Edema formation and degranulation of mast cells by Trimeresurus mucrosquamatus snake venom.
Trimeresurus mucrosquamatus venom, carrageenin, compound 48/80, trypsin and bovine serum albumin were injected s.c. into the plantar muscle to induce edema formation in the hind paw of rats. The venom was the most potent, and it and compound 48/80 induced the maximum swelling rate of edema within 15 - 30 min after injection. The edema volume induced by the venom was dose-dependent between 2.5 and 10 micrograms. Hydrocortisone, phenylbutazone, indomethacin and diphenhydramine inhibited edema induced by the venom and other inflammatory agents. Diphenhydramine was the most effective inhibitor of edema and increased vascular permeability induced by the venom. Injection of the venom i.p. caused exocytosis and degranulation of mesentery mast cells with a decreased electron density of released granules. Systemic administration of diphenhydramine inhibited the venom-induced exocytosis. Diphenhydramine and pyrilamine inhibited the contraction of guinea-pig ileum caused by venom or compound 48/80. It is concluded that histamine released from mast cells plays an important role in the causation of the edema induced by Trimeresurus mucrosquamatus snakebites.


Adolescents, parents, and peers: what is one with or without the other?
The present study investigates the relationship between Asian and white adolescents, resident in Britain, and their parents and peers. Ninety Asian and 81 white youths aged between 11 and 16 years, completed questionnaires concerning the quality of relations with parents; conflict between parents and peers; and willingness to approach parents, peers, siblings, teachers, and religious leaders in particular situations. In addition, diaries of time spent with peers were kept for a one week period. The data tend to show that relations among youths and groups of would-be advisers are influenced by both age and cultural background. Also, they would further support the view that relations with parents and peers do not represent mutually exclusive domains, but must be seen as developing from both a consideration of the appropriateness of each group in particular circumstances as well as the availability of other groups of "significant" persons.


Intrinsic and extrinsic discoloration of dimethacrylate and silorane based composites.
The purpose of this study was to evaluate the intrinsic and extrinsic color change of dimethacrylate and silorane-based composites. Five contemporary composites were included within the study (Filtek LS Low Shrink Posterior Restorative [SIL], Filtek SupremeXT [SPR], Filtek Z250 [Z25], Filtek P60 [P60], and Admira [ADM]). Twenty-five specimens (8-mm diameter, 1.5-mm thickness) were prepared for each composite. After baseline color measurements were taken, specimens were immersed in 4 staining solutions (red wine, coffee, cola, and tea) or distilled water (n=5). After a 24-h and 1-month immersion, the color values of each specimen were remeasured and the color change values (ΔE(ab)(*)) were calculated. Statistical analyses were evaluated by one-way ANOVA and Tukey HSD test. Amongst the solutions, red wine had the highest ΔE(ab)(*) value in all the composite restoratives. After the final measurement, ADM exhibited the lowest discoloration, whereas SPR exhibited the highest color change. Additionally, the color change for SIL after 1 month in distilled water was higher than the clinically accepted cut-off of 3.3. This change was correlated with an increasing L value according to the multiple regression analysis. All of the restorative materials used in this study were susceptible to staining by commonly consumed beverages drinks, especially red wine and coffee; however, in water, only SIL became whiter with time.


Shaping the sound of voice.
The proper development of the vocal cords requires embryos to contain a certain number of progenitor cells, and mutations that lead to an overflow of cells can cause malformations of the voice box.


Histone demethylase JMJD2B-mediated cell proliferation regulated by hypoxia and radiation in gastric cancer cell.
Histone modifying factors are functional components of chromatin and play a role in gene regulation. The expression level of JMJD2B, a histone demethylase, is notably up-regulated in cancer tissues. Upregulation of JMJD2B promotes cancer cell proliferation under hypoxic conditions through target gene expression. Here, we describe the patterns of histone methylation and JMJD2B expression under various stressed conditions, such as hypoxia and radiation, in a gastric cancer cell line. JMJD2B expression in AGS cells was actively regulated by hypoxia and radiation. Chromatin immunoprecipitation experiments demonstrated that binding of JMJD2B on the cyclin A1 (CCNA1) promoter resulted in CCNA1 upregulation under hypoxic conditions. Furthermore, we confirmed that AGS cell proliferation was directly affected by JMJD2B and CCNA1 expression by performing experiments with JMJD2B depleted cells. Interestingly, the effects of JMJD2B on cell growth under hypoxia were remarkably repressed after gamma-ray irradiation. These results suggest that JMJD2B may play a central role in gastric cancer cell growth and might constitute a novel therapeutic target to overcome hypoxia-induced radio-resistance, thereby improving the efficiency of radiation therapy.


Productive struggle and failing safely: implications for developing adaptive expertise in communication.
Navigating difficult conversations is a complex task that requires flexible and adaptive approaches. Residents developing this skill may initially struggle or fail, and require support. However, this experience may prepare residents for future learning which is essential to adaptive expertise. Limited understanding of how residents learn from failure in the workplace restricts the ability to maximize its potential benefits. The purpose of this study was to explore the role failure plays in learning to navigate difficult conversations during workplace learning. A constructivist grounded theory study was conducted using semi-structured interviews of 13 physicians (subspecialty residents and newly graduated physicians) from a Division of Developmental Paediatrics between 2017 and 2018. The authors used constant comparative analysis to identify themes iteratively. Themes were identified both inductively and deductively using the conceptual framework of adaptive expertise. Through independently leading difficult conversations, physicians were able to recognize that the failure that occurred in these encounters, prompted them to generate new knowledge which led to deeper conceptual understanding, thus supporting development of adaptive expertise. However, participants indicated that staff physicians often protect residents from difficult conversations, which limits their opportunity to receive feedback and engage in learning. Residents participate in difficult conversations that challenge them to go beyond their existing knowledge. Providing residents with opportunity to lead difficult conversations with patients and families while being supported by staff supervisors, allows for struggling through learning, which leads to a deeper conceptual understanding and supports development of adaptive expertise.


Aminopeptidase T of M29 Family Acts as A Novel Intracellular Virulence Factor for Listeria monocytogenes Infection.
The foodborne pathogen Listeria monocytogenes employs a number of virulence determinants including metalloproteases to infect hosts. Here for the first time, we identified an M29 family aminopeptidase T (encoded by lmo1603) from L. monocytogenes that possesses a typical feature to catalyze the cleavage of amino acids from peptide substrates, with a preference for arginine. The purified recombinant Lmo1603 was activated by Fe(3+), Zn(2+) and Mn(2+), but strongly stimulated by Co(2+), indicating that Lmo1603 is a cobalt-dependent aminopeptidase. Single mutation at any of the Glu216, Glu281, His308, Tyr315, His327, and Asp329 completely abolished the enzymatic activity of Lmo1603. More importantly, we showed that Lmo1603 was mainly involved in Listeria infection, but not required for growth in rich laboratory medium and minimal defined medium. Disruption of Lmo1603 resulted in almost complete attenuation of Listeria virulence in a mouse infection model. In addition, we demonstrated that Lmo1603 was mainly localized in the bacterial cytosol and required for invasion and survival inside human epithelial cells and murine macrophages. We conclude that Lmo1603 encodes a functional aminopeptidase T of M29 family, which acts as a novel intracellular virulence factor essential in the successful establishment of L. monocytogenes infections in a mouse model.


Is survival rate lower after breast cancer in deprived women according to disease stage?
Socioeconomic deprivation has been associated with lower breast cancer (BC) survival, but the influence of stage at diagnosis on this association merits further study. Our aim was to investigate this association using the Loire-Atlantique/Vendee Cancer Registry (France). Twelve-thousand seven-hundred thirty-eight women living in the area covered by the registry and diagnosed with invasive breast carcinoma between 2008 and 2015 were included in the study. They were censored at maximal 6 years. Deprivation was measured by the French European Deprivation Index. Excess hazard and net survival were estimated for deprivation level, stage and age at diagnosis using a flexible excess mortality hazard model. After adjustment by stage, women living in the most deprived areas had a borderline non-significant higher excess mortality hazard (+25% (95% CI: -3%; +62%)) compared to those living in the least deprived areas. Stage-adjusted 5-year net survival differed significantly between these two subgroups (respectively, 88.2% (95% CI:85.2%-90.5%) and 92.5% (95% CI:90.6%-93.9%)). BC survival remained lower in deprived areas in France, despite universal access to cancer care. Intensification of prevention measures could help to reduce advanced BC, responsible for the majority of deaths from BC. A better understanding of remaining social disparities is crucial to implement specific interventions.


APOBEC: From mutator to editor.
APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) are a family of cytidine deaminases that prefer single-stranded nucleic acids as substrates. Besides their physiological functions, APOBEC family members have been found to cause hypermutations of cancer genomes, which could be correlated with cancer development and poor prognosis. Recently, APOBEC family members have been combined with the versatile CRISPR/Cas9 system to perform targeted base editing or induce hypermutagenesis. This combination improved the CRISPR/Cas9-mediated gene editing at single-base precision, greatly enhancing its usefulness. Here, we review the physiological functions and structural characteristics of APOBEC family members and their roles as endogenous mutators that contribute to hypermutations during carcinogenesis. We also review the various iterations of the APOBEC-CRISPR/Cas9 gene-editing tools, pointing out their features and limitations as well as the possibilities for future developments.


The egghead gene is required for compartmentalization in Drosophila optic lobe development.
The correct targeting of photoreceptor neurons (R-cells) in the developing Drosophila visual system requires multiple guidance systems in the eye-brain complex as well as the precise organization of the target area. Here, we report that the egghead (egh) gene, encoding a glycosyltransferase, is required for a compartment boundary between lamina glia and lobula cortex, which is necessary for appropriate R1-R6 innervation of the lamina. In the absence of egh, R1-R6 axons form a disorganized lamina plexus and some R1-R6 axons project abnormally to the medulla instead of the lamina. Mosaic analysis demonstrates that this is not due to a loss of egh function in the eye or in the neurons and glia of the lamina. Rather, as indicated by clonal analysis and cell-specific genetic rescue experiments, egh is required in cells of the lobula complex primordium which transiently abuts the lamina and medulla in the developing larval brain. In the absence of egh, perturbation of sheath-like glial processes occurs at the boundary region delimiting lamina glia and lobula cortex, and inappropriate invasion of lobula cortex cells across this boundary region disrupts the pattern of lamina glia resulting in inappropriate R1-R6 innervation. This finding underscores the importance of the lamina/lobula compartment boundary in R1-R6 axon targeting.


