharge. We only include side-effects reported by clinics or hospitals. Altogether 56 117 induced abortions performed by public hospitals in Denmark from 1980 to 1994 were analyzed in this study. The study combined results from the mandatory reporting of side-effects to the National Induced Abortion Registry and all diagnoses reported to the Hospital Discharge Registry. Side-effects in the form of bleeding, infections or re-evacuation were recorded for about 5%. We found more side-effects in teenage women and for abortions performed late in pregnancy. We found nothing to indicate that the frequency of side-effects following an abortion changed over time. About 5% have side-effects registered by hospitals following an induced abortion. The long-term consequences of this are not known.


Xenobiotic induction of quinone oxidoreductase activity in lens epithelial cells.
Xenobiotic regulatory elements have been identified for enzymes which ameliorate oxidative damage in cells. Zeta (zeta)-crystallin, a taxon-specific enzyme/crystallin shown to be a novel NADPH-dependent quinone reductase, is found in a number of tissues and cell types. This study shows that zeta-crystallin is present in mouse lens epithelium, as well as in the alpha TN4 mouse lens epithelial cell line. To determine whether zeta-crystallin is an inducible quinone reductase, cell cultures were exposed to the xenobiotics, 1,2-naphthoquinone and beta-naphthoflavone. Assays of cellular homogenates showed that quinone reductase activity was stimulated greater than 70% and 90%, respectively, over the control cells. This observed activity was sensitive to dicumarol, a potent inhibitor of quinone reductase activity. 1,2-Naphthoquinone- and beta-naphthoflavone-exposed cells were found to exhibit 1.47- and 1.68-fold increases, respectively, in zeta-crystallin protein concentration. A comparable increase in zeta-crystallin mRNA was indicative of an induction in zeta-crystallin expression in response to naphthalene challenge. Lens epithelial cells were also checked for DT-diaphorase, a well-known cellular protective enzyme which can catalyze the two-electron reduction of quinones. Slot blot analyses indicated that alpha TN4 cells exposed to 1,2-naphthoquinone and beta-naphthoflavone exhibited 2.71- and 6.81-fold increases in DT-diaphorase concentration when compared to the control cells. The data suggest that while DT-diaphorase is most likely responsible for the majority of the observed increase in quinone reductase activity, the zeta-crystallin gene also undergoes activation which is apparently mediated by a xenobiotic-responsive element.


Intergenerational longitudinal associations between parental reading/musical traits, infants' auditory processing, and later phonological awareness skills.
The intergenerational transmission of language/reading skills has been demonstrated by evidence reporting that parental literacy abilities contribute to the prediction of their offspring's language and reading skills. According to the "Intergenerational Multiple Deficit Model," literacy abilities of both parents are viewed as indicators of offspring's liability for literacy difficulties, since parents provide offspring with genetic and environmental endowment. Recently, studies focusing on the heritability of musical traits reached similar conclusions. The "Musical Abilities, Pleiotropy, Language, and Environment (MAPLE)" framework proposed that language/reading and musical traits share a common genetic architecture, and such shared components have an influence on the heritable neural underpinnings of basic-level skills underlying musical and language traits. Here, we investigate the intergenerational transmission of parental musical and language-related (reading) abilities on their offspring's neural response to a basic auditory stimulation (neural intermediate phenotype) and later phonological awareness skills, including in this complex association pattern the mediating effect of home environment. One-hundred and seventy-six families were involved in this study. Through self-report questionnaires we assessed parental reading abilities and musicality, as well as home literacy and musical environment. Offspring were involved in a longitudinal study: auditory processing was measured at 6 months of age by means of a Rapid Auditory Processing electrophysiological paradigm, and phonological awareness was assessed behaviorally at 5 years of age. Results reveal significant correlations between parents' reading skills and musical traits. Intergenerational associations were investigated through mediation analyses using structural equation modeling. For reading traits, the results revealed that paternal reading was indirectly associated with children's phonological awareness skills via their electrophysiological MisMatch Response at 6 months, while maternal reading was directly associated with children's phonological awareness. For musical traits, we found again that paternal musicality, rather than maternal characteristics, was associated with children's phonological phenotypes: in this case, the association was mediated by musical environment. These results provide some insight about the intergenerational pathways linking parental reading and musical traits, neural underpinnings of infants' auditory processing and later phonological awareness skills. Besides shedding light on possible intergenerational transmission mechanisms, this study may open up new perspectives for early intervention based on environmental enrichment.


Adenylate cyclase and phosphodiesterase from brain tissue: different stabilities during incubation of cerebral cortical slices.
Adenylate cyclase and phosphodiesterase were prepared from brain slices from guinea-pig. The specific activity of adenylate cyclase declined rapidly with increasing incubation time of tissue slices, while phosphodiesterase activity was almost uneffected by the incubation of brain slices.


Multiple mechanisms repress N-Bak mRNA translation in the healthy and apoptotic neurons.
N-Bak is a neuron-specific BH3-only splice variant of pro-apoptotic Bcl-2 family member Bak. We have shown that its mRNA is stable in the neurons, whereas the protein cannot be detected by antibodies, suggesting a strong translational arrest of the mRNA. Here we identify two regulatory elements in the N-Bak mRNA that significantly repress translation in the luciferase reporter assay: an upstream open reading frame in the 5'-untranslated region (UTR) and naturally spliced exon-exon junction downstream of the premature translation termination codon in the 3'UTR. We also show that N-Bak mRNA is stored in granular structures in the sympathetic neurons and stays in these granules during intrinsic apoptosis. Finally, we confirm the absence of N-Bak protein by quantitative mass spectrometry analysis in the healthy, apoptotic or stressed sympathetic and cortical neurons. We conclude that N-Bak mRNA is translationally repressed by multiple mechanisms, and the protein does not participate in the classical apoptosis or cellular stress response.


Koelliker haemoglobins in developing chick embryo.
1. Three Koelliker haemoglobins, HbKE, HbKA and HbKH, derived from a post-translational loss of alpha-Arg-141, were isolated from red cells of chicken embryos. HbKE is typical of embryos up to 7 days of incubation, HbKA and HbKH are found in mature embryos. 2. All the precursor haemoglobins contain alpha A chains. HbKA derives from adult haemoglobin A whose globin composition is alpha A2 beta 2, HbKH from embryonic haemoglobin H with a globin composition alpha A2 beta H2 and HbKE from embryonic haemoglobin E with globin composition alpha A2 epsilon 2. 3. No Koelliker derivatives of haemoglobins with alpha-like chains other than alpha A were observed.


Culture media for the isolation and enumeration of pathogenic Vibrio species in foods and environmental samples.
The genus Vibrio now includes a large number of species. Clear evidence is only available for the aetiological role of V. cholerae, V. vulnificus and V. parahaemolyticus in foodborne diseases. Until recently, V. cholerae serogroup 0:1 was accepted as the cause of epidemic cholera. However, the designation of outbreaks of diarrhoeal diseases caused by V. cholerae 0:139 as clinical cholera has lead to renewed interest in Non 0:1 serogroups of V. cholerae. A wide range of enrichment and selective media for the isolation of vibrios has been developed. These media are reviewed with respect to their ability to recover and differentiate the target vibrios. Alkaline peptone water (APW) remains the recommended enrichment medium for vibrios in parallel with either salt polymyxin broth (SPB) or glucose teepol (or sodium dodecylsulphate) salt broth (GTSB) when tests for V. parahaemolyticus are required. Thiosulphate citrate bile salt agar (TCBS) in parallel with polymyxin mannose tellurite (PMT) or sodium dodecylsulphate polymyxin sucrose agar (SPS) are the recommended selective plating media.


