Exploring stimulant treatment in ADHD: narratives of young adolescents and their parents.
Young adolescents' and their parents' experiences with Attention-Deficit/Hyperactivity Disorder (ADHD) and its treatment were explored to investigate beliefs and attitudes regarding use of stimulant medication, and their influence on treatment decisions. Using in-depth qualitative interviews, 12 adolescents with ADHD aged 12 - 15 years, and their parents described their experiences of ADHD and its treatment. Twenty four interviews, 12 with adolescents and 12 with their parents elicited detailed descriptions of beliefs about ADHD, attitudes about stimulant use and the circumstances surrounding treatment decisions. Verbatim transcripts were iteratively analyzed by a team of researchers following an interpretive interactionist framework. Young people offered three themes describing ADHD: 1) personality trait, 2) physical condition or disorder, and 3) minor issue or concern. Regarding medication use, youth described 1) benefits, 2) changes in sense of self, 3) adverse effects, and 4) desire to discontinue use. Parents' beliefs were more homogeneous than youth beliefs, describing ADHD as a disorder requiring treatment. Most parents noted benefits from stimulant use. Themes were 1) medication as a last resort, 2) allowing the child to reach his or her potential; and 3) concerns about adverse and long-term effects. Families described how responsibility for treatment decisions is transferred from parent to adolescent over time. Young adolescents can have different beliefs about ADHD and attitudes about medication use from their parents. These beliefs and attitudes influence treatment adherence. Incorporating input from young adolescents when making clinical decisions could potentially improve continuity of treatment for youth with ADHD.


Effect of age at cochlear implantation on open-set word recognition in Mandarin speaking deaf children.
The purpose of this study was to determine whether age at cochlear implantation influences open-set speech perception in children after long-term use of the implant device. Twenty-eight congenitally deafened children, receiving implants of Nucleus CI24M devices, were divided into two groups: (1) CI < 3: those who received implants before 3 years of age and (2) CI > 3: those who received implants after 3 years of age. We compared open-set speech perception in CI < 3 and CI > 3 after 4-5 years of device use. Speech perception tests were conducted using the Mandarin Lexical Neighborhood Test (M-LNT). Unpaired t-test was applied for statistical analysis, and p < 0.05 was considered significant. In CI < 3, the average of percent correct was 80.0 +/- 8.8 and 70.5 +/- 9.2% on, respectively, the easy and hard versions of the M-LNT. By contrast, in CI > 3, the average percent correct was 62.5 +/- 19.9 and 59.1 +/- 15.2%, respectively. Regardless of the M-LNT version used, CI < 3 performed significantly better than CI > 3 (easy, p = 0.005 versus hard, p = 0.022). The present investigation demonstrated that age at implantation influences open-set speech perception of cochlear implanted children 4-5 years after device connection. Implantation before 3 years of age promotes the development of open-set speech perception abilities in congenitally deafened children.


Adrenoleukodystrophy. Preliminary report of a connatal case. Light- and electron microscopical, immunohistochemical and biochemical findings.
This is the first description of a connatal case of adrenoleukodystrophy. The clinical picture consisted of severe psychomotor retardation, convulsions and hypsarrhythmia, but no obvious signs of adrenal insufficiency. Pathologically, the adrenals were small. The entire cortex was largely replaced by large round cells. Ultrastructurally, some cells in the adrenal cortex contained inclusions with electron-lucent clefts surrounded by a membrane. The anterior pituitary lobe could be demonstrated to have produced ACTH. The central nervous system showed extensive zones of demyelination in the brainstem, the cerebellum and the right-sided capsula interna. In the demyelinated areas there was sudanophilic breakdown and an intense gliosis. Ongoing demyelination could also be demonstrated by the chemical analysis. In the gray matter there waere micropolygyria of the insular cortex and swollen nerve cells in the nucleus arcuatus. Ultrastructure revealed the type of inclusions in the microglia of the same type as in the adrenals, and a different type of inclusions in unidentifiable cells, possibly neurons. These latter inclusions consisted of loosely stacked lamellar material. The findings are interpreted as further evidence of storage taking place in this disease.


Young women's adolescent experiences of oral sex: relation of age of initiation to sexual motivation, sexual coercion, and psychological functioning.
Research examining oral sex during adolescence tends to investigate only potential negative consequences without considering its place in sexual development or distinctions between cunnilingus and fellatio. Using retrospective reports from 418 undergraduate women, we examined the relations among young women's ages of initiation of both cunnilingus and fellatio and sexual motives, experiences of sexual coercion, and indicators of psychological functioning. Age at cunnilingus initiation was unrelated to sexual coercion or psychological functioning; however it was related to engaging in sex for personal stimulation and gratification (personal drive motive) and to feel agentic, assertive, and skillful (power motive). Age at fellatio initiation was related to feelings of inferiority compared to others and a devaluing of the self (interpersonal sensitivity). Findings challenge the unilateral assumption that all adolescent sexual activity is negative and indicate the need for future research distinguishing between cunnilingus and fellatio.


Prevalence and genotype distribution of HPV infection among women in Xiamen, China.
This study aimed to evaluate the prevalence of HPV and genotype distribution among female populations in Xiamen, Fujian Province, China, which can be conducive for local governments to formulate cervical cancer screening and HPV vaccine strategies. Cervical swabs were collected from 47,926 participants aged 16-92 years at the Women and Children's Hospital, Xiamen University, from November 2019 to June 2020. HPV DNA was extracted and detected using conventional PCR, followed by HPV subtype-specific hybridisation. HPV infection rates based on different groups were compared using the χ2 test. HPV prevalence and the corresponding 95% confidence intervals (95% CI) were calculated using SPSS 19.0. The overall HPV prevalence among the 47,926 cervical swabs that were analysed was 15.13%, of which single, double, and multiple infections accounted for 76.83, 16.70 and 6.47%, respectively. The age-specific prevalence of HPV infection presented a "U" curve with a HPV prevalence peak observed in women aged <20 years. The gynaecology clinic group had significantly higher HPV positive rates than the health examination group (p < 0.001). The five most common HR-HPV subtypes in Xiamen were HPV52, 58, 16, 51, and 39 (2.69, 1.63, 1.23, 1.05, and 0.98%, respectively). The five most common LR-HPV subtypes were HPV54, 61, 81, 70, 34, and 84 (0.92, 0.86, 0.71, 0.45 and 0.35%, respectively). Our findings demonstrate that the 9-valent HPV vaccine is recommended for regular immunisation in Xiamen. It is necessary for elderly women to participate in HPV screening to decrease the morbidity and mortality of cervical cancer.


Gastroenterological Manifestations of Immunoglobulin G Subclass 4-Related Disease-Epidemiology, Clinical Manifestations, Diagnosis and Treatment.
Despite causing high morbidity, IgG4-related disease (IgG4-RD) and its gastroenterological manifestations lack better and greater theoretical contributions. Therefore, the objective of this work was to evaluate the clinical-epidemiological, diagnostic and treatment aspects of the gastrointestinal manifestations of this disease. A systematic review was carried out using the PubMed, Scopus and Embase databases between January 2012 and March 2023 with the following descriptors: "Immunoglobulin G4-Related Disease" (MeSH) AND #2 "Gastrointestinal Tract" (MeSH). Our data collection grouped a total of 3607 patients from mostly epidemiological cohort studies and cross-sectional follow-ups. In the subgroup analysis, IgG4-RD was associated with male gender, with an estimated prevalence between 54% and 80%. In our findings, the prevalence by topography was presented in the following ranges: lacrimal glands (17-57%); salivary glands (28-72%); pancreas (19-60%); biliary tract (5-40%); retroperitoneal cavity (9-43%). Longitudinal studies are needed to better map the natural history of the gastrointestinal manifestations of IgG4-RD and enable the formulation of individualized treatments.