Neural signatures: multiple coding in spiking-bursting cells.
Recent experiments have revealed the existence of neural signatures in the activity of individual cells of the pyloric central pattern generator (CPG) of crustacean. The neural signatures consist of cell-specific spike timings in the bursting activity of the neurons. The role of these intraburst neural fingerprints is still unclear. It has been reported previously that some muscles can reflect small changes in the spike timings of the neurons that innervate them. However, it is unclear to what extent neural signatures contribute to the command message that the muscles receive from the motoneurons. It is also unknown whether the signatures have any functional meaning for the neurons that belong to the same CPG or to other interconnected CPGs. In this paper, we use realistic neural models to study the ability of single cells and small circuits to recognize individual neural signatures. We show that model cells and circuits can respond distinctly to the incoming neural fingerprints in addition to the properties of the slow depolarizing waves. Our results suggest that neural signatures can be a general mechanism of spiking-bursting cells to implement multicoding.


Pelvic Castleman's Disease Presenting as an Adnexal Mass in an Adolescent.
Castleman disease (CD) is a rare lymphoproliferative disorder that might present as an adnexal mass. We report a case of pelvic CD in an adolescent girl who presented with abdominal pain. A 13-year-old girl presented with severe abdominal pain, nausea, and vomiting, and was found to have a solid adnexal mass. Repeat imaging revealed the mass to be retroperitoneal and in the left pelvic side wall. She underwent surgical removal via an open retroperitoneal approach, and pathology revealed CD, hyaline vascular variant subtype. Pelvic CD should be considered in the differential diagnosis for an adnexal mass in a young woman. Surgical planning is critical because of the possibility of extension and mass effect. Most pelvic CD is unicentric, hyaline vascular variant subtype, and does not recur after surgical removal.


Test characteristics of acridine orange, Gram, and May-Grünwald-Giemsa stains for enumeration of intracellular organisms in bronchoalveolar lavage fluid.
For enumeration of intracellular organisms (ICO) in bronchoalveolar lavage fluid samples, the May-Grünwald-Giemsa (MGG) stain displayed higher interobserver agreement than the acridine orange and Gram stains. The MGG stain offered a reliable enumeration of ICO when 200 cells were counted by one observer.


Techniques for choosing reference points from which to measure eruption rates of rat incisors.
Measurements of eruption rates were compared with a computer analysis of measurements of eruption rates from stable and unstable reference points. In the computer analysis, when the measurements were made from unstable reference points, there were correlations between eruption rates and changes in tooth length and between unimpeded and impeded eruption rates. These correlations were not seen in measurements made from stable reference points. The measurements from unstable reference points had greater variances. These correlations were found in measurements made from the gingival margin of the unimpeded incisor but not in measurements from the margin of the impeded incisor. The measurements from the impeded incisor had a lower variance. The ability was demonstrated of these correlations and variance ratios to detect instability of reference points.


Prognostic significance of the blast self-renewal capacity in patients with acute myeloid leukemia.
The proliferation of leukemic cells in acute myeloid leukemia (AML) is supported by a small subpopulation of leukemic blast progenitors, which can be detected in methylcellulose and suspension cultures. It is important to determine the association between the biologic properties of leukemic blast progenitors and the clinical prognosis of patients with AML. Ninety-five patients with AML and two patients with chronic myelocytic leukemia in blast crisis were studied. T-cell depleted mononuclear cells obtained from the peripheral blood cells were cultured in both methylcellulose and suspension cultures. In methylcellulose culture, primary blast colony formation (PE1) and secondary blast colony formation (PE2) were enumerated. The recovery of clonogenic cells was determined in suspension culture. The association between PE1, PE2, or clonogenic cell recovery in suspension and the remission induction outcome or survival duration of the patients were examined. PE1 was not associated with the remission induction outcome. PE2 and clonogenic cells recovered in suspension were significantly associated with the remission induction. Furthermore, the survival duration of the patients who achieved complete remission was associated significantly with the number of clonogenic cells recovered in suspension. PE1 reflects the terminal divisions of leukemic blast progenitors, whereas PE2 and the recovery of clonogenic cells in suspension culture are considered to reflect the self-renewal of leukemic blast progenitors. The results suggest that the self-renewal capacity of leukemic blast progenitors is predictive of not only remission induction outcome but also survival duration of patients with AML.


Optimizing counterdiabaticity by variational quantum circuits.
Using counterdiabatic (CD) driving-aiming at suppression of diabatic transition-in digitized adiabatic evolution has garnered immense interest in quantum protocols and algorithms. However, improving the approximate CD terms with a nested commutator ansatz is a challenging task. In this work, we propose a technique of finding optimal coefficients of the CD terms using a variational quantum circuit. By classical optimization routines, the parameters of this circuit are optimized to provide the coefficients corresponding to the CD terms. Then their improved performance is exemplified in Greenberger-Horne-Zeilinger state preparation on the nearest-neighbour Ising model. Finally, we also show the advantage over the usual quantum approximation optimization algorithm, in terms of fidelity with bounded time. This article is part of the theme issue 'Shortcuts to adiabaticity: theoretical, experimental and interdisciplinary perspectives'.


Deciphering anti-biofilm property of Arthrospira platensis-origin peptides against Staphylococcusaureus.
Arthrospira platensis is a valuable natural health supplement consisting of various types of vitamins, dietary minerals, and antioxidants. Although different studies have been conducted to explore the hidden benefits of this bacterium, its antimicrobial property has been poorly understood. To decipher this important feature, here, we extended our recently introduced optimization algorithm (Trader) for aligning amino acid sequences associated with the antimicrobial peptides (AMPs) of Staphylococcus aureus and A.platensis. As a result, similar amino acid sequences were identified, and several candidate peptides were generated accordingly. The obtained peptides were then filtered based on their potential biochemical and biophysical properties, and their 3D structures were simulated based on homology modeling techniques. Next, to investigate how the generated peptides can interact with S. aureus proteins (i.e., heptameric state of the hly and homodimeric form of the arsB), molecular docking approaches were used. The results indicated that four peptides included better molecular interactions relative to the other generated ones in terms of the number/average length of hydrogen bonds and hydrophobic interactions. Based on the outcomes, it can be concluded that the antimicrobial property of A.platensis might be associated with its capability in disturbing the membrane of pathogens and their functions.


Stimulation of nuclear receptor REV-ERBs suppresses inflammatory responses in spinal microglia.
As spinal microglia have a critical role in the development of chronic pain, regulation of their activity is essential for pain relief. Previous study has shown that stimulation of the REV-ERB nuclear receptors in the spinal dorsal horn produces antinociception in animal models of both inflammatory and neuropathic pain. However, the involvement of spinal microglia in the antinociceptive action of REV-ERBs remains to be elucidated. In the current study, we found that intrathecal treatment with the REV-ERB agonist SR9009 significantly blocked the increase in ionized calcium-binding adaptor molecule immunoreactivity in the spinal dorsal horn of mice following intrathecal administration of lipopolysaccharide and peripheral sciatic nerve ligation. Furthermore, both Rev-erbα and Rev-erbβ mRNAs were expressed in cultured rat spinal microglia. Treatment of cultured rat spinal microglia with SR9009 significantly blocked the lipopolysaccharide-induced increase in interleukin (IL)-1β and IL-6 mRNA expression. In conclusion, the current findings suggest that REV-ERBs negatively regulate spinal microglial activity and might contribute to the REV-ERB-mediated antinociceptive effect in the spinal dorsal horn.


Development, implementation and evaluation of an information model for archetype based user responsive medical data visualization.
When medical data have been successfully recorded or exchanged between systems there appear a need to present the data consistently to ensure that it is clearly understood and interpreted. A standard based user interface can provide interoperability on the visual level. The goal of this research was to develop, implement and evaluate an information model for building user interfaces for archetype based medical data. The following types of knowledge were identified as important elements and were included in the information model: medical content related attributes, data type related attributes, user-related attributes, device-related attributes. In order to support flexible and efficient user interfaces an approach that represents different types of knowledge with different models separating the medical concept from a visual concept and interface realization was chosen. We evaluated the developed approach using Guideline for Good Evaluation Practice in Health Informatics (GEP-HI). We developed a higher level information model to complement the ISO 13606 archetype model. This enabled the specification of the presentation properties at the moment of the archetypes' definition. The model allows realizing different users' perspectives on the data. The approach was implemented and evaluated within a functioning EHR system. The evaluation involved 30 patients of different age and IT experience and 5 doctors. One month of testing showed that the time required reading electronic health records decreased for both doctors (from average 310 to 220s) and patients (from average 95 to 39s). Users reported a high level of satisfaction and motivation to use the presented data visualization approach especially in comparison with their previous experience. The introduced information model allows separating medical knowledge and presentation knowledge. The additional presentation layer will enrich the graphical user interface's flexibility and will allow an optimal presentation of medical data considering the different users' perspectives and different media used for data presentation.


Phenotypic differentiation of gastrointestinal microbes is reflected in their encoded metabolic repertoires.
The human gastrointestinal tract harbors a diverse microbial community, in which metabolic phenotypes play important roles for the human host. Recent developments in meta-omics attempt to unravel metabolic roles of microbes by linking genotypic and phenotypic characteristics. This connection, however, still remains poorly understood with respect to its evolutionary and ecological context. We generated automatically refined draft genome-scale metabolic models of 301 representative intestinal microbes in silico. We applied a combination of unsupervised machine-learning and systems biology techniques to study individual and global differences in genomic content and inferred metabolic capabilities. Based on the global metabolic differences, we found that energy metabolism and membrane synthesis play important roles in delineating different taxonomic groups. Furthermore, we found an exponential relationship between phylogeny and the reaction composition, meaning that closely related microbes of the same genus can exhibit pronounced differences with respect to their metabolic capabilities while at the family level only marginal metabolic differences can be observed. This finding was further substantiated by the metabolic divergence within different genera. In particular, we could distinguish three sub-type clusters based on membrane and energy metabolism within the Lactobacilli as well as two clusters within the Bifidobacteria and Bacteroides. We demonstrate that phenotypic differentiation within closely related species could be explained by their metabolic repertoire rather than their phylogenetic relationships. These results have important implications in our understanding of the ecological and evolutionary complexity of the human gastrointestinal microbiome.