Adolescents' perceptions of cannabis use by their peers: does it have anything to do with behavior?
Young people perceive there are many more people using cannabis than any surveys can document. As part of an education program, students were exposed to survey data to influence their perceptions and in turn to affect their use and intentions to use cannabis in the future. This large study showed that perception has no relationship to use or intentions to use, and that changing perceptions of use is very difficult.


Reorganization of lipid nanocapsules at air-water interface: Part 2. Properties of the formed surface film.
The state, electrical and dilatational rheological properties of surface films formed at air-water interface from lipid nanocapsules (LNC) with various compositions as well as model monolayers formed by the LNC constituents-Labrafac, Solutol and Lipoid are investigated. These nanocapsules constitute potential drug delivery systems where lypophilic drug will be loaded in their core. The study of the model Labrafac/Solutol (Lab/Sol) mixed monolayers shows behavior close to the ideal. Small negative deviations in the mean molecular areas a and dipole moments mu are observed. All studied monolayers have elastic behavior during the small continuous compressions. The comparison between the properties of surface films formed from LNC with those of the model monolayers confirms the idea developed in the kinetic study that the surface films formed after a rapid disaggregation of the unstable nanocapsule fraction (LNC I) contains mainly Labrafac and Solutol. The Labrafac molar part (xLab) in the formed Lab/Sol mixed layer is established.


Adult frequent presentation to emergency departments and adverse childhood experiences: a scoping review.
Extensive literature reports the influence of childhood adversity on adult health, however few studies have explored these life antecedents in people who frequently present to the emergency department. This review synthesizes literature exploring childhood adversity influences on emergency department presentations, if and how it is identified, and interventions addressing the health care needs of this group. Eight electronic databases were searched. Arksey and O'Malley's framework guided this review, and a quality appraisal was undertaken. Searches included all published studies until August 2020. Twenty-one articles were included in this review. They revealed that childhood adversity is common among adults who frequently attend the emergency department. It impacts physical and psychological health into adulthood and there is no standardized approach described to documenting childhood adversity, nor any consistent intervention reported by emergency departments to address its sequelae in adulthood. Several studies call for screening, intervention, and education to identify and address impacts of childhood adversity for patients who frequently present to the emergency department. However, reliable high-level studies exploring these topics specific to the emergency department are uncommon. Consequently, definitive interventions to address the healthcare needs of this group is lacking and warrants further research.


Short- and long-term vertical diplopia secondary to blunt trauma.
This report describes the short- and long-term ocular signs and symptoms of a patient with an orbital blow-out fracture and discusses the differential diagnosis of vertical diplopia. A blow-out fracture occurs when blunt trauma is applied either directly to the eyeball itself or the orbital rim and usually results in a fracture of the orbital floor with consequential excavation and entrapment of orbital contents in the fracture. Vertical diplopia is a common presenting symptom for a blow-out fracture of the orbit but careful considerations should be given to other potential conditions leading to such diplopia. A patient is presented who suffered a blow-out fracture almost a decade earlier, secondary to blunt trauma to the globe. The clinical findings are provided immediately after the trauma, post-surgery and during a recent ocular examination.


Life events, combat stress reaction and post-traumatic stress disorder.
The implication of life events just preceding a war in acute combat stress reaction and chronic PTSD were assessed in a sample of 716 Israeli combatants. Results show that life events were unrelated to combat stress reaction but were related to subsequent PTSD. Conceptual and methodological issues were discussed to explain the results.


Mechanisms and characteristics of biofilm formation via novel DEAMOX system based on sequencing biofilm batch reactor.
A denitrifying ammonium oxidation (DEAMOX) process has been regarded as an innovative process to simultaneously treat ammonia and nitrate containing wastewaters, whereas very limited research has focused on its application in biofilm system. In this research, a novel DEAMOX process was established with fixed sponge carriers in a sequencing biofilm batch reactor (SBBR). To investigate biofilm formation process and characteristics can encourage further research on DEAMOX system optimization, deteriorated performance recovery strategies and application with actual wastewater. Total nitrogen removal efficiency was maintained at 93.0 % after 240 days of operation. With biofilm growth, the protein-like extracellular polymeric substances (EPS) and tightly-bound EPS (TB-EPS) of biofilms increased from 65.6 to 46.1, to 179.6 and 142.0 mg gVSS-1, respectively, revealing that protein-like substances and TB-EPS promote biofilm formation. The mechanism of biofilm formation was discussed by analyzing the morphological development and functional bacterial activities of biofilms. Furthermore, high anammox activity was obtained in biofilms with specific NH4+N removal rates over 4.29 mgN gVSS-1h-1, which were significantly higher than in suspended sludge (2.56 mgN gVSS-1h-1). Quantitative polymerase chain reaction results showed that the abundance of anammox bacteria in biofilms increased from 1.87 % to 11.48 % with biofilm growth. These results imply that mature biofilms formed on carriers and the anammox bacteria were sufficient enriched in DEAMOX-SBBR system.


Alzheimer's disease.
Alzheimer's disease (AD) dementia refers to a particular onset and course of cognitive and functional decline associated with age together with a particular neuropathology. It was first described by Alois Alzheimer in 1906 about a patient whom he first encountered in 1901. Modern clinical diagnostic criteria have been developed, and criteria have also been proposed to recognize preclinical (or presymptomatic) stages of the disease with the use of biomarkers. The primary neuropathology was described by Alzheimer, and in the mid-1980s subsequently evolved into a more specific neuropathologic definition that recognizes the comorbid neuropathologies that frequently contribute to clinical dementia. Alzheimer's disease is now the most common form of neurodegenerative dementia in the United States with a disproportionate disease burden in minority populations. Deficits in the ability to encode and store new memories characterizes the initial stages of the disease. Subsequent progressive changes in cognition and behavior accompany the later stages. Changes in amyloid precursor protein (APP) cleavage and production of the APP fragment beta-amyloid (Aβ) along with hyperphosphorylated tau protein aggregation coalesce to cause reduction in synaptic strength, synaptic loss, and neurodegeneration. Metabolic, vascular, and inflammatory changes, as well as comorbid pathologies are key components of the disease process. Symptomatic treatment offers a modest, clinically measurable effect in cognition, but disease-modifying therapies are desperately needed.


Varicella zoster virus antibody titers after intravenous zoster immune globulin in neonates, and the safety of this preparation.
1) To assess the safety of intravenous varicella zoster virus hyperimmune globulin G (IV-VZVIG) in neonates; 2) measure varicella zoster virus-specific IgG antibody (VZVIG) changes in newborn IV-VZVIG recipients. Eighteen neonatal intensive care unit (NICU) neonates with varicella exposure were given 1 ml/kg (43 International Units (IU)/kg) Varitect IV-VZVIG. Serum VZVIG titers were assayed in neonatal recipients 0, 1, 7, 14, 21, 28, and 35 d after IV-VZVIG. Also, serum samples for VZV-IgM antibody determinations were obtained at 4 wk post-infusion. No varicella developed in the 18 infants. Infusion of 1 ml/kg (43 IU/kg) IV-VZVIG was generally safe. The IV-VZVIG dose resulted in seroconversion of a non-immune newborn. Five infants had low basal VZVIG titers, and two of them had a 0.6-log10 increase at 24 h post-infusion. Neonatal VZVIG titers (mean+/-SEM in log(10)) before IV-VZVIG and after by 1, 7, 14, 21, 28, and 35 d were 2.22+/-0.15, 2.17+/-0.17, 2.02+/-0.12, 0.87+/-0.2, 1.09+/-0.19, 2.33+/-0.07, and 2.16+/-0.1, respectively. One ml/kg (43 IU/kg) IV-VZVIG was generally safe. Our neonatal mean VZV-immune status did not significantly increase after the 1 ml/kg (43 IU/kg) IV-VZVIG dose, although no varicella developed and it caused a VZV-specific seroconversion.


