Release characteristics of mercury in chemical looping combustion of bituminous coal.
This study evaluated the release characteristics of mercury from bituminous coal in chemical looping combustion (CLC) using Australian iron ore as the oxygen carrier in a fixed bed reactor. The effects of several parameters, such as temperature in the fuel reactor (FR) and air reactor (AR), gasification medium in the FR, and reaction atmosphere in the AR, on mercury release characteristics, were investigated. The mercury speciation and release amount in the FR and AR under different conditions were further explored. The results indicate that most of the mercury in coal was released in the FR, while the rest of it was released in the AR. Hg0 was found to be the major species in the released mercury. The results also indicate that a higher temperature in the FR led to an increase in the total mercury release amount and a decrease in Hg0 proportion. However, a higher temperature in the AR resulted in a decrease in the total mercury release amount and Hg0 proportion. The increase in the H2O/CO2 ratio of gasification mediums in the FR was beneficial for the increase in the total mercury release amount and Hg0 proportion. A higher O2 concentration in reaction atmosphere in AR had a negligible effect on the total mercury release amount, but a positive effect on Hg0 oxidization.


Isolation of metabolically active endothelial cells in high yield from bovine cavernous bodies. A model for functional studies on freshly isolated microvascular endothelial cells.
Work on endothelial cells has been limited by the availability of procedures for obtaining such cells in quantities adequate for direct in vitro analysis. The present paper describes a method for the isolation of endothelial cells from bovine cavernous bodies. A number of cells ranging from 2.5 to 4 X 10(8) per animal has been obtained. The cells were identified as follows 1) presence of the "Weibel and Palade" bodies in the isolated cells, 2) "cobblestone" appearance of cell cultures, and 3) presence of factor VIII, as demonstrated by immunofluorescence assays. The cell viability at the end of the purification procedure was tested 1) by dye-exclusion tests and 2) by metabolic assays. Features of this preparation are 1) the very high yield of viable endothelial cells, 2) the absence of contamination by fibroblasts and smooth muscle cells and a very low contamination by erythrocytes and 3) the fine dispersion of the isolated cells. These properties allow functional and subcellular fractionation studies on freshly isolated endothelial cells of microvascular origin.


MMR and autism: moving from controversy toward consensus.
As controversy swirls around the putative association between the measles-mumps-rubella vaccine and autism, the methods of scientific investigation, established more than 150 years ago, bear remembering. In this article, we will discuss the origins of this hypothesis, evidence in support of and at variance with this theory and future investigations that may help to resolve this debate.


Prevention of pregnancy in rabbits using vaginal application of prostaglandin f2alpha.
Seventy-two rabbits were artificially inseminated at the time of ovulation induced by intravenous human chorionic gonadotropin. Twenty-four hours later vaginal suppositories containing graded amounts of prostaglandin F2alpha (PGF2alpha) (5 to 25 mg) were inserted into test rabbits in each group. A control group received plain vaginal suppositories. Ten days later the rabbits were killed and examined for numbers of corpora lutea and implantation sites. The results indicate that 5 to 15 mg of PGF2alpha had no effect or a minimal effect on the number of implantation sites, that 20 mg of PGF2alpha reduced the number of implantation sites, and that 25 mg of PGF2alpha was the most effective dose. Fifteen of twenty treated rabbits were not pregnant, despite the presence of ovarian corpora lutea. Four remaining rabbits were pregnant but had markedly reduced implantation sites (four, two, three, and two fetuses, respectively. PGF2alpha is known to increase tubal motility markedly. These data are consistent with such a mechanism's inhibiting pregnancy when used postcoitally in rabbits.


A comparative study of Norinyl 1/35 versus Norinyl 1/50 in Belgrade, Yugoslavia.
A comparative study of Norinyl 1/35 and Norinyl 1/50 was conducted at the Dom Zdravlja Stari Grad in Belgrade, Yugoslavia. The study sought to evaluate the differences in continuation rates as well as the frequency of selected side effects which might contribute to method discontinuation. The trial included 299 women who were randomly allocated to one of the two oral contraceptives. In the Norinyl 1/35 group, significantly more women (p less than .05) reported a complaint of vaginal discharge as well as an increase in the occurrence of vaginal discharge compared to the Norinyl 1/50 group. There was no significant difference in continuation rates or for particular discontinuation reasons for the Norinyl 1/35 and Norinyl 1/50 groups. No accidental pregnancies were reported during this study. Both oral contraceptives appear to be safe and effective; there appears to be no difference in the acceptability of one oral contraceptive over the other among this group of Yugoslavian women.


The effect of long-term food restriction on tumours in rodents.
The effect of restricting food intake by approximately 20% was studied in rats and mice. Both species were fed as similar "natural" diet composed chiefly of cereals and bone meal. The duration of the rat study was 24 months, but mice were studied for their whole lifespan of 36 months. In the mice, restriction increased longevity, and in both species the incidence of tumours was reduced and the onset delayed. The effect upon the different types of tumour varied; some types appeared to be unaffected by restriction, but the most common types in each species, liver tumours in mice, pituitary, mammary and skin tumours in rats, were significantly reduced.


Detection rate of decreased intrinsic capacity of older adults: a systematic review and meta-analysis.
To systematically assess the prevalence of decreased intrinsic capacity in older adults, stratified by relevant factors such as country, sex, sample source, and region. We conducted a comprehensive search of PubMed, Web of Science, EMBASE, The Cochrane Library, PsychINFO, CINAHL, China Knowledge Resource Integrated Database, Wanfang Database, Weipu Database, and Chinese Biomedical Database to collect studies published on the decline of intrinsic capacity in older adults before February 24, 2023. The results of the study were analyzed using the Stata 15.0 software package, using a random-effects model to estimate the pooled detection rate of decreased intrinsic capacity in older adults. The Joanna Briggs Institute Critical Appraisal Tool was used to assess the quality of all included studies. A total of 16 studies (67,881 older adults in 4 countries) were included. The results showed that the pooled detection rate of decreased intrinsic capacity in older adults was 76.1% (95% CI: 68.0%-84.2%). The 16 studies had obvious heterogeneity, and further subgroup analysis showed that the detection rate of decreased intrinsic capacity in older adults was higher in developed countries, females, and hospitals. Thirteen studies found that the pooled detection rate was 73.7% (95%: CI 64.5%-82.8%) for decreased intrinsic capacity in Chinese older adults, with higher rates in mainland China and Hong Kong than in Taiwan. Our study suggests that intrinsic capacity declines more rapidly in older adults. Understanding the degree of decline in the intrinsic capacity of older adults will help to provide an important basis for the formulation and development of care policies for older adults. PROSPERO (CRD42023402680).


Assessing the in vitro optical quality of presbyopic solutions based on the axial modulation transfer function.
To present a metric for assessing the in vitro optical quality of rotationally symmetrical optical elements based on volume calculation under the surface defined by the axial modulation transfer function (MTF). University of Valencia, Valencia, Spain. Experimental study. The metric volume under the axial MTF was used to assess the optical quality of 2 rotationally symmetrical multifocal intraocular lenses (IOLs) within various defocus intervals (0.50 diopter [D], 0.75 D, and 1.00 D) and at various spatial frequency intervals (7.5 cycles per degree [cpd], 15.0 cpd, and 30.0 cpd). The far focus of the bifocal IOL yielded higher volume values at all spatial frequencies and defocus intervals than the trifocal IOL. The results for the near focus were similar for both IOLs. In addition, the trifocal IOL provided a distinct focus for intermediate vision. The volume under the axial MTF proved to be a useful tool for objective evaluation of multifocal IOLs. Moreover, it can be applied to evaluate the optical quality of every rotationally symmetrical IOL or optical element. None of the authors has a financial or proprietary interest in any material or method mentioned.


Differences in concentration of heavy metals between native and transplanted Plagiothecium denticulatum: a case study of soils contaminated by oil well exudates in South East Poland.
For a period of 60 days, the terrestrial moss Plagiothecium denticulatum was transplanted from a clean control site to a soil contaminated with crude oil exudates (Krosno, South East Poland). Native P. denticulatum growing on this contaminated soil was collected during the same period. Concentrations of the metals Al, Ba, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, V, and Zn as well as the macroelements N, P, K, Ca, Mg, and S were determined in P. denticulatum and in soils from the contaminated and control sites. Contaminated soil was the main contributor of Ba, Co, Cr, Cu, Fe, Mn, Ni, Pb, V, and Zn to native and transplanted P. denticulatum. Other sources of contamination apart from the soil existed for Cd and Cu. Transplanted P. denticulatum accumulated significantly more Al, Cr, Cu, Ni, Pb, and Zn, and native P. denticulatum accumulated significantly more N, P, K, and Ca. Higher levels of N, P, K, and Ca in native P. denticulatum indicates a possible mechanism to prevent the loss of these elements as observed in the transplanted P. denticulatum.


Biochemical properties of isoprene synthase in poplar (Populus x canescens).
Isoprene synthase (ISPS) catalyzes the elimination of pyrophosphate from dimethylallyl diphosphate (DMADP) forming isoprene, a volatile hydrocarbon emitted from many plant species to the atmosphere. In the present work, immunological techniques were applied to study and localize ISPS in poplar leaves (Populus x canescens). Immunogold labeling using polyclonal antibodies generated against His-tagged recombinant ISPS protein detected ca. 44% of ISPS in the stroma of the chloroplasts and ca. 56% of gold particles attached to the stromal-facing side of the thylakoid membranes. ISPS isolated from leaves exhibited the same biochemical properties as the recombinant ISPS without the plastid-targeting peptide heterologous expressed in E. coli, whereas an additional C- or N-terminal His-tag changed the biochemical features of the recombinant enzyme with regard to temperature, pH, and substrate dependence. In comparison to the closely related class of monoterpene synthases from angiosperms and ISPS of oaks, the most striking feature of the poplar ISPS is a cooperative substrate dependence which is characteristic to enzymes with positive substrate activation. The detection of four immunoreactive bands in poplar leaf extracts with isoelectric points from 5.0 to 5.5 and a native molecular weight of ca. 51 kDa give reason for future studies on post-translational modifications of ISPS.


Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression.
Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix in the pulmonary interstitium and progressive functional decline. We hypothesized that integration of multi-omics data would identify clinically meaningful molecular endotypes of IPF. The IPF-PRO Registry is a prospective registry of patients with IPF. Proteomic and transcriptomic (including total RNA [toRNA] and microRNA [miRNA]) analyses were performed using blood collected at enrollment. Molecular data were integrated using Similarity Network Fusion, followed by unsupervised spectral clustering to identify molecular subtypes. Cox proportional hazards models tested the relationship between these subtypes and progression-free and transplant-free survival. The molecular subtypes were compared to risk groups based on a previously described 52-gene (toRNA expression) signature. Biological characteristics of the molecular subtypes were evaluated via linear regression differential expression and canonical pathways (Ingenuity Pathway Analysis [IPA]) over-representation analyses. Among 232 subjects, two molecular subtypes were identified. Subtype 1 (n = 105, 45.3%) and Subtype 2 (n = 127, 54.7%) had similar distributions of age (70.1 +/- 8.1 vs. 69.3 +/- 7.6 years; p = 0.31) and sex (79.1% vs. 70.1% males, p = 0.16). Subtype 1 had more severe disease based on composite physiologic index (CPI) (55.8 vs. 51.2; p = 0.002). After adjusting for CPI and antifibrotic treatment at enrollment, subtype 1 experienced shorter progression-free survival (HR 1.79, 95% CI 1.28,2.56; p = 0.0008) and similar transplant-free survival (HR 1.30, 95% CI 0.87,1.96; p = 0.20) as subtype 2. There was little agreement in the distribution of subjects to the molecular subtypes and the risk groups based on 52-gene signature (kappa = 0.04, 95% CI= -0.08, 0.17), and the 52-gene signature risk groups were associated with differences in transplant-free but not progression-free survival. Based on heatmaps and differential expression analyses, proteins and miRNAs (but not toRNA) contributed to classification of subjects to the molecular subtypes. The IPA showed enrichment in pulmonary fibrosis-relevant pathways, including mTOR, VEGF, PDGF, and B-cell receptor signaling. Integration of transcriptomic and proteomic data from blood enabled identification of clinically meaningful molecular endotypes of IPF. If validated, these endotypes could facilitate identification of individuals likely to experience disease progression and enrichment of clinical trials. NCT01915511.


Macrophage migration inhibitory factor (MIF) plays a critical role in pathogenesis of ultraviolet-B (UVB) -induced nonmelanoma skin cancer (NMSC).
Mounting evidence suggests that macrophage migration inhibitory factor (MIF) may serve as an important link between chronic inflammation and cancer development. The proinflammatory and proangiogenic activities of MIF position it as a potentially important player in the development and progression of nonmelanoma skin cancer (NMSC). To assess the role of MIF in the development and progression of NMSC, we exposed MIF(-/-) BALB/c mice to acute and chronic ultraviolet B (UVB) irradiation. Our studies demonstrate that MIF(-/-) BALB/c mice have a significantly diminished acute inflammatory response to UVB exposure compared to wild-type mice, as measured by myeloperoxidase activity, dermal neutrophil infiltration, and edematous response. Relative to wild-type mice, MIF(-/-) mice also show significantly lower vascular endothelial growth factor (VEGF) concentrations in whole skin and significantly lower 8-oxo-dG adduct concentrations in epidermal DNA following UVB exposure. Furthermore, MIF(-/-) mice showed significant increases in p53 activity, epidermal thickness, and epidermal cell proliferation following acute UVB insult. In response to chronic UVB exposure, MIF(-/-) mice showed a 45% reduction in tumor incidence, significantly less angiogenesis, and delayed tumor progression when compared to their wild-type counterparts. These data indicate that MIF plays an important role in UVB-induced NMSC development and progression.


Transforming Growth Factor Beta Family in the Pathogenesis of Meningiomas.
Meningiomas account for 36% of primary brain tumors. The pathogenesis of these tumors is not completely established, hindering development of effective chemotherapy. Numerous studies have identified alterations in several growth factors and receptor kinases that regulate meningioma growth. These may be targets for new therapies. One of these, sometimes overlooked, is the transforming growth factor beta (TGF-β) family of proteins. Its receptors and signaling pathways play a critical role in development or progression of many forms of neoplasia. Evidence suggesting a potential role for TGF-β, bone morphogenetic protein, and their mediators is reviewed. TGF-β inhibition of growth in normal leptomeninges may be lost in neoplasia. Moreover, loss of TGF-β and bone morphogenetic protein signaling components and TGF-β type III receptor likely contribute to the development and/or progression of higher grade meningiomas. Accumulating evidence suggests that derangement of TGF-β family signaling contributes to development and progression of meningiomas. The TGF-β family may represent new targets for chemotherapy and could include inhibitors of kinases activated by TGF-β.


Single-cell RNA sequencing reveals cellular and molecular reprograming landscape of gliomas and lung cancer brain metastases.
Brain malignancies encompass gliomas and brain metastases originating from extracranial tumours including lung cancer. Approximately 50% of patients with lung adenocarcinoma (LUAD) will eventually develop brain metastases. However, the specific characteristics of gliomas and lung-to-brain metastases (LC) are largely unknown. We applied single-cell RNA sequencing to profile immune and nonimmune cells in 4 glioma and 10 LC samples. Our analysis revealed that tumour microenvironment (TME) cells are present in heterogeneous subpopulations. LC reprogramed cells into immune suppressed state, including microglia, macrophages, endothelial cells, and CD8+ T cells, with unique cell proportions and gene signatures. Particularly, we identified that a subset of macrophages was associated with poor prognosis. ROS (reactive oxygen species)-producing neutrophils was found to participant in angiogenesis. Furthermore, endothelial cells participated in active communication with fibroblasts. Metastatic epithelial cells exhibited high heterogeneity in chromosomal instability (CIN) and cell population. Our findings provide a comprehensive understanding of the heterogenicity of the tumor microenvironment and tumour cells and it will be crucial for successful immunotherapy development for brain metastasis of lung cancer.


High prevalence of hearing loss at the special olympics: is this representative of people with intellectual disability?
The Healthy Hearing (HH) programme at the Special Olympics (SO) revealed hearing disorders in between 16 and 40% of athletes. However, it is not clear whether these prevalence represents the entire population with intellectual disability. Therefore, this study compares the hearing status of SO athletes with an intellectual disability (ID) to students with ID at a special needs school. The HH screening was performed in 637 athletes (mean age 27.1 years, range 9.7-70.6 years) during the 2008 German SO Summer Games - and in 198 special needs students (mean age 12.7 years, range 6.7-20.0 years). Twenty-two per cent of athletes and 18% of students failed the HH screening. Approximately 60% of the total participants received recommendations for further follow-up and treatment without between-group differences. The results of the HH screening at SO events are assumed to be representative of children and adolescents with ID in special needs schools.


A natural compound jaceosidin ameliorates endoplasmic reticulum stress and insulin resistance via upregulation of SERCA2b.
Increased endoplasmic reticulum (ER) stress has emerged as a vital contributor to dysregulated glucose homeostasis, and impaired function of sarco-endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) is one of the central mechanisms underlying ER stress. In this study, we reported that SERCA2b upregulation contributed to the amelioration of ER stress and insulin resistance by a small natural compound jaceosidin. In a model of differentiated C2C12 myotubes, jaceosidin-triggered SERCA2b upregulation enhanced insulin sensitivity and decreased ER stress. Moreover, the activity of Ca2+-ATPase in thapsigargin-treated myotubes was also augmented by jaceosidin. Furthermore, jaceosidin significantly suppressed blood glucose levels, improved glucose tolerance and lowered body weight, but did not alter food intake in insulin-resistant obese mice. In addition, this compound markedly reduced lipid accumulation, suppressed the expression of lipogenic genes in liver and ameliorated liver injury. The ameliorative effects of jaceosidin were due to its ability to reduce ER stress via increasing the expression of SERCA2b in the muscles of obese mice. Taken together, jaceosidin could improve ER stress and attenuate insulin resistance via SERCA2b upregulation in mice skeletal muscles.


Human monocyte-mediated cytotoxicity against herpes simplex virus-infected cells: activation of cytotoxic monocytes by free and liposome-encapsulated lymphokines.
Human peripheral blood monocytes were incubated with free or liposome-encapsulated human lymphokines containing macrophage-activating factor (MAF) and tested for their effect on herpes simplex virus (HSV)-infected target cells. Activated monocytes lysed allogeneic HSV type 2 (HSV-2)-infected whole human embryo cells and xenogeneic BALB/c mouse embryo cells (10E2) without any significant effect on uninfected cells, as measured by release of 51Cr from target cells after 18 h of cocultivation. Kinetic studies revealed that lysis of virus-infected cells occurred by 10 h following cocultivation with activated monocytes. The inability of free MAF or supernatants from MAF-activated monocytes to lyse HSV-2-infected cells suggested that direct monocyte-target cell contact is required for monocyte-mediated cytotoxicity of the virus-infected cells. Monocytes activated with MAF suppressed the production of HSV-2 and HSV-1 from virus-infected cells more than control monocytes did. In addition, monocytes treated with liposome-encapsulated MAF selectively destroyed HSV-2-infected cells but left uninfected cells unharmed. The capacity of liposome-encapsulated immunomodulators to activate human monocytes to selectively lyse HSV-2-infected cells has potential therapeutic benefit and should be evaluated in vivo.


Enhanced stability of horseradish peroxidase encapsulated in acetalated dextran microparticles stored outside cold chain conditions.
Micro- and nanoparticles have been shown to improve the efficacy of safer protein-based (subunit) vaccines. Here, we evaluate a method of improving the vaccine stability outside cold chain conditions by encapsulation of a model enzyme, horseradish peroxidase (HRP), in an acid-sensitive, tunable biodegradable polymer, acetalated dextran (Ac-DEX). Vaccines that are stable outside the cold chain would be desirable for use in developing nations. Ac-DEX particles encapsulating HRP were prepared using two different methods, probe sonication and homogenization. These particles were stored under different storage conditions (-20 °C, 4 °C, 25 °C or 45 °C) for a period of 3 months. On different days, the particles were characterized for various physical and chemical measurements. At all conditions, Ac-DEX particles remained spherical in nature, as compared to PLGA particles that fused together starting at day 3 at 45 °C. Furthermore, our results indicated that encapsulation of HRP in Ac-DEX reduces its storage temperature dependence and enhances its stability outside cold chain conditions. Homogenized particles performed better than probe sonicated particles and retained 70% of the enzyme's initial activity as compared to free HRP that retained only 40% of the initial activity after 3 months of storage at 25 °C or 45 °C. Additionally, HRP activity was more stable when encapsulated in Ac-DEX, and the variance in enzyme activity between the different storage temperatures was not observed for either particle preparation. This suggests that storage at a constant temperature is not required with vaccines encapsulated in Ac-DEX particles. Overall, our results suggest that an Ac-DEX based micro-/nanoparticles system has wide applications as vaccines and drug delivery carriers, including those in developing nations.