Stimulation of lipid-linked oligosaccharide assembly during oviduct differentiation.
Regulation of dolichyl phosphate-linked oligosaccharide assembly has been studied during the course of diethylstilbestrol-induced chick oviduct differentiation. Oviduct membranes from treated chicks form 4.6 times as much GlcNAc-P-P-Dol and GlcNAc2-P-P-Dol upon incubation with UDP-[14C]GlcNAc and MgCl2 than do membranes from untreated chicks. Assembly of oligosaccharide-lipid was studied by incubation of membranes with purified exogenous [14C]GlcNAc2-P-P-Dol and GDP-Man. Man transfer required a divalent cation (10 mM Mg2+) and detergent (0.5% Nonidet P-40 is optimal) and occurs in the presence of amphomycin (500 micrograms/ml). The apparent Km for GDP-Man is 1 microM and for [14C]GlcNAc2-P-P-Dol is 0.45 microM. The products are a series of sequentially formed dolichyl pyrophosphate-linked saccharides up to Man5GlcNAc2, the first of which is Man beta 1,4GlcNAc2. The same products are formed either in the presence or absence of amphomycin. Conversion of GlcNAc2-P-P-Dol to higher oligosaccharides is stimulated 3-fold by estrogen treatment of chicks. Similarly, the conversion of partially purified exogenously added Man beta-[14C]GlcNAc2-P-P-Dol is 4.6-fold higher after diethylstilbestrol treatment.


Peptic digestion of beta-casein. Time course and fate of possible bioactive peptides.
Numerous peptides obtained by enzymatic digestion of food proteins have been reported to exhibit biological activities. In this study, the focus was placed on peptides of beta-casein from bovine milk after a gastro-analogous in vitro digestion with pepsin, a protease with broad specificity. In order to study the time course of the digestion, the process was stopped after specific times and the samples were subjected to HPLC separation followed by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) and nanoelectrospray (nanoESI) quadrupole time-of-flight (qTOF) mass spectrometry. A combined sequencing approach using de novo interpretation and databases was employed. Overall, 100% of the beta-casein sequence was covered by identifying 125 peptides of 4-84 residues in length, including 3 phosphorylated species. The results show that the peptic hydrolysis starts at the C-terminus of the protein. The release of known bioactive peptides from beta-casein following the peptic digestion under simulated gastric conditions is unlikely with a few exceptions. Furthermore, an amino acid variation was found, providing evidence for the existence of an additional genetic variant of beta-casein.


Xylazine-ketamine-oxymorphone: an injectable anesthetic combination in swine.
A xylazine, ketamine, and oxymorphone combination was investigated to determine its effectiveness as an injectable anesthetic regimen for use in swine. The combination was found to provide good narcosis, analgesia, and muscle relaxation, and was considered to be adequate for minor surgery. The intravenous dose rate was xylazine, 2mg/kg; ketamine, 2mg/kg; and oxymorphone, 0.075mg/kg. The dose of each component was doubled when the intramuscular route was used.


Intraventricular haemorrhage, CT and arteriographic findings in thirty-five patients.
Thirty-five patients with intraventricular haemorrhage shown by CT underwent cerebral arteriography. In 15 patients arteriography showed an occlusion of a carotid or middle cerebral artery. Secondary bleeding into an infarction caused the intraventricular haemorrhage. All 15 patients were aged over 40 years.


Enhanced production of recombinant Escherichia coli glutamate decarboxylase through optimization of induction strategy and addition of pyridoxine.
This report describes the optimization of recombinant Escherichia coli glutamate decarboxylase (GAD) production from engineered E. coli BL21(DE3) in a 3-L fermentor. Investigation of different induction strategies revealed that induction was optimal when the temperature was maintained at 30°C, the inducer (lactose) was fed at a rate of 0.2 g L(-1)h(-1), and protein expression was induced when the cell density (OD600) reached 50. Under these conditions, the GAD activity of 1273.8 U mL(-1) was achieved. Because GAD is a pyridoxal 5'-phosphate (PLP)-dependent enzyme, the effect of supplementing the medium with pyridoxine hydrochloride (PN), a cheap and stable PLP precursor, on GAD production was also investigated. When the culture medium was supplemented with PN to a concentration of 2mM at the initiation of protein expression, and then again 10h later, the GAD activity reached 3193.4 U mL(-1), which represented the highest GAD production ever reported.


Direct evidence of plant-pathogenic activity of fungal metabolites of Trichothecium roseum on apple.
Apples were exposed to various concentrations of roseotoxins - metabolites of Trichothecium roseum and kinetic fluorescence imaging was used to detect the area influenced by the phytotoxin. Contrast was quantified within these images between the areas exposed to roseotoxins and the untreated areas. It was proved that roseotoxin B is able to penetrate apple peel and produce chlorotic lesions. Activity of roseotoxin B is similar as the activity of destruxins, host specific phytotoxins of Alternaria brassicae parasitic on canola.


Blood management in a patient with anti-Oka antibody who underwent cardiac surgery using cardiopulmonary bypass: a case report.
Cardiac surgery under cardiopulmonary bypass (CPB) is often associated with massive bleeding and blood transfusion. For patients requiring specific blood products, meticulous blood management is critical to reduce blood loss, as well as the need for transfusion. Here, we have described the intraoperative blood management in a patient with anti-Oka antibody, who underwent cardiac surgery with CPB. A 79-year-old woman was scheduled for open aortic valve replacement and tricuspid valve annuloplasty under hypothermic CPB. Her blood type was A RhD(+) Ok(a-), and anti-Oka, an extremely rare antibody against erythrocyte antigen, was detected. Eight units of Ok(a-) frozen thawed red cells (FTRCs), and six units of red blood cells donated by three Ok(a-) individuals were collected just prior to surgery. Although she was anemic, acute normovolemic hemodilution was conducted after anesthesia induction to preserve the autologous whole blood. Four units of FTRCs were loaded in the CPB priming solution, and modified ultrafiltration was adopted during CPB to prevent further hemodilution. After CPB termination, two units of FTRCs, four units of fresh frozen plasma, and ten units of platelet concentrate were intensively transfused, facilitating surgical hemostasis and stable hemodynamics. The autologous whole blood was returned to the patient in the intensive care unit. Since the hemoglobin and hematocrit levels were maintained postoperatively, no additional transfusion was required throughout her hospital stay. Multidisciplinary intraoperative blood management in a patient with anti-Oka antibody facilitated successful cardiac surgery using CPB, along with effective use of limited blood products.


Pathways to similar executive impairment: comparison of schizophrenia patients and healthy aging individuals.
Executive impairment is prominent in schizophrenia, in conditions such as Parkinson's disease and dementia and in healthy aging. Identifying processes that critically constrain executive function can advance investigation of their biological basis and treatment planning. Recent findings that elderly healthy individuals showed similar impairment on conditional exclusion task as schizophrenia patients raised the question whether similar processes are impaired. To test this we compared 56 schizophrenia patients, 57 elderly and 77 young healthy individuals on three executive tests: conditional exclusion, abstraction and inhibition and tests of working memory and psychomotor speed. Schizophrenia patients performed worse than elderly healthy on abstraction, inhibition and verbal working memory. They were similarly impaired on Penn Conditional Exclusion Test (PCET) outcome measures but differed in performance characteristics. Schizophrenia patients needed relatively more trials to learn the first PCET category than the second or the third. This correlated with other cognitive impairments, particularly in working memory. Elderly healthy individuals found it most difficult to learn the last category. The two groups showed different error patterns. We propose that schizophrenia patients have particular difficulty in early (probabilistic) learning ("what to do") while aging individuals have selective impairment in executive integration. These constitute distinct targets for customized treatment in the two conditions.


Fibroblast growth factor receptor 1 and cytokeratin 20 expressions and their relation to prognostic variables in bladder cancer.
Tumor grade and stage are currently the most important prognostic variables in bladder cancer but establishing additional criteria is still needed for effective treatment. The aim of the study was to assess the expression of fibroblast growth factor receptor 1 (FGFR1) and cytokeratin 20 (CK20) in cancer bladder (CB) and to evaluate their association with the clinicopathological features of the disease. The study included 80 patients diagnosed as bladder cancer of different stages and grades and 80 patients with nonmalignant urothelial diseases of matched age and sex to the malignant group. The expressions of FGFR1 and CK20 in tissue samples were determined by RT-PCR and immunohistochemistry. The expression levels of FGFR1 and CK20 were increased in the malignant group when compared to the control group (P<0.001 for each). Analysis of their expression showed that levels of FGFR1 and CK20 were significantly higher in invasive tumor stages (pT2-pT4) than in non-invasive stages (pTis, pTa, pT1) (P<0.001). Interestingly, the sensitivity and specificity of combined detection with CK20 and FGFR1 for the differentiation between invasive and non-invasive stages of bladder cancer reached 97.5% and 92.5%, respectively. Our results determined overexpression of both FGFR1 and CK20 in CB specimens. The alterations in the expression of FGFR1 and CK20 were associated with disease stage and grade. Lastly, combined detection of FGFR1 and CK20 had a high predictive prognostic value in differentiating invasive from non-invasive carcinoma.


18p--syndrome resulting from 14q/18q 'dicentric' fusion translocation.
A child with nasal hypoplasia, growth and developmental delay, and 18p--due to 14q/18q apparent dicentric fusion is reported. Review of ten previously reported patients with 18p--due to fusion translocations involving the long arm of chromosome 18 reveals clinical features ranging from arrhinencephaly to minimal dysmorphic changes and mild retardation. This spectrum of clinical expression is similar to that seen in patients with partial 18p deletions. Since the same range of clinical features is observed whether there is partial or apparent total deletion of 18p, it is suggested that only a distal segment of the short arm of chromosome 18 may be etiologically related to the clinical phenotype in the 18p--syndrome.


Colitis cystica profunda: a pediatric case report.
A case of colitis cystica profunda in a 14-year-old male is presented. The clinical and pathologic management are reviewed. Differentiation from adenocarcinoma by careful histologic evaluation of the epithelium is fundamental in avoiding overtreatment.


Cytokine and eicosanoid regulation by Schistosoma mansoniduring LSE penetration.
Cercarial penetration, in low to moderate numbers, does not cause a normal skin inflammatory response; therefore, the authors sought to determine whether cercariae can down-regulate keratinocyte activation and thus the secretion of pro-inflammatory cytokines and eicosanoids. Human living skin equivalent (LSE, Organogenesis) consisting of dermal, epidermal and stratum corneum-like layers was used as the skin substrate. The surface of the LSE membrane was exposed to 100 ng IFNgamma or ~850 cercariae for 18 h. Incubation media and tissue was then assayed for IL-1alpha, IL-6, IL-8, TNFalpha, 5-HETE, 12-HETE, PGF(2), LTB(4), and LTC(4) via RIA and Western Blots. TNFalpha was not detected. Secreted IL-1alpha levels were (mean +/- S.E.M. (n)): Control, 1.03 ng +/- 0.15 (11); IFNgamma 1.90 ng +/- 0.48 (5); cercariae, 1.79 ng +/- 0.22 (22). In spite of this increase, cercariae down-regulated IL-8 (cercariae 11.13 +/- 1.70 ng vs. IFNgamma = 16.47 +/- 0.29 ng, p = 0.04) and LTB(4) (cercariae = 98.86 +/- 19.65 pg/0.1 ml vs. IFNgamma = 193.42 +/- 44.21 pg/0.1 ml p = 0.02). No changes were seen in IL-6, 12-HETE, 5-HETE, and PGE(2) levels. It is concluded that cercarial penetration causes a release of IL-1alpha consistent with skin trauma; however, schistosomulae may regulate the production of chemotactic (neutrophils, macrophages, T-cells, etc.) and activation factors such as IL-8 and LTB(4).