High-gain and high-speed wavefront shaping through scattering media.
Wavefront shaping (WFS) is emerging as a promising tool for controlling and focusing light in complex scattering media. The shaping system's speed, the energy gain of the corrected wavefronts, and the control degrees of freedom (DOF) are the most important metrics for WFS, especially for highly scattering and dynamic samples. Despite recent advances, current methods suffer from trade-offs that limit satisfactory performance to only one or two of these metrics. Here, we report a WFS technique that simultaneously achieves high speed, high energy gain, and high control DOF. By combining photorefractive crystal-based analog optical phase conjugation (AOPC) and stimulated emission light amplification, our technique achieves an energy gain approaching unity, more than three orders of magnitude larger than conventional AOPC. The response time of ~10 μs with about 106 control modes corresponds to an average mode time of about 0.01 ns/mode, which is more than 50 times lower than some of the fastest WFS systems to date. We anticipate that this technique will be instrumental in overcoming the optical diffusion limit in photonics and translate WFS techniques to real-world applications.


Tendon transfers for radial nerve palsy: use of superficialis tendons for digital extension.
Since 1959, 22 patients have had wrist extension restored by transfer of the pronator teres to the extensor carpi radialis longus and brevis, common finger extension by transfer of the superficialis of the long finger, independent thumb and index finger extension by transfer of the superficialis of the ring finger, and abduction of the thumb by transfer of the flexor carpi radialis at the wrist joint level. Twenty-one of 22 patients have been evaluated from 8 months to 15 years after operation, with an average follow-up of 4.5 years. By our new system of evaluation, there were 10 excellent results, six good results, five fair results, and all patients improved. Sixteen patients obtained full, independent thumb-index finger extension, three had fair function, and two obtained thumb-index extension by tenodesis of the transfer. This procedure allows full metacarpophalangeal extension independent of wrist position, provides thumb-index finger extension independent of the ulnar three digits, and maintains the dorsal-radial-to-volar-ulnar plane of functional motion of the wrist by retaining the flexor carpi ulnaris.


Anti-thyroid drug methimazole: X-ray characterization of two novel ionic disulfides obtained from its chemical oxidation by I(2).
Interaction of methimazole (MMI, 1-methyl-imidazole-2-thione) with I2 in solvents having different polarity gives two new stable compounds containing a dication disulfide and a monocation disulfide arranged in dimers, respectively. These two species could represent effective intermediates in the reaction of MMI with an active iodine species in the thyroid gland and therefore shed more light on the mechanism of action of MMI as an antithyroid drug.


The protein profile of mouse mature cumulus-oocyte complex.
In mammals, the cumulus-oocyte complex (COC) is the main component of ovarian follicles. Bi-directional communication between oocytes and surrounding cumulus granulosa cells is essential for the development of oocytes and ovarian follicles. In this study, we performed proteomic profiling of mouse mature COC, using two-dimensional gel electrophoresis and mass spectrometry. A total of 259 protein spots were identified, which correspond to 156 individual proteins. We also discovered some protein families, which may play important roles in ovarian follicular development. Immunostaining was conducted to determine the subcellular localization of specific proteins from selected protein families of interest, and to examine their expression patterns during follicle development. These data provide valuable information for future studies to identify proteins involved in ovarian follicular development and related reproductive abnormalities.


Kidney size in childhood. Sonographical growth charts for kidney length and volume.
Kidney size was determined in a sonographic study of 325 children without kidney pathology. Real-time ultrasound equipment adjusted for the pediatric age group, provided standardized renal biometry. Outer kidney diameters showed a linear correlation to somatic developmental parameters. Renal volume was established by the formula for an ellipsoid and showed good correlation to body weight. Growth charts for kidney length and volume in childhood are constructed and provide the basis for objective intra- and interindividual determination of renal size.


Followup of ureterosigmoidostomy diversion for bladder exstrophy--behavioral biofeedback as an alternative treatment for fecal-urinary incontinence: a case report.
A total of 6 children underwent primary ureterosigmoidostomy diversion between 1972 and 1979. Despite preoperative testing of rectal competence all 6 children now experience rectal leakage. Behavioral biofeedback has been used in a 7-year-old boy who had learned to isolate and to contract the perineal muscles appropriately by 12 months of followup. The incidence of incontinence has been reduced from 15 to 5 per cent of the total hours recorded. The amount of waking hours in which the patient is wet has decreased from 31 to 6 per cent. Satisfaction of the child and parents is high.


Dietary pattern trajectories during 15 years of follow-up and HbA1c, insulin resistance and diabetes prevalence among Chinese adults.
Most research on dietary patterns and health outcomes does not include longitudinal exposure data. We used an innovative technique to capture dietary pattern trajectories and their association with haemoglobin A1c (HbA1c), homeostasis model of insulin resistance (HOMA-IR) and prevalence of newly diagnosed diabetes. We included 4096 adults with 3-6 waves of diet data (1991-2006) and biomarkers measured in 2009 from the China Health and Nutrition Survey. Diet was assessed with three 24-h recalls and a household food inventory. We used a dietary pattern previously identified with reduced rank regression that positively predicted diabetes in 2006 (high in wheat products and soy milk and low in rice, legumes, poultry, eggs and fish). We estimated a score for this dietary pattern for each subject at each wave. Using latent class trajectory analysis, we grouped subjects with similar dietary pattern score trajectories over time into five classes. Three trajectory classes were stable over time, and in two classes the diet became unhealthier over time (upward trend in dietary pattern score). Among two classes with similar scores in 2006, the one with the lower (healthier) initial score had an HbA1c 1.64% lower (-1.64 (95% CI -3.17 to -0.11)) and non-significantly a HOMA-IR 6.47% lower (-6.47 (-17.37 to 4.42)) and lower odds of diabetes (0.86 (0.44 to 1.67)). Our findings suggest that dietary pattern trajectories with healthier scores longitudinally had a lower HbA1c compared with those with unhealthier scores, even when the trajectories had similar scores in the end point.


Autologous stem cell transplantation in diffuse scleroderma: impact on hand structure and function.
The aim of the study was to assess the structural and functional effects of autologous stem cell transplantation (ASCT) on scleroderma finger clawing. Using photocopies of hands of five scleroderma patients who underwent ASCT using photocopies of hands. Functional assessments used a standardized questionnaire. Pre-ASCT, synovitis and tenosynovitis were present in five and four patients, respectively. Modified Rodnan hand skin scores ranged from 6-12/12. Following pulsed chemotherapy, synovitis resolved. Tenosynovitis often did not. Post-ASCT, skin scores fell in four patients (range 0-6/12). Hand tenosynovitis resolved. With disease remission hand function globally improved. Functional improvement, noted early (+3 months) and continuously (+12 months) in disease remitters, occurred in all areas of function. Greatest hand-functional improvement related to paid employment, followed by self-care and hygiene, home-care activities and least by hobbies/sports. The second to fifth metacarpophalangeal width was reproducible and independent of ASCT therapy. In contrast, hand length and measures of abducted finger span (first to fifth fingertip and second to fifth fingertip distance) improved. Finger abduction (abducted first to fifth fingertips/second to fifth metacarpophalangeal width) was a more sensitive discriminator of finger clawing than hand length or hand length/second to fifth metacarpophalangeal width. ASCT improved hand scleroderma over 12 months and resolved previously refractory tenosynovitis. ASCT was unnecessary to treat scleroderma synovitis. ASCT secondarily improved hand function (paid employment, followed by self-care, home care, then by sport/hobbies). Loss of finger abduction was a more sensitive measure of finger clawing than apparent loss of hand length.