Short-Term Reloading After Prolonged Unloading Ensures Restoration of Stromal but Not Hematopoietic Precursor Activity in Tibia Bone Marrow of C57Bl/6N Mice.
Bone and muscle tissues are mostly susceptible to different kinds of hypodynamia, including real and simulated microgravity (sμg). To evaluate the effect of sμg on bone marrow (BM), male C57Bl/6N mice were divided into three groups: vivarium control (VC), 30-day hindlimb suspension (HS), and subsequent 12-h short-term support reloading (RL). The effects on BM total mononucleated cells (MNCs) as well as stromal and hematopoietic progenitors from murine tibia were studied. The number of BM MNCs, immunophenotype, proliferation, colony-forming units (CFUs), differentiation and secretory activity of hematopoietic and stromal BM cells were determined. HS led to a twofold decrease in MNCs, alteration of surface molecule expression profiles, suppression of proliferative activity of BM cells, and change of soluble mediators' levels. The stromal compartment was characterized by a decrease of CFU of fibroblasts and suppression of spontaneous osteo-commitment after HS. Among the hematopoietic precursors, a decrease in the total number of CFUs was found mainly at the expense of suppression of CFU-GM and CFU-GEMM. After RL, restoration of the stromal precursor's functional activity to control levels and overabundance of paracrine mediator's production were detected, whereas the complete recovery of hematopoietic precursor's activity did not occur. These data demonstrate the fast functional reaction of the stromal compartment on restoration of loading support.


Use of folic acid and vitamin supplementation among adults with depression and anxiety: a cross-sectional, population-based survey.
Evidence suggests that folate deficiency may be causatively linked to depressive symptoms. However, little is known on the status of use of folic acid and vitamin supplements among people with mental disorders. This study examined the prevalence and the likelihood of use of folic acid or vitamin supplements among adults with depression and anxiety in comparison to those without these conditions. Using data from 46, 119 participants (aged ≥ 18 years) in the 2006 Behavioral Risk Factor Surveillance System survey, we estimated the adjusted prevalence and odds ratios with 95% confidence intervals for taking folic acid and vitamin supplements among those with ever diagnosed depression (n = 8, 019), ever diagnosed anxiety (n = 5, 546) or elevated depressive symptoms (n = 3, 978, defined as having a depression severity score of ≥ 10 on the Patient Health Questionnaire-8 diagnostic algorithm). Overall, women were more likely than men to take folic acid supplements 1-4 times/day (50.2% versus 38.7%, P < 0.001) and vitamin supplements (62.5% versus 49.8%, P < 0.001). After multivariate adjustment, men with ever diagnosed depression or anxiety were 42% and 83%, respectively, more likely to take folic acid supplements < 1 time/day; 44% and 39%, respectively, more likely to take folic acid supplements 1-4 times/day; and 40% and 46%, respectively, more likely to take vitamin supplements compared to men without these conditions (P < 0.05 for all comparisons). Women with ever diagnosed depression were 13% more likely to take folic acid supplements 1-4 times/day and 15% more likely to take vitamin supplements than women without this condition (P < 0.05 for both comparisons). Use of folic acid and vitamin supplements did not differ significantly by elevated depressive symptoms in either sex. The prevalence and the likelihood of taking folic acid and vitamin supplements varied substantially by a history of diagnosed depression among both men and women and by a history of diagnosed anxiety among men, but not by presence of elevated depressive symptoms in either sex.


Rapid-response vaccines--does DNA offer a solution?
In responding to future influenza pandemics and other infectious agents, plasmid DNA overcomes many of the limitations of conventional vaccine production approaches.


The activity of the von Willebrand factor cleaving protease ADAMTS-13 in newborn infants.
Unusually large von Willebrand factor (VWF) multimers have been observed in patients with thrombotic microangiopathies (TMA), and absence of the VWF cleaving protease ADAMTS-13 activity is considered to be involved in the etiology of TMA. Increased amounts of large multimers of VWF have also been identified in neonates. We assessed ADAMTS-13 activity in healthy neonates, children and adults to establish baseline levels. Cord blood was collected from 38 full-term newborns; venous samples were taken from 15 neonates on day 2-3 of life. Seventeen children, 24 healthy adults and seven patients with TMA were studied as well. ADAMTS-13 activity was quantified by the binding of the subjects' plasma VWF to collagen before and after enzyme activation. The multimer distribution of VWF was also determined. Neonates and children had percentage ADAMTS-13 activity similar to adults. However, two groups were apparent in the cord blood samples: while 28/38 newborns had percentage activity within the normal range of healthy adults (102 +/- 3.0%), 10 had significantly lower percentage activity (53 +/- 1.1%; P < 0.0001) that normalized by day 2-3. The VWF multimer distribution was the same in all cord blood samples and was not different compared with children and adults. High-molecular-weight VWF multimers were significantly increased in the 2-3-day-old neonates and in TMA patients. Although ADAMTS-13 activity was similar in neonates compared with adults, 26% of neonates had mildly reduced activity. Further studies are needed to investigate the complex interaction of VWF production and secretion with its size control by ADAMTS-13 in different age groups.


Domain-specific CCN3 antibodies as unique tools for structural and functional studies.
CCN3 is a member of the CCN family of cell growth and differentiation regulators that play key roles during embryonic development, and are associated with severe human pathologies. The level of CCN genes' expression is of prognostic value in several types of tumors. In the present manuscript, we report the isolation and characterization of a new set of antibodies targeted against each individual module of the human CCN3 protein. The need for module-specific antibodies stemmed from recent reports indicating that the expression of truncated CCN variant proteins was associated with development of cancers. Each of the four CCN3 modules were expressed as GST fusion proteins and used for rabbits immunization. Polyclonal IgGs purified by two rounds of affinity-chromatography specifically detected both the individual CCN3 domains and the full length CCN3 protein expressed in mammalian cell lines and tissues, as well as recombinant full length and truncated CCN3 proteins. The purified module-specific antibodies were successfully used for Western blotting, immunoprecipitation, immunofluorescence and immunocytochemistry. These antibodies permitted the detection of CCN3 proteins under native and denaturing conditions, and confirmed the sublocalisation of CCN3 proteins in the extracellular compartment, at the cell membrane, in the cytoplasm and in the nucleus of positive cells. Immunocytochemistry and Western blotting studies performed with the module-specific antibodies identified truncated CCN3 proteins in kidney tumor samples. The detection of these rearranged variants provides clues for their involvement in tumorigenesis. Therefore, these antibodies constitute unique tools for the identification of truncated CCN3 proteins in human tissues and may be of great interest in molecular medicine.


New synthetic inhibitors of microtubule depolymerization.
A new class of borneol esters that might be considered as biological analogs of paclitaxel regarding their action on microtubules has been found. By structure-activity optimizations, compounds stabilizing microtubules much better than paclitaxel while showing a remarkably reduced cytotoxic activity were obtained. This dissoziation will open completely new therapeutic areas.


One-shot Federated Learning without server-side training.
Federated Learning (FL) has recently made significant progress as a new machine learning paradigm for privacy protection. Due to the high communication cost of traditional FL, one-shot federated learning is gaining popularity as a way to reduce communication cost between clients and the server. Most of the existing one-shot FL methods are based on Knowledge Distillation; however, distillation based approach requires an extra training phase and depends on publicly available data sets or generated pseudo samples. In this work, we consider a novel and challenging cross-silo setting: performing a single round of parameter aggregation on the local models without server-side training. In this setting, we propose an effective algorithm for Model Aggregation via Exploring Common Harmonized Optima (MA-Echo), which iteratively updates the parameters of all local models to bring them close to a common low-loss area on the loss surface, without harming performance on their own data sets at the same time. Compared to the existing methods, MA-Echo can work well even in extremely non-identical data distribution settings where the support categories of each local model have no overlapped labels with those of the others. We conduct extensive experiments on two popular image classification data sets to compare the proposed method with existing methods and demonstrate the effectiveness of MA-Echo, which clearly outperforms the state-of-the-arts. The source code can be accessed in https://github.com/FudanVI/MAEcho.


The hyaluronan receptor, CD44.
CD44 is a widely expressed cell surface hyaluronan receptor which plays a key role in mediating cell migration. A number of recent papers demonstrating an interplay between CD44 and matrix metalloproteinases (MMPs) have shed important insights into the molecular mechanisms underlying these events. This has important implication for understanding how mis-regulation of CD44 can contribute to disease pathologies.


Anesthetic Implications of Obesity and Obstructive Sleep Apnea.
The incidence of morbid obesity has tripled within the past 25 years in developed countries, with the highest rate of growth noted among people with body mass index (BMI) greater than 50. The physiologic derangements that accompany obesity affect almost every organ system leading to a vast array of comorbid conditions including obstructive sleep apnea (OSA). This review focuses on the unique perioperative management considerations that the nurse anesthetist must address when caring for these patients as well as the impact of obesity and OSA on postoperative complications and mortality rates. Current research is reviewed to highlight best practice recommendations for all phases of anesthetic management including implications for bariatric surgery and office-based practice.


Development of biliary and hepatic neoplasms in guinea pigs treated with N-nitrosobis(2-oxopropyl)amine.
N-Nitrosobis(2-oxopropyl)amine (BOP) was administered subcutaneously to 29 male inbred strain 13 guinea pigs at weekly intervals for 4 weeks. The guinea pigs were observed until their death or termination of the experiment at the end of 55 weeks. Of 14 guinea pigs that survived more than 30 weeks, 7 animals developed cholangiocarcinomas and 2 developed hepatocellular carcinomas. Tumors of other sites were not found.


