Paternal depression during pregnancy and postpartum: An international Delphi study.
Fathers are at risk for depression during a mother's gestation and postpartum. Assessment, detection, and treatment are hampered by the lack of consensus on this issue. The purpose of this study was to reach expert consensus through the Delphi method on the defining factors of depression in peripartum fathers. Purposive sampling resulted in the surveying of 14 international expert panelists. The study used a modified Delphi approach in which experts participated in two rounds of open-ended and scale questionnaires, followed by two rounds of opportunities to adjust their responses and/or comment on evolving data until consensus was achieved. Experts responded to 10 questions on terminology, diagnostics, symptomology, risk/protective factors, biological factors, assessment tools/protocol, cost implications, and key stakeholders. Of these 10 questions presented for discussion, the analysis resulted in 197 coded themes. Consensus was met for 119 of the 197 coded responses (60.41%). Diversity of opinion within this Delphi Study was excluded for the sake of consensus. Regression to the mean may have occurred after continuous surveying and when evolving results were shared with panelists. Critics of Delphi methodologies have pointed to the issue of small expert samples typically used and the subjectivity of "expert." Consensus identified diagnostic criteria and symptomology that differentiates the paternal experience of peripartum depression. Experts indicated the importance of a father's social context, biological risk factors, limitations of current assessment tools, key stakeholders, and potential financial costs. Stakeholders on this issue would benefit from translating consensus into assessment and treatment.


High mobility group B1 up-regulates angiogenic and fibrogenic factors in human retinal pigment epithelial ARPE-19 cells.
Hypoxia-induced retinal neovascularization plays a central role in the pathogenesis of diabetic retinopathy. This study aimed to investigate whether hypoxia leads to the release of nuclear high mobility group box 1 (HMGB1) peptides from cultured retinal pigment epithelial ARPE-19 cells, to determine the effect of HMGB1 on angiogenic cytokine production and elucidate the involved signaling pathways. A chemical hypoxia mimetic agent, cobalt chloride, induced SIRT1 downregulation, HMGB1 nucleocytoplasmic relocation and extracellular release from ARPE-19 cells, implicating its autocrine function. Resveratrol treatment significantly reduced secretion of HMGB1 from ARPE-19 cells exposed to hypoxia. Cell proliferation and cell cycle analyses demonstrated that exogenous HMGB1 caused significant growth suppression and G1 cell cycle arrest in ARPE-19 cells. Morphological observations showed that HMGB1 enhanced adhesion, but suppressed migration of ARPE-19 cells. More intriguingly, HMGB1 up-regulated expression of angiofibrogenic factors in ARPE-19 cells, including VEGF, bFGF, TGF-β2, and CTGF. Signal profiling characterization indicated that HMGB1 triggered hyperphosphorylation of Akt, p38 MAPK, and NF-κB, but not that of ERK, JNK, and Smad2, whereas inhibition of PI3K, MAPK, or NF-κB significantly attenuated the HMGB1-driven cytokine overproduction in ARPE-19 cells. Functional neutralization with anti-TLR4 and -RAGE antibodies confirmed that both receptors were involved in the cytokine overproduction. In conclusion, chemically-mimicked hypoxia induced nucleocytoplasmic relocation and release of HMGB1 peptides, which in turn up-regulated the production of angiofibrogenic factors in RPE cells, thereby contributing to the pathogenesis of hypoxia-associated diabetic retinopathies. Conversely, blockades of intraocular HMGB1 bioavailability or signal activation may prevent angiofibrogenesis in development of diabetic retinopathy.


Membrane-type-1 matrix metalloproteinase, matrix metalloproteinase 2, and tissue inhibitor of matrix proteinase 2 in prostate cancer: identification of patients with poor prognosis by immunohistochemistry.
Overexpression of the matrix metalloproteinase (MMP) 2 is associated with poor prognosis in many tumor types. Membrane-type-1 MMP (MMP14) activates MMP2 using pro-MMP2 specific inhibitor, tissue inhibitor of matrix proteinase 2 (TIMP2), as a receptor. We evaluated, by immunohistochemistry on 189 T3N0-2M0 prostate cancer (Pca) cases, the influence of MMP2, MMP14, and TIMP2 expression, individually and in association, on Pca disease-free survival (DFS). We evaluated marker expression separately in cancer, stromal, and benign epithelial (BE) cells according to a percentage scale (0%, <10%, 10%-50%, and >50%). Median follow-up was 4.61 years. In BE cells, there was an inverse relationship between initial prostate-specific antigen serum level and T3 stage with MMP14 expression (P = .003) and between pN stage and TIMP2 expression (P = .04). The most significant results with survival were obtained by dichotomizing the cases between those with less than 10% and at least 10% of cells expressing the marker, the latter category representing overexpression. TIMP2 overexpression in stromal cells was associated with a longer DFS with a hazard ratio of 0.573 (P = .02) for time to recurrence. MMP2 overexpression by BE cells correlated with a shorter DFS using a multivariate trend test (hazard ratio = 1.46, P = .02). Stromal cells expressing less than 10% TIMP2 and MMP2 overexpression was the only combination that was significantly associated with a shorter DFS (log-rank test, P = .0001). This study suggests that MMP14 is involved mostly in Pca implantation and that MMP2 and TIMP2 expression by reactive stromal cells might be used as predictors of DFS in T3N0-2M0 Pca.


The Last Decade of Optically Active α-Aminophosphonates.
α-Aminophosphonates and related compounds are important due to their real and potential biological activity. α-Aminophosphonates may be prepared by the Kabachnik-Fields condensation of oxo compounds, amines and dialkyl phosphites, or by the aza-Pudovik addition of the same P-reagents to imines. In this review, the methods that allow for the synthesis of α-aminophosphonates with optical activity are surveyed. On the one hand, optically active catalysts or ligands may induce enantioselectivity during the Kabachnik-Fields reaction. On the other hand, asymmetric catalysis during the aza-Pudovik reaction, or hydrogenations of iminophosphonates, may prove to be a useful tool. Lastly yet importantly, it is possible to start from optically active reagents that may be associated with diastereoselectivity. The "green" aspects of the different syntheses are also considered.


Dental and periodontal status of 12-year-old Dai school children in Yunnan Province, China: a cross-sectional study.
The Dai people are one of the ethnic minorities in China and have a population of 1,260,000. They have the same origin as one of the main ethnic groups in Laos and Thailand. The study aims to describe the dental caries and gingival status of 12-year-old Dai children in China and to study the factors affecting their oral-health status. This cross-sectional oral-health survey was conducted from 2011-2012 with ethics approval. A sample of 12-year-old Dai children living in Yunnan, China, was selected using a multistage and cluster sampling method. One trained examiner performed the clinical examination. Caries experience was measured using DMFT index, and gingival status was assessed with CPI index. A self-completed questionnaire was sent to the children, and they were asked about their backgrounds and oral-health-related behaviors and oral-health knowledge. Binary logistic regression analysis was performed to investigate the factors that affected the caries status. A total of 875 children were invited, and 823 (94 %) joined the survey. The prevalence of caries experience among the participants was 40 %. The mean DMFT and DT scores were 0.9 and 0.8, respectively. Most children (93 %) had gingivitis, and many (46 %) had calculus. Girls and those who had visited a dentist during the previous year had a higher prevalence of caries. Dental caries were prevalent among 12-year-old Dai children in China. The periodontal condition of most of the children was poor. Caries were associated with gender and dental attendance.


The cerebellum involvement in the generation of saccades.
It was assumed that the cerebellum is not essential for eye movements, playing only a modifying and influencing role. Recently it has been shown that the directions of the saccades can be related to a stimulated cerebellar site. This study was done on patients who underwent partial vermis and hemisphere ablations as a result of severe cranial or cerebellar tumors. The results further indicate that lack that lack of some cerebellar neural structure affects the nature of the saccade: it does not move the eyes in one saccade to acquire the new target and its amplitude duration relationship changes. It is suggested that cerebellar cortex generates a neural pulse based on teleceptive information about stimulus location with respect to an observer's head, corrects this information for initial eye position and sends out a signal to the saccadic pulse generators which move the eyes to acquire the new target.


[Current situation of domiciliary enteral nutrition in Galicia. A multicenter study].
To determinate the prevalence of patients with Home Enteral Nutrition (HEN) in Galicia. Transversal study. Patients aged > or = 14 years, treated with HEN in our community since January 1998 to December 1999. Population of reference was 1.789.983. Questionnaire previously designed. During the study period were treated 2,784 patients which represent a prevalence of 10.34 cases/10,000 inhabitants, being 18.8 for La Coruña, 1.3 for Lugo, 0.4 for Ourense and of the 20.85 for Pontevedra. The mean age of the patients was of 56 +/- 2.29 years (range 14-96). The Clinics units that required more frequently HEN were the Medical Units (48.3%), followed of the Surgery Units (20.2%) and the Primary Care Units (19.2%). Neurological abnormalities (43.6%), Neoplasias (30.7%) and Intestinal Inflammatory Disease (10.5%) were patients more frequently required HEN. Regarding to administration route 58.3%, 28.46%, 9.87%, 0.5% and 0.65% used oral, nasogastric tube, PEG, gastrostomy and yeyunostomy respectively. The Index of complications was 0.18 of patient-year, due to gastrointestinal anomalies 0.12 patient-year, mechanical 0.09 patient-year. The index of hospitalizations in relation to the nutritional treatment was 0.026 patient-year. The prevalence of HEN in our community is of 10.34 cases/10,000 inhabitants. This kind of treatment is more frequently in the areas with high-density population. The frequency of complications was low. This data may be useful to compare with date from other areas and countries.


Circadian rhythm of histamine release from the hypothalamus of freely moving rats.
Using an in vivo microdialysis technique coupled with HPLC-fluorometry, the release of neuronal histamine from the anterior hypothalamic area was monitored continuously in conscious, freely moving rats under a 12:12 h light:dark cycle. Spontaneous locomotor activity of the rats was measured simultaneously using a locomotor activity counter. Histamine release gradually increased in the second half of the light period (1400-2000) and the average histamine release during the dark period (2000-0800, 0.20 +/- 0.02 pmol/30 min) was significantly higher than that during the light period (0.12 +/- 0.01 pmol/30 min). This clear circadian change in the release suggests that the central histaminergic system is related to the circadian rhythm of rats.