Lower Cardiovascular Reactivity is Associated with More Childhood Adversity and Poorer Midlife Health: Replicated Findings from the Dunedin and MIDUS Cohorts.
Cardiovascular reactivity has been proposed as a biomarker linking childhood adversity and poorer health. The current study examined the association of childhood adversity, cardiovascular reactivity, and health in the Dunedin (n=922) and MIDUS studies (n=1,015). In both studies, participants who experienced more childhood adversity had lower cardiovascular reactivity. In addition, people with lower cardiovascular reactivity had poorer self-reported health and greater inflammation. Dunedin participants with lower cardiovascular reactivity were aging biologically faster, and MIDUS participants with lower heart rate reactivity had increased risk of early mortality. Cardiovascular reactivity was not associated with hypertension in either study. Results were partially accounted for by greater reactivity among more conscientious, less depressed, and higher-functioning participants. These results suggest that people who experienced childhood adversity have a blunted physiological response, which is associated with poorer health. The findings highlight the importance of accounting for individual differences when assessing cardiovascular reactivity using cognitive stressor tasks.


Factors affecting the continuous wave Doppler spectrum for the diagnosis of carotid arterial disease.
Spectral analysis of continuous wave (CW) Doppler signals is used for the diagnosis of carotid arterial disease. Previous clinical and in vitro studies have documented that the peak Doppler frequency is increased in recordings made directly over a stenosis and that spectral broadening is observed beyond a stenosis in the region of disturbed flow. However, certain hemodynamic and technical factors can effect the Doppler spectrum and in particular cause spectral broadening although they are not related to the severity of the arterial stenosis. In this in vitro study, Doppler spectra were quantified by (1) measurements of the peak, mean and mode frequencies, and (2) measurements that quantify changes in the shape of the spectra and thus can potentially detect the presence of spectral broadening. The latter measurements included the spectral broadening index (SBI), coefficient of variation (CV), coefficient of skewedness (CS), and coefficient of kurtosis (CK). Using straight tubes without a bifurcation in a steady flow model, we found that the peak frequency and the extent of spectral broadening were dependent upon the severity of the stenosis, the relation of the recording site to the stenosis or bulb, and the flow rate. Comparison of the severity of Doppler spectral broadening from bulb and stenosis recordings allowed us to conclude that any observed changes in spectral broadening measurements are probably due to a significant stenosis and not to the presence of a normal bulb. If the tube is not completely insonated by the CW Doppler beam, an error of between 4 and 35% can be read in the spectral broadening measurements. The peak frequency, mean frequency, and SBI are not altered significantly by the automatic gain control or dynamic range and noise level settings usually chosen by the spectrum analyzer. Because of the variability of individual Doppler spectra, one should be cautious about deriving quantitative data from one individual spectrum. The results of quantitative analysis of the amplitude spectrum are different from the power spectrum. In conclusion, this in vitro study identified several hemodynamic and technical factors that affect the CW Doppler spectrum; however, in the clinical setting, their influence on quantitative measurements of the extent of spectral broadening likely can be minimized by a skilled technologist who uses a standardized technique.


Cocaethylene produces discriminative stimulus properties in the rat: effect of cocaine and ethanol coadministration.
Experimentally naive Sprague-Dawley male rats were trained to discriminate the interoceptive stimulus cues produced by either 10.0 mg/kg cocaine or 10.0 mg/kg cocaethylene from their saline vehicles. Although it required more sessions to train the cocaethylene rats, once they were trained to criterion performance the ED50 value for cocaethylene (2.89 mg/kg) was very similar to that of cocaine (3.04 mg/kg). Coadministration of a 300-mg/kg dose of ethanol that produced saline-like responding in cocaethylene-trained rats with 2.5 mg/kg cocaine allowed for 88.9% of first lever selections being made on the cocaethylene-appropriate lever. Time-course evidence using coadministered (1.25-mg/kg) cocaine and (300-mg/kg) ethanol indicated that the formation of cocaethylene was highest, as indicated by discriminative performance, at 15 min and progressively decreased as the postinjection interval was increased to 30, 60, and 120 min. The results are discussed in light of rapid formation of cocaethylene from cotreatment with ethanol and cocaine in the mouse, rat, and human subject. The suggestion is made as to the prevalent, and growing, use of this drug combination in the human population of cocaine abusers.


Outcome of patients with acute coronary syndrome admitted to hospitals with or without onsite cardiac catheterization laboratory: a TACTICS-TIMI 18 substudy.
In the TACTICS-TIMI-18 trial, patients with acute coronary syndrome were treated with aspirin, heparin, and tirofiban and were randomized to an invasive strategy with routine catheterization or to a conservative strategy with catheterization (only if the patient had objective evidence of ischemia). Eighty-two of 2,220 patients were treated in 13 peripheral hospitals without an onsite catheterization laboratory. Tirofiban was administered to the peripheral hospital group (which was treated invasively) for 28.4 hours before coronary angiography, compared with 20.6 hours in the tertiary center group (P = 0.01). There is a similar trend in outcomes with benefit of invasive therapy among patients treated in peripheral and tertiary hospitals, without increase risk of major bleeding.


Histopathological study with immunohistochemical expression of vascular endothelial growth factor in placentas of hyperglycemic and diabetic women.
Spectrum of hyperglycemia in pregnancy includes gestational diabetes mellitus (GDM), mild hyperglycemia, and overt diabetes. Many authors have worked on morphological changes of the placenta in diabetes, but few studies have correlated histopathological changes with vascular endothelial growth factor (VEGF) immunoexpression. The aim of this study was to detect different histopathological changes in various groups of diabetic placentas and to correlate with VEGF immunoexpression. Pregnant women were screened for diabetes. They were subsequently divided into normoglycemic (12 cases), GDM (33 cases), mild hyperglycemic (13 cases), and overt diabetes (18 cases). Placentas collected were subjected to histopathological examination. VEGF expressions were studied by immunohistochemistry. Overt diabetic placenta displayed villous immaturity (44.4%), villous edema (38.9%), chorangiosis (61.1%), fibrinoid substance deposition (38.9%), and Hofbauer cell hyperplasia in 44.4% cases. GDM placentas displayed villous immaturity (45.5%), villous edema (45.5%), chorangiosis (42.4%), and fibrinoid substance deposition in 75.6% cases. Mild hyperglycemic placentas displayed villous immaturity (38.5%), chorangiosis (61.5%), and fibrinoid substance deposition in 61.5% cases. VEGF immunoexpression in GDM placentas was absent in all placental components except syncytiotrophoblast. VEGF expression in overt diabetic placentas was increased in syncytiotrophoblast and capillary endothelium compared to normoglycemic placentas. Mild hyperglycemic placentas expressed similar VEGF expression in all components when compared to normoglycemic controls. However, it displayed weak expression in vessel endothelium. Histopathological changes in diabetic placentas might be a consequence of altered or abnormal VEGF expression in diabetic placentas. Pathogenesis and VEGF expression in GDM placentas are significantly different from overt diabetic placentas.


Cytotoxicity of arctigenin and matairesinol against the T-cell lymphoma cell line CCRF-CEM.
Arctigenin and matairesinol possess a diversity of bioactivities. Here we investigated the cytotoxicity of arctigenin and matairesinol against a T-cell lymphoma cell line CCRF-CEM and the underlying mechanisms that have not been explored before. The cytotoxic activity was investigated using MTT assay. The cell cycle arrest and reactive oxygen species (ROS) accumulation were determined by flow cytometric analysis. The apoptosis induction was assessed using Annexin V/Propidium Iodide assay. The gene quantification analysis was measured through real-time polymerase chain reaction. Arctigenin and matairesinol exhibited significant antiproliferative activity against CCRF-CEM cells after 72 h treatment with IC50 values of 1.21 ± 0.15 μm and 4.27 ± 0.41 μm, respectively. In addition, both lignans arrest CCRF-CEM cells in the S phase. Furthermore, they could induce apoptosis in CCRF-CEM cells in a concentration- and time-dependent manner. Interestingly, the lignans differentially regulated the expression of several key genes involved in apoptosis pathways, including Bax, Bad and caspase-9. Moreover, both lignans could increase ROS levels in CCRF-CEM cells. Our study provides an insight into the potential of arctigenin and matairesinol as good candidates for the development of novel agents against T-cell lymphoma.