Implementation of the World Health Organization checklist and debriefing improves accuracy of surgical wound class documentation.
Surgical wound classification (SWC) is a component of surgical site infection risk stratification. Studies have demonstrated that SWC is often incorrectly documented. This study examines the accuracy of SWC after implementation of a multifaceted plan targeted at accurate documentation. A reviewer examined operative notes of 8 pediatric operations and determined SWC for each case. This SWC was compared with nurse-documented SWC. Percent agreement pre- and postintervention was compared. Analysis was performed using chi-square and a P value less than .05 was significant. Preintervention concordance was 58% (112/191) and postintervention was 83% (163/199, P = .001). Appendectomy accuracy was 28% and increased to 80% (P = .0005). Fundoplication accuracy increased from 44% to 84% (P = .016) and gastrostomy tube from 56% to 100% (P = .0002). The most accurate operation preintervention was pyloromyotomy and postintervention was gastrostomy tube and inguinal hernia. The least accurate pre- and postintervention was cholecystectomy. Implementation of a multifaceted approach improved accuracy of documented SWC.


Influence of tendon healing after arthroscopic rotator cuff repair on clinical outcome using single-row Mason-Allen suture technique: a prospective, MRI controlled study.
The reported functional results of rotator cuff repair performed arthroscopically have been good. Only little is known about the cuff integrity after arthroscopic repair and how it influences the outcome. The aim of the study is to set a baseline of what rate of healing response respectively re-tears to expect and how cuff integrity alters the outcome. Fifty-three consecutive patients with an isolated supraspinatus tendon tear were arthroscopically operated and their tendons repaired. All pre- and postoperative data were prospectively collected. At a minimum follow-up after 24 months (average 26.4 months), the integrity of the cuff was evaluated by an open magnetic resonance imaging and the patients' function and satisfaction were documented and graded to the sex- and age-related Constant-score also using a dynamometer for strength testing. The re-tear rate was 24.5% with 13 non-healed tendons. The Constant-score of all patients improved significantly. The scores of the patients with a re-tear were significantly lower than those of the patient with an intact cuff. That was due to a less good performance in strength testing. The other categories of the Constant-score did not show any differences. The age of the patients with a re-tear was significantly higher. With the exception of age, we did not find any negative prognostic factor for a re-tear, and with the exception of re-tear no other factor influenced the Constant-score. Arthroscopic supraspinatus tendon repair yields a re-tear rate of 25% which is comparable with the results of open or mini/open repair. Cuff integrity influences postoperative strength and Constant-score. Patients older than 65 years show a higher re-tear rate. Therapeutic Level IV is the level of evidence.


Trauma to the lacrimal system in children.
We repaired damage to the lacrimal drainage system in a series of 393 children who had lacrimal obstruction caused by congenital obstruction or facial injuries. Delayed surgery for traumatic obstruction of the nasolacrimal duct in children, including infants, was successful in all cases.


Excitation spectra and brightness optimization of two-photon excited probes.
Two-photon probe excitation data are commonly presented as absorption cross section or molecular brightness (the detected fluorescence rate per molecule). We report two-photon molecular brightness spectra for a diverse set of organic and genetically encoded probes with an automated spectroscopic system based on fluorescence correlation spectroscopy. The two-photon action cross section can be extracted from molecular brightness measurements at low excitation intensities, while peak molecular brightness (the maximum molecular brightness with increasing excitation intensity) is measured at higher intensities at which probe photophysical effects become significant. The spectral shape of these two parameters was similar across all dye families tested. Peak molecular brightness spectra, which can be obtained rapidly and with reduced experimental complexity, can thus serve as a first-order approximation to cross-section spectra in determining optimal wavelengths for two-photon excitation, while providing additional information pertaining to probe photostability. The data shown should assist in probe choice and experimental design for multiphoton microscopy studies. Further, we show that, by the addition of a passive pulse splitter, nonlinear bleaching can be reduced--resulting in an enhancement of the fluorescence signal in fluorescence correlation spectroscopy by a factor of two. This increase in fluorescence signal, together with the observed resemblance of action cross section and peak brightness spectra, suggests higher-order photobleaching pathways for two-photon excitation.


Non-canonical mTORC1 signaling at the lysosome.
The mechanistic target of rapamycin complex 1 (mTORC1) signaling hub integrates multiple environmental cues to modulate cell growth and metabolism. Over the past decade considerable knowledge has been gained on the mechanisms modulating mTORC1 lysosomal recruitment and activation. However, whether and how mTORC1 is able to elicit selective responses to diverse signals has remained elusive until recently. We discuss emerging evidence for a 'non-canonical' mTORC1 signaling pathway that controls the function of microphthalmia/transcription factor E (MiT-TFE) transcription factors, key regulators of cell metabolism. This signaling pathway is mediated by a specific mechanism of substrate recruitment, and responds to stimuli that appear to converge on the lysosomal surface. We discuss the relevance of this pathway in physiological and disease conditions.


Lichen myxedematosus. An unusual case with rapid progression and possible internal involvement.
Lichen myxedematosus (papular mucinosis) is a slowly progressive mucinous disorder that is thought by many to have no internal organ involvement. We report a case of lichen myxedematosus (lichenoid plaque type) that is remarkable for the sudden and rapid nature of the infiltrative process with both cutaneous and possibly systemic manifestations. The cutaneous abnormalities were successfully treated with cyclophosphamide and intralesional steroids. The fact that our patient's systemic signs and symptoms also responded to therapy supports the concept of internal involvement in lichen myxedematosus.


Standardization of a colorimetric technique for determination of enzymatic activity of diamine oxidase (DAO) and its application in patients with clinical diagnosis of histamine intolerance.
Diamine Oxidase (DAO) has an essential role for degradation of exogenous histamine in the intestine; thus, histamine intolerance (HI) mainly has been correlated to a low concentration and/or activity of this enzyme. The objective of the study was to standardize a colorimetric technique to measure the enzymatic activity (function) of hDAO to then apply it to a series of 22 patients with a clinical diagnosis of HI. For the standardization variables such as volume and type of sample, incubation time, wavelength of maximum absorption, types of substrates, and concentration of oxidized ascorbate were evaluated. Then the activity and concentration of DAO was determined in 22 patients diagnosed with HI and 22 healthy subjects. The mean of serum DAO concentration in the 22 patients was of 9.268 ± 1.124 U/mL. The mean of serum DAO concentration in the 22 controls was of 20.710 ± 2.509 U/mL, being significantly higher (P value 0.0002) the mean of the samples. The mean of serum DAO activity of the patients was of 1.143 ± 0.085 U/L and the controls was 1.533 ± 0.119 U/L, significantly greater than the patients (P value 0.011). In addition, the sensitivity of both techniques was 0.63. In the measuring of DAO concentration the specificity was 0.9, constituting a good diagnostic test, especially to rule out the true negatives. The determination of DAO activity had a specificity of 0.68. Although we used a small number of patients and controls and the absorbance values were lower than expected, statistically significant differences were found in the levels of concentration and DAO activity between the patients with histamine intolerance and the controls. Therefore, the measuring of DAO concentration and DAO activity is a good diagnostic strategy for study suspect cases of HI. The simultaneous use of both assays allows to reduce positive and negative false results, for example, patients with normal DAO levels that could present a dysfunction in the activity of this enzyme.


The Impact of Maternal Gestational Stress on Motor Development in Late Childhood and Adolescence: A Longitudinal Study.
The number and timing of stressors experienced during pregnancy were investigated using longitudinal data from the Western Australian Pregnancy (Raine) Study cohort (N = 2,900). Motor development data were collected at 10 (n = 1,622), 14 (n = 1,584), and 17 (n = 1,222) years using the McCarron Assessment of Neuromuscular Development. Linear mixed models were used to examine the effect of stress on motor development, accounting for repeated measures. Number of stressful events and mean Neuromuscular Development Index were negatively related (β = -1.197, p = .001). Stressful events experienced in late pregnancy were negatively related with offspring motor development (β = -0.0541, p = .050), while earlier stressful events had no significant impact.


Clinical characteristics of patients double positive for CASPR2 and LGI1-antibodies.
This study described the clinical characteristics of autoimmune neurological diseases with dual seropositive antibodies of CASPR2 and LGI1. Three patients, with antibodies targeting both CASPR2 and LGI1 (EUROIMMUN, FA 112d-1, Germany), hospitalized in Department of Neurology, Xuanwu Hospital, Capital Medical University from June 2016 to June 2019 were collected in this study. We summarized the clinical characteristics of patients with CASPR2 and LGI1 antibodies from a targeted literature review. Three patients reported were all middle-aged and elderly male with diverse neurological symptoms, including seizures, psychological abnormalities, limb weakness and hyperhidrosis. Interestingly, three patients displayed three different clinical syndromes (isolated epilepsy, Morvan syndrome and limbic encephalitis, respectively). White blood cell and glucose in Cerebrospinal fluid (CSF) were normal and CSF for protein was slightly elevated. Electromyography (EMG) showed abnormal spontaneous firing in case 2. Brain magnetic resonance imaging (MRI) revealed bilateral hyper-intensity of the temporal lobe on T2 and FLAIR sequence in case 3. Cancer screening program of patient 2 showed thymoma. Cell based assay was positive in serum for both LGI1 and CASPR2 antibodies, while these antibodies were negative in CSF. They were treated with glucocorticoid or intravenous immunoglobulin (IVIG). Followed up for 6 months to 1 year, all patients got remission to different extent. Through the detailed analysis of three patients, the combination of both antibodies contributes to a broad spectrum of neurological symptoms in the central, peripheral, and autonomic nervous systems. The patients with same antibodies can have different clinical syndromes. Early tumor screening and immunotherapy will improve the prognosis of the disease.


Cusatuzumab plus azacitidine in Japanese patients with newly diagnosed acute myeloid leukemia ineligible for intensive treatment.
We present the results of a phase 1 study that evaluated the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary disease response to cusatuzumab, a novel anti-CD70 monoclonal antibody, in combination with azacitidine, in newly diagnosed acute myeloid leukemia Japanese participants who were not candidates for intensive treatment. In this multicenter, single-arm study, six participants were enrolled and treated. Only in cycle 1, participants received cusatuzumab monotherapy on day 14. Subsequently, cusatuzumab was administered intravenously on days 3 and 17 at 20 mg/kg in combination with azacitidine (75 mg/m2 ) on days 1-7 of each 28-day cycle. All six participants had at least one treatment-emergent adverse event, and the most common treatment-emergent adverse events (all grades) were leukopenia (four participants [66.7%]) and constipation (three participants [50.0%]). No dose-limiting toxicity was observed during the study period. The combination of cusatuzumab and azacitidine is generally well tolerated in Japanese participants, and further exploration of this combination is warranted.