Exploring stakeholder views on intervening in hospital around childhood secondhand smoke exposure (Precedent): a protocol for a qualitative study.
Secondhand smoke exposure (SHSe) in childhood is linked with increased morbidity and mortality. Hospital or secondary care contact may present a 'teachable moment' to provide parents with support to change their home smoking behaviours to reduce children's SHSe. There is a lack of robust qualitative evidence around parents and healthcare professionals (HCPs) views on using this teachable moment to successfully initiate behavioural change. We aim to identify and understand what is important to stakeholders with a view to informing the development of a support package to help parents change their home smoking behaviours. This qualitative study will be theoretically underpinned by the Capability, Opportunity and Motivation Behaviour (COM-B) model of behavioural change. It will involve semistructured interviews and/or discussion groups with up to 20 parents who smoke and up to 25 HCPs. Stakeholders will be recruited from a single National Health Service children's hospital in England. Interviews and/or discussion groups will be audio recorded, transcribed and anonymised. The transcripts and any field notes will be analysed using the framework method. Initially, we will apply COM-B to the data deductively and will then code inductively within each domain. The protocol for this study received a favourable outcome from the East Midlands Leicester Central Research Ethics Committee (19/EM/0171). Results will be written up as part of a PhD thesis, submitted for publication in peer-reviewed journals and presentation at conferences. ISRCTN40084089.


The effect of maternal and grandmaternal age in benign and high temperature environments.
Maternal age is known to be of importance for the fitness of the offspring. Few studies have, however, been able to analyse this phenomenon as an isolated effect without confounding effects through genetic variation. This difficulty can be circumvented by working with parthenogenetic organisms. We investigated the effect of maternal and grandmaternal age on wing traits, pupal survival and developmental instability (DI) in both a benign and a high temperature environment using two different parthenogenetic strains of Drosophila mercatorum. Both the maternal and grandmaternal age was found to influence all the traits. Two opposing factors seem to shape the effects of maternal age. Senescence in older mothers leads to a reduction in offspring fitness, whereas, plastic responses lead to more competitive and stress resistant offspring from older mothers. The relative importance of these factors is trait specific and is influenced by environmental factors. DI is mostly influenced by senescence whereas wing sizes are influenced mostly by plastic responses towards higher competition. This means that any analysis of fitness should take age composition of at least two generations into account.


Vine-shoot waste aqueous extract applied as foliar fertilizer to grapevines: Effect on amino acids and fermentative volatile content.
The aim of this work was to study the influence of foliar applications of different wood aqueous extracts on the amino acid content of musts and wines from Airén variety; and to study their relationship with the volatile compounds formed during alcoholic fermentation. For this purpose, the foliar treatments proposed were a vine-shoot aqueous extract applied in one and two times, and an oak extract which was only applied once. Results obtained show the potential of Airén vine-shoot waste aqueous extracts to be used as foliar fertilizer, enhancing the wine amino acid content especially when they were applied once. Similar results were observed with the aqueous oak extract. Regarding wine fermentative volatile compounds, there is a close relationship between musts and their wines amino acid content allowing us to discuss about the role of proline during the alcoholic fermentation and the generation of certain volatiles.


[Diagnostic imaging of traumatic brain injury].
Traumatic brain injury (TBI)--either in isolation or within the context of multiple trauma--is a major cause of disability and death in young adults. The prognosis depends not only on the extent and localization of traumatic lesions, but also on the promptness of surgical intervention if indicated. The following article presents diagnostic imaging strategies in the acute and sub-acute phases of head injury, discussing their relevance with regard to various clinical situations. In addition to standard CT and MRI techniques, the use of other methods such as perfusion measurements, magnetic resonance spectroscopy or diffusion tensor imaging is briefly discussed. By means of these relatively new techniques it is possible to visualize not only structural changes but also gain information relating to functional and metabolic aspects of traumatic brain injury.


Characterization of water treatment-resistant and multidrug-resistant urinary pathogenic Escherichia coli in treated wastewater.
A growing body of evidence has demonstrated that extraintestinal pathogenic E. coli (ExPEC), such as the urinary pathogenic E. coli (UPEC), are common constituents of treated wastewater, and therefore represent a potential public health risk. However, no single virulence gene, or set of virulence genes, can be used to conclusively identify this genetically diverse pathotype. As such we sought to identify and characterize the public health relevance of potential UPEC found in treated sewage/wastewater using a comparative genomics approach. Presumptive wastewater UPEC (W-UPEC) were initially identified by virulence gene screening against 5 virulence genes, and for which isolates containing ≥3 virulence genes were whole genome sequenced (n = 24). Single nucleotide polymorphic (SNP) spanning tree analysis demonstrated that many of these wastewater UPEC (WUPEC) were virtually identical at the core genome (0.4 Mbp) when compared to clinical UPEC (C-UPEC) sequences obtained from NCBI, varying by as little as 1 SNP. Remarkably, at the whole genome level, W-UPEC isolates displayed >96% whole genome similarity to C-UPEC counterparts in NCBI, with one strain demonstrating 99.5% genome similarity to a particular C-UPEC strain. The W-UPEC populations were represented by sequence types (ST) known to be clinically important, including ST131, ST95, ST127 and ST640. Many of the W-UPEC carried the exact same complement of virulence genes as their most closely related C-UPEC strains. For example, O25b-ST131 W-UPEC strains possessed the same 80 virulence genes as their most closely related C-UPEC counterparts. Concerningly, W-UPEC strains also carried a plethora of antibiotic resistance genes, and O25b-ST131strains were designated as extended spectrum beta-lactamase (ESBL) producing E. coli by both genome profiling and phenotypic resistance testing. W-UPEC ST131 strains were found in the effluents of a single treatment plant at different times, as well as different wastewater treatment plants, suggesting a differentially ability to survive wastewater treatment. Indeed, in sewage samples treated with chlorine doses sufficient for inducing a ∼99.99% reduction in total E. coli levels, UPEC represented a significant proportion of the chlorine-resistant population. By contrast, no Shiga toxin-producing E. coli were observed in these chlorinated sewage libraries. Our results suggest that clinically-relevant UPEC exist in treated wastewater effluents and that they appear to be specifically adapted to survive wastewater treatment processes.


Conducting publishable research under conditions of severely limited resources.
Doing research when resources are severely limited will always be challenging. But by sharing resources, collaborating internationally as well as locally, developing sustainable research lines and optimizing study concept and design, researchers can significantly increase their research output and enhance its quality.


[Clinical and etiological aspects of uveitis: a retrospective study of 121 patients referred to a tertiary centre of ophthalmology].
Uveitis consists of a large group of diseases characterized by intraocular inflammation involving the uveal tract. This heterogeneity makes the diagnosis and the treatment of uveitis frequently challenging. The purpose of this study was to describe the various clinical and etiologic aspects of uveitis, through the new standardized uveitis classification and the use of modern investigations for its diagnostic work-up. The medical records of 121 new patients with uveitis referred to our tertiary ophthalmologic centre between January 2002 and December 2006 were retrospectively reviewed. Uveitis associated to human immunodeficiency virus and secondary to exogenous endophthalmitis were excluded. All patients had a complete ophthalmological examination and appropriate clinical and paraclinical examination. The diagnosis was established according to the recent international criteria. One hundred and twenty-one patients were included. The four main etiologies were: toxoplasmosis (14%), sarcoidosis (11.6%), spondylarthritis or HLA B27-associated uveitis (13.2%) and Herpes virus infections (9.1%) that represented almost half of the uveitis causes (47.9%). Various diseases constituted the remaining causes of the uveitis (20.9%). Uveitis remained unexplained in the remaining 36 patients (29.7%). Overall, associated systemic diseases were diagnosed in 35.5% of our uveitis patients (34 patients), associated infectious conditions in 26.4% (32 patients) and specific ocular diseases in 8.3% (12 patients). Despite a limited number of patients, our study showed an etiologic distribution similar to that of the main series reported in the literature. Nevertheless, we observed an elevated frequency of sarcoidosis and systemic diseases, which emphasizes a management that takes into account standardized clinical and paraclinical criteria and the usefulness of a collaboration with the internist.


Prostate Cancer Prevention: Concepts and Clinical Trials.
Prevention is an important treatment strategy for diminishing prostate cancer morbidity and mortality and is applicable to both early- and late-stage disease. There are three basic classifications of cancer prevention: primary (prevention of incident disease), secondary (identification and treatment of preclinical disease), and tertiary (prevention of progression or recurrence). Based on level I evidence, 5-alpha reductase inhibitors (5-ARIs) should be considered in selected men to prevent incident prostate cancer. Level I evidence also supports the consideration of dutasteride, a 5-ARI, for tertiary prevention in active surveillance and biochemical recurrence patients. Vitamins and supplements, including selenium or vitamin E, have not been proven in clinical trials to prevent prostate cancer and in the case of Vitamin E has been found to increase the risk of incident prostate cancer. Ongoing and future trials may further elucidate the role of diet and immunotherapy for prevention of prostate cancer.


Local selection in the presence of high levels of gene flow: Evidence of heterogeneous insecticide selection pressure across Ugandan Culex quinquefasciatus populations.
Culex quinquefasciatus collected in Uganda, where no vector control interventions directly targeting this species have been conducted, was used as a model to determine if it is possible to detect heterogeneities in selection pressure driven by insecticide application targeting other insect species. Population genetic structure was assessed through microsatellite analysis, and the impact of insecticide pressure by genotyping two target-site mutations, Vgsc-1014F of the voltage-gated sodium channel target of pyrethroid and DDT insecticides, and Ace1-119S of the acetylcholinesterase gene, target of carbamate and organophosphate insecticides. No significant differences in genetic diversity were observed among populations by microsatellite markers with HE ranging from 0.597 to 0.612 and low, but significant, genetic differentiation among populations (FST = 0.019, P = 0.001). By contrast, the insecticide-resistance markers display heterogeneous allelic distributions with significant differences detected between Central Ugandan (urban) populations relative to Eastern and Southwestern (rural) populations. In the central region, a frequency of 62% for Vgsc-1014F, and 32% for the Ace1-119S resistant allele were observed. Conversely, in both Eastern and Southwestern regions the Vgsc-1014F alleles were close to fixation, whilst Ace1-119S allele frequency was 12% (although frequencies may be underestimated due to copy number variation at both loci). Taken together, the microsatellite and both insecticide resistance target-site markers provide evidence that in the face of intense gene flow among populations, disjunction in resistance frequencies arise due to intense local selection pressures despite an absence of insecticidal control interventions targeting Culex.