Healed corneal ulcer with keloid formation.
We are reporting a 34-year-old Arabic white female patient who presented with a white mass covering her left cornea following multiple ocular surgeries and healed corneal ulcer. The lesion obscured further view of the iris, pupil and lens. The patient underwent penetrating keratoplasty and the histopathologic study of the left corneal button showed epithelial hyperplasia, absent Bowman's layer and subepithelial fibrovascular proliferation. The histopathologic appearance was suggestive of a corneal keloid which was supported by further ultrastructural study. The corneal graft remained clear 6 months after surgery and the patient was satisfied with the visual outcome. Penetrating keratoplasty may be an effective surgical option for corneal keloids in young adult patients.


Glycolic acid: Characterization of a new final irrigant and effects on flexural strength and structural integrity of dentin.
The aim of this study was to characterize glycolic acid (GA) and examine its effects on powder and flexural strength of dentin. Particle size and energy-dispersive EDS in GA powder was performed for chemical analysis. Surface tension and pH levels of ethylenediaminetetraacetic acid (EDTA), citric acid (CA), and GA solutions were evaluated at different times and temperatures. Dentin powder and mineralized dentin beams were immersed for 1 min in EDTA, CA, or GA solutions and subjected to Fourier transform infrared spectroscopy for apatite/collagen ratio analysis and 3-point flexure test, respectively. GA showed the largest particle size (μm), and its surface tension was similar to that of EDTA and CA. Surface tension decreased in solutions of higher concentrations. GA showed pH stability at all times and temperatures evaluated. The apatite/collagen ratio reduced with increased GA concentrations, while flexural strength was not significantly affected by GA concentration. GA seems a good choice as a final irrigation solution after root canal preparation.


Tumor immunology meets oncology (TIMO) XVI, July 07-09 2022 in Halle/Saale, Germany.
During the TIMO meeting 2022, national and international scientists as well as clinicians gave novel insights as well as perspectives into basic and translational tumor immunology.


Presumed Bietti crystalline dystrophy with optic nerve head drusen: a case report.
Bietti crystalline dystrophy is primarily a retinal dystrophy caused by a CYP4V2 mutation and typically presents with crystalline retinal deposits in the posterior fundus. We present the case of an otherwise healthy 39-year-old Iranian woman with no family history of ocular disease who suffered with progressive vision loss that had started 2 years prior to presentation. Ocular examination revealed blurry optic nerve head margin and diffuse retinal crystalline deposit in both eyes. Spectral domain optical coherence tomography images showed retinal crystals, located mostly in outer retinal layers, with some areas of outer retinal tubulation and attenuation of outer retinal layers. Crystalline deposits were better visualized on near-infrared images as hyperreflective spots. Fundus autofluorescence images showed hyperautofluorescence areas on optic nerve head consistent with optic nerve head drusen and large hypoautofluorescence areas in posterior retina consistent with retinal pigment epithelium atrophy. Cystinosis was ruled out by blood testing. Bietti crystalline dystrophy may be associated with optic nerve head drusen.


Macrosialin increases during normal brain aging are attenuated by caloric restriction.
During normal aging, microglia develop an activated phenotype characterized by morphologic changes and induction of CD11b, MHC II, and other inflammatory markers. We show that macrosialin (CD68), a macrophage-specific protein, is increased by aging in selected brain regions of male C57BL/6NNia mice. In corpus callosum and striatum, macrosialin mRNA and protein increased >or=50% (24 months versus 4 months); hippocampus and cerebellum were unchanged. Caloric restriction (CR) attenuated these age-related increases. Since CR attenuates age-related increases in oxidative damage and inflammation, we examined whether oxidized lipoproteins and inflammatory processes regulate macrosialin using murine BV-2 microglial cells as a model. Oxidized low-density lipoproteins (oxLDL) induced macrosialin protein by 50%. Moreover, macrosialin was induced in response to lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) which activates inflammatory pathways in BV-2 cells. Thus, the previously documented increase in oxidized lipoproteins, inflammation, and microglial activation during normal aging may contribute to the age-related increase in macrosialin expression.


The effect of text message reminders on nausea, vomiting and quality of life in children with cancer receiving cisplatin.
This study was conducted to examine the effect of text message reminders on nausea, vomiting, and quality of life in children with cancer receiving cisplatin. The study was conducted with a pretest-posttest unpaired group model design. The study included 80 children with cancer and their parents (40 controls and 40 experiments) aged between 8 and 18 years, who were on cisplatin treatment, who did not have cognitive disability as a clinical diagnosis, who received chemotherapy during their stay in the clinic, who were literate in Turkish and who volunteered to participate in the study. The educational contents prepared by the researchers to reduce nausea and vomiting were sent to the parents in the experimental group in the form of a text message every day for three weeks. Descriptive statistics, correlation analysis, and regression analysis were used to evaluate the data. While NVTS, ARINVc, ARINVp, Quality of Life Scale pretest and posttest mean scores of both 8-12 and 13-18 age control group children were similar, it was determined that the experimental group's posttest mean scores were higher than the pretest mean scores, and there was a statistically significant difference between the experimental group's pretest and posttest mean scores in terms of the group, time and group*time. In this study, the education program explains 42%, 15%, 16%, 43%, and 43% of the increase in the mean scores of NVTS, ARINVc, ARINVp, Quality of Life Scale Child and Parent Form, respectively, in children aged 8-12. Also, the education program explains 10%, 27%, 28%, 38%, and 39% of the increase in the mean scores of NVTS, ARINVc, ARINVp, Quality of Life Scale Adolescent and Parent Form, respectively, in children aged 13-18. It has been observed that text message reminders effectively reduce the level of nausea and vomiting and increase the quality of life. The results of this study, text message reminders can be applied as an alternative intervention method, and including technology-based practices in the care of children with cancer is important in increasing the quality of care.


Rat BM-MSCs secretome alone and in combination with stiripentol and ISRIB, ameliorated microglial activation and apoptosis in experimental stroke.
Stroke, a devastating neurological emergency, is the leading cause of worldwide mortality and functional disability. Combining novel neuroprotective drugs offers a way to improve the stroke intervention outcomes. In the present era, the combination therapy has been proposed as a plausible strategy to target multiple mechanisms and enhance the treatment efficacy to rescue stroke induced behavioral abnormalities and neuropathological damage. In the current study, we have investigated the neuroprotective effect of stiripentol (STP) and trans integrated stress response inhibitor (ISRIB) alone and in combination with rat bone marrow derived mesenchymal stem cells (BM-MSCs) secretome in an experimental model of stroke. Stroke was induced in male Wistar rats (n = 92) by temporary middle cerebral artery occlusion (MCAO). Three investigational agents were selected including STP (350 mg/kg; i.p.), trans ISRIB (2.5 mg/kg; i.p.) and rat BM-MSCs secretome (100 µg/kg; i.v). Treatment was administered at 3 hrs post MCAO, in four doses with a 12 hrs inter-dose interval. Post MCAO, neurological deficits, brain infarct, brain edema, BBB permeability, motor functional and memory deficits were assessed. Molecular parameters: oxidative stress, pro inflammatory cytokines, synaptic protein markers, apoptotic protein markers and histopathological damage were assessed. STP and trans ISRIB, alone and in combination with rat BM-MSCs secretome, significantly improved neurological, motor function and memory deficits along with significant reduction in pyknotic neurons in the brain of post MCAO rats. These results were correlating with significant reduction in pro-inflammatory cytokines, microglial activation and apoptotic markers in the brain of drug treated post MCAO rats. STP and trans ISRIB, alone and in combination with rat BM-MSCs secretome, might be considered as potential neuroprotective agents in the acute ischemic stroke (AIS) management.