Life history patterns in birds and mammals and their evolutionary interpretation.
It is argued that allometric principles account for most of the observed variation in the life history patterns amongst birds. To test this contention it is shown that traits such as incubation time, growth rates, age at first reproduction, lifespan, clutch weight and egg weight all scale to body weight with exponents similar to those found for analogous traits in mammals. It is then shown that most of the variation amongst bird taxa and between birds and mammals based on body weight allometry can be explained by variations in brain size, body temperature and metabolic rate, consistent with theories of growth and ageing derived from mammalian studies. Finally, it is suggested that the evidence for life histostory allometry is sufficiently strong that it argues for a more epigenetic view of life history patterns and their evolution than is generally conceded in most adaptation theories.


HoloMentor: A Novel Mixed Reality Surgical Anatomy Curriculum for Robot-Assisted Radical Prostatectomy.
The disruption to surgical training and medical education caused by the global COVID-19 pandemic highlighted the need for realistic, reliable, and engaging educational opportunities available outside of the operating theatre and accessible for trainees of all levels. This article presents the design and development of a virtual reality curriculum which simulates the surgical mentorship experience outside of the operating theatre, with a focus on surgical anatomy and surgical decision-making. This was a multi-institutional study between London's King's College and Imperial College. The index procedure selected for the module was robotic radical prostatectomy. For each stage of the surgical procedure, subject-matter experts (N = 3) at King's College London, identified (1) the critical surgical-decision making points, (2) critical anatomical landmarks, and (3) tips and techniques for overcoming intraoperative challenges. Content validity was determined by an independent panel of subject-matter experts (N = 8) at Imperial College, London, using Fleiss' kappa statistic. The experts' teaching points were combined with operative footage and illustrative animations, and projected onto a virtual reality headset. The module was piloted to surgical science students (N = 15). Quantitative analysis compared participants' confidence regarding their anatomical knowledge before and after taking the module. Qualitative data were gathered from students regarding their views on using the virtual reality model. Multi-rater agreement between experts was above the 70.0% threshold for all steps of the procedure. Seventy-three percentage of pilot study participants "agreed" or "strongly agreed" that they achieved a better understanding of surgical anatomy and the rationale behind each procedural step. This was reflected in an increase in the median knowledge score after trialing the curriculum (p < 0.001). 100% of subject-matter experts and 93.3% of participants "agreed" or "strongly agreed" that virtual mentorship would be useful for future surgical training. This study demonstrated that virtual surgical mentorship could be a feasible and cost-effective alternative to traditional training methods with the potential to improve technical skills, such as operative proficiency and nontechnical skills such as decision-making and situational judgement.


Current issues in global tuberculosis control.
Despite attempts to standardize tuberculosis (TB) control strategies, there remains wide variation in the selection and implementation of control strategies within and among nations. Some of this variation is appropriate; based on wide variations in the available resources, the prevalence of TB infection, the incidence of TB disease, the relative contribution of reactivation versus recent transmission to incident cases, and the rate of HIV co-infection. This review will discuss three controversial questions relevant to global TB control: (1) What is the role of the treatment of latent TB infection in global TB control? (2) What are successful strategies to control immigrant TB in low incidence countries? (3) What are successful strategies to control TB in persons with HIV infection?


Psychological Patient Reactions after Septorhinoplasty - Our Personal View.
The aim of our study is to observe adequate and inadequate psychological reactions in patients who are candidates for septorhinoplasty, before and after surgery and to create an adequate psychological model of a person suitable for septorhinoplasty in this group of patients. In this study, 140 patients with nasal septal deviation (deviatio septi nasi), alone or together with other nasal deformities, were observed in the period of 4 years (2011-2015 year). Our patients were psychologically observed using two standard psychological tests: Patients selection for septorhinoplasty and their psychological abilities ("Self-body image" questionnaire) and Brief Symptom Inventory (BSI) test. Most of the patients 43 (39.8%), thought that after rhinoseptoplasty their self-confidence arise, 32 (29.63%) expected changing's in their life's, few of them 9 (8, 3%) thought that the environment will act different with them. The Brief Symptom Inventory (BSI) in women group was shown that most of the women patients presented symptoms of somatisation; 23 (23.33%) and 15 (25%) one year after surgery. The patients made a sound decision for intervention, which was useful for the surgeon too, because it helped them choose an adequate operative technique and especially helped them in the postoperative period.


CD34+ cell count predicts long lasting life in the oldest old.
Circulating progenitor cells (CPCs) represent a pool of cells capable of differentiating into mature cells of different organs and systems, promoting tissue maintenance and repair. Among CPCs, CD34+cells (CD34+CPCs) seem to predict outcome in CV disease, also in elderly people. A decline in CD34+CPCs was reported with advancing age. Moreover, aging is associated with a state of chronic inflammation, influencing life expectancy. Our purpose was to investigate a 10-year predictive ability of CD34+CPCs, inflammatory marker levels, classic CV risk factors (CVRFs), and Framingham Risk Score (FRS) in a population of healthy, self-sufficient octogenarians. We found that baseline CD34+CPCs was strongly associated with mortality, showing a significant difference in CD34+CPC numbers between deceased and living patients. Moreover, by dividing our patients into tertiles based on age reached, this difference was more remarkable the higher the age reached. Regressive analyses suggested that the chances of reaching an older age depend on higher CD34+CPCs at baseline and are not significantly affected by inflammatory markers levels, FRS, CVFRs, or HDL-C levels. We found that higher CD34+CPCs predict longer life also in the oldest old, providing additional insights on the predictive role of CD34+CPCs in subjects aged 80 years or more.


Sympathetic nervous function and renin activity in hypertensives on long term drug treatment with propranolol, methyldopa or bendrofluazide.
Plasma noradrenaline and plasma renin activity were measured as indices of sympathetic activity and renin angiotensin system in similar groups of hypertensive patients receiving either propranolol, bendrofluazide or methyldopa. Plasma renin activity was similar in the propranolol and methyldopa groups and significantly lower (p less than 0.01) in both these groups than the diuretic treated subjects. Plasma noradrenaline was significantly lower (p less than 0.01) on methyldopa than either propranolol or bendrofluazide. These different effects on the renin angiotensin system and the sympathetic nervous system of these drugs may be relevant in the choice of long term therapy in hypertension.


New silica-immobilized hydroxypyrimidinone as sorbent of hard metal ions from aqueous fluids.
The chemical modification of solid supports with chelators for the sorption of residual amounts of specific metal ions is of environmental and biological current interest. The present work describes the preparation and chelating properties of a new hydroxypyrimidinone-functionalized silica, (HOPY-PrN)-Si, with high affinity for hard metal ions. The new chelating matrix was obtained by coupling a 1-hydroxy-2-(1H)-pyrimidinone derivative, HOPY-PrN, to an epoxy-activated silica. It showed good stability at neutral and acidic conditions and high sequestering capacity for hard metal ions, namely Fe3+ and Al3+, as previously found for the corresponding sepharosic derivative. However, the fact that the present silica-gel derivative is considerably less expensive gives support to its potential interest as a sorbent of traces of toxic hard metal ions from water streams or even from physiological fluids, aided by extracorporeal devices containing the immobilized chelator.


[Spasmolytic properties of pyrrolizidine alkaloids].
Acute toxicity, spasmolytic and hypotensive properties of the alkaloids senecionine, d-otocenine and floridanin isolated from Senecio Erraticum L. were studied. D-otocenine and floridanin elicited low toxicity, while senecionine and d-otosenine showed spasmolytic and floridanin predominantly hypotensive properties.


Heparin: does it act as an antioxidant in vivo?
Previous studies have shown that heparin antagonizes oxygen radical-mediated injury to endothelial cells, suggesting an antioxidant role of the drug. In the present investigation, the hypothesis that heparin exerts direct antioxidant effects was tested in several experimental models. We have found that 1, 3, 5, 10, 20, 40 and 80 U/mL of heparin do not scavenge superoxide anion, hydrogen peroxide, hydroxyl radical or the stable free radical 1,1-diphenyl-2-pycrylhydrazyl. Moreover, the drug is ineffective towards iron-driven linolenic acid peroxidation, autooxidation of brain homogenate and linolenic acid peroxidation mediated by human internal mammary artery homogenate. Specific studies on the potential iron-binding-inactivating capacity of heparin prove the drug to be totally ineffective. Finally, the loss of protein sulphydryls from human plasma induced by hypoxanthine-xanthine oxidase-generated oxygen radicals is not prevented by heparin. In conclusion, heparin, even at concentrations far higher than those usually used therapeutically, has no direct antioxidant properties. Thus, other mechanisms not strictly antioxidant-type must be involved in heparin-mediated cell protection against toxic oxygen metabolites.


Complement in cancer and cancer immunotherapy.
Recently, there has been an increase of interest in the use of biological or immune-based therapies for patients with malignancies. This has been informed by the deeper understanding of the crosstalk between the host immune system and malignant tumours, as well as the potential advantages of immunotherapy-high specificity and less toxicity compared to standard approaches. The particular emphasis of this article is on the role of the complement system in tumour growth and antibody-based cancer immunotherapy. The functional consequences from overexpression of complement regulators by tumours and the development of strategies for overcoming this are discussed in detail. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of cancer.


Adult-young interactions in island and mainland populations of the deermouse Peromyscus maniculatus.
The demographic and ecological characteristics of island populations of small mammals have received increasing attention in recent years, but few studies have compared the behavioral characteristics of island populations with those of mainland populations. Behavior is considered an important variable because it is believed by many to be a crucial factor affecting the population dynamics and demography of natural populations. In particular, among many species of rodents, the social behavior of adults towards juveniles is cited as an important factor influencing dispersal patterns and population regulation. The present study compares social interactions between adults and juveniles of island and mainland populations of the deermouse Peromyscus maniculatus, and attempts to relate differences in behavior to the demographic differences between the two populations. Adult mice were trapped on the mainland of British Columbia and on one of the Gulf Islands off the British Columbia coast, and allowed to breed in the laboratory. Male and female juveniles from both populations were then tested with their own parents and with unrelated male and female adults. The results demonstrate that island adults show almost no aggression towards either own or unrelated young. Mainland adults likewise show little aggression towards their own young, but a proportion of the population, consisting of both male and female adults, shows severe aggression towards unrelated juveniles of both sexes. These results suggest four major conclusions: 1) behavior may be the mechanism responsible for the demographic differences reported for these island and mainland populations; 2) female aggression may be a more important factor in deermouse population dynamics than has been previously recognized; 3) since parents show little aggression towards their own young, adult aggression may be a significant factor in juvenile mortality and emigration only after juveniles have initiated dispersal away from their natal sites; and 4) adult aggression controls the number of both male and female juveniles which are recruited into the population.