Beilunmycin, a new virginiamycins antibiotic from mangrove-derived Streptomyces sp. 2BBP-J2 and the antibacterial activity by inhibiting protein translation.
One new virginiamycin derivative, 'beilunmycin' (1), and three known virginiamycin antibiotics, 16-hydroxy-virginiamycin M1 (2), virginiamycin M2 (3), and virginiamycin M1 (4), were isolated from the culture of a mangrove-derived endophytic Streptomyces sp. 2BBP-J2. The structures were characterized on the basis of their spectroscopic data, and the absolute configuration of 1 was established by ECD calculations. Compounds 1-4 exhibited antibacterial activities against Gram-positive bacteria, with MIC values in the range of 0.5-16 μg/ml. All the compounds demonstrated strong protein translation-stalling activity, with minimal concentrations detected with pDualrep2 in the range of 1.9-5.9 nmol.


Extracellular levels of amino acids and choline in human high grade gliomas: an intraoperative microdialysis study.
The concentrations of endogenous amino acids and choline in the extracellular fluid of human cerebral gliomas have been measured, for the first time, by in vivo microdialysis. Glioblastoma growth was associated with increased concentrations of choline, GABA, isoleucine, leucine, lysine, phenylalanine, taurine, tyrosine, and valine. There was no difference between grade III and grade IV tumors in the concentrations of phenylalanine, isoleucine, tyrosine, valine, and lysine, whereas the concentrations of choline, aspartate, taurine, GABA, leucine, and glutamate were significantly different in the two tumor-grade subgroups. In contrast to the other compounds, the concentration of glutamate was decreased in glioma. The parenchyma adjacent to the tumor showed significant changes only in the extracellular concentration of glutamate, isoleucine, and valine. The concentrations of choline and the amino acids, glutamate, leucine, taurine, and tyrosine showed significant positive correlations with the degree of cell proliferation. Epilepsy, which is relatively common in subjects with gliomas, was shown to be a significant confounding variable when the extracellular concentrations of aspartate, glutamate and GABA were considered.


[Bronchial asthma in children. Furthering compliance].
Success in treating and managing bronchial asthma in children and adolescents is known to rely on active cooperation on behalf of both the patients and their parents. Compliance in terms of pharmaceutical or behavioural intervention is often insufficient to prevent further aggravation and exacerbation. Specific measures for enhancing therapy compliance have been well received in the German Health Care System, and research results indicate their effectiveness in reducing health care utilization and in improving quality of life. Studies that would ascribe such effects to regular medication intake or reduced exposure to allergic elicitors, however, are still lacking.


Health Research in JFEI Over a Decade: 2009-2019.
This article is a review of thirty health-related articles published in the Journal of Family and Economic Issues from 2009 until 2019. This review discusses how the thirty studies have addressed broad areas of concern around health care access, health utilization and health status as well as health policy and implications and contributed to the advancement of knowledge in these areas. Articles mostly focused on health outcomes for families or demographic groups within families, with an emphasis on socio-economic inequalities and inequitable burdens faced. The emphasis over the last decade has been research on chronic or non-communicable health conditions and none on communicable diseases.


Purification of human hemoglobin valence intermediates by preparative immobilized pH gradients.
We compare three separation techniques for preparative purposes, i.e. ion-exchange chromatography on CM-cellulose, conventional isoelectric focusing in polyacrylamide gel slabs and immobilized pH gradients. The biological system used to test the three methods is a solution containing four hemoglobin (Hb) valence intermediates, i.e. metHb, oxyHb, (alpha + beta O2)2 and (alpha O2 beta +)2. The delta pI between the two valence intermediates is 0.04 pH units. Immobilized pH gradients give the best performance in terms of resolving power, total amount of protein which can be loaded and retention of biological activity by the protein (the latter assessed by determination of CO dissociation rates).


Rituximab treatment for relapsed opsoclonus-myoclonus syndrome.
Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder that is associated with paraneoplastic diseases. Because OMS can frequently relapse, patients may be inflicted with neurological problems for a long time. Recently, rituximab (RTX) was introduced as a drug to treat OMS. To assess RTX treatment, we studied a patient who experienced recurrence of OMS. A 2-year-old Japanese boy, who had left adrenal neuroblastoma, suddenly showed OMS symptoms, including ataxia and opsoclonus. Surgical resection of the tumor and subsequent steroid therapy ameliorated his symptoms. When OMS relapsed during the time when prednisolone was reduced, he was treated with full-dose RTX therapy (375 mg/m2/week) for 4 consecutive weeks. However, 1year later, he presented again with OMS symptoms. This time, we only administered an additional single dose of RTX treatment (375 mg/m2), allowing remission of OMS symptoms. During 2 years after the additional RTX treatment, OMS symptoms did not appear, even when prednisolone was reduced. He had no adverse events associated with RTX during the whole treatment period. An additional single-dose RTX therapy might be effective for relapsed OMS patients who were previously treated with full-dose RTX therapy.


Mushroom (Agaricus bisporus) polyphenoloxidase inhibited by apigenin: Multi-spectroscopic analyses and computational docking simulation.
It has been revealed that some polyphenols can prevent enzymatic browning caused by polyphenoloxidase (PPO). Apigenin, widely distributed in many fruits and vegetables, is an important bioactive flavonoid compound. In this study, apigenin exhibited a strong inhibitory activity against PPO, and some reagents had synergistic effect with apigenin on inhibiting PPO. Apigenin inhibited PPO activity reversibly in a mixed-type manner. The fact that inactivation rate constant (k) of PPO increased while activation energy (Ea) and thermodynamic parameters (ΔG, ΔH and ΔS) decreased indicated that the thermosensitivity and stability of PPO decreased. The conformational changes of PPO were revealed by fluorescence emission spectra and circular dichroism. Atomic force microscopy observation suggested that the dimension of PPO molecules was larger after interacting with apigenin. Moreover, computational docking simulation indicated that apigenin bound to PPO and inserted into the hydrophobic cavity of PPO to interact with some amino acid residues.


Infrequent loss of heterozygosity at adenomatous polyposis coli gene locus in Indian oral cancers.
We have investigated loss of heterozygosity (LOH) of the adenomatous polyposis coli (APC) tumor suppressor gene using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) in 86 untreated oral cancer patients, using matched oral cancer tissue and corresponding peripheral blood cell (PBC) DNA samples. PBC from 70 normal healthy individuals, were also analyzed for allelic distribution of APC gene. A 133 bp fragment, spanning exon 11 of the APC gene was amplified, and RsaI digestion of the PCR product defined the alleles as either homozygous 133 bp (Rsa(-/-)) or 87 and 46 bp (Rsa(+/+)) fragments, and heterozygous (Rsa(+/-)) exhibiting the three fragments. Distribution of the three alleles, Rsa(-/-), Rsa(+/+), and Rsa(+/-) in the oral cancer patients was observed as 10.5, 51.1 and 38.4%; whereas normal healthy individuals showed 11.4, 37.1 and 51.4%, respectively. In the informative heterozygous (Rsa(+/-)) oral cancer patients, LOH was infrequent, demonstrated in two of 33 (6%) samples. Thus, the APC gene was infrequently altered by LOH at the polymorphic RsaI locus in exon 11 in the tobacco associated Indian oral cancer, unlike the smoking tobacco/alcohol associated oral cancers from Western countries.


Placental oleic acid uptake is lower in male offspring of obese women.
The fetus is dependent on the placenta for its supply of long chain polyunsaturated fatty acids (LCPUFA), which are essential in fetal growth and development. Previous work suggests that high maternal body mass index (BMI) inhibits fetal LCPUFA delivery and males have greater fatty acid requirements than females during development. We hypothesized that male placental fatty acid uptake would be more sensitive to maternal BMI compared to females. Term placental samples were collected from healthy women receiving Cesarean section (n = 38). Placental fatty acid transporter and binding protein gene expression and uptake of oleic acid (OA), arachidonic acid, (AA) and docosahexanoic acid (DHA) were measured. Two-way ANOVA was used to assess the effects of fetal sex and maternal overweight/obesity (BMI >26 kg/m2). Placental fatty acid uptake of OA was 43% lower in male offspring and 73% higher in female offspring of obese compared to normal BMI women (P < 0.05). The interaction between fetal sex and maternal BMI had a significant effect on both OA (P = 0.002) and AA uptake (P = 0.01). DHA uptake was not affected by fetal sex or maternal obesity. Placental fatty acid transporter CD36 and binding protein FABP5 gene expression levels were lower in male offspring of obese mothers but were not affected by BMI among females. Maternal obesity and fetal sex significantly affect the placental uptake of oleate and arachidonate. Placental fatty acid uptake in both male and female fetuses is sensitive to maternal BMI, but males may have inadequate acquisition of the unsaturated fatty acid OA, when exposed to maternal obesity.


Development and validation of implantable sensors for monitoring function of prosthetic heart valves: in vitro studies.
The development of a 'smart' heart valve prosthesis, with the intrinsic ability to monitor thrombus formation, mechanical failure and local haemodynamics and to relay this information externally, would be of significant help to clinicians. The first step towards such a valve is development of the sensors and examination of whether sensor output provides predictive information on function. Custom-made piezo-electric sensors were mounted onto the housing of mechanical valves with various layers of simulated thrombus and bioprosthetic valves with normal and stiffened leaflets. Sensor output was examined using joint time-frequency analysis. Sensors were able to detect leaflet opening and closing with high fidelity for all types of valve. The frequency content of the closing sounds for the mechanical valves contained several peaks between 100 Hz and 10 kHz, whereas closing sounds for the bioprosthetic valve contained energy in a lower frequency range (<1 kHz). A frequency peak of 47 +/- 15 Hz was seen for the normal bioprosthetic valve; this peak increased to 115 +/- 12 Hz for the valve with visibly stiffened leaflets. Total low-frequency (80-3500 Hz) energy content diminished predictably with increasing levels of thrombus for the mechanical valves. Lastly, closing sound intensity correlated well with closing pressure dynamics (dp/dt) (y = 190x - 443; r = 0.90), indicating that the sensors also provide information on haemodynamics. These studies provide initial evidence regarding the use of embedded sensors to detect prosthetic valve function. Efforts to encapsulate these sensors with telemetry into a custom valve are currently underway.