Development of monoclonal antibody-linked ELISA for sero-diagnosis of vesicular stomatitis virus (VSV-IN) using baculovirus expressed glycoprotein.
The gene encoding the envelope glycoprotein (GP) of vesicular stomatitis virus serotype, Indiana (VSV-IN), was expressed under the polyhedron promoter of baculovirus. The recombinant GP was applied as a diagnostic antigen for the detection of cattle and horse antibodies to VSV. In addition, the neutralizing monoclonal antibody (Mab) to GP of VSV-IN was used as trapping antibody in a Mab-linked indirect ELISA (MLI-ELISA) or detecting antibody in a Mab-linked competitive ELISA (MLC-ELISA). The diagnostic efficiencies of MLI-ELISA and MLC-ELISA were evaluated with currently available C-ELISA from OIE reference laboratory for vesicular stomatitis as a gold standard by using VSV-positive equine sera and negative bovine sera vaccinated against foot-and-mouth disease (FMD) in the field. When naturally infected equine sera and FMDV vaccinated bovine sera were tested, MLI-ELISA and MLC-ELISA showed relative sensitivities of 80% and 95% with relative specificity of 97% and 99%, respectively. However, both ELISAs cross-reacted with equine sera against New Jersey (VSV-NJ) serotype. The comparison of the two ELISAs revealed that MLC-ELISA was relatively more sensitive and specific than MLI-ELISA, indicating that MLC-ELISA can be applied to sero-diagnosis for VSV-IN infection.


In search of flavivirus inhibitors: evaluation of different tritylated nucleoside analogues.
Following up on a hit that was identified in a large scale cell-based antiviral screening effort, a series of triphenylmethyl alkylated nucleoside analogues were synthesized and evaluated for their in vitro antiviral activities against the dengue virus (DENV) and the yellow fever virus (YFV). Hereto, trityl moieties were attached at various positions of the sugar ring combined with subtle variations of the heterocyclic base. Several triphenylmethyl modified nucleosides were uncovered being endowed with submicromolar in vitro antiviral activity against the YFV. The most selective inhibitor in this series was 3',5'-bis-O-tritylated-5-chlorouridine (1b) affording a selectivity index of over 90, whereas the 3',5'-bis-O-tritylated inosine congener (5b) displayed the highest activity, but proved more toxic. The finding of these lipophilic structures being endowed with high antiviral activity for flaviviruses, should stimulate the interest for further structure-activity research.


Recent advances in our understanding of intercalated cells.
This review will summarize newly described novel functions of renal intercalated cells. Over the past 20 years, the importance of intercalated cells in the process of renal net acid excretion has been recognized. More recently, many of the molecular mechanisms responsible for this cellular function have been described. Functionally, type A and type B intercalated cells are largely mirror images in that type A intercalated cells are H secreting cells, whereas type B intercalated cells are OH secreting cells. Whether non-A, non-B intercalated cells represent H or OH secreting cells or whether they interconvert between these functions is unclear. Transporters such as pendrin (Slc26a4, Pds), AE1 (Slc4a1), the H-ATPase, and NBC3 (Slc4a7) contribute to the ability of intercalated cells to secrete H or OH equivalents. In addition to mediating secretion of H or OH equivalents, however, intercalated cells also regulate vascular volume, and hence blood pressure, likely by regulating renal Cl excretion. The molecular mechanisms of net H/OH secretion by intercalated cell subsets have been largely defined over the past decade. Moreover, targeted genetic disruption of these transporters has revealed novel roles, such as blood pressure regulation. Thus, some of these transporters might be the target of future antihypertensive drugs.


Study of otitis media and malaria among pyrexic attender of an under-fives clinic.
All 138 children attending two under-five clinics with a rectal temperature of 100 degrees F or over had their ears examined and a blood film taken for malaria parasites. Twenty-eight per cent were found to have otitis media and 37 per cent to have malaria. No symptom was found to be sufficiently discriminating for a diagnosis to be made on history alone in either condition.


You can go your own way: SNX-BAR coat complexes direct traffic at late endosomes.
The endolysosomal network consists of highly dynamic membrane-bound compartments that control subcellular degradative and recycling processes. A conserved family of endosomal coat complexes known as SNX-BARs drive the formation of tubular membrane transport carriers for cargo retrieval. Whereas SNX1-related SNX-BARs were previously thought to rely on their association with the retromer complex to recognize cargo, recent work shows this class of SNX-BARs can directly bind and deliver cargo. In this review, we examine the retromer-independent roles of SNX-BAR proteins in yeast and metazoans and explore their functional overlap with endosomal sorting complexes and accessory factors. We also discuss new work that highlights the role of the disordered N-terminal regions of SNX-BARs in complex assembly and function.


Optimization of solid-phase extraction and liquid chromatography-tandem mass spectrometry for the determination of domoic acid in seawater, phytoplankton, and mammalian fluids and tissues.
We previously reported a solid-phase extraction (SPE) method for determination of the neurotoxin domoic acid (DA) in both seawater and phytoplankton by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with the purpose of sample desalting without DA pre-concentration. In the present study, we optimized the SPE procedure with seawater and phytoplankton samples directly acidified with aqueous formic acid without addition of organic solvents, which allowed sample desalting and also 20-fold pre-concentration of DA in seawater and phytoplankton samples. In order to reduce MS contamination, a diverter valve was installed between LC and MS to send the LC eluant to waste, except for the 6-min elution window bracketing the DA retention time, which was sent to the MS. Reduction of the MS turbo gas temperature also helped to maintain the long-term stability of MS signal. Recoveries exceeded 90% for the DA-negative seawater and the DA-positive cultured phytoplankton samples spiked with DA. The SPE method for DA extraction and sample clean-up in seawater was extended to mammalian fluids and tissues with modification in order to accommodate the fluid samples with limited available volumes and the tissue extracts in aqueous methanol. Recoveries of DA from DA-exposed laboratory mammalian samples (amniotic fluid, cerebrospinal fluid, plasma, placenta, and brain) were above 85%. Recoveries of DA from samples (urine, feces, intestinal contents, and gastric contents) collected from field stranded marine mammals showed large variations and were affected by the sample status. The optimized SPE-LC-MS method allows determination of DA at trace levels (low pg mL(-1)) in seawater with/without the presence of phytoplankton. The application of SPE clean-up to mammalian fluids and tissue extracts greatly reduced the LC column degradation and MS contamination, which allowed routine screening of marine mammalian samples for confirmation of DA exposure and determination of fluid and tissue DA concentrations in experimental laboratory animals.


Metastatic glioblastoma: case presentations and a review of the literature.
Extracranial metastases from glioblastoma (GBM) are uncommon with an estimated incidence of less than 2%. We report two cases of metastatic GBM seen within an 8-week period followed by a literature review. We attempted to identify common factors or a causative mechanism. Factors that predominated among the reviewed cases included male gender, tumor location, and younger age. Causative mechanisms were not apparent. While metastatic disease remains rare, it might be occurring with increasing frequency. This trend might be due to increased diagnosis, better imaging, a more extensive physician workup, or an increase in survival. Metastatic GBM can present and progress quite rapidly, and repeat evaluations of persistent or worsening complaints among GBM patients are warranted. Early diagnosis of metastatic disease spread can help to expedite alleviation of patients' discomfort, in an already aggressive disease process.


Postcoital testing in relation to circulating sperm-agglutinating antibodies in women.
Repeated postcoital tests (PCTs) were evaluated in couples with unexplained infertility, in couples with circulating sperm-agglutinating antibodies of the head-to-head (H-H) or tail-to-tail (T-T) type in serum, and in couples without any antibodies. The results were compared with those of PCTs in the conception cycle from women undergoing gonadotropin treatment for anovulation. Only limited differences in the PCT results were noted between couples with sperm-agglutinating antibodies, couples without such antibodies, and fertile couples.