Shortened-Interval Dual-Session EDGE Reduces the Risk of LAMS Dislodgement While Facilitating Timely ERCP.
EUS-directed transgastric ERCP (EDGE) is an endoscopic modality for treating pancreaticobiliary disorders after Roux-en-Y gastric bypass. EDGE consists of EUS-directed gastrogastrostomy/jejunogastrostomy creation (EUS-GG; step 1), followed by transgastric ERCP (step 2). The two steps can be performed in the same or separate endoscopic session(s). Single-session EDGE is immediately therapeutic but risks perforation via LAMS dislodgement. Dual-session EDGE does not risk perforation, but the clinical malady festers during the 10-14-day interval required for fistula maturation. A "shortened-interval dual-session" EDGE (2-4 day interval) may resolve this dilemma. Our study compares 20-mm LAMS dislodgement risk between single-session and shortened-interval dual-session EDGE. We conducted a single-center retrospective study of 21 RYGB patients who underwent EDGE using 20-mm LAMS by one advanced endoscopist between 3/2018 and 2/2020. Given the small sample size, a permutation of regressor residuals test was conducted to investigate the association between EDGE interval type and LAMS dislodgement, controlling for the effect of fistula type. Eleven patients (six female; mean age 55 years old) underwent single-session EDGE; LAMS dislodgement occurred in five cases (45%). Ten patients (eight female; mean age 60 years old) underwent shortened-interval dual-session EDGE (median interval 2 days); LAMS dislodgement occurred in one case (10%). The odds of LAMS dislodgement during single-session EDGE was 817% that of shortened-interval dual-session EDGE (OR 8.17; p = 0.05), after controlling for the effect of fistula type. Shortened-interval dual-session EDGE decreases the risk of intraprocedural 20-mm LAMS dislodgement while allowing for timely transgastric ERCP.


Bilirubin in the Vitreous Body of the Eye of Human Fetuses.
The bilirubin content in the vitreous body of the eye of human fetuses of gestation week 17-31 was measured. During gestation weeks 17-19, the mean bilirubin concentration was 8.67 μmol/liter; then, decreased to 1.37 μmol/liter (gestation weeks 20 to 31). Bilirubin, being an endogenous antioxidant, is probably involved in protection of the retina and lens from LPO processes that intensively develop in retinal neurons and lens fibers.


Polymorphisms of the eNOS gene are associated with disease activity in rheumatoid arthritis.
Nitric oxide (NO) is a mediator in autoimmune responses and thus involved in the pathogenesis of a variety of rheumatic diseases. Genetic factors that influence the expression of the enzyme endothelial nitric oxide synthase (eNOS) that catalyzes NO synthesis are important for the control of NO level and consequently its activity. We have analyzed three functionally relevant polymorphisms of eNOS gene: T-786C, G894T and VNTR (4a/b), to investigate whether they are predisposing factors in pathogenesis of RA in Serbian population and to evaluate their role in clinical manifestations of RA. We performed genotyping of 196 patients with RA and the control group of 132 healthy individuals from Serbian population, using PCR and polymerase chain reaction-restriction fragment length polymorphism methods. Disease activity was prospectively assessed using number of tender joints, number of swollen joints and 28-joints disease activity score (DAS28). There were no differences between the patients and control groups in the genotypes and alleles frequencies of the three analyzed SNPs. Our results showed statistically significant differences in all three analyzed parameters of disease severity between 786TT/786CT and 786CC genotypes and between 894GG/894GT and 894TT genotypes. In the case of 4a/b polymorphism, carriers of minor allele had significantly lower DAS28 values. In conclusion, our results do not support the implication of analyzed eNOS gene polymorphisms in susceptibility to RA but associate them with the disease activity and give assumption that minor alleles are indicators of better clinical course.


Mechanistic studies on the formation of glycosidase-substrate and glycosidase-inhibitor covalent intermediates.
Glycoside hydrolases catalyze the breaking of the glycosidic bond. This type of bond fashioned between two monosaccharides is very stable, and the polymers created are involved in multiple cellular processes, being crucial to life. In this article, computational methods were used to study the first step of the mechanism of reaction of retaining glycoside hydrolases in atomic detail. The systems modeled included a simplified reaction center and a small substrate/inhibitor. Using DFT calculations we were able to corroborate and provide molecular-level detail to the dissociative mechanism proposed in the literature. The role of the hydrogen bridge between the nucleophile and the C(2)--OH group of the ring was also investigated. Therefore, we concluded that this bridge is responsible for lowering the activation barrier by 5.1 kcal mol(-1) with functional BB1K/6-311+G(2d,2p), and the absence of the bridge explains, at least in part, the inhibitory effect of fluoro-substituted glycosides in the -2 position. The hydrogen bridge could also be involved in favoring the ring distortion verified in the transition state, and the dissociative character of the reaction mechanism. Using the NBO method, point atomic charges were calculated. In the transition state, the positive charge generated in the sugar ring is distributed nearly equally between the anomeric carbon and the ring oxygen, through a partial double bond involving the two atoms.


Nanopore sequencing technology for clinical diagnosis of infectious diseases where laboratory capacity is meager: A case report.
In resource-limited settings, patients are often first presented to clinical settings when seriously ill and access to proper clinical microbial diagnostics is often very limited or non-existing. On February 16th, 2022 we were on a field trip to test a completely field-deployable metagenomics sequencing set-up, that includes DNA purification, sequencing, and bioinformatics analyses using bioinformatics tools installed on a laptop for water samples, just outside Moshi, Tanzania. On our way to the test site, we were contacted by the nearby Machame hospital regarding a child seriously ill with diarrhea and not responding to treatment. Within the same day, we conducted an onsite metagenomics examination of a fecal sample from the child, and Campylobacter jejuni was identified as the causative agent. The treatment was subsequently changed, with almost immediate improvement, and the child was discharged on February 21st.


Gelatin/poly(vinyl alcohol)-based dual functional composite films integrated with metal-organic frameworks and anthocyanin for active and intelligent food packaging.
Innovative active and pH-colorimetric composite films were fabricated from gelatin/poly(vinyl alcohol) (Gel/PVA) integrated with copper-based metal-organic frameworks (Cu-MOFs) and red cabbage anthocyanin (RCA). The incorporation of Cu-MOFs improved the tensile strength, water resistance, and UV shielding properties of the developed composite films. The addition of anthocyanins and 3 wt% Cu-MOFs endowed the polymer matrix with excellent antioxidant (100 % against ABTS and DPPH radicals) and antibacterial (against Gram-positive and Gram-negative foodborne pathogenic bacteria) functions. The fabricated composite films exhibited significant color change at alkaline conditions of pH 7-12 and a marked color change upon exposure to ammonia. The designed indicator films used for shrimp freshness tracking and a visual color change from pink (for fresh shrimp) to green (for spoiled shrimp) was observed during storage at 28 °C for 24 h. The potential applications of the engineered composite films were studied by shrimp packaging, and the quality parameters of packaged samples were monitored during storage. The synergistic effects of adding anthocyanins and MOF nanostructures works for better product freshness preservation and responds well to shrimp spoilage level, introducing novel active and intelligent packaging options for practical smart packaging applications.


Human papillomavirus detection and typing using a nested-PCR-RFLP assay.
It is clinically important to detect and type human papillomavirus (HPV) in a sensitive and specific manner. Development of a nested-polymerase chain reaction-restriction fragment length polymorphism (nested-PCR-RFLP) assay to detect and type HPV based on the analysis of L1 gene. Analysis of published DNA sequence of mucosal HPV types to select sequences of new primers. Design of an original nested-PCR assay using the new primers pair selected and classical MY09/11 primers. HPV detection and typing in cervical samples using the nested-PCR-RFLP assay. The nested-PCR-RFLP assay detected and typed HPV in cervical samples. Of the total of 128 clinical samples submitted to simple PCR and nested-PCR for detection of HPV, 37 (28.9%) were positive for the virus by both methods and 25 samples were positive only by nested-PCR (67.5% increase in detection rate compared with single PCR). All HPV positive samples were effectively typed by RFLP assay. The method of nested-PCR proved to be an effective diagnostic tool for HPV detection and typing.


The role of total antioxidant capacity and malondialdehyde of seminal plasma in the association between air pollution and sperm quality.
Accumulating evidence has suggested that men exposed to air pollution are associated with decreased sperm quality, and seminal plasma plays a pivotal role in maintaining sperm viability. However, the role of seminal plasma in air pollution related sperm quality decline remain unestablished. In current study, we recruited 524 participants from couples who underwent in vitro fertilization treatment due to female factors at a fertility clinic in China from March to August 2020. Conventional sperm parameters, total antioxidant capacity (T-AOC), malondialdehyde (MDA) and testosterone were measured using semen samples. The six main air pollutants (PM2.5, PM10, NO2, SO2, CO, O3) during four key periods of sperm development (meiotic stage, spermiogenesis stage, epididymal stage and total sperm cycle period) were estimated using inverse distance weighting method. Multiple linear regression models were employed to investigate the exposure-outcome relationships. And we found that PM10 exposures were negatively related to sperm total motility and the exposures of PM2.5 and PM10 were inversely associated with sperm progressive motility during epididymal stage. Furthermore, PM2.5 and PM10 exposures were positively associated with seminal plasma MDA and PM10 was negatively related to seminal plasma T-AOC during epididymal stage. PM2.5, PM10 and CO exposures during total sperm cycle period might relate to increased seminal plasma testosterone. Mediation analysis indicated seminal plasma MDA and T-AOC partially mediated PM10 associated reduction of sperm motility during epididymal stage. Our study suggested MDA and T-AOC of seminal plasma played a role in air pollution associated decline of sperm motility.