Skeletal stem cell and bone implant interactions are enhanced by LASER titanium modification.
To evaluate the osteo-regenerative potential of Titanium (Ti) modified by Light Amplification by Stimulated Emission of Radiation (LASER) beam (Yb-YAG) upon culture with human Skeletal Stem Cells (hSSCs(1)). Human skeletal cell populations were isolated from the bone marrow of haematologically normal patients undergoing primary total hip replacement following appropriate consent. STRO-1(+) hSSC(1) function was examined for 10 days across four groups using Ti discs: i) machined Ti surface group in basal media (Mb(2)), ii) machined Ti surface group in osteogenic media (Mo(3)), iii) LASER-modified Ti group in basal media (Lb(4)) and, iv) LASER-modified Ti group in osteogenic media (Lo(5)). Molecular analysis and qRT-PCR as well as functional analysis including biochemistry (DNA, Alkaline Phosphatase (ALP(6)) specific activity), live/dead immunostaining (Cell Tracker Green (CTG(7))/Ethidium Homodimer-1 (EH-1(8))), and fluorescence staining (for vinculin and phalloidin) were undertaken. Inverted, confocal and Scanning Electron Microscopy (SEM) approaches were used to characterise cell adherence, proliferation, and phenotype. Enhanced cell spreading and morphological rearrangement, including focal adhesions were observed following culture of hSSCs(1) on LASER surfaces in both basal and osteogenic conditions. Biochemical analysis demonstrated enhanced ALP(6) specific activity on the hSSCs(1)-seeded on LASER-modified surface in basal culture media. Molecular analysis demonstrated enhanced ALP(6) and osteopontin expression on titanium LASER treated surfaces in basal conditions. SEM, inverted microscopy and confocal laser scanning microscopy confirmed extensive proliferation and migration of human bone marrow stromal cells on all surfaces evaluated. LASER-modified Ti surfaces modify the behaviour of hSSCs.(1) In particular, SSC(1) adhesion, osteogenic gene expression, cell morphology and cytoskeleton structure were affected. The current studies show Ti LASER modification can enhance the osseointegration between Ti and skeletal cells, with important implications for orthopaedic application.


Human monoclonal antibody-based quantification of group 2 grass pollen allergens.
Grasses belong to the most potent allergen sources worldwide. Group 2 grass pollen allergens are recognized by more than 100 million allergic patients. The aim was to develop an assay for the specific detection and quantification of group 2 grass pollen allergens. We have isolated a monoclonal human IgE Fab specific for group 2 grass pollen allergens by combinatorial cloning from lymphocytes of a grass pollen-allergic patient. This Fab was converted into a complete human IgG1 antibody and used together with rPh1 p 2 to develop a competitive ELISA for the specific measurement of group 2 allergens. ELISA plate-bound purified recombinant human Ph1 p 2-specific IgG1 is incubated with a constant amount of biotinylated rPh1 p 2 competing with increasing concentrations of group 2 allergens to be determined. Defined concentrations of purified rPhl p 2 are used to establish a standard curve. The concentration of unlabeled group 2 allergens can thus be deduced from the displacement of biotinylated rPh1 p 2, which can be detected with peroxidase-labeled streptavidin. The competition-ELISA measured rPh1 p 2 concentrations ranging from 10 ng/mL to 500 ng/mL and allowed to quantify group 2 allergens from 9 different grass families. The results were in good agreement with immunoblot data. The described assay can be used for standardization of diagnostic and therapeutic vaccines as well as for the quantification of group 2 allergens in environmental samples.


Serosurvey of antibodies against zoonotic pathogens in free-ranging wild canids (Cerdocyon thous and Lycalopex gymnocercus) from Southern Brazil.
The expansion of urbanization on natural areas is increasing contact between human populations with wild animals. Wild carnivores can act as sentinel hosts or environmental health indicators. Thus, the aim of this work was to investigate the exposure of two major species of wild canids from Southern Brazil to selected pathogens. For that, we live-trapped free-ranging Cerdocyon thous and Lycalopex gymnocercus in five localities and determined the frequency of animals with antibodies against Toxoplasma gondii, Trypanosoma cruzi, Leishmania infantum, Neospora caninum, and Leptospira spp. Among the canids sampled, 23% (12/52) (95%CI: 13-36%) had antibodies against T. gondii, with titers ranging from 64 to 512. For T. cruzi, 28% (15/52) (95%CI: 18-42%) of sampled canids were seropositive, with titers ranging from 8 to 64. Concerning the protozoan pathogen N. caninum, a total of 5% (3/52) (95%CI: 2-15%) of wild canids had antibodies against it. None of the sampled canids showed the presence of antibodies against L. infantum. On the other hand, 44% (23/52) (95%CI: 31-57%) of the wild canids showed antibodies against Leptospira spp. The set of results presented here, show that free-ranging neotropical wild canids are exposed and have antibodies against to T. gondii, T. cruzi, Leptospira spp., and to a lesser degree to N. caninum. We found no evidence of L. infantum circulation among the studied populations. These results highlight some of the major pathogens which may represent risks for populations of these wild canids. DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available from the corresponding author upon reasonable request.


Adenine aminohydrolase from Leishmania donovani: unique enzyme in parasite purine metabolism.
Adenine aminohydrolase (AAH) is an enzyme that is not present in mammalian cells and is found exclusively in Leishmania among the protozoan parasites that infect humans. AAH plays a paramount role in purine metabolism in this genus by steering 6-aminopurines into 6-oxypurines. Leishmania donovani AAH is 38 and 23% identical to Saccharomyces cerevisiae AAH and human adenosine deaminase enzymes, respectively, catalyzes adenine deamination to hypoxanthine with an apparent K(m) of 15.4 μM, and does not recognize adenosine as a substrate. Western blot analysis established that AAH is expressed in both life cycle stages of L. donovani, whereas subcellular fractionation and immunofluorescence studies confirmed that AAH is localized to the parasite cytosol. Deletion of the AAH locus in intact parasites established that AAH is not an essential gene and that Δaah cells are capable of salvaging the same range of purine nucleobases and nucleosides as wild type L. donovani. The Δaah null mutant was able to infect murine macrophages in vitro and in mice, although the parasite loads in both model systems were modestly reduced compared with wild type infections. The Δaah lesion was also introduced into a conditionally lethal Δhgprt/Δxprt mutant in which viability was dependent on pharmacologic ablation of AAH by 2'-deoxycoformycin. The Δaah/Δhgprt/Δxprt triple knock-out no longer required 2'-deoxycoformycin for growth and was avirulent in mice with no persistence after a 4-week infection. These genetic studies underscore the paramount importance of AAH to purine salvage by L. donovani.


Effect of Klebsiella ozaenae on ciliary activity in vitro: implications in the pathogenesis of atrophic rhinitis.
Klebsiella ozaenae is a gram-negative rod that has been isolated with relative frequency from patients with atrophic rhinitis. The relationship of this bacterium to the pathogenesis of atrophic rhinitis is not understood, and whether this bacterium is simply an opportunistic colonizer of the injured nose or the etiologic agent of the disease is unclear. This study was designed to investigate a potential role for bacterially produced cilioinhibition as a mechanism for the pathogenesis of atrophic rhinitis.


Metal-Free Photochemical Radical Cyclization for the Synthesis of Pyrrolo[3,2-c]-quinolines with One-Carbon Unit.
An efficient and environmentally-friendly method for carbon-centered radical cyclization of olefins via visible light photoredox catalysis to afford pyrrolo[3,2-c]-quinolines, oxindoles and quinoline-2,4-diones is described. This novel reaction successfully activated the α C-H bonds in one-carbon units such as esters, chlorinated hydrocarbons and cyano compounds via HAT (hydrogen atom transfer) process by means of aryldiazonium salts. The transformation features good functional group tolerance, broad substrate scope, high atom economy, no need for transition metal or high temperature.


Labelless impedance immunosensor based on polypyrrole-pyrolecarboxylic acid copolymer for hCG detection.
In this work, a sensitive label-free impedimetric hCG-immunosensor was constructed by using a commercial screen-printing carbon ink electrode (namely disposable electrochemical printed chip) as the basis. The carbon ink electrode of DEP chip is modified first by deposition of polypyrrole-pyrole-2-carboxylic acid copolymer and thence hCG antibody immobilization via the COOH groups of pyrrole-2-carboxylic acid, which can serve as a linker for covalent biomolecular immobilization. The experimental results exposed that the designed immunosensor is more sensitive than other previously reported immunosensors, in the case of detection limit and linear range for antigen detection. With optimal fabrication parameters, the detection limit for α-hCG was 2.3 pg/mL in 10mM phosphate buffer saline (PBS) solution containing 1% bovine serum albumine (BSA). Moreover, the use of inexpensive DEP chip as a basis for these immunosensors will allow for simple instrumentation, disposable and portable at low cost. This work also demonstrates a new approach to develop a sensitive and label-free impedimetric immunosensor based on screen-printed electrode for applications in clinical diagnosis.


Solution-Processed All-Ceramic Plasmonic Metamaterials for Efficient Solar-Thermal Conversion over 100-727 °C.
Low-cost and large-area solar-thermal absorbers with superior spectral selectivity and excellent thermal stability are vital for efficient and large-scale solar-thermal conversion applications, such as space heating, desalination, ice mitigation, photothermal catalysis, and concentrating solar power. Few state-of-the-art selective absorbers are qualified for both low- (<200 °C) and high-temperature (>600 °C) applications due to insufficient spectral selectivity or thermal stability over a wide temperature range. Here, a high-performance plasmonic metamaterial selective absorber is developed by facile solution-based processes via assembling an ultrathin (≈120 nm) titanium nitride (TiN) nanoparticle film on a TiN mirror. Enabled by the synergetic in-plane plasmon and out-of-plane Fabry-Pérot resonances, the all-ceramic plasmonic metamaterial simultaneously achieves high, full-spectrum solar absorption (95%), low mid-IR emission (3% at 100 °C), and excellent stability over a temperature range of 100-727 °C, even outperforming most vacuum-deposited absorbers at their specific operating temperatures. The competitive performance of the solution-processed absorber is accompanied by a significant cost reduction compared with vacuum-deposited absorbers. All these merits render it a cost-effective, universal solution to offering high efficiency (89-93%) for both low- and high-temperature solar-thermal applications.