Implementation of informed consent for a cystic fibrosis newborn screening program in France: low refusal rates for optional testing.
The French Association for Neonatal Screening implemented cystic fibrosis neonatal screening (CF NBS) region by region in France, from the beginning of the year 2002 to early 2003. The program uses an immunoreactive trypsinogen/DNA testing algorithm on dried blood samples obtained at 3 days of age. Incorporation of DNA testing necessitated compliance with official regulations and French "bioethics" laws: the need for a written consent from the patient/guardian and specific circulation of the prescription, sample, and results. To fulfill these obligations, the Ethics and Genetics committee of the French Association for Neonatal Screening recommended that informed consent should be obtained for all neonates at birth by having the parents sign directly on the sampling paper. This study was designed to evaluate the effect of the educational efforts used to obtain informed consent on acceptance of CF NBS. Data from the screening center in Lille, France, were analyzed to determine the rate of refusal of CF NBS in the 18 months after initiation of the informed consent process. The number of refusals for CF NBS declined from 0.8% at the start of the program to 0.2% at the end of the first year of the new process for obtaining written consent. Efforts to inform parents and professionals resulted in a significant decrease in the number of refusals for CF NBS.


Reproductive outcomes in women with classic bladder exstrophy: an observational cross-sectional study.
We sought to examine the reproductive outcomes of 52 women with classical bladder exstrophy. This was an observational study with cross-sectional and retrospective arms. The average age of the sample was 33 years (range, 17-63). Of those who had tried, 19/38 (66%) had conceived. A total of 57 pregnancies (3 sets of twins) were reported for the 19 patients and resulted in 34/57 live births (56%), 21/57 miscarriages (35%), 1/57 (2%) termination, and 4/57 (7%) stillbirths or neonatal deaths. Four deliveries resulted in major complications including 1 transection of the ureter (4%), 1 fistula formation (4%), and 2 postpartum hemorrhages (8%). There were 2 admissions to intensive care, one for urinary sepsis and another for massive obstetric hemorrhage. Fertility is impaired in women with bladder exstrophy. Pregnancy is high risk both for the mother and baby. Delivery should be at a tertiary referral obstetric unit with urology cover. In the majority of cases planned cesarean section is the most appropriate mode of delivery.


Influence of chemical modifications on dynamic rheological behaviour, thermal techno-functionalities, morpho-structural characteristics and prebiotic activity of banana starches.
Banana starch is explored for its use in food and pharmaceutical applications. In this study, in order to improve the techno-functional properties of native banana starch (NS), different chemical modifications namely acid thinning (AT), oxidation (OX), sodium-trimetaphosphate method (STMP), cross linking phosphorylation (CLP), hydroxypropylation (HYP) were employed. Among the modified starches, amylose content was higher in CLP starch and the least was observed in AT. Resistant starch (RS) of HYP (65.38 %) and CLP starches (62.76 %) were significantly higher than other modified starches. Lesser amylose, higher water solubility and lower swelling of AT starch resulted in inferior paste clarity and inability to make a firm gel. Non-Newtonian behaviour of starch gels were observed from static viscosity observations. The dynamic rheological behaviour of the starch gels affirmed the higher gel strength of STMP (0.46) and CLP (0.56) starches. Imperfection and exo-corrosion in starch morphology was observed through SEM and influence of chemicals on the starch structure was elucidated through FTIR and XRD analyses. Except AT starch, modified starches with higher RS resulted in lowering glycemic index (57-69 %). STMP starches recorded highest prebiotic activity score of 0.88. Chemical modifications enable to enhance the functionalities of banana starch and offers potential industrial uses.


Noninvasive liver fibrosis assessment in chronic viral hepatitis C: agreement among 1D transient elastography, 2D shear wave elastography, and magnetic resonance elastography.
To assess the agreement of one-dimensional transient elastography (1D-TE), two-dimensional shear wave elastography (2D-SWE), and magnetic resonance elastography (MRE) in a consecutive cohort of patients affected by hepatitis C virus (HCV) and to understand which patient-related factors are associated with disagreement. Ninety-one consecutive patients with current or previous chronic HCV infection were enrolled between March 2017 and September 2018. We assessed the correlation between stiffness measurements expressed in kilopascals (kPa). After converting kPa values in three groups of increasing fibrosis burden using validated cut-off values, we assessed the agreement among the different techniques. Factors influencing inter-modality disagreement were examined by employing multivariate logistic regression analysis. Seventy-seven patients met the inclusion criteria and had reliable measurements by all stiffness imaging techniques. At the quantitative analysis, a strong correlation between stiffness measurements was found (Spearman's rho values ranging from 0.7 to 0.89 in all pairs of techniques). Complete concordance among MRE, 1D-TE, and 2D-SWE was found in 64.9% of patients, and the agreement was highest between MRE and 1D-TE, with κ value of 0.801. In only 2/77 patients (2.6%), there was complete disagreement. High body mass index (BMI) was the only factor significantly associated with inter-modality discordance. MRE, 1D-TE, and 2D-SWE assigned the majority of patients to the same fibrosis group. The agreement was at least good, and there was a strong correlation between kPa values in all three pairs of techniques. Highest agreement was found between MRE and 1D-TE. High BMI was associated with discordance among the techniques.


Bactericidal activity of topical antiseptics and their gargles against Bordetella pertussis.
Bordetella pertussis is the etiological agent of whooping cough, a common cause of respiratory illness in both children and adults. In the present study, we investigated the bactericidal activity of four antiseptics-povidone-iodine (PVP-I), benzethonium chloride (BEC), chlorhexidine gluconate (CHG) and benzalkonium chloride (BAC)-against B. pertussis ATCC9797 and clinical isolates. Among the topical antiseptics, PVP-I, BEC, and BAC, PVP-I and BAC in particular, showed high bactericidal activity, whereas CHG had low activity. PVP-I gargle also showed high bactericidal activity, similar to topical PVP-I. However, BEC gargle had low bactericidal activity. Our results indicate that topical PVP-I and BAC, and PVP-I gargle would be useful as effective antiseptics against B. pertussis.


Coats' disease. Evaluation of management.
Forty-one patients representing 43 eyes with retinal telangiectasia and subretinal exudates (Coats' Disease) were managed between 1966 and 1980. Thirty-three eyes in 31 patients between 4 and 45 years of age had an average of two quadrants involved with telangiectasia. Of four untreated eyes, three deteriorated and one stabilized. In contrast, of 29 eyes treated with cryotherapy or photocoagulation, eight deteriorated, 15 stabilized, and six improved. Ten patients in the series were under 4 years of age and had more severe disease than older patients. On the average three quadrants were involved with telangiectasia and subretinal exudate. Three untreated eyes rapidly progressed to total retinal detachment with glaucoma. The seven treated children required frequent assessment and repeated treatment. Of these, one stabilized but had no light perception, and the remaining six improved. The authors stress that the disease can be controlled with aggressive treatment. Their treatment methods are described.


Corrigendum: Identification of the first congenital ichthyosis case caused by a homozygous deletion in the ALOX12B gene due to chromosome 17 mixed uniparental disomy.
[This corrects the article DOI: 10.3389/fgene.2022.931833.].