The Impact of Urate-Lowering Therapy in Post-Myocardial Infarction Patients: Insights From a Population-Based, Propensity Score-Matched Analysis.
The role of urate-lowering therapy (ULT) for the primary prevention of cardiovascular (CV) events has been widely discussed, but its evidence for the secondary prevention of myocardial infarction (MI) is limited. Therefore, we conduct a population-based, propensity score-matched cohort study to investigate the CV outcomes among patients with post-MI with and without ULT. A total of 19,042 newly diagnosed in-hospital patients with MI were selected using the Taiwan National Health Insurance Database between January 1, 2005, and December 31, 2016. After 1:1 propensity score matching with covariates, patients with MI with (n = 963) and without (n = 963) ULT were selected for further analysis. The primary outcome was the all-cause mortality and the secondary outcomes were composite CV outcomes, including hospitalization for recurrent MI, stroke, heart failure, and cardiac arrhythmias. ULT users were associated with lower all-cause mortality (adjusted hazard ratio (adjHR), 0.67; 95% confidence interval (CI), 0.51-0.87) compared to the ULT nonusers. In addition, ULT users had a significantly lower risk of recurrent MI, which needed revascularization by percutaneous coronary intervention or coronary artery bypass grafting (adjHR, 0.67; 95% CI, 0.53-0.86) than the ULT nonusers. The primary and secondary outcomes were not different between patients with post-MI who received uricosuric agents and xanthine oxidase inhibitors. The anti-inflammatory effect of ULT plays an essential role in MI management. From a real-world setting, this study shows that ULT is associated with the lower risk of all-cause mortality in patients with post-MI. In addition, the result shows the possible lower incidence of repeat revascularization procedures in the ULT users.


Quantum-dot-assisted fluorescence resonance energy transfer approach for intracellular trafficking of chitosan/DNA complex.
Fluorescence resonance energy transfer (FRET) was employed to monitor the molecular dissociation of a chitosan/DNA complex with different molecular weights of chitosan. Chitosan with different molecular weights was complexed with plasmid DNA and the complex formation was monitored using dynamic light scattering and a gel retardation assay. As the chitosan molecular weight increased, a more condensed complex was prepared at various ratios of chitosan to DNA. Plasmid DNA and chitosan were separately labeled with quantum dots and Texas red, respectively, and the dissociation of the complex was subsequently monitored using confocal microscopy and fluorescence spectroscopy. As the chitosan molecular weight in the chitosan/DNA complex increased, the Texas red-labeled chitosan gradually lost FRET-induced fluorescence light when HEK293 cells incubated with chitosan/DNA complex were examined with confocal microscopy. This suggests that the dissociation of the chitosan/DNA complex was more significant in the high molecular weight chitosan/DNA complex. Fluorescence spectroscopy also monitored the molecular dissociation of the chitosan/DNA complex at pH 7.4 and pH 5.0 and confirmed that the dissociation occurred in acidic environments. This finding suggests that the high molecular weight chitosan/DNA complex could easily be dissociated in lysosomes compared to a low molecular weight complex. Furthermore, the high molecular weight chitosan/DNA complex showed superior transfection efficiency in relation to the low molecular weight complex. Therefore, it could be concluded that the dissociation of the chitosan/DNA complex is a critical event in obtaining the high transfection efficiency of the gene carrier/DNA complex.


Case planning and execution of inframalleolar bypass for chronic limb-threatening ischemia.
Chronic limb-threatening ischemia is challenging to treat because of the complex patient population, heterogeneity of limb presentations, and complicated arterial pathology. To meet this challenge, vascular surgeons need a broad range of skills to appropriately tailor interventions to each patient's specific needs. One tool in the armamentarium for patients with extensive arterial occlusive disease below the knee is an inframalleolar bypass. However, these procedures require a systematic approach to surgical planning and a high degree of technical competence. We describe our approach to inframalleolar bypass for limb preservation in suitable patients with advanced tibial artery disease.


RA-SIFA: Unsupervised domain adaptation multi-modality cardiac segmentation network combining parallel attention module and residual attention unit.
Convolutional neural network has achieved a profound effect on cardiac image segmentation. The diversity of medical imaging equipment brings the challenge of domain shift for cardiac image segmentation. In order to solve the domain shift existed in multi-modality cardiac image segmentation, this study aims to investigate and test an unsupervised domain adaptation network RA-SIFA, which combines a parallel attention module (PAM) and residual attention unit (RAU). First, the PAM is introduced in the generator of RA-SIFA to fuse global information, which can reduce the domain shift from the respect of image alignment. Second, the shared encoder adopts the RAU, which has residual block based on the spatial attention module to alleviate the problem that the convolution layer is insensitive to spatial position. Therefore, RAU enables to further reduce the domain shift from the respect of feature alignment. RA-SIFA model can realize the unsupervised domain adaption (UDA) through combining the image and feature alignment, and then solve the domain shift of cardiac image segmentation in a complementary manner. The model is evaluated using MM-WHS2017 datasets. Compared with SIFA, the Dice of our new RA-SIFA network is improved by 8.4%and 3.2%in CT and MR images, respectively, while, the average symmetric surface distance (ASD) is reduced by 3.4 and 0.8mm in CT and MR images, respectively. The study results demonstrate that our new RA-SIFA network can effectively improve the accuracy of whole-heart segmentation from CT and MR images.


Aggressive behavior of squamous cell carcinoma in a patient with preceding lymphocytic lymphoma.
Actinically induced squamous cell carcinomas of the skin (SCC) are generally considered nonaggressive and usually curable tumors. However, in patients with lymphoma or leukemia, these tumors may behave in an extremely aggressive manner. We report a case in which an actinically induced SCC occurred in a patient with preceding lymphocytic lymphoma. The tumor progressed from a localized lesion to an invasive destructive lesion which resulted in death. The occurrence of SCC in patients with lymphoma or leukemia possibly should be more aggressively treated, early in its course.


Niche separation of seven lemur species in the eastern rainforest of Madagascar.
This study examines segregation of seven lemur species in an eastern rainforest of Madagascar by a numerical analysis of microhabitats using structural and phenological data. These data are combined with the results of a previous study on food selection by these species in relation to plant chemistry. Description of some 441 10×10 m2 microhabitats yields clear separation of the frugivorous from the more folivorous guild of lemurs. Within each guild there are subgroups of two species each, which use similar microhabitats. The two species of the subgroups are separated by their different reactions towards food chemicals. Thus food chemistry and microhabitat structure are two complementary axes sufficient to separate lemur species in the Malagasy rainforest. Species using the same microhabitats choose food items with different chemical properties and species eating the same food differ in their utilization of microhabitats. Only Cheirogaleus major can not be separated from the other lemur species based on habitat utilization and the chemical composition of their food. This species, however, is active only at times of food abundance and reduces its activity at times of scarcity thus avoiding potential competition. The folivorous species Avahi laniger and Indri indri use similar micro habitats for feeding and for resting, reflecting the strategy of low energy cost and fow energy return. A more folivorous species, Lemur fulvus, discriminates between feeding and resting sites based on phenological and structural variables, representing an example for behavior shaped by high cost and high energy return. Feeding sites of this species are linked to fruit abundance but the need to see but not to be seen seems to determine their choice of resting sites. This discrimination is similar to habitat choices of frugivorous primates in other tropical rainforests which have been linked to anti-predator behavior and suggests convergent evolution due to similar evolutionary selection pressure.