Infection levels of Gnathostomatidae (Nematoda) larvae in commercial fishes in north-eastern Australian waters and related food safety concerns.
The majority of research on the safety of marine edible fish has primarily focused on anisakid nematodes, neglecting the potential risks posed by other parasites, including those belonging to the family Gnathostomatidae. In Australia, there have been few reported cases of human infections with gnathostomatid parasites since 2011. However, due to the absence of a standardized diagnostic test in the country, it is believed that the actual number of infections is higher than reported. This study aimed to assess the occurrence and prevalence of infectious gnathostomatid parasites in selected commercial fish species in Australia. A total of 1947 marine fish from northern Australia, representing 9 families, 16 genera, and 30 species, were examined for gnathostomatid nematode infections. Overall, 12.3 % of the fish were found to be infected with at least one gnathostomatid larva. Among the species examined, the yellow-dabbled flounder (Branchypleura novaezeelandiae) exhibited the highest prevalence (83.3 %; n = 6) and the largest number of gnathostomatid larvae. The identification of the gnathostomatid larvae was confirmed as belonging to the genus Echinocephalus based on both morphological characteristics and sequence data. No significant correlation was observed between the prevalence, mean abundance, and mean intensity of infection with the length or weight of the examined fish species. Notably, several of the infected fish species are considered popular choices in the Australian market. Hence, it is imperative to raise awareness among relevant food safety authorities regarding the occurrence of these parasites. The findings from this study should be taken into consideration for the revision of current seafood safety protocols in the country.


Buffer standards for the physiological pH of N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) from (278.15 to 328.15) K.
This paper reports the results for the pH of six buffer solutions free of chloride ion with compositions: (a) BES (0.03 mol·kg(-1)) + NaBES (0.09 mol·kg(-1)); (b) BES (0.02 mol·kg(-1)) + NaBES (0.04 mol·kg(-1)); (c) BES (0.04 mol·kg(-1)) + NaBES (0.08 mol·kg(-1)); (d) BES (0.04 mol·kg(-1)) + NaBES (0.04 mol·kg(-1)) (e) BES (0.05 mol·kg(-1)) + NaBES (0.05 mol·kg(-1)); and (f) (0.06 mol·kg(-1)) + NaBES (0.06 mol·kg(-1)). The remaining eight buffer solutions (g) to (n) have saline media of the ionic strength I = 0.16 mol·kg(-1), matching closely to that of the physiological sample. Conventional pa(H) values, designated as pH(s), for all six buffer solutions (a) - (f) without the chloride ion and eight buffer solutions with the chloride ion (g) - (n) at I = 0.16 mol·kg(-1) from (278.15 K to 328.15) K have been calculated. The operational pH values for five buffer solutions at T = 298.15 K and T = 310.15 K have been determined based on the difference in the values of the liquid junction potentials between the blood phosphate standard and the experimental buffer solutions. Five of these buffers are recommended as secondary standards for the physiological pH range 7.5 to 8.5.


Compassion for others, self-compassion, quality of life and mental well-being measures and their association with compassion fatigue and burnout in student midwives: A quantitative survey.
compassion fatigue and burnout can impact on the performance of midwives, with this quantitative paper exploring the relationship between self-compassion, burnout, compassion fatigue, self-judgement, self-kindness, compassion for others, professional quality of life and well-being of student midwives. a quantitative survey measured relationships using questionnaires: (1) Professional Quality of Life Scale; (2) Self-Compassion Scale; (3) Short Warwick and Edinburgh Mental Well-being Scale; (4) Compassion For Others Scale. a purposive and convenience sample of student midwives (n=103) studying at university participated in the study. just over half of the sample reported above average scores for burnout. The results indicate that student midwives who report higher scores on the self-judgement sub-scale are less compassionate towards both themselves and others, have reduced well-being, and report greater burnout and compassion fatigue. Student midwives who report high on measures of self-compassion and well-being report less compassion fatigue and burnout. student midwives may find benefit from 'being kinder to self' in times of suffering, which could potentially help them to prepare for the emotional demands of practice and study. developing, creating and cultivating environments that foster compassionate care for self and others may play a significant role in helping midwives face the rigours of education and clinical practice during their degree programme.


Comparative study of 3 types of toothbrushes in patients with fixed orthodontic appliances.
Plaque and trapped debris that accumulate gingivally to orthodontic wire are difficult to remove. The triple-headed toothbrush (TH-TB) was designed to reach the gingival tooth margin. In this study, we examined its effectiveness in improving the oral health of orthodontic patients as compared with conventional and orthodontic toothbrushes. Orthodontic patients (n = 94; mean age, 15.6 +/- 3.9 years) receiving edgewise treatment in both arches were randomly assigned to 1 of 3 groups (TH-TB, orthodontic toothbrush, and conventional toothbrush). After toothbrushing instruction, each participant received professional tooth cleaning. Tooth plaque index, bracket plaque index, gingival index, and bleeding index were recorded at baseline and after 4 weeks of usage. Satisfaction level was obtained after 4 weeks. The TH-TB was significantly more effective than conventional and orthodontic toothbrushes in tooth-plaque removal by 2-fold and 1.5-fold, respectively (P < .001); in bracket-plaque removal by 3-fold and 2-fold, respectively (P < .001); and in improving gingival health by 6-fold and 1.5-fold, respectively (P = .011). Patients who used the TH-TB were significantly more satisfied than those who used the other toothbrushes (P < .001). The TH-TB is a practical alternative to other manual toothbrushes to improve tooth and gingival health in orthodontic patients wearing fixed appliances.


Point mutations in the topoisomerase I gene in patients with non-small cell lung cancer treated with irinotecan.
Reverse transcription polymerase chain reaction (RT-PCR) single-strand conformation polymorphism analysis was used to detect topoisomerase I (top1) mutations in total RNA from 16 specimens that were excised during surgery from eight patients with non-small cell lung cancer (NSCLC) who had received preoperative chemotherapy consisting of irinotecan (CPT-11) and cisplatin. PCR single-strand conformation polymorphism and subsequent DNA sequencing analysis showed two nucleotide substitutions resulting in Trp736stop (TGG to TGA) and Gly737Ser (GGT to AGT) in one tumor specimen. The mutations were located near a site in top1 that was previously reported to harbor a mutation in the human lung cancer cell line PC7/CPT, which was selected for CPT resistance. These results demonstrate that mutations in top1 occur after chemotherapy with CPT-11 in NSCLC patients and suggest that development of resistance to CPT-11 in some patients may involve mutation of top1. However, the significance of top1 mutations to CPT resistance needs to be further investigated.


Immunocytochemical identification of human chorionic gonadotropin- and alpha-fetoprotein-producing cells of hepatoblastoma associated with precocious puberty.
A one-year-five-month-old boy with hepatoblastoma producing both human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) is presented. Histologically, the primary tumor was mainly composed of well differentiated hepatoblastoma cells, with minor areas of poorly differentiated cells. Immunoperoxidase staining of the tumor for hCG and AFP showed that a few well differentiated, fetal type cells and multinucleated giant cells were positive for hCG, and AFP was never stained in the same cells. In areas where cells were poorly differentiated, positive reactions for either hCG or AFP were not observed. Electron microscopic studies revealed focal aggregates of cytoplasmic cored vesicles in some tumor cells, similar to secretory granules.


Identification of intestinal metabolic activation of loganin generated dialdehyde reactive intermediates improves intestinal bile salt hydrolase activities.
Loganin is an iridoid with potent pharmacological effects. Loganin contains a hemiacetal structure and can convert to dialdehyde intermediates after deglycosylation. We hypothesized that the metabolites of loganin with hemiacetal can generate reactive dialdehyde intermediates. This study aims to characterize the metabolic profiling of loganin and especially for the unstable dialdehyde intermediates by using ultra-performance liquid chromatograph-quadrupole orbitrap mass spectrometry. In this study, a total of 26 stable metabolites were identified in loganin-treated rats. Loganin underwent different metabolism in the intestine and liver, which was confirmed mainly by the metabolites in the hepatic portal vein. In the intestine, the major metabolic pathways were ester hydrolysis and deglycosylation, followed by methylation and dehydrogenation. The hepatic metabolism pathways were hydrogenation, hydroxylation, glucuronidation, and sulfonation. The circulating metabolites with high abundance were mainly derived from intestinal metabolism. Importantly, 11 unstable dialdehyde intermediates of loganin were identified and described for the first time. The dialdehyde intermediates were identified by their dihydropyridine conjugates with amino acids. The dialdehyde intermediates were mainly produced in the intestine. The dialdehyde intermediates enable covalent modification of intestinal proteins. Loganin can up-regulate the activity of intestinal bile salt hydrolase (BSH), catalyzing bile acid metabolism. The level of protein adducts was positively associated with BSH activity, indicating dialdehyde intermediates played a key role in the up-regulation of BSH activities. In conclusion, this study not only demonstrates the characteristic metabolic fate of loganin but also facilitates the understanding of the pharmacologic effects of dialdehyde intermediates.


Assessing attitudes about hate: Further validation of the hate crime beliefs scale.
The Hate Crime Beliefs Scale (HCBS) is an assessment of attitudes about hate crime laws, offenders, and victims. The original HCBS includes four subscales (negative beliefs, offender punishment, deterrence, and victim harm), while a shortened and modified version from the United Kingdom (UK; HCBS-UK) consists of three subscales (denial, sentencing, and compassion). We conducted a psychometric test of the HCBS in order to identify a best fitting structure with possible item reduction. A total of 463 participants completed the original HCBS, measures of social dominance orientation (SDO) and right-wing authoritarianism (RWA), and demographic questions. Factor analyses revealed good fit of the data for a Hate Crime Beliefs Scale-Short Form (HCBS-SF), largely modeled after the HCBS-UK. The three subscales were: denial (i.e., downplaying hate crime severity and low support for hate crime laws), sentencing (i.e., support for more punitive offender punishment), and compassion (i.e., understanding and concern for victims). All subscales possessed acceptable internal consistency. The denial subscale was positively associated with RWA subscale and SDO scores. The sentencing and compassion subscales were significantly negatively correlated with SDO and RWA subscale scores. Republicans held the least supportive views of hate crime laws, concern for victims, and punishment of offenders. Data underscore the importance of evaluating hate crime beliefs in public opinion and other contexts. The HCBS-SF better captures hate crime related attitudes than the previously developed longer version of the HCBS.