Antithrombotic therapy in heart failure: a randomized comparison of warfarin vs. aspirin (HELAS).
It is uncertain whether anti-thrombotic treatment reduces the incidence of thrombo-embolism in patients with heart failure, so there is a need for a large scale controlled study to assess the effects of anti-thrombotic therapy in this setting. We report the design of a randomized controlled multicenter double blind trial examining the effects of aspirin, warfarin and placebo in patients with heart failure on the risk of thrombo-embolism. We planned to recruit 6000 patients with heart failure without contraindications to anticoagulants or antiplatelet agents and to follow them for a mean time of 2 years following randomization. The study was planned to determine the rate of thrombo-embolic and haemorrhagic events and death among patients randomized to aspirin, warfarin and placebo, stratified according to the presence or absence of underlying coronary disease. Ancillary studies parallel to the main study will attempt to identify clinical and echocardiographic risk factors for thrombo-embolism and will also examine whether hemostatic or neurohormonal mechanisms contribute to an increase in the risk of thrombo-embolism in patients with heart failure. We hoped that the results of the study would improve the clinical management and cost-effectiveness of treatment for patients with heart failure. However, the recruitment of patients proved more difficult than expected and a number of centers decided not to participate. To avoid a great delay it was decided by the principal investigators and submitted to the executive committee to terminate enrolment in this study when 300 patients had been enrolled, and accept that this is a pilot study.


Serum omega-3 fatty acids are associated with ultimatum bargaining behavior.
In the ultimatum game (UG), two players are involved to bargain over a division of a given sum of money. The proposer makes an ultimatum offer of a fraction of money, while the responder can either accept or reject the proposer's decision. In case of rejection of the proposed splitting by the responder, neither player gets anything. Adverse psychological reactions are deemed to play a role in the rejection of unfair offers. Low serum levels of omega-3 polyunsaturated fatty acids have been linked to impulse control and hostility. This study examined the serum omega-3 and omega-6 fractions in relation to the ultimatum bargaining behavior. Participants were sixty economy students (31 males and 29 females, mean age: 24.4+/-2.3 years) who played a euro 10 ultimatum game. Ultimatum offers were constrained to be euro 5 (proposer keeps euro 5) or euro 1 (proposer keeps euro 9) to generate a roughly even split between fair (5:5) and unfair (1:9) offers. Fasting serum alpha-linolenic (ALA), eicosapentaenoic (EPA), docosahexaenoic acid (DHA), linoleic acid (LA) and arachidonic acid (AA) were assayed with gas chromatography. In participants who rejected unfair offers there was a significant depletion of ALA, EPA and DHA. Moreover, the ratio of serum omega-3/omega-6 fatty acids was significantly lower in patients who rejected unfair offers as compared to those who did not. The results of this study suggest that a depletion of the serum omega-3 fatty acids is associated with rejections of unfair ultimatum offers in an experimental neuroeconomic setting.


[Expressions of chloride channel ClC-2 and ClC-3 in human nasal polyps].
To investigate the role of chloride channel ClC-2 and ClC-3 in human nasal polyps. Two chloride channels ClC-2 and ClC-3 were studied in 27 cases of nasal polyps with immunochemistric staining. Nasal polyps revealed strong positive staining of ClC-2 and ClC-3, the ClC-2 and ClC-3 proteins localized mainly in epithelial cells, sub-epithelial mucous glands without significant distinction. The number of positive cells of ClC-2 and ClC-3 are 17.6 +/- 6.33 and 23.49 +/- 6.14. The chloride channels ClC-2 and ClC-3 may play a role in the formation of nasal polyps.


Polyphenolic compounds: Synthesis, assessment of antimicrobial effect and enzymes inhibition against important medicinal enzymes with computational details.
Phenolic compounds mainly benefit human health and have many biological activities. Their activities are related to their structure, which allows them to interact with enzymes. The inhibition potencies of synthesized polyphenolic compounds (3a and 3b) were investigated on cholinesterases, α‑Gly, and tyrosinase activities. The structures of 3a and 3b were determined based on spectral data (NMR, UV-vis, XRD pattern, SEM, and EDX). The compounds have effective inhibitory potential with IC50 value between 2.25 ± 0.35-5.66 ± 0.75 µM and Ki values 2.95 ± 0.37-14.86 ± 4.99 µM for AChE, BChE, and tyrosinase. It was determined that the synthesized compounds have biological activities by the MIC and cytotoxicity tests, and they have IC50 values of 16.15 µg/mL and 12.16 µg/mL for the PC-3 cell line, respectively. According to the calculated molecular docking results, these compounds showed the highest binding energy against AChE and tyrosinase enzymes (-11.3 and -10.4 kcal/mol, respectively). The compounds have synthetic accessibility scores of 2.75 and 4.55 based on the drug-likeness properties.


A theory on the differentiation of bone-marrow stem cells.
Differentiation of pluripotent stem cells is viewed in parallel with maturation of lymphoid cells. Both processes share many features each occurring within a reticular framework with its component RE cells. RE cells are seen as providing control over stem cell differentiation in marrow thus minimizing stem cell competition by concentrating differentiation stimuli of a particular kind. The differentiation molecules are considered to be histocompatibility and tissue specific antigen components derived from aging or activated mature blood cells. They are probably low molecular weight glycoproteins. Evidence that histocompatibility antigens are of importance in cellular differentiation is presented. The hypothesis presupposes positive feedback mechanisms to bone-marrow with threshold responses being determined by RE cells.


Phenotypic, molecular characterization, antimicrobial susceptibility and draft genome sequence of Corynebacterium argentoratense strains isolated from clinical samples.
During a 12-year period we isolated five Corynebacterium argentoratense strains identified by phenotypic methods, including the use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) and 16S rRNA gene sequencing. In addition, antimicrobial susceptibility was determined, and genome sequencing for the detection of antibiotic resistance genes was performed. The organisms were isolated from blood and throat cultures and could be identified by all methods used. All strains were resistant to cotrimoxazole, and resistance to β-lactams was partly present. Two strains were resistant to erythromycin and clindamycin. The draft genome sequences of theses isolates revealed the presence of the erm(X) resistance gene that is embedded in the genetic structure of the transposable element Tn5423. Although rarely reported as a human pathogen, C. argentoratense can be involved in bacteraemia and probably in other infections. Our results also show that horizontal transfer of genes responsible for antibiotic resistance is occurring in this species.


Management of pyloric stricture in children: endoscopic balloon dilatation and surgery.
Surgical correction is the most preferred treatment modality in pyloric stricture (PS). Recently a few studies reported the experience of balloon dilation in children with PS. This study was designed to present our experiences of the management of the patients with PS with balloon dilation and corrective surgery. The records of 14 patients who were treated with the diagnosis of PS between August 2003 and August 2011 were reviewed retrospectively. There were nine boys and five girls (mean age, 3.4 ± 1.7 years). The history of caustic ingestion was detected in eight patients; six of them were admitted on the day of ingestion. Two patients were admitted with nonbilious vomiting more than 2 weeks after ingestion. Four patients did not have a remarkable medical history, including caustic ingestion. They admitted with the complaint of nonbilious vomiting. PS was detected during endoscopy in two patients who had a diagnosis of peptic ulcer disease. PS was shown by barium meal study in all patients. Endoscopy was performed in all patients. Endoscopic balloon dilation was tried in 12 patients. Overall eight patients required surgical procedures for PS. The complaints were resolved by endoscopic balloon dilation of pylorus in the remaining six patients. Although endoscopic balloon dilatation for benign PS in adults is a generally accepted method of treatment, there is less experience with endoscopic balloon dilatation for PS in children. PS due to benign disorders can be effectively and successfully treated through endoscopic balloon dilatation in suitable patients. In patients with successful pyloric balloon dilatation, surgery can be avoided.


The effect of growth media and physical treatments on the adhesion properties of canine probiotics.
The manufacturing processes have been reported to influence the properties of probiotics with potential impact on health properties. The aim was to investigate the effect of different growth media and inactivation methods on the properties of canine-originated probiotic bacteria alone and in combination mixture. Three established dog probiotics, Lactobacillus fermentum VET9A, Lactobacillus plantarum VET14A and Lactobacillus rhamnosus VET16A, and their combination mixture were evaluated for their adhesion to dog mucus. The effect of different growth media, one reflecting laboratory and the other manufacturing conditions, and inactivation methods (95°C, 80°C and UV irradiation) on the mucus adhesion of the probiotic strains was characterized. Evaluation of dog probiotics was supported by cell visualization using transmission electron microscopy (TEM). Higher adhesion percentage was reported for probiotic strains growing in laboratory rather than in manufacturing conditions (P < 0.05). Inactivation by heat (95°C, 80°C) decreased the adhesion properties when strains were cultivated in soy-based growth media compared with those grown in MRS broth (P < 0.05). TEM observations uncovered differences in cell-surface components in nonviable forms of probiotic strains as compared with their viable forms. Manufacturing process conditions such as growth media and pretreatment methods may significantly affect the adhesive ability of the tested strains. Growth conditions, growth media, pretreatment methods and different probiotic combinations should be carefully considered for quality control of existing probiotics and for identification of new probiotics for dogs. These may also have an impact on health benefits for the host.


Utilization and costs of injury-related acute care services among children and adolescents in a state Medicaid program.
Injuries are a leading cause of death, significant disability, and utilization of acute medical care. This study describes patterns of acute care services use related to injury and associated costs among children and adolescents in a state Medicaid population. A retrospective, cross-sectional, descriptive research design was used to analyze 2003 West Virginia Medicaid fee-for-service computerized claims for acute care medical services with a primary diagnosis of injury or complication due to injury for recipients below 21 years of age. Medical services utilization rates were calculated and stratified by demographic categories as well as by type of injury. Costs associated with the claims were from the perspective of Medicaid. There were 33,599 children who were hospitalized or visited the emergency department for injury or complication due to injury at a rate of 227.2 per 1,000. Children who were white, male, and 15-20 years of age had the highest rate of acute care use by demographic groups. Medicaid paid approximately $7.4 million for injury-related acute care visits. Acute care was mostly delivered in the emergency department, although hospitalizations contributed to one-third of the total costs. The average length of hospital stay for any type of injury or complication due to injury was 4 days. Overall, a diagnosis of traumatic complication was the most frequently occurring, followed by open wounds, contusions, sprains and strains, and fractures. E-codes were not readily recorded. The use of injury-related acute medical care varied by demographic variables and diagnosis. Findings from this study can be used as a baseline for further surveillance, and to guide the development of interventions to contain preventable injuries and associated treatment costs.