Elevated level of peripheral CD8(+)CD28(-) T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy.
Suppression of cellular immunity resulting from tumorigenesis and/or therapy might promote cancer cells' growth, progression and invasion. Here, we explored whether T lymphocyte subtypes from peripheral blood of metastatic breast cancer (MBC) female patients could be used as alternative surrogate markers for cancer progress. Additionally, plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, and transforming growth factor-β1 were quantitated from MBC and healthy volunteers. This study included 89 female MBC patients during the post-salvage chemotherapy follow-up and 50 age- and sex-matched healthy volunteers as control. The percentages of T lymphocyte subpopulations from peripheral blood and plasma levels of cytokines were measured. Both CD8(+)CD28(-) and CD4(+)CD25(+) were elevated in MBC patients compared to the control cohort (P < 0.05). In contrast, CD3(+) and CD8(+)CD28(+)cells were significantly lower in MBC patients (P < 0.0001, P = 0.045, respectively). MBC patients had elevated levels of immunosuppressive cytokines IL-6 and IL-10. Patients with elevated CD8(+)CD28(-) and CD4(+)CD25(+) cells showed increased levels of IL-6, and only patients with elevated CD8(+)CD28(-) had decreased interferon-γ. Univariate analysis indicated increased CD3(+)CD4(+) or CD8(+)CD28(+)correlated with prolonged progression-free survival (PFS), while elevated CD8(+)CD28(-)associated with shorten PFS. The percent of CD8(+)CD28(-) T lymphocytes is an independent predictor for PFS through multivariate analysis. This study suggests that progressive elevated levels of CD8(+)CD28(-) suppressor T lymphocytes represent a novel independent predictor of PFS during post-chemotherapy follow-up.


The generation of T cell memory: a review describing the molecular and cellular events following OX40 (CD134) engagement.
OX40 (CD134), a membrane-bound member of the tumor necrosis factor-receptor superfamily, is expressed primarily on activated CD4(+) T cells. Following engagement on the cell surface, OX40 delivers a costimulatory signal that leads to potent, proinflammatory effects. Engagement of OX40 during antigen (Ag)-specific stimulation of T cells leads to increased production of memory T cells, increased migration of Ag-specific T cells, enhanced cytokine production by effector T cells, and the ability to break peripheral T cell tolerance in vivo. Therefore, OX40 engagement in vivo could have important ramifications for the enhancement of vaccine strategies and inhibition of unwanted inflammation. This review summarizes the molecular and cellular events that occur following OX40 engagement during Ag-specific T cell activation.


New liposome-radionuclide-chelate combination for tumor targeting and rapid healthy tissue clearance.
Radionuclide imaging and therapy are promising methods for controlling systemic cancers; however, their clinical application has been limited by excessive radionuclide accumulation in healthy tissues. To minimize radionuclide accumulation in non-cancerous tissues while ensuring sufficient build up in tumors, we aimed to develop a method that controlled the in vivo dynamics of radionuclides post-administration. To this end, we describe a novel strategy that combines liposomes, a potent carrier system for drug delivery, with unique radionuclide-ligand complexes based on 111In-ethylenedicysteine. Conventional 111In-ligand-complexes-carrying liposomes delivered substantial amounts of radionuclides to tumors; however, they also accumulated in the liver and spleen. In contrast, 111In-ethylenedicysteine-carrying liposomes greatly reduced non-specific accumulation, while being retained selectively at high doses within tumors. Liposomes were rapidly broken down in the liver, releasing encapsulated 111In-ligand complexes. Among the chelates used, only 111In-ethylenedicysteine could escape from the liver and be excreted in the urine. Instead, most liposomes remained intact in tumors, retaining the radionuclide-ligand complexes within them. Therefore, high tumor accumulation was obtained regardless of the type of 111In-ligand complexes in the liposomes. In vivo single photon emission computed tomography/computed tomography imaging with 111In-ethylenedicysteine-carrying liposomes accurately revealed tumor-selective radionuclide retention with little background. Hence, our new strategy could greatly enhance tumor-to-healthy tissue ratios, improve diagnostic imaging, boost therapeutic efficacy, reduce toxicity to healthy tissues, and facilitate radionuclide imaging and therapy.


An account of noncovalent interactions in homoleptic palladium(II) and platinum(II) complexes within the DFT framework: A correlation between geometries, energy components of symmetry-adapted perturbation theory and NCI descriptors.
The present work addresses the underlying nature of weak noncovalent interactions (NCIs) in the self-assembled dimers of two square planar palladium(II) and platinum(II) complexes trans-[Pd(Hida)2] (1) and trans-[Pt(Hida)2] (2) (Hida = monoprotonated iminodiacetate) within the framework of density functional theory (DFT) in gas phase. Initial geometries of the dimers in different spatial orientations were extracted from the X-ray crystal structures, reported earlier, and optimized with three dispersion-corrected functionals that are frequently used to explore NCIs. The BP86-D3, M062X-D3 and ωB97X-D3 functionals have been used to test their performances over the present systems. The SARC-ZORA-TZVP and ZORA-def2-TZVP basis sets were applied for the metals and the remaining elements, respectively. The optimizations resulted in equilibrium geometries where the monomers are self-assembled through NCIs to form dimers in a cyclic fashion. This type of structural pattern is absent in the crystal structures of both 1 and 2. Physical components of interaction energies were investigated by symmetry-adapted perturbation theory (SAPT). The UV-Vis absorption spectra of the dimers are described by time-dependent density functional theory (TD-DFT). Global reactivity parameters for the dimers have been computed within the framework of conceptual density functional theory (CDFT). Detailed investigations on NCIs were performed for all dimer geometries. Simulated IR and 1H NMR spectra, charge transfer, QTAIM, NCI-RGD, IGM, ETS-NOCV and ELF studies confirmed the presence of intermolecular hydrogen bonds (HBs) and weak van der Waals interactions. Energies of the hydrogen bonds and associated orbital interaction energies were computed by QTAIM and ETS-NOCV methods, respectively.


Hydrophilic-subtraction model for the characterization and comparison of hydrophilic interaction liquid chromatography columns.
Nowadays more and more hydrophilic interaction liquid chromatography (HILIC) columns with diverse functional groups have become commercially available, which pose a challenge to select an appropriate one. However, there is no universal model to provide guidance for selecting HILIC columns. To handle this problem, a retention model named "hydrophilic-subtraction model" was developed to characterize and compare HILIC columns. The hydrophilic-subtraction model, which was designed based on the widely recognized HILIC retention mechanisms including hydrophilic partitioning, hydrogen-bonding and electrostatic interactions, was established by the retention of 41 solutes with various properties on 8 representative HILIC columns. High correlation coefficients (R(2)≥0.990) and small standard deviations (SD≤0.041) indicated that this model correlated effectively the retention with solute descriptors and column parameters. To evaluate reliability of the model, the model was further applied to characterize 15 additional HILIC columns using 41 solutes. The results of multiple linear regression confirmed the significance of the model. The regression coefficients of the model were used to investigate retention mechanisms occurring in different chromatographic systems. Based on these regression coefficients, selectivities of HILIC stationary phases were exhibited intuitively by an angle graph and a spider diagram, which could be used as guidance for researchers to select appropriate columns for HILIC separation. Additionally, a rapid and convenient procedure was proposed for characterizing HILIC columns.


FMD virus spillover from domestic livestock caused outbreak in captive wild ungulates: First report from Pakistan.
The potential spillover of foot and mouth disease (FMD) virus at the wildlife-livestock interface is mainly responsible for the outbreaks in captive wild ungulates. The current study was planned to investigate an FMD outbreak in the wild ungulate species in the Jallo Wildlife Park and breeding facility, Lahore, Pakistan from Mar 2021- Jun 2021. The disease was confirmed based on ELISA through the detection of antibodies against the non-structural protein of FMD virus and typical clinical signs of oral and feet lesions, and even partial or complete hoof shedding in severe cases. To investigate the possible cause of FMD spillover and its pattern, a series of interviews were conducted with wildlife practitioners, animal handlers, and the local veterinarians in villages adjacent to the park. The data revealed neither vaccination nor any FMD outbreak in the last 10 years. The epidemic curve and time-series analysis showed a mixed outbreak characterized by the introduction of disease and then propagative spread from infected to susceptible animals. After the first reports of clinical signs in Blackbuck, Urial and Mouflon sheep were infected while in the end, the cases were reported from the enclosures of Sambar deer and Spotted deer. The morbidity rate among all the wild ungulate species was 92% and the mean mortality rate was 27%. The study concluded that possible sources for primary disease incidence might be animal handlers having FMD infected animals in their houses and transport vehicles coming from adjacent disease-affected villages. For the disease spread between enclosures, another possibility of wind-borne FMD virus spread could also be considered. This is the first report regarding the FMD outbreak and its spillover pattern in captive wild ungulates in Pakistan. These findings will be helpful in understanding the importance of wildlife livestock interface in FMD transmission and to design effective strategies to control the disease.


Optic pathway tumor in children: Toward a new classification for neurosurgical use.
Optic pathway tumors (OPT) represent a challenge for pediatric neurosurgeons. Role of surgery is debated due to the high risk of iatrogenic damage, and in lasts decades it lost its importance in favor of chemotherapy. However, in some cases surgery is necessary to make biomolecular and histological diagnosis, to manage intracranial hypertension (IH) and to cooperate with medical therapies in controlling tumor relapse. With the aim to standardize selection of surgical OPT cases, we propose a simple, practical and reproducible classification. We retrospectively analyzed data of 38 patients with OPT treated at our institution (1990-2018). After careful analysis of MRI images, we describe a new classification system. Group 1: lesion limited to one or both optic nerve(s). Group 2: chiasmatic lesions extending minimally to hypothalamus. Group 3: hypothalamo-chiasmatic exophitic lesions invading the third ventricle; they can be further divided on the base of concomitant hydrocephalus. Group 4: hypothalamo-chiasmatic lesions extending widely in lateral direction, toward the temporal or the frontal lobes. Patients' data and adopted treatment are reported and analyzed, also depending on this classification. Twenty children were operated on for treatment of OPT during the study period. Permanent clinical impairment was noted in 5 (25%) of operated patients, while visual improvement was noted in 1 patient. OS rate was 100% at 5 years, with a median follow up of 9 years (ranging from 2 to 23). Prevalence of intracranial hypertension and proportion of first-line surgical treatment decision were significantly higher in groups 3-4 compared to groups 1-2 (P<0.001 for both tests). Surgery can offer a valuable therapeutic complement for OPT without major risk of iatrogenic damage. Surgery is indispensable in cases presenting with IH, as in groups 3 and 4 lesions. Eligibility of patients to surgery can be based on this new classification system.