Multisystem inflammatory syndrome in adults with COVID-19 requiring mechanical ventilation: A retrospective cohort study.
Multisystem inflammatory syndrome in adults (MIS-A) is a hyperinflammatory multisystem condition associated with coronavirus disease (COVID-19). Critically ill COVID-19 patients may develop multiorgan damage and elevated inflammatory responses, thus making it difficult to differentiate between progression to organ damage due to COVID-19 itself or MIS-A. This study aimed to explore the characteristics and complications of MIS-A in critical COVID-19 patients. The Japan Extracorporeal Membrane Oxygenation (ECMO) Network and ICU Collaboration Network developed a web-based database system called the CRoss Intensive Care Unit Searchable Information System (CRISIS) to monitor critical COVID-19 patients throughout Japan. We retrospectively identified patients with MIS-A among critical COVID-19 patients enrolled from March 2020 to December 2021, using CRISIS. Our MIS-A definition required patients to be at least 18 years of age, have laboratory evidence of inflammation, severe dysfunction of at least two extrapulmonary organ systems, and no plausible alternative diagnoses. Of the 1052 patients, 26 (2.5%) were diagnosed with MIS-A. The MIS-A patients had a higher likelihood of using ECMO (13% vs. 46%, p < 0.001) and lower overall survival (77% vs. 42%, p < 0.001) than non-MIS-A patients. More than 80% of the MIS-A cases occurred 3 weeks after the COVID-19 onset. Multisystem inflammatory syndrome in adults can occur in 2.5% of critically ill COVID-19 patients, and the mortality rate is high. Multisystem inflammatory syndrome in adults may be considered when there is a re-elevation of the unexplained inflammatory response and severe dysfunction of at least two extrapulmonary organ systems several weeks after the onset of COVID-19.


Brain specific creatine kinase isoenzyme behavior in rat serum after bile acid, sodium oleate and albumin injection.
In this investigation we have shown that severe liver disease with cerebral involvement can be followed by the presence of BB creatine kinase isoenzyme in serum. Groups of rats were injected with a bile acid mixture, oleic acid, albumin and normal saline respectively. Bile acids or/and oleic acid induced BB isoenzyme to leak from central nervous tissue and this can be measured in serum. Albumin binding prevented this leakage. The experiments support our hypothesis, based on biochemical findings in human liver failure, that detergent and surface activity properties of the above mentioned components are able to produce this specific brain isoenzyme leakage.


From XML to RDF: how semantic web technologies will change the design of 'omic' standards.
With the ongoing rapid increase in both volume and diversity of 'omic' data (genomics, transcriptomics, proteomics, and others), the development and adoption of data standards is of paramount importance to realize the promise of systems biology. A recent trend in data standard development has been to use extensible markup language (XML) as the preferred mechanism to define data representations. But as illustrated here with a few examples from proteomics data, the syntactic and document-centric XML cannot achieve the level of interoperability required by the highly dynamic and integrated bioinformatics applications. In the present article, we discuss why semantic web technologies, as recommended by the World Wide Web consortium (W3C), expand current data standard technology for biological data representation and management.


Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.
Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia-preconditioned MSCs (PC-MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC-MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR-21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aβ levels in the brain; could decrease the activation of astrocytes and microglia; could down-regulate proinflammatory cytokines (TNF-α and IL-1β); and could up-regulate anti-inflammatory cytokines (IL-4 and -10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC-MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aβ levels were lower, and expression of growth-associated protein 43, synapsin 1, and IL-10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, TNF-α, IL-1β, and activation of STAT3 and NF-κB were sharply decreased. More importantly, exosomes from PC-MSCs effectively increased the level of miR-21 in the brain of AD mice. Additionally, replenishment of miR-21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC-MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR-21.-Cui, G.-H., Wu, J., Mou, F.-F., Xie, W.-H., Wang, F.-B., Wang, Q.-L., Fang, J., Xu, Y.-W., Dong, Y.-R., Liu, J.-R., Guo, H.-D. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.


How Age and Life Stage of Relocation Fosters Social Belonging: Comparing Two Groups of Older Migrants in the US.
The presumed "ossification effect" of the past on older generations remains influential in the scholarship on aging and migration, orienting scholars to highlight the vulnerability of senior migrants in new societies. As a result, the ability of older generations to adapt to receiving societies has been underestimated and largely undifferentiated, little is known about how age and life stage at arrival matter for how older individuals manage later-life transitions across borders. This article compares two groups of Han Chinese senior migrants: recent arrivals (who migrated to the US later in life) and long-term residents (who migrated to the US during adulthood). We draw on 112 qualitative interviews and four years of ethnographic observation in two northeastern cities in the US. We argue that the life stage at arrival, coupled with class (dis)advantages, are central to analyzing the diverse ways older migrants stake claims to their belonging to American society. We offer the concept of "economies of belonging" to delineate the ways recent arrivals and long-term migrants anchor themselves socially and emotionally in the US. Through examining the social relationships and state-provided resources that recent arrivals and long-term migrants use to cultivate social belonging and justify their social membership to American society, our analysis reveals that both groups of older migrants have preconceived American dreams before they emigrate, but their age at arrival offers differential opportunities to fulfil those dreams and influences how a sense of belonging unfolds later in life.


Expression of c-myc gene in human ovary carcinoma cells treated with vanadate.
The widely accepted hypothesis of vanadate action on cells postulates that this ion inhibits protein phosphatase(s) that dephosphorylates protein phosphotyrosine residues. This inhibition causes tyrosine hyperphosphorylation of cell proteins followed by changes in physiological action of phosphoproteins resulting in stimulation of cell proliferation, expression of protooncogenes, and transient cell transformation. We have found that treatment of human ovary carcinoma (CaOv) cells with vanadate causes the increase in total protein phosphorylation from 1.5- to 2.0-fold whereas the ratio between phosphoserine, phosphothreonine, and phosphotyrosine content remains unchanged. At the same time, enhancement of c-myc gene expression (not c-fos) was observed. Hence, the increase in the ratio of phosphotyrosine to phosphoserine and phosphothreonine is not an obligatory intermediate stage before vanadate-dependent activation of c-myc expression.


Isolation of cDNA clones encoding T cell-specific membrane-associated proteins.
Of 10 distinct cloned DNA copies of mRNAs expressed in T lymphocytes but not in B lymphocytes and associated with membrane-bound polysomes, one hybridizes to a region of the genome that has rearranged in a T-cell lymphoma and several T-cell hybridomas. These characteristics suggest that it encodes one chain of the elusive antigen receptor on the surface of T lymphocytes.