Drug Development for Hypertension: Do We Need Another Antihypertensive Agent for Resistant Hypertension?
The prevalence of resistant hypertension is seemingly much lower than had been reported in early studies. Recent analyses suggest that <5 % of treated hypertensive patients remain uncontrolled if fully adherent to an optimized antihypertensive treatment. However, these patients do have increased cardiovascular risk and need effective therapeutic approaches. Drug development is a high-risk, complex, lengthy, and very expensive process. In this article, we discuss the factors that should be considered in the process of developing a new agent for treatment of resistant hypertension.


NOR activity and repeat sequences of the paternal sex ratio chromosome of the parasitoid wasp Trichogramma kaykai.
Part of the male population of the wasp Trichogramma kaykai carries a B chromosome that manipulates its host sex ratio in favour of males. The only known repeat on this paternal sex ratio (PSR) chromosome is the 45S rDNA, which includes here five different internal transcribed spacer 2 (ITS2) sequences. In this report, we describe that only part of these ITS2 sequences is transcribed. The absence of transcription of some ITS2 sequences might explain the presence of multiple ITS2 sequences on the PSR chromosome since homogenization of rDNA spacers is thought to occur only in transcribed regions. Analysis of the only other known tandem repeat in Trichogramma, the EcoRI repeat, showed that it is absent from the PSR chromosome, and that the T. kaykai EcoRI repeat has 98 and 77% DNA sequence homology with the T. deion and T. brassicae EcoRI repeats, respectively. The size of the PSR chromosome measures 9 Mbp and is equal to 3.9% of the haploid T. kaykai genome. Finally, fluorescent in situ hybridization with a pool of high and moderate repetitive T. kaykai DNA (C0t-50) revealed only a very few major tandem repeats on the Trichogramma genome and only 45S rDNA on the PSR chromosome.


The neck injury criterion: future considerations.
The cost of whiplash injuries--both in dollars spent for medical care and disability, and in terms of human suffering--are quite high in westernized nations. This is of particular interest both from a public health perspective and a general societal one because the disorder is theoretically preventable: in the very least it can be minimized. This can be achieved with crash prevention strategies and improvements in vehicle safety design--especially with more effective seat back and head restraint systems. Toward the goal of developing a gold standard for safety research in this area, a neck injury criterion (NIC) was proposed by Boström et al. in 1996 (Boström O., Svennson, M.Y., Aldman, B. et al., 1996. In: Proceedings of the International Conference on the Biomechanics of Impact, Dublin, Ireland). This criterion considers the relative horizontal acceleration and velocity between the bottom (T1) and top (C1) of the cervical spine and has face validity based on current literature. However, the NIC has still not been subjected to rigorous scientific investigation or validation in terms of its representativeness of human occupant injury. Such investigation should specifically consider, first, whether the NIC provides an adequate proxy for all potential neck injuries due to whiplash and, secondly, whether the proposed threshold value of 15 m2/s2 is an appropriate level for the stated goal. Based on a review of recent literature, recent human volunteer crash tests by Wheeler et al. and the those of the Spine Research Institute of San Diego, and based on mathematical MADYMO analysis of the first real world crash pulse data, it appears that the threshold for acute injury in the general population is likely to require a lowering of the originally proposed NIC value, and additional parameters, such as considering a forward rebound phase or neck extension criteria may be necessary. The conclusions of this paper should be considered preliminary because the numbers of crash test subjects and real world injury victims does not allow for rigorous statistical analysis. Certainly, ongoing work will be necessary to investigate this further and larger scale analysis of more onboard crash data will prove invaluable.


Identifying drinking problems in V.A. hospital patients.
Of 147 patients studied, clinicians identified 28 as problem drinkers; the patients' responses to interview items indicated as normal drinkers or abstainers, 9 indicated by interview responses that they were problem drinkers.


Relationship between anaemia management at haemodialysis initiation and patient prognosis.
It has been suggested that anaemia management during a transition period to haemodialysis could influence prognosis. In this paper, we have conducted a retrospective investigation on how Hb levels at haemodialysis initiation in patients with chronic kidney disease (CKD) influence the risk of cerebral infarction and cardiovascular events. Seventy-two patients who underwent initial haemodialysis between May 2012 and April 2014 were designated as subjects of the study and the patients were divided into a cohort with Hb levels ≥8 g/dL and a cohort with <8 g/dL at haemodialysis initiation. The occurrence of cardiovascular events was analyzed using the Kaplan-Meier method and Cox proportional hazards model. The cohort with <8 g/dL Hb levels at haemodialysis initiation demonstrated a tendency toward low dosage of ESA or iron preparation in the pre-haemodialysis (maintenance) phase. Significant incidence of cardiovascular (log rank, P = 0.002) and cerebrovascular (log rank, P = 0.02) events was observed. The results of multivariate analysis of the Cox proportional hazards model indicated that anaemia with <8 g/dL Hb levels at haemodialysis initiation was a significant risk factor for coronary artery (hazard ratio = 12.85, P = 0.003) and cerebrovascular (hazard ratio = 5.11, P = 0.04) diseases post-haemodialysis. The results of this investigation indicate the possible involvement of low Hb levels at haemodialysis initiation as a factor in cardio- and cerebrovascular events. There, our results suggested that the administration of adequate dosage of iron preparations and ESA in the pre-haemodialysis period could help prevent cardio- and cerebrovascular events.


Pharmacogenetic study of anxiolytic effects of new cholecystokinin receptor antagonists in animals with different levels of emotionality.
Effects of two new peptide antagonists of central cholecystokinin receptors, GB-101 (0.05-0.40 mg/kg) and GB-115 (0.006-0.100 mg/kg), on the behavior of inbred animals differing by the reactions to emotional stress were studied in standard tests for evaluation of tranquilizers. The test drugs dose-dependently increased the total locomotor activity in the open field test in Balb/c mice and had no effect on the behavior of C57Bl/6 mice. GB-101 (0.4 mg/kg) and GB-115 (0.025 and 0.05 mg/kg) produced an anxiolytic effect on MR rats (but not on MNRA rats) in the elevated plus-maze and conflict tests. These data confirm anxioselective effects of the test compounds.


Schizophrenia: an update and review.
Schizophrenia is a common complex disorder characterized by psychosis, cognitive dysfunction and negative symptoms, whose etiology involves interactions between both genetic and environmental vulnerability factors. Recently, ongoing research attempting to elucidate the nature of these vulnerability factors has been generating exciting findings. The advances in understanding of environmental risk factors for mental illnesses and in genetic research into mental illnesses will be reviewed. Limitations of the findings and implications of these advances for genetic counseling practice will also be discussed.


Insights into the multi-scale structure and in vitro digestibility changes of rice starch-oleic acid/linoleic acid complex induced by heat-moisture treatment.
The study presents an innovative approach using heat-moisture treatment (HMT) to prepare rice starch-oleic acid (OA)/linoleic acid (LOA) complex. Relationship of the multi-scale structure-in vitro digestibility of rice starch-OA/LOA complex induced by HMT was established in this work. Herein, HMT induced the formation of single helices complex between OA/LOA and amylose or long side chains of amylopectin, which formed more V-type crystallite. HMT assisted complexation with OA/LOA resulted in higher ordered molecular chain aggregations in amorphous amylose background area, reduced the amorphous lamellae and made the double helices and A-type crystallite perfectly arranged. These structural alternations inhibited the molecular interactions (e.g., binding ability, catalyzed location) between rice starch and α-amylase, which eventually increased the resistant starch (RS) content and decreased the slow digestible starch (SDS) content. Moreover, HMT treated rice starch formed type II complex with OA and type I complex with LOA, and all the referred changes went more obvious with the increasing amount of OA than LOA. The results suggested that the OA/LOA was inserted inside the amylose spiral cavity and the amorphous lamellae of rice starch. The current study exhibited an in-depth research of the multi-scale structure within rice starch-OA/LOA complex and proposes a promising approach to ensure the starch products have designated digestibility.


Investigating spike backpropagation induced Ca2+ influx in models of hippocampal and cortical pyramidal neurons.
We modeled the influx of calcium ions into dendrites following active backpropagation of spike trains in a dendritic tree, using compartmental models of anatomically reconstructed pyramidal cells in a GENESIS program. Basic facts of ion channel densities in pyramidal cells were taken into account. The time scale of the backpropagating spike train development was longer than in previous models. We also studied the relationship between intracellular calcium dynamics and membrane voltage. Comparisons were made between two pyramidal cell prototypes and in simplified model. Our results show that: (1) sodium and potassium channels are enough to explain regenerative backpropagating spike trains; (2) intracellular calcium concentration changes are consistent in the range of milliseconds to seconds; (3) the simulations support several experimental observations in both hippocampal and neocortical cells. No additional parameter search optimization was necessary. Compartmental models can be used for investigating the biology of neurons, and then simplified for constructing neural networks.


[The role of ventilatory disturbances in the late postoperative hypoxaemia after upper abdominal surgery. A contribution to the risk of upper abdominal surgery in patients with respiratory damage (author's transl)].
The purpose of our investigations was to evaluate the influence of disturbed inspiratory gas distribution on postoperative hypoxemia in patients with abnormal lung function undergoing upper abdominal surgery. The lung function analyzer Hewlett-Packard 47402 A was used (Volume-time and flow-volume curves of forced expiration, single and multiple breath nitrogen washout tests with indices of ventilatory gas distribution). It was demonstrated that postoperative hypoxaemia in the undamaged lung is almost exclusively the result of augmented true right to left shunt. In patients with abnormal lung function the cause of postoperative hypoxaemia is, for the most part, an increase of disturbances of ventilatory gas distribution. These changes in the postoperative period can be explained by a reduction of FRC, that follows from changing of position (sitting-lying) and from pain. In patients with borderline lung function this reduction of FRC postoperatively may limit surgical treatment. The management of pain is of great importance in these patients. Continuous epidural anaesthesia certainly produces the best results in this respect.


Corrigendum: Service evaluation of the impact of capnography on the safety of procedural sedation.
[This corrects the article DOI: 10.3389/fmed.2022.867536.].