Molecular insights of Carbapenem resistance Klebsiella pneumoniae isolates with focus on multidrug resistance from clinical samples.
Carbapenem are the last-line antibiotic, defence against Gram-negative extended spectrum ß-lactamases producers (ESBLs). Carbapenem resistance Enterobacteriaceae especially Carbapenem resistant-Klebsiella pneumoniae (CR-KP) is recognized as one of the well-known public health problem, which is increasingly being reported around the world. The present study was focused to analyse the prevalence and characterization of antibiotic resistance K. pneumoniae in centre region of Tamil Nadu, India. Totally 145 suspected K. pneumoniae isolates [Urine, Pus, Sputum, Blood and Biopsy] obtained from hospitals of Central South India. The isolates were subjected to biochemical and molecular identification technique, following with antibiotic resistance pattern by standard antibiotic sensitivity test. Multidrug resistance (MDR) with β-lactamase producing Carbapenem resistant K. pneumoniae (CR-KP) strains were screened by classical sensitivity method and also drug resistance encoded gene. Also, molecular typing of the MDR strains were characterized by Pulsed-Field Gel Electrophoresis (PFGE). Further, the outer membrane protein (OmpK35 and 36) related Carbapenem resistance were characterized. Totally, 61% of isolates were confirmed as K. pneumoniae, 75 % of isolates were MDR including 58% carbapenem and 97% ESBL antibiotics and grouped into 17 distinct resistant patterns. The MDR KP isolates shows positive for blaCTXM-1 (92 %) gene followed by blaSHV (43 %), blaTEM (36 %), blaNDM-1 (26 %), blaGES (20 %) and blaIMP-1 (8 %). Moreover, 62 % CR-KP isolates loses OmpK36 and 33% isolates loses OmpK35. Loss of OmpK36 were highly an influence the cefoxitin and carbapenem resistance. Sixteen different PFGE patterns have been observed among the 18 MDR isolates. Eventually, ESBL as well as CR-KP were diverse in genetic makeup and often associated with hyper virulence hvKP should be of serious concern.


Methylated oxypurines and induction of differentiation of murine erythroleukemia cells.
Murine erythroleukemia cell lines derived from Friend virus infected mice can be induced to differentiate in vitro by numerous agents. Among these compounds are certain naturally occurring purines such as hypoxanthine or 1-methylhypoxanthine. We have extended these studies to other modified oxypurines and have identified some areas of cell regulation with which they may be interacting. Monomethylated derivatives of guanine, hypoxanthine or xanthine are active as inducers of differentiation. Excluding hypoxanthine, the parent oxypurines guanine and xanthine are ineffective in inducing differentiation. The dimethyl- and trimethylxanthine derivatives are also inactive as inducers. The methylated oxypurines are not metabolized to nucleotides by the cell and, therefore, probably do not interact with nucleic acid synthesis directly. We have investigated one cellular process of possible regulatory significance with which they do interact. ADP-ribosylation has been implicated in control of gene expression and differentiation. The methylated oxypurines inhibit this reaction, as measured in permeabilized cells, in the same concentration range at which they are effective as inducers of differentiation. Additionally, 1-methylguanine and 7-methylguanine decrease incorporation of mannose and glucosamine into glycoprotein and into dolichol-oligosaccharide precursors. These effects may be related to cell surface alterations observed during differentiation.


Acetazolamide-Induced Nephrolithiasis in Idiopathic Intracranial Hypertension Patients.
Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure of unknown cause. Acetazolamide is widely used as the initial treatment option; however, previously published evidence suggests that this drug may also increase the risk of nephrolithiasis. The purpose of this study was to examine daily acetazolamide use and its relationship to nephrolithiasis and compare clinical presentation of IIH between those with and without nephrolithiasis. We conducted a case-control study using patient data collected by the Intracranial Hypertension Registry. A total of 670 patients were identified as potential study participants, 19 meeting the case definition of developing a stone during acetazolamide treatment for IIH. From the remaining pool of eligible participants, 40 controls were randomly selected. Two-sampled t tests, Fisher exact testing, and exact logistic regression were used to examine differences between cases and controls and to ascertain associations with IIH clinical features and mean daily acetazolamide dosage. Among all eligible patients, 19 (2.8%) developed a stone during acetazolamide treatment for IIH. Among these patients, 17 (89.5%) developed a stone within 1.5 years of initial acetazolamide treatment. Daily acetazolamide use was not significantly related to stone development (odds ratio = 0.95; 95% confidence intervals: 0.86-1.05). Additionally, the relationship between the clinical presentation of IIH at the time of diagnosis (signs and symptoms) and stone development did not reach statistical significance (P > 0.05). Our results demonstrate that: 1) stone formation during acetazolamide treatment is a relatively infrequent occurrence within the IIH population; 2) among patients who develop a stone, formation is likely to occur within the first year and half; 3) there is no evidence to support the association between acetazolamide daily dosage and stone development; and 4) no unique IIH disease features at the time of diagnosis are associated with stone development. Treatment with acetazolamide should be administered to IIH patients with caution and closely monitored for stone development especially within the first year and a half of treatment.


Functional analysis of the 3'-terminal part of the Balbiani ring 2.2 gene by interspecies sequence comparison.
An interspecies comparison was made between the 3' ends of Balbiani ring genes from Chironomus. The comparison was focused on the BR2.2 gene, and a part at the 3' end from Chironomus pallidivittatus (which included also a segment of the gene core) was cloned. Its sequence, and other previously published BR sequences from this species and from Chironomus tentans were used in the analysis. The 3' parts of these repetitive genes can be divided into a region belonging to the core of the genes followed by a terminal region. In the core region the repeats (each of which consists of a constant part and a subrepeated part) are highly similar and the constant parts show little interspecies differentiation. Furthermore, the two parts of the repeats are units in an evolutionary and probably also functional sense. The terminal region contains modified constant units, usually isolated between acidic so-called cys regions, the whole arrangement lying upstream of an intron toward a 3'-terminal exon. Most of the modified constant units are mosaics in rates of evolution with stable outer quarters bordering to equally stable cys regions and a central half with a very high rate of evolution. One of the terminal units, present only in the BR2.2 gene and second from the end, differs distinctly not only from corresponding core units but also from other terminal units in the three normally active BR genes. It lies upstream of all cys regions and is evolutionarily conserved over most of its length. Furthermore, two-dimensional protein structure prediction does not exclude an endoproteolytic cleavage site in this unit.(ABSTRACT TRUNCATED AT 250 WORDS)


Generation of pH gradient across the rabbit collecting duct segments perfused in vitro.
Ability of pH gradient generation was examined in three segments of rabbit collecting duct, cortical collecting duct (CCD), outer medullary collecting duct (OMCD) and inner medullary collecting duct (IMCD). These segments were perfused in vitro, and the steady-state luminal pH in stop-flow condition (pHs) and the electrochemical potential difference of H+ (EH) were determined using double-barreled liquid membrane pH microelectrode punctured into the lumen. In CCD, pHs was 7.71 +/- 0.08 in normal rabbits, 7.72 +/- 0.08 in DOCA-treated rabbits and 7.27 +/- 0.05 in starved rabbits, while peritubular fluid was kept at pH 7.5 EH (positive value means H+ accumulation in the lumen above electrochemical equilibrium) was -15.3 +/- 5.2, -31.3 +/- 3.7 and 10.3 +/- 3.1 mV, respectively. Peritubular acidification (peritubular pH 6.8) by reducing HCO3-concentration decreased pHs, but increased its negativity of EH in all groups. In OMCD pHs was 6.57 +/- 0.08 in normal, 6.58 +/- 0.11 in DOCA-treated and 6.47 +/- 0.12 in starved animals. EH was 54.5 +/- 4.6, 57.7 +/- 6.8 and 64.2 +/- 6.9 mV, respectively. Peritubular acidification lowered pHs further, 5.51 +/- 0.07, 5.67 +/- 0.16 and 5.41 +/- 0.19, respectively. EH was enhanced in all groups. In IMCD pHs was 7.36 +/- 0.04 with EH being 6.8 +/- 2.9 mV, and peritubular acidification did not generate pH gradient. These data suggest that the generation of a steep acid pH gradient is mainly due to OMCD. Luminal alkalinization predominated in CCD except in starved rabbits. IMCD did not generate appreciable pH gradient.(ABSTRACT TRUNCATED AT 250 WORDS)


Modified thalamocortical model: a step towards more understanding of the functional contribution of astrocytes to epilepsy.
It is evident that the cortex plays a primary role in seizure generation. At the same time, various experimental results clearly confirm that thalamic neurons are also actively involved in seizure generation and spreading. On the other hand, recent neurophysiologic findings suggest that astrocytes regulate dynamically the synaptic activity in neuronal networks. Therefore, in the present study, the thalamocortical neural population model (TCPM) is modified by embedding into the model the functional role of astrocytes in the regulation of synaptic transmission. Using the modified TCPM (MTCPM) we examined the hypothesis that one of the possible causes of neural hypersynchronization is the dysfunction of astrocytes in the regulatory feedback loop. Then, two MTCPMs are coupled via excitatory synapses and the astrocytes are also coupled together through gap junctions. Utilizing the MTCPM and CMTCPM, the transition from normal to malfunctioned states is analyzed using a dynamical system approach. In this way, the hypothesis is investigated and it is demonstrated that the healthy astrocytes provide feedback control to regulate neural activity. That is, the astrocytes compensate to a large extent variations in the coupling between neural populations and maintain the balance between the excitation and inhibition levels. However, the malfunctioned astrocytes are no longer able to regulate and/or compensate the excessive increase of the inter-population coupling strength. As a consequence, disruption of the signaling function of astrocytes could contribute to the neuronal hyperexcitability and generating epileptiform activity. These results suggest that astrocytes might be one of the potential targets for the treatment of epilepsy.