Expression of type VI collagen α3 chain in canine mammary carcinomas.
This study aimed to investigate the expression of type VI collagen α3 chain (COL6a3) in neoplastic cells of canine mammary gland carcinomas (CMGCs) using immunohistochemistry (IHC) and to evaluate the association between COL6a3 expression and tumor histological features, histological grades, and the differentiation status of neoplastic epithelial cells. COL6a3 expression in carcinoma cells was significantly associated with histologically low malignancy and low mitotic indices. In addition, COL6a3+ carcinoma cells were more frequently detected in simple carcinomas (tubular and tubulopapillary types) than in solid carcinomas. These findings indicate that reduced expression of COL6a3 in carcinoma cells contributes to the malignant phenotype in CMGCs. We also showed that COL6a3 expression in the carcinoma cells was more frequently detected in CK19+/CD49f + and/or CK19+/CK5+ tumors. In addition, COL6a3+/CK19+/CD49f + and COL6a3+/CK19+/CK5+ tumors consisted of CK19+/CD49f + and CK19+/CD49f- cells, and CK19+/CK5+ and CK19+/CK5- cells, respectively. Most of these tumors more frequently expressed GATA3, but not Notch1. These results indicate that COL6a3 is expressed in CMGCs containing both luminal progenitor-like and mature luminal-like cells and showing differentiation ability into mature luminal cells. It is possible that COL6 may be involved in the differentiation of luminal progenitor-like carcinoma cells into mature luminal-like carcinoma cells in CMGCs, which may suppresses the development of malignant phenotypes in CMGCs.


The bio refinery; producing feed and fuel from grain.
It is both possible and practicable to produce feed and fuel from grain. Using the value of grain to produce renewable energy for transport, while using the remaining protein content of the grain as a valuable protein source for livestock and for fish, can be seen as a complimentary and optimal use of all the grain constituents. Consideration must be given to maximise the value of the yeast components, as substantial yeast is generated during the fermentation of the grain starch to produce ethanol. Yeast is a nutritionally rich feed ingredient, with potential for use both as feed protein and as a feed supplement with possible immunity and gut health enhancing properties. Bioprocessing, with the consequent economies of scale, is a process whereby the value of grain can be optimised in a way that is traditional, natural and sustainable for primarily producing protein and oil for feed with a co-product ethanol as a renewable fuel.


Profibrinolytic effects of metalloproteinases during skin wound healing in the absence of plasminogen.
Genetic ablation of plasminogen (Plg) and pharmacological inhibition of metalloproteinase activity by galardin delay skin wound healing in mice, whereas the combined inhibition of these two enzyme systems completely prevents healing. In this study, the impact of plasmin and metalloproteinases as profibrinolytic enzymes has been investigated by comparing skin wound healing in the absence and presence of fibrin. Plg deficiency impairs skin wound healing kinetics, but this delay is only partially restored in the absence of fibrin. This suggests that plasmin-mediated fibrinolysis is the primary, but not the exclusive, requirement for healing of wounds in these mice. In addition, we observe that lack of fibrin reduces Plg activation significantly during wound healing. The profibrinolytic role of metalloproteinases is revealed by the finding that lack of fibrin partially restores the otherwise arrested healing of Plg-deficient wounds after metalloproteinase inhibition. In conclusion, the residual impairment of skin wound healing in the absence of fibrin suggests the existence of a fibrin-independent substrate(s) for plasmin and metalloproteinases. Furthermore, these in vivo data reveal that galardin-sensitive metalloproteinases mediate compensatory fibrinolysis to facilitate wound healing in the absence of plasmin.


Effects of increased potassium in scala tympani on auditory nerve sensitivity.
Raising the K+ concentration in scala tympani of the guinea-pig cochlea generally caused a substantial increase in the spontaneous firing rate of single auditory nerve fibres. This effect was not accompanied by any observed reduction in the threshold sensitivity of these fibres. These findings cast doubt on current theories of cochlear transduction.


Synthesis of nanoscale zero-valent iron/ordered mesoporous carbon for adsorption and synergistic reduction of nitrobenzene.
Nanoscale zero-valent iron (NZVI) supported on ordered mesoporous carbon (OMC) was synthesized through liquid phase reduction route. The NZVI/OMC composite was characterized by X-ray diffraction, N(2) adsorption/desorption and transmission electron microscopy. Results reveal that the composite possesses ordered mesostructure with NZVI distributing homogeneously on the surface of OMC support. The removal effects of nitrobenzene (NB) in water with OMC, NZVI/OMC and non-supported NZVI were evaluated. Results indicate that NZVI/OMC shows enhanced removal efficiency, which is attributed to its adsorption and synergistic reduction for NB. The transformation process of NB was further investigated by HPLC. Nitrosobenzene and phenylhydroxylamine were detected as intermediate products and aniline was the final reductive product.


Targeting phagocytosis to enhance antitumor immunity.
Many patients with metastatic or treatment-resistant cancer have experienced improved outcomes after immunotherapy that targets adaptive immune checkpoints. However, innate immune checkpoints, which can hinder the detection and clearance of malignant cells, are also crucial in tumor-mediated immune escape and may also serve as targets in cancer immunotherapy. In this review, we discuss the current understanding of immune evasion by cancer cells via disruption of phagocytic clearance, and the potential effects of blocking phagocytosis checkpoints on the activation of antitumor immune responses. We propose that a more effective combination immunotherapy strategy could be to exploit tumor-intrinsic processes that inhibit key innate immune surveillance processes, such as phagocytosis, and incorporate both innate and adaptive immune responses for treating patients with cancer.


Quantification and parametric imaging of renal cortical blood flow in vivo based on Patlak graphical analysis.
Patlak graphical analysis was applied to quantify renal cortical blood flow with N-13 ammonia and dynamic positron emission tomography. Measurements were made in a swine model of kidney transplantation with a wide range of normal and abnormal renal blood flows (N = 57 studies) and in 20 healthy human volunteers (N = 45 studies). Estimates of renal cortical blood flow by the Patlak method were compared to those from a two-compartment model for N-13 ammonia. In addition, estimates of renal cortical blood flow by the N-13 ammonia PET approach were compared in 10 normal human volunteers to estimates by the metabolically inert, freely diffusible O-15 water and a one-compartment model. Patlak graphical analysis estimates of renal cortical blood flow correlated linearly with the standard two-compartment model in pigs (y = -0.05 + 1.01x, r = 0.99) and in humans (y = 0.57 + 0.88x, r = 0.93). Estimates of renal cortical blood flow by O-15 water in human volunteers were also linearly correlated with those by N-13 ammonia and the Patlak graphical analysis (y = 0.71 + 0.84x, r = 0.86). Renal cortical blood flow estimates were highly reproducible both with N-13 ammonia and O-15 water measurements in humans. It is concluded that the Patlak graphical analysis with N-13 ammonia dynamic positron emission tomograpic imaging renders accurate and reproducible estimates of renal cortical blood flow. Moreover, the graphical analysis approach is 1,000 times faster than the standard model fitting approach and suitable for generating parametric images of renal blood flow in the clinical setting.


Spatial and temporal variability of dissolved methane concentrations and diffusive emissions in the Three Gorges Reservoir.
Methane (CH4) emissions from freshwater aquatic systems such as rivers and reservoirs are an important component of the global methane budget. However, the estimation can be largely affected by the spatial and temporal resolutions of measurements. Especially, the lack of high-resolution studies in the Three Gorges Reservoir (TGR), one of the largest reservoirs in the world, has led to a longstanding debate on its CH4 emissions. In this study, the spatial distribution and seasonal variations of dissolved CH4 concentrations were measured using a fast-response automated gas equilibrator in the TGR. We observed large spatiotemporal variations of dissolved CH4 (mean ± SD: 0.26 ± 0.19 μM in summer and 0.24 ± 0.17 μM in winter). Higher concentrations with stronger variations were found in the upstream than in the section close to the Three Gorges Dam. The dissolved CH4 concentration in the TGR was mainly influenced by sewage discharge, sedimentation, topographical conditions, tributaries, and spatial and seasonal variations in hydrodynamics. Regression analyses suggest that the concentration can be characterized by sewage discharge, water depth, and electrical conductivity to a certain extent. Mean diffusive CH4 fluxes from the TGR in summer and winter were 16.2 mg m-2 d-1 and 3.1 mg m-2 d-1, respectively. Downsampling simulations show that scaling dissolved CH4 in the TGR from one site likely involves large errors, and at least ∼38 sites and ∼52-58 sites are needed to achieve an accurate estimate in summer and winter, respectively. Due to the large spatial and temporal heterogeneity, high-resolution measurements are key to improving the reliability of CH4 estimates and assessing the contribution of the TGR to regional and global CH4 budgets.