Normal pediatric values of carotid artery intima-media thickness measured by B-mode ultrasound and radiofrequency echo tracking respecting the consensus: a systematic review.
Carotid artery intima-media thickness (IMT) is a sub-clinical radiologic marker of atherosclerosis in children. It is associated with adult-onset vascular disease. To determine normal pediatric values of IMT from results observed in the literature. Our systematic review was conducted according to PRISMA guidelines. We reviewed 2298 English articles from inception to February 2023. Inclusion criteria included studies evaluating B-mode and radiofrequency (RF)-based IMT measurements based on the American Heart Association, the Association for European Pediatric Cardiology, the Mannheim Consensus, and the American Society of Echocardiography recommendations. A meta-analysis of aggregate data was conducted to obtain the confidence interval (CI) for IMT, using a 95% confidence level. We obtained 88 B-mode-based IMT measurement studies with 6184 children and six radiofrequency echo-tracking-based studies with 766 children. Mean IMT in the pediatric population was 0.43 mm, 95% [CI] 0,42 to 0.44, using the B-mode technique, and 0.41 mm, 95% [CI] 0.36 to 0.45 using the radiofrequency technique. No significant relationship was detected between IMT and age (p value = 0.83). Finally, no significant effect of sex on IMT was found (p value = 0.82 for B-mode and p value = 0.62 for RF). Based on the studies selected in this literature review, we were unable to conclude that there was a significant difference between the average IMT of boys and girls. No relationship was demonstrated between age and IMT. IMT is technique-specific, and normal values should be interpreted according to recommendations of recognized consensus to counteract the current heterogeneity in literature. Technique and children-specific Intima media thickness measurements help clinicians and scientists to assess the risk of atherosclerosis in children. • Intima-media thickness (IMT) does not correlate with age in children without risk factors. • According to current literature, there is no difference in IMT between healthy boys and girls. • There is heterogeneity, even with studies abiding by the official consensus.


Content Analysis of US FDA Warning Letters Issued to Compounding Pharmacies Regarding Violations of Current Good Manufacturing Practices Between 2017 and 2022.
Assessment of the US FDA-issued WLs content is an educational tool that can be used in the continuous training program of community pharmacists in compounding pharmacies. The study was designed to critically assess FDA warning letters (WLs) issued to compounding pharmacies in 2017-2022 for violations of Current Good Manufacturing Practices (cGMP). Content analysis was used to evaluate WLs issued concerning (1) type of violations; (2) frequency of violations mentioned in the WLs; (3) specific evaluations of the deviations related to compounded sterile products, and (4) evaluation of corrective measures requested by the US FDA. A total of 141 WLs were evaluated. The main observed violations in the analyzed WLs were adulterated drug products (130), misbranded drugs (103), unapproved new drug products (42), failure to report adverse events (22), and failure to report drugs (11). Other violations were evaluated related to sterile product compounding with emphasis on personnel qualifications, quality control procedures, equipment, etc. The continuous issuance of WLs by the FDA indicates the need for compounding pharmacies become more vigilant to reduce the recurrence of the addressed violations through establishing adequate training/retraining programs. The analysis of issued WLs can serve as a learning tool to help improve compounding procedures, reduce the recurrence of these violations, and enhance patient safeguards. The online version contains supplementary material available at 10.1007/s12247-022-09692-4.


Nervous system Lyme disease.
Lyme disease affects the nervous system in about 10% to 15% of infected individuals, most commonly causing lymphocytic meningitis. Cranial neuropathies, particularly facial nerve palsy, also occur frequently. Figuring prominently in the European literature, but less emphasized in the United States, is painful radiculitis, radicular pain involving a limb or trunk dermatome. Treatment of neuroborreliosis is usually straightforward; oral antibiotics may suffice in many patients. In severe cases, 2 to 4 weeks of parenteral therapy is necessary. All available evidence indicates that treatment of more than 4 weeks' duration carries substantial risk but minimal if any additional benefit.


Structural modeling, energetic analysis and molecular design of a π-stacking system at the complex interface of pediatric respiratory syncytial virus nucleocapsid with the C-terminal peptide of phosphoprotein.
Human respiratory syncytial virus (RSV) is a primary cause of lower respiratory tract infections and hospital visits during infancy and childhood. The RSV phosphoprotein (P) is a major polymerase cofactor that interacts with nucleoprotein (N) to promote the recognition of ribonucleoprotein complex (RNP) by viral RNA polymerase. The binding pocket of N protein is chemically diverse, in or around which a number of aromatic and charged amino acid residues are observed. Previously, a nonapeptide segment (P peptide, 233DNDLSLEDF241) representing the C-terminal tail of P protein was identified to mediate the N-P interaction with a moderate affinity, in which the Phe241 at the end of P's C-terminus plays a critical role in the binding of P peptide to N protein. Here, we found that the side-chain aromatic phenyl moiety of P Phe241 residue can form short- and long-range cation-π interactions with N Arg132 and Arg150 residues, respectively, as well as T-shaped and parallel-displaced π-π stackings with N Tyr135 and His151 residues, respectively, which co-define a geometrically satisfactory π-stacking system at the complex interface of N protein with P peptide, thus largely stabilizing the complex architecture. The stacking effect was further optimized by systematically mutating the P Phe241 residue to other natural and non-natural aromatic amino acids with diverse chemical substitutions at the phenyl moiety to examine their structural and energetic effects on π-stacking system and on protein-peptide binding. The electron-donating mutations at the phenyl moiety of P Phe241 residue can effectively enhance the π-stacking system and then promote peptide binding, whereas the bulky and positively charged mutations would considerably impair the peptide potency by introducing steric hindrance and electrostatic repulsion. The [Tyr]P, [Thp]P and [Fph]P mutants were determined to have an increased affinity relative to wild-type P peptide, which could be used as self-inhibitory peptides to competitively disrupt the native interaction between N and P proteins.


Urbanicity and depression: A global meta-analysis.
Previous meta-analyses have revealed that in adult and older adult populations of developed countries, depression is more prevalent in urban than rural areas. No meta-analyses have identified the effects of urbanicity on the general age demographic for developing countries. We conducted a meta-analysis of urban-rural differences in depression across all age demographics for developed and developing countries. PubMed and PsycINFO databases were searched for studies published between 1980 and 2020. Studies were included if they reported prevalences of urban and rural depression, or odds ratios comparing urban-rural depression prevalence. Studies were excluded for: nonrepresentative samples, non-standard measures of depression, and reporting continuous outcomes only. Meta-analytic models of urban-rural differences in the odds of depression were conducted across country development levels and age demographics. From 1597 records screened and 302 full texts assessed for eligibility, 80 studies (N = 539,557) were included for meta-analysis. Urban residence was significantly associated with a higher prevalence of depression in developed countries (OR = 1.30, 95 % CI [1.17, 1.46], z = 4.75, p < .001), which was primarily driven by urban-rural differences in the general population age demographic (OR = 1.37, 95 % CI [1.22, 1.54], z = 5.38, p < .001). Studies reporting urban-rural differences in depression in terms of continuous symptom severity scores were not included. Urbanicity appears to uniquely be associated with a higher prevalence of depression in developed countries, but not in developing countries.


Hypersplenism in Hodgkin's disease: a report of three cases presenting with cytopenias.
A review of the last seventy-eight consecutive cases of Hodgkin's disease seen at our hospital revealed that two presented several hematologic cytopenias. These two cases and a similar case first seen at an associated hospital revealed pancytopenia in two and leukopenia in the third. All responded to splenectomy with hematologic improvement. All met the criteria for hypersplenism. This report illustrates that Hodgkin's disease can present cytopenias due to hypersplenism, and that early splenectomy can lead to hematologic improvement and tolerance of subsequent chemotherapy.


Central obesity and risk of cardiovascular disease in the Asia Pacific Region.
This paper compares body mass index, waist circumference, hip circumference, and waist-hip ratio as risk factors for ischaemic heart disease and stroke in Asia Pacific populations. We undertook a pooled analysis involving six cohort studies (45 988 participants) and used Cox proportional hazards regression to assess the associations of the four anthropometric indices with stroke and ischaemic heart disease by age, sex and region. During a mean follow-up of six years, 346 stroke and 601 ischaemic heart disease events (fatal and non-fatal) were documented. Overall, a one-standard deviation increase in index was associated with an increase in risk of ischaemic heart disease of 17% (95% CI 7-27%) for body mass index, 27% (95% CI 14-40%) for waist circumference, 10% (95% CI 1-20%) for hip circumference, and 36% (95% CI 21-52%) for waist-hip ratio. There were no significant differences between age groups, sex, and region. None of the four anthropometric indices had a strong association with risk of stroke. These data indicate that measures of central obesity such as waist circumference and waist-hip ratio are strongly associated with risk of ischaemic heart disease in this region. Therefore, we suggest that, along with calculation of body mass index, measures of central obesity such as waist circumference and waist-hip ratio should be undertaken routinely.


Comparison of intraocular pressure measurements between Easyton transpalpebral tonometry and Perkins, iCare iC100 and Corvis ST, and the influence of corneal and anterior scleral thickness.
To compare intraocular pressure (IOP) measurements between Easyton transpalpebral tonometry and Perkins, iCare iC100 and Corvis ST. Also, to assess the influence of corneal characteristics and anterior scleral thickness (AST) on the IOP measurements. Sixty-nine eyes from 69 healthy subjects were included. IOP was measured by Easyton, Perkins, iC100 and Corvis ST (corrected IOP, bIOP; and non-corrected IOP, IOPnct). Other variables studied were AST, axial length (AL), and Corvis parameters: Length 1, velocity 1, length 2, velocity 2, peak distance, radius, deformation amplitude, and central corneal thickness (CCT). Pearson correlation, limits of agreement (LoA), and multiple regression analysis were calculated. No significant differences in IOP between Easyton and Perkins, iC100, and bIOP were observed (all p > 0.05), being significant only between Perkins and IOPnct ( - 1.49 mmHg, p < 0.001). Bland-Altman graphs showed that the mean difference between Perkins and Easyton was 0.07 mmHg (p < 0.001), and LoA - 7.49 to + 7.39 mmHg. Significant correlations were found between the measurements of Perkins and iC100, IOPnct, bIOP (r = 0.710, 0.628, 0.539; p < 0.001 respectively), iC100 and IOPnct, bIOP (r = 0.627, 0.513; p < 0.001, respectively). The multivariate regression analysis revealed that differences between Perkins and Easyton (adjusted R2 = 0.25) were influenced by AL (B = 1.28, p < 0.008), length 1 (B = 3.13, p < 0.018), and the radius (B = 1.26, p < 0.010). Differences between Perkins and bIOP (adjusted R2 = 0.21) were affected by the CCT (B = 0.029, p < 0.003). There are no significant differences in the IOP measurements between Perkins and Easyton, iC100 or bIOP. Length 1, radius, and CCT have limited influence on these differences, while AST did not show any effect.