Lipid nanoparticle-based mRNA delivery systems for cancer immunotherapy.
Cancer immunotherapy, which harnesses the power of the immune system, has shown immense promise in the fight against malignancies. Messenger RNA (mRNA) stands as a versatile instrument in this context, with its capacity to encode tumor-associated antigens (TAAs), immune cell receptors, cytokines, and antibodies. Nevertheless, the inherent structural instability of mRNA requires the development of effective delivery systems. Lipid nanoparticles (LNPs) have emerged as significant candidates for mRNA delivery in cancer immunotherapy, providing both protection to the mRNA and enhanced intracellular delivery efficiency. In this review, we offer a comprehensive summary of the recent advancements in LNP-based mRNA delivery systems, with a focus on strategies for optimizing the design and delivery of mRNA-encoded therapeutics in cancer treatment. Furthermore, we delve into the challenges encountered in this field and contemplate future perspectives, aiming to improve the safety and efficacy of LNP-based mRNA cancer immunotherapies.


15N tracer techniques for the differential diagnosis of dwarfism and prediction of growth hormone action in children.
[15N]Glycine in a single oral dose was used to study nitrogen turnover in 18 short children, aged 3-14 yr. On the basis of their serum GH responses to insulin-induced hypoglycemia, the patients were divided into 3 groups: complete GH deficiency (GHD; n = 5); partial GH deficiency (pGHD; n = 6), and children with constitutional growth delay and familial short stature (CGD/FSS; n = 7). The mean 48-h renal excretion of 15N by patients with GHD was 66.09 +/- 14.12% (+/- SD) of the tracer dose. This decreased to 27.64 +/- 5.33% after two injections of 10 IU/m2 GH (P less than 0.001). 15N excretion by patients with pGHD was 47.19 +/- 13.42%, and it decreased after GH injection to 22.69 +/- 4.58% (P less than 0.005). Patients with CGD/FSS had 15N excretion of 37.27 +/- 5.68%, and it did not change in response to GH. The mean protein synthesis rate in GHD patients was extremely low, and it increased after GH injection from 0.99 +/- 0.46 to 3.53 +/- 0.43 g/kg X day. In pGHD patients the protein synthesis rate increased from 2.62 +/- 0.84 to 4.50 +/- 1.09 g/kg X day. The CGD/FSS patients had no change in protein synthesis rate after GH. Our results suggest that studies of the metabolism of [15N]glycine might be of value in predicting responsiveness to GH therapy.


Generalist vs specialist acute medical admissions - What is the impact of moving towards acute medical subspecialty admissions on efficacy of care provision?
The discussion surrounding generalist versus specialist acute medical admissions continues to stimulate debate and patients with certain conditions benefit from specialist care. To determine whether a specialty medical admission program would reduce inpatient length of stay (LOS), mortality and readmission rates. A prospective cohort study of inpatients admitted under a general internal medicine (GIM) service before and after introduction of a specialty-directing programme. We hypothesized that early transfer of patient care to a specialty suited to their presenting complaint would reduce LOS and a specialty-directing early redistribution of care programme was introduced. Seven of the ten clinical teams participating in the GIM roster adopted the programme. On the morning following a specialty-directing team being on call for all new GIM admissions during a 24-hour period, specialty-directing teams were allocated one patient appropriate to their specialty. 5,144 patient-care episodes were analysed over the two-year study period. LOS increased by greater than 15%, one year after introducing the specialty-directing programme (8.5±8.4 vs 7.3±7.5 days, p < 0.001). LOS did not differ between teams that participated and those who did not (8.4±8.1 vs 8.1±7.9 days, p = 0.298). No differences were found in the proportion of patients who were discharged home, died while an inpatient or re-admitted within 30 days of discharge. The proportion of patients aged greater than 80 years increased significantly also - from 24.7% in 2017 to 27.9% in 2019(p == 0.009). Widespread adoption of specialist care may not be beneficial for all medical inpatients and physicians should continue to undergo dual specialist and GIM training.


Efficient natural pyrrhotite activating persulfate for the degradation of O-isopropyl-N-ethyl thionocarbamate: Iron recycle mechanism and degradation pathway.
Natural pyrrhotite (NP) shows promising future in activating persulfate (PS) due to its easy availability at a low cost and easy separation. This study discussed the degradation of O-isopropyl-N-ethyl thionocarbamate (IPETC) in NP/PS system. NP-PS system showed the best IPETC mineralization at the initial pH of 6.0 (62.84%). The kinetics study suggested that the IPETC degradation followed the pseudo-first-order equation in the NP-PS system. NP-PS system worked better in bottled water (96.46%) and tap water (85.14%) than river water (31.28%). Combined with Fourier transform-infrared spectroscopy, gas chromatography-mass spectrometry and computational calculation, the degradation products, including acetone, formic acid isopropyl ester and ethylamine, were identified and the degradation pathway of IPETC in NP-PS system was proposed. The S, O and N atoms in IPETC are easier to be attacked by. SO4-Ethylamine and reduced S ions coordinately worked to recycle Fe2+ in NP/PS/IPETC system.


Gas chromatographic determination with flash methylation of palmitic acid in amniotic fluid in prediction of fetal lung maturity.
A new method for determination of palmitic acid in amniotic fluid was developed. The dipalmitoyl lecithin was hydrolysed, and after extraction the palmitic acid was flash methylated in the injector of the gas chromatograph. The between batch coefficient of variation was 6.0% at 40 and 70 mumol/l of palmitic acid concentrations in 500 microliters amniotic fluid. The accuracy of the method was demonstrated by linearity, recovery and correlation studies. The correlation coefficient was 0.98 between the new and bortrifluoride methylating method. The concentrations of lecithin and palmitic acid in amniotic fluid showed a correlation coefficient of 0.97. If the concentration of palmitic acid falls below 80 mumol/l respiration distress syndrome is likely. The new method was simple and easy to carry out and could be adjusted for haemoglobin contamination of the amniotic fluid. It was concluded that the determination of palmitic acid in amniotic fluid was a reliable method for the assessment of fetal lung maturity that could replace the determination of lecithin concentration.


Chemometric assisted solid-phase microextraction for the determination of anti-inflammatory and antiepileptic drugs in river water by liquid chromatography-diode array detection.
In the present work, an analytical method for the simultaneous determination of seven non steroidal anti-inflammatory drugs (naproxen, ketoprofen, diclofenac, piroxicam, indomethacin, sulindac and diflunisal) and the anticonvulsant carbamazepine is reported. The method involves preconcentration and clean-up by solid-phase microextraction using polydimethylsiloxane/divinylbenzene fibers, followed by liquid chromatography with diode array detection analysis. Parameters that affect the efficiency of the solid-phase microextraction step such as soaking solvent, soaking period, desorption period, stirring rate, extraction time, sample pH, ionic strength, organic solvent and temperature were investigated using a Plackett-Burman screening design. Then, the factors presenting significant positive effects on the analytical response (soaking period, stirring rate, stirring time) were considered in a further central composite design to optimize the operational conditions for the solid phase microextraction procedure. Additionally, multiple response simultaneous optimization by using the desirability function was used to find the optimum experimental conditions for the on-line solid-phase microextraction of analytes in river water samples coupled to liquid chromatography and diode array detection. The best results were obtained using a soaking period of 5 min, stirring rate of 1400 rpm and stirring time of 44 min. The use of solid-phase microextraction technique avoided matrix effect and allowed to quantify the analytes in river water samples by using Milli-Q based calibration graphs. Recoveries ranging from 71.6% to 122.8% for all pharmaceuticals proved the accuracy of the proposed method in river water samples. Method detection limits were in the range of 0.5-3.0 microgL(-1) and limits of quantitation (LOQs) were between 1.0 and 4.0 microgL(-1) for pharmaceutical compounds in river water samples. The expanded uncertainty associated to the measurement of the concentration ranged between 8.5% and 29.0% for 20 microgL(-1) of each analyte and between 9.0% and 29.5% for the average of different concentration levels. The main source of uncertainty was the calibration step in both cases.


Keyhole and zero-padding approaches for reduced-encoding diffusion tensor imaging of the mouse brains.
Keyhole diffusion tensor imaging (keyhole DTI) was previously proposed in cardiac imaging to reconstruct DTI maps from the reduced phase-encoding images. To evaluate the feasibility of keyhole DTI in brain imaging, keyhole and zero-padding DTI algorithms were employed on in vivo mouse brain. The reduced phase-encoding portion, also termed as the sharing rate, was varied from 50% to 90% of the full k-space. Our data showed that zero-padding DTI resulted in decreased fractional anisotropy (FA) and decreased mean apparent diffusion coefficient (mean ADC) in white matter (WM) regions. Keyhole DTI showed a better edge preservation on mean ADC maps but not on FA maps as compared to the zero-padding DTI. When increasing the sharing rate in keyhole approach, an underestimation of FA and an over- or underestimation of mean ADC were measured in WM depending on the selected reference image. The inconsistency of keyhole DTI may add a challenge for the wide use of this modality. However, with a carefully selected directive diffusion-weighted image to serve as the reference image in the keyhole approach, this study demonstrated that one may obtain DTI indices of reduced-encoding images with high consistency to those derived with full k-space DTI.


Determination of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole) in blood and urine by chemical ionization-mass fragmentography.
A combined gas chromatographic-mass spectrometric technique is described for the quantification of virazole in serum and urine. Proteins are removed by molecular filtration, lipids by extraction with dichloromethane and interfering endogenous constituents by acidic and basic ion-exchange resins. Virazole is quantified by monitoring the protonated molecular ions of the fully silylated derivatives of virazole (m/e 533) and the arabinose analog (internal standard) obtained by methane chemical ionization. The detection limit is 150 pg (0.6.10(-12) mole) of virazole injected. In serum 10 ng/ml (4.10(-8) mole) can be detected, 25 ng/ml quantified. In urine 0.5 microgram/ml can be quantified without preconcentration. Virazole was detected in serum for at least 96 h at the 70-ng/ml level.


Survival prediction for gallbladder carcinoma after curative resection: Comparison of nomogram and Bayesian network models.
In this study, we developed a nomogram and a Bayesian network (BN) model for prediction of survival in gallbladder carcinoma (GBC) patients following surgery and compared the performance of the two models. Survival prediction models were established and validated using data from 698 patients with GBC who underwent curative-intent resection between 2008 and 2017 at one of six Chinese tertiary hospitals. Model construction and internal validation were performed using data from 381 patients at one hepatobiliary center, and external validation was then performed using data from 317 patients at the other five centers. A BN model and a nomogram model were constructed based on the independent prognostic variables. Performance of the BN and nomogram models was compared based on area under receiver operating characteristic curves (AUC), model accuracy, and a confusion matrix. Independent prognostic variables included age, pathological grade, liver infiltration, T stage, N stage, and margin. In internal validation, AUC was 84.14% and 78.22% for the BN and nomogram, respectively, and model accuracy was 75.65% and 72.17%, respectively. In external validation, AUC was 76.46% and 70.19% for the BN and nomogram, respectively, with model accuracy of 66.88% and 60.25%, respectively. Based on the confusion matrix, the nomogram had a higher true positive rate but a substantially lower true negative rate compared to the BN. A BN model was more accurate than a Cox regression-based nomogram for prediction of survival in GBC patients undergoing curative-intent resection.