Growth and activity but not maturation are affected by perinatal diet.
Growth, maturation and activity in Sprague-Dawley rat offspring were studied as a function of two diets which were offered both pre- and postnatally. Day 1 gravid rats were placed ad lib on either Purina chow or Ensure, a total liquid diet. Half of each group was switched to the other diet on day 21 of gestation and maintained on it through weaning. Offspring remained on the same diet until sacrificed on postnatal day 60. Seven developmental measures were assessed daily until all of the animals reached criterion. The type of diet significantly affected maternal weight gain during the second third of gestation, and neonatal weight gain as measured on days 7, 14, 21, 28 and 45. Females were affected more than were male littermates. Males were significantly heavier than female littermates at all postnatal weighings. Diet had little or no effect on the developmental measures. Male/female differences were found for voluntary activity in the wheel which was measured on day 45. The use of liquid diets in behavioral teratology studies and the wisdom of using pellet diets as a control are discussed. The possibility of substituting careful measures of growth as an alternative to developmental testing is discussed.


Parental Nurturance Moderates the Etiology of Youth Resilience.
Parenting behaviors are among the most robust predictors of youth resilience to adversity. Critically, however, very few studies examining these effects have been genetically-informed, and none have considered parenting as an etiologic moderator of resilience. What's more, despite the multidimensionality of resilience, extant etiologic literature has largely focused on a single domain. The current study sought to fill these respective gaps in the literature by examining whether and how parental nurturance shapes the etiology of academic, social, and psychological resilience, respectively. We employed a unique sample of twins (N = 426 pairs; ages 6-11) exposed to moderate-to-severe levels of environmental adversity (i.e., family poverty, neighborhood poverty, community violence) from the Twin Study of Behavioral and Emotional Development in Children. As expected, parental nurturance was positively correlated with all forms of resilience. Extended univariate genotype-by-environment interaction models revealed that parental nurturance significantly moderated genetic influences on all three domains of resilience (academic resilience A1= -0.53, psychological resilience A1= -1.22, social resilience A1= -0.63; all p < .05), such that as parental nurturance increased, genetic influences on youth resilience decreased. Put another way, children experiencing high levels of parental nurturance were more resilient to disadvantage, regardless of their genetic predisposition towards resilience. In the absence of nurturing parenting, however, genetic influences played an outsized role in the origins of resilience. Such findings indicate that parental nurturance may serve as a malleable protective factor that increases youth resilience regardless of genetic influences.


Cooperative evolution with opinion formation in a complex social environment.
Cooperation is a significant aspect in the daily activities of human or animal populations that involves the process of agents making decisions based in part on the ideas or beliefs of cooperators. The importance of communication in the evolutionary game cannot be overstated. In this paper, we offer a co-evolutionary game model on a communication network, including expressed and private opinions. Then, we present our theoretical analysis of scenarios characterized by different parameters, elucidating the relationship between the agents' opinion formation process and the decision-making process. Finally, we run simulations with our proposed model. Surprisingly, we discover that whereas communication does not increase cooperation on Erdös-Rényi random networks, it does so on the Barabási-Albert scale-free network. Meanwhile, we discover that in the simulation results, the average of private opinions (simplified as values within [0,1]) changes in the same direction of the percentage of cooperators. Furthermore, we discover that deceivers who conceal their true private opinions may, to some extent, foster the formation of collaboration in the human population, which goes against our common sense.


Inherited susceptibility for aggressive prostate cancer.
Whether or not there is inherited basis for prostate cancer aggressiveness is not clear, but advances in DNA analysis should provide an answer to this question in the very near future.


Glucocorticoid hormone interactions with cloned proviral DNA of mouse mammary tumor virus.
The molecular details of glucocorticoid hormone regulation of expression of the mouse mammary tumor virus (MMTV) proviral gene have been investigated. Cloned proviral DNA was introduced into cultured cells by a gene transfer procedure. DNA acquired by transfection was shown to be expressed in a hormone regulated fashion. The proviral DNA was fragmented and recombined in vitro with an indicator gene to delimit the hormone response sequence. Inducibility of the indicator gene (thymidine kinase gene from Herpes Simplex Virus, tk) was observed upon recombination with the long terminal repeat (LTR) sequence of MMTV. Further delimitation of the LTR DNA demonstrated that 202 nucleotides located 5' of the RNA initiation site are sufficient to confer glucocorticoid regulation. In vitro interaction of LTR DNA with glucocorticoid hormone receptor complex, showed a preferential affinity to the same sequence which mediated hormonal regulation in transfected cells. Evidence for a direct receptor gene interaction in the process of gene induction was gained by the measurement of the kinetics of induction and the use of a glucocorticoid antagonist (RU 486). The induction of the transfected gene is very rapid, independent of simultaneous protein synthesis and requires a functional glucocorticoid receptor hormone complex.


The structure of neurofibromin isoform 2 reveals different functional states.
The autosomal dominant monogenetic disease neurofibromatosis type 1 (NF1) affects approximately one in 3,000 individuals and is caused by mutations in the NF1 tumour suppressor gene, leading to dysfunction in the protein neurofibromin (Nf1)1,2. As a GTPase-activating protein, a key function of Nf1 is repression of the Ras oncogene signalling cascade. We determined the human Nf1 dimer structure at an overall resolution of 3.3 Å. The cryo-electron microscopy structure reveals domain organization and structural details of the Nf1 exon 23a splicing3 isoform 2 in a closed, self-inhibited, Zn-stabilized state and an open state. In the closed conformation, HEAT/ARM core domains shield the GTPase-activating protein-related domain (GRD) so that Ras binding is sterically inhibited. In a distinctly different, open conformation of one protomer, a large-scale movement of the GRD occurs, which is necessary to access Ras, whereas Sec14-PH reorients to allow interaction with the cellular membrane4. Zn incubation of Nf1 leads to reduced Ras-GAP activity with both protomers in the self-inhibited, closed conformation stabilized by a Zn binding site between the N-HEAT/ARM domain and the GRD-Sec14-PH linker. The transition between closed, self-inhibited states of Nf1 and open states provides guidance for targeted studies deciphering the complex molecular mechanism behind the widespread neurofibromatosis syndrome and Nf1 dysfunction in carcinogenesis.