Hot exciplexes in U-shaped TADF molecules with emission from locally excited states.
Fast emission and high color purity are essential characteristics of modern opto-electronic devices, such as organic light emitting diodes (OLEDs). These properties are currently not met by the latest generation of thermally activated delayed fluorescence (TADF) emitters. Here, we present an approach, called "hot exciplexes" that enables access to both attributes at the same time. Hot exciplexes are produced by coupling facing donor and acceptor moieties to an anthracene bridge, yielding an exciplex with large T1 to T2 spacing. The hot exciplex model is investigated using optical spectroscopy and quantum chemical simulations. Reverse intersystem crossing is found to occur preferentially from the T3 to the S1 state within only a few nanoseconds. Application and practicality of the model are shown by fabrication of organic light-emitting diodes with up to 32 % hot exciplex contribution and low efficiency roll-off.


Assessing the effects of the dating violence prevention program "safe dates" using random coefficient regression modeling.
The Safe Dates Project is a randomized trial for evaluating a school-based adolescent dating violence prevention program. Five waves of data were used to examine the effects of Safe Dates over time including primary and secondary prevention effects, moderators, and mediators of program effects. Using random coefficients models, with multiple imputation of missing data, significant program effects were found at all four follow-up periods on psychological, moderate physical, and sexual dating violence perpetration and moderate physical dating violence victimization. Marginal effects were found on sexual victimization. Effects on severe physical perpetration at all four follow-up periods were moderated by prior involvement in that type of violence. Primary and secondary prevention effects were found and the program was equally effective for males and females and for whites and non-whites. Program effects were mediated by changes in dating violence norms, gender-role norms, and awareness of community services.


A discoordinate increase in the cellular amount of 3-hydroxy-3-methylglutaryl-CoA reductase results in the loss of rate-limiting control over cholesterogenesis in a tumour cell-free system.
Cholesterol biosynthesis was characterized in cell-free post-mitochondrial supernatant systems prepared from both normal rat liver and Morris hepatoma 3924A. The rate of cholesterol synthesis per cell was 9-fold greater in the tumour system than in that from normal liver, and the tumour systems showed the loss of rate-limiting control at the hydroxymethylglutaryl-CoA reductase (HMGR)-catalysed step. The apparent absence of rate-limiting control over cell-free tumour cholesterogenesis was traced primarily to a discoordinate and dramatic increase in the amount of HMGR in the tumour relative to the liver system. Preliminary evidence for an altered control of the post-lanosterol portion of the pathway was also obtained with the tumour system.


Clinicopathological and Radiological Study of Thyroid Swelling.
Thyroid swelling is the most common swelling among the endocrine disorder. It can affect any age group. USG neck will help to diagnose the solid and cystic lesions. The treatment is surgical excision. FNAC is a good diagnostic tool to minimize the incidence of thyroidectomy. FNAC is cost effective, reliable and OPD procedure. Final diagnosis can only be made by HPE postoperatively. The aim of this study is to find out the relative occurrence of various pathological conditions presenting as midline thyroid swellings and clinicopathological and radiological examination of the thyroid swellings. A one and half year prospective study which was carried out from October 2016 to April 2018 in ENT department of MMIMSR, Mullana, Ambala. Informed written consent was taken from all the patients. A complete clinical, radiological, cytological an HP Examination was done. Total 50 patients were included in the study. Complete clinical data of the patient was gathered from medical records. The maximum number of patients in present study was found in an age group of 31-40 years (34%). There was female predominance with female to male ratio of 7.3:1. Most of the patients belonged to rural background i.e. 42 (84%) patients. Most of the patients present with Left sided neck swelling i.e. 18 (36%) patients. Ultrasound revealed that non neoplastic lesions were present in 44 (88%) patients and 6 (12%) patients had neoplastic lesions. FNAC showed that non neoplastic lesions were present in 38 (76%) patients and 12 (24%) patients had neoplastic lesions. On HPE, non neoplastic and neoplastic lesions were present in 36 (72%) and 14 (28%) patients respectively. Colloid goiter was the most common among the non neoplastic lesions in 29 (58%) patients. Papillary carcinoma was the most common malignant disease in 4 (8%) patients. Thyroid swelling was most commonly seen during the 3rd and 4th decade of life, with a female preponderance. Most common benign thyroid swelling is Colloid goiter and papillary carcinoma was the most common malignant disease. Histopathology is considered as a gold standard.


Differential sensitivity of paclitaxel-induced apoptosis in human esophageal squamous cell carcinoma cell lines.
Paclitaxel is a highly effective chemotherapy agent against adenocarcinomas and squamous cell carcinomas of the esophagus. However, its precise effects in human esophageal cancer cells are not well understood. This study was designed to examine the relationship between cell-cycle phases of paclitaxel-activated checkpoints and to elucidate the molecular pathway of the effect of paclitaxel in human esophageal squamous cell carcinoma (ESCC) cell lines. The three human ESCC cell lines--TE-2, TE-13 and TE-14--were examined for their response to paclitaxel. ESCC cells were treated with various concentrations of paclitaxel for 1-3 days using MTT assay. The cell-cycle progression and apoptosis were examined by flow cytometry. DNA fragmentation assay was carried out to confirm the fragmented cells as hallmark for apoptotic cells. In additional, the expression of apoptosis-related proteins in ESCC-treated cells was then examined by Western blot analysis. TE-14 cells demonstrated the highest sensitivity among all cells. G2/M cell-cycle arrest occurs prior to paclitaxel-induced apoptosis in ESCC cells. The fragmentation of chromatin was observed in drug treated TE-13 and TE-14 cells by flow cytometry and DNA ladder formation. In contrast, the measurement for TE-2 cells was more suggestive of phenotype a resistant in response to paclitaxel treatment. Western blot analysis results showed that the mitochondrial pathway might be involved in paclitaxel-induced apoptosis in ESCC cell lines. Differential sensitivity was observed in human ESCC cell lines in response to paclitaxel treatment. G2/M arrest occurs with a prior to paclitaxel-induced apoptosis and might be mediated by the mitochondrial (intrinsic) apoptosis pathway in human ESCC cells.


Clinical heterogeneity of PLA2G6-related Parkinsonism: analysis of two Saudi families.
Recessive mutations in PLA2G6 have been associated with different neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation and more recently, early-onset dystonia parkinsonism. Targeted-next generation sequencing using a custom Neurology panel, containing 758 OMIM-listed genes implicated in neurological disorders, was carried out in two index cases from two different Saudi families displaying early-onset levodopa-responsive Parkinsonism with pyramidal signs and additional clinical features. The detected mutations were verified in the index cases and available family members by direct sequencing. We identified a previously described PLA2G6 homozygous p.R741Q mutation in three affected and two asymptomatic individuals from two Saudi families. Our finding reinforces the notion of the broadness of the clinical spectrum of PLA2G6-related neurodegeneration.


Time course of the regression of asymptomatic bacterial vaginosis in pregnancy with and without treatment.
The purpose of this study was to determine the effectiveness of treatment over time for bacterial vaginosis in pregnancy and the probability of spontaneous resolution with placebo. Women with asymptomatic bacterial vaginosis on Gram stain were assigned randomly at 16 to 23 weeks of gestation to receive two 2-g doses of metronidazole or placebo 48 hours apart and were re-evaluated for changes in Gram stain score on one occasion > or =2 weeks later. Of 658 women who underwent metronidazole therapy, treatment was successful (score, <7) in 78% of those women who were seen at 2 to 3.9 weeks of gestation, which was similar to women seen > or =10 weeks after treatment. In 683 women who underwent placebo therapy, spontaneous resolution increased significantly from 13% at 2 to 3.9 weeks of gestation to 36% at > or =10 weeks of gestation. Spontaneous resolution was more common with lower vaginal pH or lactobacilli on Gram stain at the time of random assignment. The effectiveness of metronidazole therapy of bacterial vaginosis persists for > or =10 weeks. Women who underwent placebo therapy had significant remission of bacterial vaginosis over > or =10 weeks. Remission was more common when the initial vaginal microbiologic disturbances were less severe.


Genetic variations in CYP17A1, CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China.
Two large-scale genome-wide association studies (GWAs) have identified multiple variants associated with blood pressure (BP) or hypertension. The present study was to investigate whether some variations were associated with BP traits and hypertension or even prehypertension in adult She ethnic minority of China. The population of the present study comprised 4460 (1979 males and 2481 females, respectively) unrelated she ethnic minority based on a cross-sectional study from Ningde City in Fujian province of China. There were 1692 hypertensives, 1600 prehypertensives and 1168 normotensive controls, respectively. We genotyped 7 variants in CYP17A1, PLEKHA7, CACNB2, ATP2B1, TBX3-TBX5, CSK-ULK3 and SH2B3 reported by the previous GWAs on Europeans. All analyses were performed in an additive genetic model. As the minor allele of rs653178 in/near SH2B3 was very rare with the frequency of 0.018, we excluded this single nucleotide polymorphism (SNP) in the further analyses. Of the other 6 loci, linear regression analyses revealed that rs11191548 in CYP17A1 and rs11014166 in CACNB2 were significantly associated with systolic BP (β = -1.17, P = 0.002 and β = -0.50, P = 0.006, respectively), while only SNP rs11191548 was significantly associated with diastolic BP (β = -0.56, P=0.002) after adjusted by age, sex and BMI. Two variants in CACNB2 and PLEKHA7 were found to be significantly related to hypertension (odds ratios [OR] and (95% confidence interval [CI]): 0.79 (0.65-0.97) and 1.19 (1.01-1.41), respectively) in logistic regression analyses after adjusted by age, sex and BMI. In addition, we found that combined risk alleles of the 6 SNPs increased risk of hypertension in a stepwise fashion (P for trend < 0.001). However, none of the 6 SNPs was significantly associated with BMI or prehypertension status. While logistic analysis showed that subjects with cumulative risk alleles more than 9 had significantly higher risk for prehypertension (adjusted OR: 3.10, P < 0.001) compared with those with risk alleles less than 4. We replicated that variations in CYP17A1, CACNB2 and PLEKHA7 were related to BP traits and/or hypertension in She population. In addition, although we failed to observe single gene associated with prehypertension, we first found that conjoint effect of multiple risk alleles on BP might increase the risk of progressing to prehypertension.