The impact of urbanization and wealth on house dust mite sensitization in children from north-central Nigeria.
The impact of socio-economic status on the risk of allergy in African children is not clear.This was a cross sectional study including children aged 6-14 years from urban and rural settings in north-central Nigeria. Participants underwent skin prick tests to house dust mite (HDM) and an interview investigating socio-economic status through the Family Affluence Scale (FAS) based on a score of 0-6.A total of 346 children were enrolled (52.8% boys; mean age ± SD 9.6 ± 2.0 years), including 142 (41% of total) rural and 204 (59% of total) urban pupils. Prevalence of HDM sensitivity was 2.8% (4/142) in the rural setting and 15.6% (32/204) in the urban setting (P < 0.001). Among urban children, frequency of HDM sensitization was 8.6% (7/81) in the lowest socio-economic group (FAS 0-1), 13.1% (8/61) in the intermediate one (FAS 2-3) and 27.4% (17/62) in the highest one (FAS ≥ 4).Urbanization and increasing wealth are associated with a higher frequency of sensitization to HDM in Nigerian children.


Mesonephric-like adenocarcinoma arising from endometrioid adenofibroma in a patient with in-utero exposure to diethylstilbestrol: A case report.
Mesonephric-like adenocarcinomas are newly classified rare neoplasms of the upper genital tract. They share identical features with mesonephric adenocarcinomas, with the exception of location. There is ongoing discussion on whether mesonephric-like adenocarcinomas arise from mesonephric remnants or are of Müllerian origin. A 65-year-old woman (G2P1) presented with pelvic pain. Transvaginal ultrasound revealed multiple fibroids, and a robotic total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was planned. Intraoperatively, a complex mass with cystic and solid components was found on the left ovary, which also adhered to the rectosigmoid colon. Pathologic reports documented mesonephric-like adenocarcinoma that appeared to be arising in association with an endometrioid adenofibroma. This case is notable due to the patient's unique background of in-utero exposure to diethylstilbestrol (DES) and multiple gynecological malignancies within her mother, as well as the associated endometrioid adenofibroma. This case contributes evidence to two seemingly opposing theories of mesonephric-like adenocarcinoma histogenesis: the mesonephric remnant theory (supported by the patient's DES exposure), and the Müllerian theory (supported by the associated endometrioid adenofibroma).


Head and facial trauma.
Computed tomography (CT) plays a vital role in the evaluation of head and facial trauma. This article describes various lesions in such patients and details their CT findings.


Rapidly destructive osteonecrosis of the humeral head after arthroscopic rotator cuff repair: a case report.
Cases of rapidly destructive osteonecrosis (RDON) of the humeral head after arthroscopic rotator cuff repair (RCR) have rarely been reported, which has prevented a clear consensus on the cause of osteonecrosis. A 63-year-old woman without a history of trauma underwent arthroscopic RCR after being diagnosed with a medium-sized full-thickness rotator cuff tear for symptoms of left shoulder pain for six months. The patient had no medical history other than hypertension, and no other potential cause was found for osteonecrosis of the left shoulder prior to surgery. Four months after surgery, pain and range of motion improved. Six months after surgery, the patient complained of an increase in shoulder pain. While follow-up ultrasonography did not show a re-tear of the repaired tendon, osteonecrosis of the humeral head could not be confirmed as plain radiography was not performed. Follow up MRI performed a year after surgery revealed RDON of the humeral head. Despite mild improvement in the shoulder pain, the Shoulder Rating Scale of the University of California at Los Angeles (UCLA) and Constant score were poor at 23 and 69, respectively. In the present case, the arthroscopic RCR was performed using two anchors; for the repair of the anterior of the supraspinatus and the rotator interval, a 2.8-mm all-suture anchor was inserted into the upper part of the intertubercular groove. The cause of RDON is presumed to be the damage to the anterolateral and intraosseous branches of the anterior humeral circumflex artery (AHCA) for anchor positioning and insertion. A poor outcome was obtained in the case of RDON, despite the integrity of the repaired rotator cuff tendon after arthroscopic RCR was intact. Although the cause of RDON has not been clearly established, care should be taken not to damage the anterolateral and intraosseous branches of the AHCA regarding the insertion location of the suture anchor, and to prepare the anchor in the vicinity of the intertubercular groove.


Glandular neoplasia of the lung. A proposed analogy to colonic tumors.
In 62 consecutive resections for adenocarcinoma of the lung, 50 cases (81%) had single adenocarcinomas and 12 (19%) had multiple adenocarcinomas. In seven of these 12 patients, two adenocarcinomas were found. In the other five patients, the specimen contained a dominant adenocarcinoma and several 0.1- to 1-cm nodules of similar histologic appearance. In four of the 50 single tumor patients and one of seven double tumor patients, 1- to 2-mm nodules were found along with adenocarcinomas that we interpreted as being bronchioloalveolar tumors of uncertain malignant potential. An analogy is drawn between these four types of findings and single tumors of the colon, double tumors of the colon, polyposis syndromes, and tubular adenomas of the colon, respectively.


Cyclosporine A-loaded chitosan extra-fine particles for deep pulmonary drug delivery: In vitro and in vivo evaluation.
In this study, the extra-fine dry powder inhalers (DPIs) with chitosan (CS) as carrier were successfully prepared by ionic gel method combined with spray drying technique for deep pulmonary drug delivery of Cyclosporine A (CsA), using sodium hyaluronate (SHA) and sodium polyglutamate (SPGA) as polyanions. The CsA-loaded DPIs of CS-SHA-CsA and CS-SPGA-CsA were spherical particles with wrinkles on the surface, which were more conducive to improving the aerosol properties. The aerodynamic evaluation of CS-SHA-CsA and CS-SPGA-CsA showed that the fine particle fraction (FPF) reached up to 79.22 ± 2.12% and 81.55 ± 0.43%, while the emitted fraction (EF) reached 77.15 ± 1.46% and 78.29 ± 2.10%. In addition, the mass median aerodynamic diameter (MMAD) was calculated as 1.58 ± 0.04 μm and 1.94 ± 0.02 μm for CS-SHA-CsA and CS-SPGA-CsA, indicating that they were all extra-fine particles (d < 2 μm). These in vitro aerodynamic results showed that CS-SHA-CsA and CS-SPGA-CsA could reach the smaller airways, further improving therapeutic efficiency. The cell viability on A549 cell line results showed that CS-SHA-CsA and CS-SPGA-CsA were safe to deliver CsA to lungs. The in vivo pharmacokinetics consequence proved that inhalation administration of CS-SHA-CsA and CS-SPGA-CsA could significantly improve the bioavailability of CsA in vivo compared with oral administration of Neoral®, effectively reducing the risk of a series of adverse effects caused by systemic overexposure. In addition, the safety and compatibility of DPIs using SHA, SPGA, and CS as carriers for pulmonary drug delivery was verified by in vivo repeated dose inhalation toxicity. From these findings, the extra-fine DPIs with CS as carrier could be a viable delivery option for the deep pulmonary drug delivery of CsA relative to orally administered drug.


Intrahepatic cholestasis of pregnancy - Time to redefine the reference range of total serum bile acids: A cross-sectional study.
To establish pregnancy-specific reference ranges for fasting and postprandial total serum bile acid (TSBA) concentrations. Cross-sectional study. Tertiary-care university hospital. Healthy pregnant women at term admitted to the Obstetrics Department over a period of 1 year. Exclusion criteria were an established diagnosis of intrahepatic cholestasis of pregnancy (ICP) or any coexisting condition of increased risk for ICP. Both fasting (after 8-14 h of fasting) and postprandial (2 h after meal) TSBA concentrations were measured in 612 women (with 528 fasting samples and 377 postprandial samples) by automated enzymatic spectrophotometric assay. Fasting and postprandial TSBA concentrations in 612 women. Reference intervals of 4.4-14.1 μmol/L for fasting TSBA and 4.7-20.2 μmol/L for postprandial TSBA were established. The postprandial values were significantly higher than the fasting values, with a median increase of 1.0 μmol/L (p < 0.0001). A correlation between fasting TSBA concentrations and postprandial concentrations was found, as well as correlations with fetal sex, parity and assisted reproductive technologies. A seasonal pattern was noticed for both fasting and postprandial TSBA, with the highest values measured in the winter season (p < 0.01 and 0.02, respectively) CONCLUSIONS: Normal pregnancy is associated with mild hypercholanaemia, and therefore a higher threshold should be considered for the diagnosis of ICP. We suggest using the upper reference limits observed in our healthy pregnant population (14 μmol/L for fasting TSBA and 20 μmol/L for postprandial TSBA). As the fasting measurement is more specific for the diagnosis, and the postprandial measurement is essential for the assessment of severity, it is recommended to measure both values rather than use random sampling. Normal pregnancy is associated with mild hypercholanaemia, a higher threshold should be considered for the diagnosis of ICP.


Comparison of Two Types of Patient Specific Implants (PSI) and Quad Zygoma Implant (QZI) for Rehabilitation of Post-COVID Maxillary Mucormycosis Defect (PCMMD): Finite Element Analysis.
The residual post-COVID maxillary mucormycosis defect (PCMMD) were extensive, due to unilateral or bilateral maxillectomies. The Goal of rehabilitation of PCMMD is to deliver a prosthetically driven reconstruction. FEA was to evaluate the biomechanical response of PSI struts (PSI 1), PSI Screw retained (PSI 2) and QZI to masticatory load on virtual simulation to improve accuracy and enhance the design. To validate and compare the Biomechanical benefit of the PSI struts, PSI Screw retained, QZI in a case of rehabilitation of post-COVID maxillary mucormycosis defect (PCMMD) by FEA study. The result of stress to masticatory load on virtual simulation for (1) Maximum and minimum stress (Von Mises stress); (2) the Displacement (in three positions) and (3) the Deformation (Plastic strain) was compared on virtual simulation for PSI 1 and PSI 2 and QZI. The FEA and comparative evaluation of PSI 1, PSI 2 and QZI showed a good resistance to displacement. The stress and strain values are low and acceptable. In comparison QZI shows more stress in the anterior region.