Fever at Diagnosis of Pediatric Acute Lymphoblastic Leukemia: Are Antibiotics Really Necessary?
With new multidrug-resistant microbes and the paucity of new antibacterial agents, we must identify opportunities to safely minimize antibiotics. Current guidelines encourage empiric antibiotics in febrile patients with chemotherapy-induced neutropenia to reduce infection-related mortalities. No guidelines exist for children with isolated fever at presentation/diagnosis of acute lymphoblastic leukemia (ALL) and before starting chemotherapy. This study evaluates the incidence of bacteremia in this subpopulation. We retrospectively analyzed medical records of 230 consecutive patients under 21 years of age diagnosed with ALL at Children's Hospital & Research Center Oakland (CHRCO) from January 2003 through October 2013. We focused on blood cultures obtained within 24 hours of presentation to CHRCO, which was before general anesthesia for a procedure or systemic chemotherapy. Among 221 patients who met the inclusion criteria, 126 (57%) were febrile and had blood cultures obtained. Two patients (1.6%) had positive blood cultures consistent with bacteremia; 1 had group A β-hemolytic streptococcus and the other had Escherichia coli. Given the rarity of bacteremia in this subpopulation at our institution, we recommend more judicious use of antibiotics in children with isolated fever at time of ALL diagnosis. We encourage other institutions to conduct similar investigations.


Bioequivalence for topical products--an update.
With the exception of topical glucocorticoids, demonstrating bioequivalence between generic and reference topical products entails conducting clinical end-point trials which are both lengthy and expensive. Considerable effort has been channeled towards development and validation of alternative approaches to demonstrate bioequivalence of topical and transdermal products. The critical opportunity pathways identified by the FDA for the industry for topical bioequivalence include the following surrogate methods: in vitro studies, dermatopharmacokinetic method, dermal microdialysis and near infrared spectroscopy. This review provides an update of recent advances in these methodologies.


The Effect of Earlier Bone Grafting, Prior to Orthodontic Treatment, on SWAG Ratings of Graft Outcomes.
To compare the outcomes between 2 groups of patients with complete clefts treated with early secondary alveolar bone grafting (ABG) at 2 centers (5-7 years, before orthodontic intervention) and to a third group of patients treated at one of those centers (center 1) who had received later secondary ABG (8-10 years, after orthodontic intervention). Blind retrospective analysis of cleft site radiographs using Americleft Standardized Way to Assess Grafts (SWAG) scale. A total of 99 patients with complete clefts from 2 North American cleft/craniofacial centers. Secondary ABG representing 2 protocols: early grafting at a mean age of 6.6 years prior to any orthodontic intervention, and later grafting at a mean age of 10.2 years following pregrafting orthodontic intervention. Using occlusal radiographs, the SWAG scale from 0 (failed graft) to 6 (ideal) was used. Six trained, calibrated raters scored each radiograph twice, with the average of the 2 ratings used as the final score. Reliability was assessed using the weighted κ statistic. The significance of differences between groups was determined using the Kruskal-Wallis test and Dunn test for pairwise comparisons. Inter-rater reliability of SWAG method was good (0.631). Intra-rater reliability was excellent (0.817). There was a tendency for improved total graft outcome in the early grafted group from center 1 compared to the later grafted group with improvement being significantly different in only the coronal third of the early, preorthodontic grafted group. However, the difference was not statistically significant for the graft overall.


The effects of the phospholipase A2 inhibitors aristolochic acid and PGBx on A23187-stimulated mobilization of arachidonate in human neutrophils are overcome by diacylglycerol or phorbol ester.
Aristolochic acid and PGBx, two structurally unrelated, protein-targeted inhibitors of isolated phospholipases A2, are effective antagonists of calcium ionophore A23187-stimulated mobilization of [3H]arachidonate from human neutrophils. We now report that preincubation of neutrophils with oleoylacetylglycerol (OAG, 15 microM) substantially reverses the inhibitory effect of 200 microM aristolochic acid (from 70 to 24% inhibition). Similarly, OAG increases the IC50 for PGBx from 2.5 to greater than 20 microM. The effects of OAG on inhibition by either aristolochic acid or PGBx are dose-dependent, with an ED50 of 2.5 microM. Protection against inhibition by either aristolochic acid or PGBx is also observed with phorbol myristate acetate (PMA, ED50 3 nM), but not 4-alpha-phorbol didecanoate. Aristolochic acid and PGBx do not inhibit PMA-stimulated superoxide generation, and are thus not protein kinase C inhibitors. Furthermore, neither aristolochic acid nor PGBx inhibit diglyceride generation through the phospholipase D/phosphatidate phosphohydrolase pathway. A23187-stimulated [3H]arachidonate mobilization is increased by 20-50% when neutrophils are preincubated with OAG or PMA. The present results indicate that OAG and PMA also modulate the A23187-stimulated [3H]arachidonate mobilization so as to render it less sensitive to inhibitors of phospholipase A2.


Action of lipid peroxidation products on phosphoinositide specific phospholipase C.
4-Hydroxynonenal (HNE), a major lipid peroxidation product, displays several biological actions. Among them, the differentiation of human HL-60 cells and the stimulation of neutrophil oriented migration occur at concentrations which can be actually found in normal tissues and in body fluids. In spite of its chemotactic activity, HNE fails to increase neutrophil oxidative metabolism. The action of the aldehyde on cell migration appears to be mediated by a phosphoinositide specific phospholipase C. The acceleration of phosphatidylinositol turnover induced by 10 pM 4-hydroxyoctenal, another lipid peroxidation product, is prevented by the pretreatment of neutrophils with pertussis toxin. The mechanism of action of these 4-hydroxyalkenals appears to follow pathways common to other chemoattractants, but some differences can be found too. In particular HNE seems unable to stimulate phospholipase D activity. The action of 4-hydroxyalkenals and other lipid peroxidation products on transmembrane signalling systems and on phospholipid metabolism might regulate several cell functions, such as motility, proliferation and differentiation.


No linkage or linkage disequilibrium between brain-derived neurotrophic factor (BDNF) dinucleotide repeat polymorphism and schizophrenia in Irish families.
There is increasing evidence that a neurodevelopmental process is accountable for at least a proportion of schizophrenic cases. Brain-derived neurotrophic factor (BDNF), a member of a group of proteins that includes neurotrophin-3/4/5 and nerve growth factor (NGF), is an attractive candidate gene. We have performed a case control association study using the BDNF dinucleotide repeat polymorphism in a sample of familial schizophrenic individuals and in healthy, ethnically matched control subjects. We also performed a linkage analysis on 265 multiplex families using the same marker. We found no differences in allele frequencies between the patient and control groups nor any evidence for transmission disequilibrium or linkage with the multiply affected families. We conclude that DNA variation at or near the BDNF gene is unlikely to contribute to the genetic predisposition to schizophrenia.


Outcome of cataract surgery associated with posterior staphyloma.
To assess the outcome of cataract surgery in eyes with posterior staphyloma and identify predictors of surgical success. Tertiary care referral center. A retrospective analysis was conducted of 107 consecutive patients with posterior staphyloma and 107 control patients who had cataract surgery. Potential associations of preoperative variables with surgical success were analyzed using the chi-square test, multivariate linear regression, and Student t test. The staphyloma group was younger, had more women, and had a lower mean visual acuity preoperatively than the control group. All patients in the control group and all but 1 in the staphyloma group had intraocular lens (IOL) implantation at the time of cataract extraction. The rates of posterior capsule tear and vitreous loss were similar in the staphyloma and control groups. There was 1 case each of retinal detachment and IOL dislocation in the staphyloma group. The staphyloma group had significantly lower postoperative visual acuity than the control group; however, the percentage in the staphyloma group with a visual acuity of finger counting or worse decreased from 80.4% preoperatively to 16.8% postoperatively and the percentage with an uncorrected visual acuity of 20/160 or better increased from 5.6% to 67.3%. Myopic degeneration was judged to be the cause of postoperative acuity worse than 20/100 in 22.4% in the staphyloma and 0% in the control group; other causes for poor postoperative acuity were similar in the 2 groups. In the staphyloma but not the control group, decreased postoperative acuity was independently associated with age greater than 65 years and axial length greater than 29.0 mm. Myopic degeneration may limit the results of cataract extraction in up to one fourth of patients with posterior staphyloma. Nevertheless, a substantial improvement in mean visual acuity resulted that was not associated with a significant increase in surgical complications.