Morphological and biochemical signs of age-related neurodegenerative changes in klotho mutant mice.
Klotho mutant mice, defective in the klotho gene, develop multiple age-related disorders with very short lifespans. Introduction of the exogenous klotho gene into these mutant mice leads to an improvement in their phenotypes, while overexpression of this gene in wild-type mice significantly extends their lifespan. These observations suggest that the klotho gene/protein has an anti-aging function. Since there have been only a few reports with some disagreement about results on the CNS of the mutant mice, we tried to clarify whether the CNS neurons generate aging-like features, even in premature stages, using biochemical and morphological approaches. Results obtained from the mutant mice, when compared with wild-type mice, were as follows. Neurofilaments (NFs) were increased significantly in axons, with the subunit proteins showing a significant enhancement in phosphorylation or expression of NF-H or NF-L, respectively. Microtubules in Purkinje cell dendrites were closer to each other, and in the CNS tissue tubulin was unaltered, but microtubule-associated protein (MAP) 2 was significantly reduced in expression. Neuronal cellular organelles were morphologically disordered. Lysosomes, cathepsin D and light chain 3 of MAP1A/B (LC3) were augmented with the appearance of putative autophagy-related structures. Antiapoptotic Bcl-xL and proapoptotic Bax were reduced and enhanced, respectively, and mitogen-activated protein kinase was reduced. Synapse-related proteins and structures were decreased. Neuronal degeneration was evident in hippocampal pyramidal cells, and possibly in Purkinje cells. Astrocytic glial filaments and glial fibrillary acidic protein were increased in density and expression, respectively. Together, the CNS neuronal alterations in klotho mutant mice were quite similar to those found in aged animals, including even premature death, so this mouse should be a more appropriate animal model for CNS aging than those previously reported.


Xen45 gel stent ab interno trimming for ostium occlusion: case report.
Despite the XEN gel stent low-risk profile, various complications following the implant have been described, including internal and external occlusion, with a consequent postoperative rise in intraocular pressure (IOP). In this case report we aimed to present a XEN45 stent internal occlusion successfully treated by trimming in situ its proximal end with a 25 G vitreous scissors using a bimanual technique. A 63-year-old male patient affected by primary open angle glaucoma (IOP = 25 mmHg) and a full thickness macular hole in his right eye, underwent ab-interno Xen gel stent implantation and, 1 month later, a 25 G vitrectomy surgery. Despite a significant IOP reduction after stent implant, 6 days after vitrectomy, IOP increased (25 mmHg) and the conjunctival bleb flattened following occlusion of stent internal ostium by a clot of presumed fibrinous material. The Nd:YAG laser failed to remove the clot, so that we decided to snip a small bit of the proximal end of the Xen tube (about 0,5 mm length) with a 25 G vitreous scissors, using a bimanual technique. In the postoperative day 1 and month 1, the IOP was 8 mmHg and 12 mmHg, respectively. The Anterior Segment OCT confirmed a functional, layered, filtering bleb, and the normal appearance and patency of the XEN proximal segment. No side effects from the intervention were observed. Ab interno trimming with vitreous scissors of the occluded proximal end of the XEN stent may represent a safe, rapid and efficient method to restore aqueous humor subconjunctival drainage.


Self-replicating RNA nanoparticle vaccine elicits protective immune responses against SARS-CoV-2.
The creation of safe and effective vaccines that induce potent cellular and humoral immune responses against SARS-CoV-2 is urgently needed to end the global COVID-19 epidemic. Here, we developed an alphavirus-derived self-replicating RNA (repRNA)-based vaccine platform encoding the receptor-binding domain (RBD) of SARS-CoV-2 spike glycoprotein. The repRNA triggers prolonged antigen expression compared with conventional mRNA due to the replication machinery of repRNA. To improve the delivery and vaccine efficacy of repRNA, we developed a self-assembling liposome-protamine-RNA (LPR) nanoparticle with highly efficient encapsulation and transfection of repRNA. LPR-repRNA vaccines substantially activated type I interferon response and innate immune signaling pathways. Subcutaneous immunization of LPR-repRNA-RBD led to prolonged antigen expression, stimulation of innate immune cells, and induction of germinal center response in draining lymph nodes. LPR-repRNA-RBD induced antigen-specific T cell responses and skewed cellular immunity toward an effector memory CD8+ T cell response. Immunizations with LPR-repRNA-RBD triggered the production of anti-RBD IgG antibodies and induced neutralizing antibody response against SARS-CoV-2 pseudovirus. LPR-repRNA-RBD vaccines reduced SARS-CoV-2 infection and lung inflammation in mice. Altogether, these data suggest that the LPR-repRNA platform can be a promising avenue for COVID-19 vaccine development.


Apparent diffusion coefficient (ADC) measurements may be more reliable and reproducible than lesion volume on diffusion-weighted images from patients with acute ischaemic stroke-implications for study design.
Early ischemic change after stroke can be demonstrated with diffusion-weighted imaging (DWI) and quantified by measuring the apparent diffusion coefficient (ADC) and/or lesion volume. We examined the reliability and reproducibility of lesion volume and ADC measurement on DWI images, and discuss the implications for clinical studies. Using 38 DWI scans from 15 stroke patients, two observers (a physicist and a neuroscience graduate) blind to each other, recorded the lesion volume on DWI sequences, measured the ADC values in this volume and calculated the ratio of ischemic: control ADC (ADCr). One observer repeated his measurements blind to his first, and also examined the effect on lesion volume and ADC of deliberately varying by only one pixel, the outline of the visible boundary of the lesion. The inter and intra-rater reliability were worse for lesion volume than ADC or ADCr measurements: lesion volume, inter-rater coefficient of variation (CoV) 85 +/- 130%, intra-rater CoV 20+/-SD80% (p < 0.05); ADC inter-rater CoV 7.7 +/- SD 19%, intra-rater CoV 0.2 +/- SD 12% (p = NS); and ADCr inter-rater CoV 8 +/- SD27%, intra-rater CoV 0.8 +/- SD73% (p = NS). Altering the position of the outline tracing of the lesion boundary by one pixel altered the measured volumes by 22 +/- SD25% (p < 0.05), but ADC values were altered by only 2.9 +/- SD4.9% and ADCr by 2.7 +/- SD4.8% (p = NS). ADC and ADCr values are more reliable and reproducible than DWI lesion size in acute ischemic stroke because altering where the lesion boundary is measured has a much greater impact on lesion volume than on the ADC or ADCr. This effect is greatest in large lesions.


Effects of introducing eels on the yields and availability of fertilizer nitrogen in an integrated rice-crayfish system.
Recently, many new rice-fish co-culture models have been developed to increase economic and ecological benefits. In this study, we added eels (Monopterus albus) to a rice-crayfish system and conducted a 3-year field investigation to compare the yields and availability of fertilizer N among groups with a low density of eels, high density of eels and no eels. We performed a mesocosm experiment and used an isotope tracer technique to detect the fate of fertilizer N. The results showed that the rice yields significantly improved after the introduction of the eels. However, the introduction of a high density of eels significantly limited the crayfish yield, increased water N and N2O emissions and decreased soil N content. The mesocosm experiment suggested that the use efficiency of fertilizer N was significantly increased after the introduction of the eels. The fertilizer N used by rice was significantly higher in rice-crayfish-eel system than in rice-crayfish system. This study indicated that the introduction of eels may be a good practice for improving yields and availability of fertilizer N in a rice-crayfish system.


Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns.
To compare the efficacy of intravenous ibuprofen at high (20-10-10mg/kg/dose) and low doses (10-5-5mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns. A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (p>0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p>0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p=0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p>0.99). Twenty-two (50%) low-dose patients died vs. 15 (45.5%) high-dose patients (p=0.86). There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens.


Epidemiological analysis of the association between hearing and barium in humans.
Our previous study experimentally showed barium (Ba)-mediated hearing loss in mice. To our knowledge, however, it remains unknown whether Ba affects hearing in humans. This epidemiological study aimed at investigating ototoxicity of Ba in humans. Associations of Ba levels in hair, toenails and urine with hearing levels (1, 4, 8 and 12 kHz) were analyzed in 145 Bangladeshi subjects. Binary logistic regression analysis with adjustment for age, sex, body mass index (BMI) and smoking showed that Ba levels in hair had significant associations with hearing loss at 8 kHz (OR=4.75; 95% CI: 1.44, 17.68) and 12 kHz (OR=15.48; 95% CI: 4.04, 79.45). Ba levels in toenails were also associated with hearing loss at 8 kHz (OR=3.20; 95% CI: 1.35, 7.85) and 12 kHz (OR=3.63; 95% CI: 1.58, 8.55), whereas there was no correlation between Ba level in urinary samples and hearing. There was a significant correlation between hearing loss and Ba levels in hair and toenails in the model adjusted with arsenic levels as the confounder. In conclusion, this study suggested that Ba levels could be a new risk factor for hearing loss, especially at high frequencies of 8 and 12 kHz, in humans.


The RNA repair proteins RtcAB regulate transcription activator RtcR via its CRISPR-associated Rossmann fold domain.
CRISPR-associated Rossmann fold (CARF) domain signaling underpins modulation of CRISPR-Cas nucleases; however, the RtcR CARF domain controls expression of two conserved RNA repair enzymes, cyclase RtcA and ligase RtcB. Here, we demonstrate that RtcAB are required for RtcR-dependent transcription activation and directly bind to RtcR CARF. RtcAB catalytic activity is not required for complex formation with CARF, but is essential yet not sufficient for RtcRAB-dependent transcription activation, implying the need for an additional RNA repair-dependent activating signal. This signal differs from oligoadenylates, a known ligand of CARF domains, and instead appears to originate from the translation apparatus: RtcB repairs a tmRNA that rescues stalled ribosomes and increases translation elongation speed. Taken together, our data provide evidence for an expanded range for CARF domain signaling, including the first evidence of its control via in trans protein-protein interactions, and a feed-forward mechanism to regulate RNA repair required for a functioning translation apparatus.