MS2-MBP-Based Affinity Purification of Nucleus- or Cytoplasm-Localized lncRNA-Protein Complexes Formed In Vivo.
With recent emergence of huge number of long noncoding RNAs (lncRNAs), purification of lncRNA-protein (lncRNP) complexes is fundamental to understand the role of lncRNA and its biological function. However, lncRNP purification is still a daunting challenge. Here we describe a protocol to purify lncRNP formed in vivo with MS2-MBP-based affinity purification. Inducible lncRNA tagged with MS2 RNA hairpins is introduced into cells of interest, and RNP on tagged lncRNA is formed in vivo. MS2-MBP fusion protein is expressed in Escherichia coli and purified with amylose resin and HiTrap heparin column. The MS2 part of MS2-MBP fusion protein binds to the hairpins, and MBP part binds to amylose resin. We also describe a protocol to separate the nucleus and the cytoplasm so that lncRNP localized in the nucleus or cytoplasm can be individually purified. The amount of lncRNP purified is well sufficient for mass spectrometry analysis.


Characterization of the Heat Shock Transcription Factor Family in Medicago sativa L. and Its Potential Roles in Response to Abiotic Stresses.
Heat shock transcription factors (HSFs) are important regulatory factors in plant stress responses to various biotic and abiotic stresses and play important roles in growth and development. The HSF gene family has been systematically identified and analyzed in many plants but it is not in the tetraploid alfalfa genome. We detected 104 HSF genes (MsHSFs) in the tetraploid alfalfa genome ("Xinjiangdaye" reference genome) and classified them into three subgroups: 68 in HSFA, 35 in HSFB and 1 in HSFC subgroups. Basic bioinformatics analysis, including genome location, protein sequence length, protein molecular weight and conserved motif identification, was conducted. Gene expression analysis revealed tissue-specific expression for 13 MsHSFs and tissue-wide expression for 28 MsHSFs. Based on transcriptomic data analysis, 21, 11 and 27 MsHSFs responded to drought stress, cold stress and salt stress, respectively, with seven responding to all three. According to RT-PCR, MsHSF27/33 expression gradually increased with cold, salt and drought stress condition duration; MsHSF6 expression increased over time under salt and drought stress conditions but decreased under cold stress. Our results provide key information for further functional analysis of MsHSFs and for genetic improvement of stress resistance in alfalfa.


Imitating the oracle: Towards calibrated model for class incremental learning.
Class-incremental learning (CIL) aims to recognize classes that emerged in different phases. The joint-training (JT), which trains the model jointly with all classes, is often considered as the upper bound of CIL. In this paper, we thoroughly analyze the difference between CIL and JT in feature space and weight space. Motivated by the comparative analysis, we propose two types of calibration: feature calibration and weight calibration to imitate the oracle (ItO), i.e., JT. Specifically, on the one hand, feature calibration introduces deviation compensation to maintain the class decision boundary of old classes in feature space. On the other hand, weight calibration leverages forgetting-aware weight perturbation to increase transferability and reduce forgetting in parameter space. With those two calibration strategies, the model is forced to imitate the properties of joint-training at each incremental learning stage, thus yielding better CIL performance. Our ItO is a plug-and-play method and can be implemented into existing methods easily. Extensive experiments on several benchmark datasets demonstrate that ItO can significantly and consistently improve the performance of existing state-of-the-art methods. Our code is publicly available at https://github.com/Impression2805/ItO4CIL.


Mechanism insights into photo-assisted peroxymonosulfate activation on oxygen vacancy-enriched nolanites via an electron transfer regime.
The utilization of photo-assisted persulfate activation for the removal of organic contaminants in water has garnered significant research interest in recent times. However, there remains a lack of clarity regarding specific contributions of light irradiation and catalyst structure in this process. Herein, a photo-assisted peroxymonosulfate (PMS) activation system is designed for the highly efficient degradation of organic contaminants on oxygen vacancy-enriched nolanites (Vo-FVO). Results suggest that the degradation of bisphenol A (BPA) in this system is a nonradical-dominated process via an electron transfer regime, in which VO improves the local electron density and thus facilitates the electron shuttling between BPA and PMS. During BPA degradation, PMS adsorbed at the surface of FVO-180 withdraws electrons near VO and forms FVO-PMS* complexes. Upon light irradiation, photoelectrons effectively restore the electron density around VO, thereby enabling a sustainable electron transfer for the highly efficient degradation of BPA. Overall, this work provides new insights into the mechanism of persulfate activation based on defects engineering in nolanite minerals.


Golf-shaped Bi2Se3 microparticles based-immunochromatographic strip for ultrasensitive detection of Acetamiprid.
Rapid and sensitive detection of pesticide is of significance to the field of food safety and human health, but it is still challenging due to interferents from complex food matrices. Herein, a superb golf-shaped Bi2Se3 microparticles-based immunochromatographic strip (BS MPs-ICS) was constructed for ultrasensitive detection of acetamiprid (ATM). The novel immune signal tag demonstrated outstanding luminance, excellent biocompatibility, and high affinity with ATM (affinity constant was 3.874 ×107 M-1), which not only possessed a preeminent labeling efficiency but also significantly improved detection sensitivity. After optimization, the limit of detection (LOD) of the BS MPs-ICS was 8.780 pg/mL with an excellent linear relationship at the range of 0.010-6.000 ng/mL, which was approximately 62-fold lower than that of conventional gold nanoparticles-ICS (0.545 ng/mL), The BS MPs-ICS biosensor was well applied in apple and tomato samples with satisfactory recoveries of 83.823-99.223% (relative standard deviation < 1.739%). Therefore, the BS MPs-ICS could serve as a promising candidate for ATM detection in complicated samples and develop a new method in real-time monitoring.


Sensor and biosensor preparation, optimisation and applications of Prussian Blue modified electrodes.
Being one of the most commonly used electrochemical mediators for analytical applications, Prussian Blue has found a wide use in the biosensor field during the last years. Its particular characteristic of catalysing hydrogen peroxide reduction has been applied in the construction of a large number of oxidase enzyme-based biosensors for clinical, environmental and food analysis. By modifying an electrode surface with Prussian Blue, it is in fact possible to easily detect hydrogen peroxide at an applied potential around 0.0 V versus Ag/AgCl, thus making possible coupling with oxidase enzymes while also avoiding or reducing electrochemical interferences. Papers dealing with glucose, lactate, cholesterol and galactose biosensors that are based on the use of Prussian Blue have recently appeared in the most important analytical chemistry journals. Another recent trend is the use of a choline probe based on choline oxidase for pesticide determination to exploit the inhibition of acetylcholinesterase by these compounds. In addition, the use of Prussian Blue in the development of biosensors for food analysis has captured the interest of many research groups and led to improved methods for the detection of glutamate, galactose, alcohol, fructosyl amine, formate, lysine and oxalate. This review will focus on the biosensing aspects of Prussian Blue-based sensors giving a general overview of the advantages provided by such mediator as well as its drawbacks. A comprehensive bibliographic reference list is presented together with the most up to date research findings in this field and possible future applications. The commercial potential of sensors based on this mediator will also be discussed.


Oxidative DNA damage of mixed copper(II) complexes with sulfonamides and 1,10-phenanthroline. Crystal structure of [Cu(N-quinolin-8-yl-p-toluenesulfonamidate)2(1,10-phenanthroline)].
Mixed coordination compounds of Cu(II) with sulfonamides and 1,10-phenanthroline as ligands have been prepared and characterised. Single crystal structural determination of the complex [Cu(N-quinolin-8-yl-p-toluenesulfonamidate)(2)(phen)] shows Cu(II) ions are located in a highly distorted octahedral environment, probably as a consequence of the Jahn-Teller effect. The FT-IR and electronic paramagnetic resonance (EPR) spectra are also discussed. The mixed complexes prepared undergo an extensive DNA cleavage in the presence of ascorbate and hydrogen peroxide. Two of the complexes have higher nucleolytic efficiency than the bis(o-phenanthroline)copper(II) complex.