Inotropic response of the neonatal canine myocardium to dopamine.
The inotropic responsiveness of the developing myocardium to dopamine and isoproterenol was evaluated using isolated, perfused ventricles and atrial strips from puppies ages 15 hr to 33 days. Responses were compared to those in adult animals. The maximum percentage of increase of left ventricular dF/dt increased from 12 +/- 5 (mean +/- SEM) at 0-7 days (n = 6) to 100 +/- 40 at 21-33 days (n = 3) of postnatal age. At 7-14 days (n = 4) and 15-20 days (n = 5) of age the maximum percentage of increase of left ventricular dF/dt was 28 +/- 10 and 39 +/- 17, respectively. Puppy ventricle responded to isoproterenol at all ages equally (maximum percentage increase of left ventricular dF/dt = 46 +/- 13). Atrial muscle strips from puppies, ages 15 hr to 35 days (n = 22), and adult dogs (n = 19) demonstrated equal responsiveness to dopamine as well as to isoproterenol. The maximum percentage of increase of dF/dt was 117 +/- 18 with dopamine. Maximum percentage of increase of dF/dt with dopamine after propranolol (10(-7) M) was 52 +/- 18. Haloperidol (1.10(-7)-2.10(-6) M) did not alter responsiveness of atria to dopamine.


The Accountable Care Organization for Surgical Care.
Rising health care costs superimposed on uncertainty surrounding the relationship between health care spending and quality have resulted in an urgent need to develop strategies to better align health care payment with value. Such approaches, at least in theory, work to achieve the dual aims of reducing growth in health care spending and improving population health. To date, surgery has not been prioritized in accountable care organizations (ACOs). Nonetheless, it is critically important to begin to consider strategic and impactful mechanisms through which surgery can be seamlessly woven into innovative population health models.


Mismatch negativity and behavioural discrimination in humans as a function of the magnitude of change in sound duration.
This study investigated how duration changes are processed in the human brain as indexed by the mismatch negativity (MMN), a component of the auditory event-related potential (ERP) reflecting sensory memory. Subjects were presented with sequences of repetitive 100-ms white noise bursts interspersed by occasional duration deviants which were 1, 10, or 50 ms (decrements) or 110, 150, or 200 ms (increments) in duration. In a separate task, subjects were asked to detect deviants within the sequence via a button-press. MMN was elicited by both stimulus decrements and increments and increased in amplitude as a function of the amount of deviation from the standard duration except for the shortest, 1-ms deviant. Behavioural detection paralleled the MMN responses, suggesting a link between the processes underlying MMN and behavioural measures.


Bone marrow stromal cells stimulate an angiogenic program that requires endothelial MT1-MMP.
Bone marrow-derived stromal/stem cells (BMSCs) have recently been characterized as mediators of tissue regeneration after injury. In addition to preventing fibrosis at the wound site, BMSCs elicit an angiogenic response within the fibrin matrix. The mechanistic interactions between BMSCs and invading endothelial cells (ECs) during this process are not fully understood. Using a three-dimensional, fibrin-based angiogenesis model, we sought to investigate the proteolytic mechanisms by which BMSCs promote vessel morphogenesis. We find that BMSC-mediated vessel formation depends on the proteolytic ability of membrane type 1-matrix metalloproteinase (MT1-MMP). Knockdown of the protease results in a small network of vessels with enlarged lumens. Contrastingly, vessel morphogenesis is unaffected by the knockdown of MMP-2 and MMP-9. Furthermore, we find that BMSC-mediated vessel morphogenesis in vivo follows mechanisms similar to what we observe in vitro. Subcutaneous, cellular fibrin implants in C.B-17/SCID mice form aberrant vasculature when MMPs are inhibited with a broad-spectrum chemical inhibitor, and a very minimal amount of vessels when MT1-MMP proteolytic activity is interrupted in ECs. Other studies have debated the necessity of MT1-MMP in the context of vessel invasion in fibrin, but this study clearly demonstrates its requirement in BMSC-mediated angiogenesis.


Overactive type 2 cannabinoid receptor induces meiosis in fetal gonads and impairs ovarian reserve.
Type 2 cannabinoid receptor (CB2R) has been proposed to promote in vitro meiotic entry of postnatal male germ cells and to maintain the temporal progression of spermatogenesis in vivo. However, no information is presently available on the role played by CB2R in male and female fetal gonads. Here we show that in vitro pharmacological stimulation with JWH133, a CB2R agonist, induced activation of the meiotic program in both male and female fetal gonads. Upon stimulation, gonocytes initiated the meiotic program but became arrested at early stages of prophase I, while oocytes showed an increased rate of meiotic entry and progression toward more advanced stage of meiosis. Acceleration of meiosis in oocytes was accompanied by a strong increase in the percentage of γ-H2AX-positive pachytene and diplotene cells, paralleled by an increase of TUNEL-positive cells, suggesting that DNA double-strand breaks were not correctly repaired during meiosis, leading to oocyte apoptosis. Interestingly, in vivo pharmacological stimulation of CB2R in fetal germ cells through JWH133 administration to pregnant females caused a significant reduction of primordial and primary follicles in the ovaries of newborns with a consequent depletion of ovarian reserve and reduced fertility in adult life, while no alterations of spermatogenesis in the testis of the offspring were detected. Altogether our findings highlight a pro-meiotic role of CB2R in male and female germ cells and suggest that the use of cannabis in pregnant female might represent a risk for fertility and reproductive lifespan in female offspring.


Experience-dependent refinement of inhibitory inputs to auditory coincidence-detector neurons.
The spatial arrangement of inputs on to single neurons is assumed to be crucial in accurate signal processing. In mammals, the most precise temporal processing occurs in the context of sound localization. Medial superior olivary neurons can encode microsecond differences in the arrival time of low-frequency sounds at the two ears. Here we show that in mammals with well developed low-frequency hearing, a spatial refinement of ionotropic inhibitory inputs occurs on medial superior olivary neurons during development. This refinement is experience dependent and does not develop in mammals that do not use interaural time differences for sound localization.


[Study of the Accumulation of Rec A from Bacillus subtilis in the Mitochondria of a Recombinant Strain of the Yeast Yarrowia lipolytica].
No eukaryotic species has a system for homologous DNA recombination of the mitochondrial genome. We report on an integrative genetic systembased on the pQ-SRUS construct that allows the expression of the RecA recombinase from Bacillus subtilis and its transportation to mitochondria of Yarrowia lipolytica. The targeting of recombinant RecA to mitochondria is provided by leader sequences (5'-UTR and 3-UTR) derived from the SOD2 gene mRNA, which exhibit affinity to the outer mitochondrial membrane and provides cotranslational import of RecA to the inner space of mitochondria. The accumulation of RecA in mitochondria of the Y. lipolytica recombinant strain bearing the pQ-SRUS construct has been shown by immunoblotting of purified mitochondrial preparations.


Structural and Ecofriendly Holocellulose Materials from Wood: Microscale Fibers and Nanoscale Fibrils.
Mildly delignified wood holocellulose fibers show well-preserved cellulose nanofibril (CNF) structure in the fiber cell wall. Fibers, paper, biocomposites, and compression-molded fiber materials demonstrate excellent mechanical properties. Here, wood holocellulose fibers and corresponding CNFs are discussed with respect to nanostructure, mechanical performance, and advanced materials potential. Functionalization routes are discussed, as well as materials selection, nanoscience of recycling, and the embodied energy in cellulosic candidates for multifunctional structural materials.


The Effects of Pemafibrate in Japanese Patients with Type 2 Diabetes Receiving HMG-CoA Reductase Inhibitors.
The combination therapy of HMG-CoA reductase inhibitors (statins), which are anti-hyperlipidemic agents, and fibrates may increase the risk of hepatic dysfunction and myopathy, therefore, this combination required careful administration for patients. In the present study, the effects of combination therapy of pemafibrate, a novel fibrate, and statins, was evaluated. Pemafibrate was administered for 6 months as an add-on to statin therapy in 27 type 2 diabetes patients with dyslipidemia already receiving statins for 6 months (combination group), and the efficacy and safety of the combination therapy in comparison with a pemafibrate monotherapy group was examined. In the combination group, a decrease in serum total cholesterol levels was observed after 6 months of pemafibrate treatment compared to baseline, along with an increase in HDL-cholesterol. While serum triglyceride level was reduced, HbA1c level was elevated in both the groups. Serum creatinine kinase level, which is an indicator of myopathy, was lowered in the combination group. In addition, a decrease in γ-glutamyl transpeptidase, a parameter of hepatic dysfunction, was observed in the combination group. The statin-pemafibrate combination therapy in type 2 diabetes patients with dyslipidemia improved lipid metabolism safely without increasing the risk of hepatic dysfunction and myopathy.


Genes associated with human glaucoma.
Glaucoma is a common blinding disease worldwide. Most forms of the disease are inherited in some way. The identification of genes responsible for glaucoma will lead to insights into the underlying biochemical defects as well as provide the basis for new methods of diagnosis and therapy. Glaucoma patients who are identified early and treated appropriately have the best chance of maintaining useful sight.


[Peritonitis: attempt to evaluate therapeutic surgical options].
The choice of optimal concept in the therapy of severe peritonitis is essential to outcome. In approximately 10-15% of patients suffering severe peritonitis, single-stage surgery is not sufficient and additional operative therapy is required. Different therapeutic strategies such as the open-package procedure, staged abdominal repair, and on-demand relaparotomy have been developed for these situations. However, it is difficult to compare the effectiveness of each regimen because stratification tools are lacking. This paper describes advantages and disadvantages of the various therapeutic options in peritonitis and their clinical implementation.


Orgasmic dysfunction among Malay diabetic women in Malaysia.
The present study aimed to determine the prevalence and associated factors of orgasmic dysfunction among Malay women with type 2 diabetes mellitus in Malaysia. This cross-sectional study involved 347 women (174 non diabetic and 173 diabetic subjects) who attended the diabetic clinic in a university hospital. Orgasmic dysfunction was assessed using the orgasmic subscale of Malay Version of the Female Sexual Function Index (MVFSFI). Sociodemographic information of the subjects was collected with a pre-designed questionnaire. Prevalence of orgasmic dysfunction among Malay women was 13.3% and 10.3% in type 2 diabetes mellitus and control group, respectively. However, the difference was not statistically significant. Multivariate logistic regression analysis showed that unemployment (Adjusted Odds Ratio, AOR=2.69, 95% CI=1.22, 5.97) and lower academic status (AOR=0.35, 95% CI=0.17, 0.72) were significantly associated with sexual orgasmic dysfunction in diabetic women. Orgasmic dysfunction was highly prevalent among the Malay women regardless of the diabetic state. It is recommended that orgasmic dysfunction in women with diabetes should be assessed during routine clinical health visit to the hospital for early treatment.