Effect of age on in vivo urinary bladder function in the rat.
The effects of age on micturition in male Fischer 344 rats, ages five to seven, 16 to 18 and 22 to 24 months, were studied. The 24 hr. water intake, 24 hr. urine output, frequency and volume of each micturition were obtained from rats housed individually in metabolic cages. Intravesical pressure and volume at which the micturition contraction occurred were evaluated using natural-fill cystometry. The 24 hr. water intake and urine output increased significantly with advancing age; 22 to 24 months rats showed a 39% increase in water intake and a 93% increase in urine output compared to five to seven month rats. The increase in urine output observed in the 22 to 24 month old rats was manifested by a 95% increase in volume per micturition and a 52% increase in frequency of micturition compared to five to seven month old rats. The pressure at micturition (PAM) was 100% greater in 22 to 24 and 16 to 18 month old rats compared to five to seven month old rats with no age-related difference in bladder volume at micturition (BVM). These studies demonstrate that in vivo micturition changes with age in the male F344 rat. Although there were no overt urological dysfunctions observed in the aging rats, the alterations in function would indicate that there were changes in either the mechanisms controlling micturition, or changes in the musculature itself. These possibilities will be the subject of further investigations.


Metabolism of the neurotoxin in MPTP by human liver monoamine oxidase B.
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was oxidized to dihydropyridine MPDP+ and pyridine MPP+ by preparations of monoamine oxidase B (MAO B), including pure human liver MAO B:monoclonal antibody complex, Km,app values for MPTP and benzylamine, a preferred MAO B substrate, were 316 and 64 microM, respectively. 4-Phenyl-1,2,3,6-tetrahydropyridine (PTP), the nor derivative of MPTP, was also a substrate (Km,app = 221 microM). MPDP+, MPTP, and MPP+, but not PTP, were found to be irreversible inhibitors of MAO B. Our studies support the hypothesis that MPTP is oxidized in primate brain by MAO B to MPDP+, which is then converted to MPP+, a major metabolite found in the substantia nigra.


Dimethyl sulfoxide perfusion in caprine ovarian tissue and its relationship with follicular viability after cryopreservation.
Ovarian cortical fragments (3 x 3 x 1 mm) were exposed to dimethyl sulfoxide (DMSO) in different concentrations for further analysis of cryoprotectant perfusion by applying high-performance liquid chromatography (HPLC) and conventional cryopreservation. This simple perfusion test can predict the efficiency of the cryopreservation procedure.


Corrigendum: A toolkit of tagged glp-1 alleles reveals strong glp-1 expression in the germline, embryo, and spermatheca.
[This corrects the article DOI: 10.17912/micropub.biology.000271.].


Effects of L-tryptophan and ethanol on sleep parameters in the rat.
Sleep parameters were monitored following (1) a single 2 g/kg oral dose of ethanol, (2) an oral dose of L-tryptophan (600 mg/kg), and (3) administration of both drugs simultaneously. Ethanol reduced REM and increased slow wave significantly. The effects of L-tryptophan were apparent only in the case of one parameter, REM latency. Administration of both drugs resulted in a significantly shorter REM latency than that observed for ethanol alone. Results are discussed in terms of possible changes in the biosynthesis of 5-HT.


Lysophosphatidylglycerol stimulates chemotactic migration in human natural killer cells.
We observed that lysophosphatidylglycerol (LPG) stimulates chemotactic migration in human natural killer (NK) cells. The LPG-induced chemotactic migration of NK cells was completely inhibited by pertussis toxin (PTX). LPG also stimulated the extracellular signal-regulated kinase (ERK) and Akt activities in NK cells. LPG-stimulated ERK activity was inhibited by PTX, indicating the involvement of PTX-sensitive G-proteins. The preincubation of NK cells with an ERK inhibitor (PD98059) or phosphoinositide-3-kinase (PI3K) inhibitors (wortmannin and LY294002) completely inhibited LPG-induced chemotactic migration, suggesting the essential role of ERK and PI3K in the process. Moreover, LPG-induced chemotactic migration in NK cell was inhibited by Ki16425, an LPA(1/3) receptor-selective antagonist, suggesting the involvement of the Ki16425-sensitive G-protein coupled receptor (GPCR) in the process. Taken together, the results indicate that LPG stimulates chemotactic migration in NK cells through GPCR, suggesting a new function of LPG as a modulator of NK cell functioning.


Proteasome inhibition induces neurite outgrowth through posttranslational modification of TrkA receptor.
The ubiquitin-proteasome pathway regulates many biological processes, including protein degradation, receptor endocytosis, protein sorting, subnuclear trafficking and neuronal differentiation. While proteasome inhibition is known to induce neurite outgrowth, the signaling mechanisms that mediate these effects have not been defined. In this study, we investigated the underlying mechanisms that link proteasome inhibition with neurite generation. We found that the proteasome inhibitors, MG132 and lactacystin, induced neurite outgrowth and also activated extracellular signal-regulated kinase/mitogen activated protein kinase and phosphatidylinositol-3-kinase/AKT pathways. These proteasome inhibitors also induced phosphorylation and ubiquitination of TrkA receptors, indicating that proteasome inhibition activates the major pathways of TrkA signaling. However, in contrast to nerve growth factor stimulation, which induces internalization of surface TrkA receptors, proteasome inhibitor-induced neurite outgrowth did not require TrkA receptor internalization. These results indicate that the ubiquitin-proteasome system regulates neurite formation through posttranslational modification of TrkA receptors.


Electrophysiological evidence for a tonic activity of the spinal cord intrinsic opioid systems in a chronic pain model.
The aim of this electrophysiological investigation was to evaluate the activity of the spinal endogenous opioid systems in a chronic pain model, the arthritic rat. The activity of nociceptive non-specific dorsal horn neurons (n = 23) were recorded in 23 spinal unanesthetized decerebrated rats. Naloxone (1 mg/kg i.v.) induced a highly significant increase in the spontaneous firing rate of these neurons. This observation is in favor of a tonic activity of spinal opioid endogenous systems in such a disease. In addition, the same dose of naloxone facilitates the transmission of noxious messages at the spinal level as revealed by the large enhancement of the responses of these neurons to C-fiber stimulation. These results are in good agreement with behavioral data showing that such a relatively high dose of naloxone induced well-reproducible hyperalgesia and with some biochemical observations showing an increase of levels and biosynthesis of endogenous opioids in the spinal cord of the arthritic rat.


Assessment of the facial features and chin development of fetuses with use of serial three-dimensional sonography and the mandibular size monogram in a Chinese population.
Our purpose was to evaluate whether the application of serial three-dimensional (3D) sonography and the mandibular size monogram can allow observation of dynamic changes in facial features, as well as chin development in utero. The mandibular size monogram has been established through a cross-sectional study involving 183 fetal images. The serial changes of facial features and chin development are assessed in a cohort study involving 40 patients. The monogram reveals that the Biparietal distance (BPD)/Mandibular body length (MBL) ratio is gradually decreased with the advance of gestational age. The cohort study conducted with serial 3D sonography shows the same tendency. Both the images and the results of paired-samples t test (P<.001) statistical analysis suggest that the fetuses develop wider chins and broader facial features in later weeks. The serial 3D sonography and mandibular size monogram display disproportionate growth of the fetal head and chin that leads to changes in facial features in late gestation. This fact must be considered when we evaluate fetuses at risk for development of micrognathia.


Natural anti-inflammatory products for osteoarthritis: From molecular mechanism to drug delivery systems and clinical trials.
Osteoarthritis (OA) is a degenerative joint disease that affects millions globally. The present nonsteroidal anti-inflammatory drug treatments have different side effects, leading researchers to focus on natural anti-inflammatory products (NAIPs). To review the effectiveness and mechanisms of NAIPs in the cellular microenvironment, examining their impact on OA cell phenotype and organelles levels. Additionally, we summarize relevant research on drug delivery systems and clinical randomized controlled trials (RCTs), to promote clinical studies and explore natural product delivery options. English-language articles were searched on PubMed using the search terms "natural products," "OA," and so forth. We categorized search results based on PubChem and excluded "natural products" which are mix of ingredients or compounds without the structure message. Then further review was separately conducted for molecular mechanisms, drug delivery systems, and RCTs later. At present, it cannot be considered that NAIPs can thoroughly prevent or cure OA. Further high-quality studies on the anti-inflammatory mechanism and drug delivery systems of NAIPs are needed, to determine the appropriate drug types and regimens for clinical application, and to explore the combined effects of different NAIPs to prevent and treat OA.


The effect of general anesthesia and strabismus surgery on the intellectual abilities of children: a pilot study.
To determine the influence of general anesthesia and strabismus surgery on children's intellectual abilities. Prospective, observational study. Institutional. Children 5 to 10 years of age receiving general anesthesia with sevoflurane and undergoing strabismus surgery were included. Intellectual abilities were examined before and 4 weeks after surgery using the Kaufman Assessment Battery for Children. Four subtests representing intellectual abilities related to complex cortical function were examined: identification of objects in a partially completed picture, reproduction of a presented design by using rubber triangles, selecting a picture that completes or is similar to another picture, and memory for location of pictures presented on a page. Preoperative and postoperative age-adjusted scores of the 4 subtests of the Kaufman Assessment Battery for Children. The study group consisted of 21 children who underwent strabismus surgery under general anesthesia (mean duration, 51.3 minutes). The mean preoperative total score of the 4 subtests was 49.4±6.2. The mean postoperative total score adjusted for potential learning effects and test-retest reliability was 48.1±7.7. There was no significant postoperative change in the total score (P=.108). However, the triangle test score decreased significantly after operation (P=.019), particularly in patients with decreased stereoacuity after surgery. General anesthesia with sevoflurane and strabismus surgery generally do not affect the intellectual abilities of complex cortical function in children 5 to 10 years of age at 4 weeks after surgery. Cortical functions related to hand-eye coordination may be affected by transient changes in postoperative stereoacuity.


"We Should Talk"-Moving knowledge into action by learning to engage patients, families, and healthcare staff to communicate for patient safety.
Innovation in patient engagement and empowerment has been identified as a priority area in the Canadian healthcare system. This article describes the development and implementation of the We Should Talk campaign at an academic pediatric hospital. Through the use of a guiding theoretical framework and a multidisciplinary project team, a multimedia campaign was designed to inspire staff, patients and families to effectively communicate to improve patient safety. The We Should Talk campaign provides a case study for how an organization can foster frontline improvement through the engagement of patient, families, and healthcare providers.


Should We Care About Adolescents Who Care for Themselves? What We've Learned and What We Need to Know About Youth in Self-Care.
This article provides an overview of existing research on the prevalence and predictors of adolescent self-care and on the consequences associated with it. Self-care, in which the young are left unsupervised during out-of-school hours, is a common experience for millions of American youth, and existing studies suggest that this arrangement may represent a risk for the development of behavior problems. However, the behavior problems associated with self-care depend on both individual and environmental factors and are most likely to develop when self-care (1) occurs out of the home, (2) involves permissive parenting and/or low parental monitoring, (3) takes place in neighborhoods with high levels of crime and disorganization, (4) involves adolescents with preexisting behavioral problems, and (5) represents an intensive and persistent arrangement. Following our survey of current research on self-care, we offer recommendations regarding future research and policy.


Taste perception: how to make a gourmet mouse.
Sugars and amino acids are mainly associated with desirable taste sensation. A new study using knockout mouse models shows that the detection of various sugars, artificial sweeteners and L-amino acids is exclusively mediated by taste cells that express one or pair-wise combinations of three G protein coupled receptors, T1R1, T1R2 and T1R3


Effects of continuous positive airway pressure treatment on coronary vasoreactivity measured by (82)Rb cardiac PET/CT in obstructive sleep apnea patients.
Obstructive sleep apnea syndrome (OSA) increases the risk of cardiovascular disease. We aimed at evaluating the effect of continuous positive airway pressure (CPAP) treatment on coronary endothelium-dependent vasoreactivity in OSA patients by quantifying myocardial blood flow (MBF) response to cold pressure testing (CPT). In the morning after polysomnography (PSG), all participants underwent a dynamic (82)Rb cardiac positron emitting tomography/computed tomography (PET/CT) scan at rest, during CPT and adenosine stress. PSG and PET/CT were repeated at least 6 weeks after initiating CPAP treatment. OSA patients were compared to controls and according to response to CPAP. Patients' characteristics and PSG parameters were used to determine predictors of CPT-MBF. Thirty-two untreated OSA patients (age 58 ± 13 years, 27 men) and 9 controls (age 62 ± 5 years, 4 men) were enrolled. At baseline, compared to controls (apnea-hypopnea index (AHI) = 5.3 ± 2.6/h), untreated OSA patients (AHI = 48.6 ± 19.7/h) tend to have a lower CPT-MBF (1.1 ± 0.2 mL/min/g vs. 1.3 ± 0.4 mL/min/g, p = 0.09). After initiating CPAP, CPT-MBF was not different between well-treated patients (AHI <10/h) and controls (1.3 ± 0.3 mL/min/g vs. 1.3 ± 0.4 mL/min/g, p = 0.83), but it was lower for insufficiently treated patients (AHI ≥10/h) (0.9 ± 0.2 mL/min/g vs. 1.3 ± 0.4 mL/min/g, p = 0.0045). CPT-MBF was also higher in well-treated than in insufficiently treated patients (1.3 ± 0.3 mL/min/g vs. 0.9 ± 0.2 mL/min/g, p = 0.001). Mean nocturnal oxygen saturation (β = -0.55, p = 0.02) and BMI (β = -0.58, p = 0.02) were independent predictors of CPT-MBF in OSA patients. Coronary endothelial vasoreactivity is impaired in insufficiently treated OSA patients compared to well-treated patients and controls, confirming the need for CPAP optimization.


Autosomal Clonal Monoallelic Expression: Natural or Artifactual?
The prevalence of mitotically heritable clonal random monoallelic expression of autosomal genes (aRME) remains controversial. Specifically, presence of clonal aRME is well supported in vitro but remains elusive in vivo. Here, we provide critical insights into this matter and discuss whether prevalent clonal aRME is natural or artifactual.


Psychoacoustic Studies of Spotted (Phoca largha) and Ringed (Pusa hispida) Seals.
Human development of the marine environment raises questions regarding the potential adverse effects of anthropogenic noise on marine mammals. For species that live in remote Arctic regions, recent and expanding human intrusions may pose a particular threat. Northern seals are poorly studied relative to their temperate counterparts and little is known of their acoustic ecology or behavior. Given this scarcity of relevant data, studies of hearing in Arctic seals are essential to characterize their auditory capabilities and to inform management decisions. This paper describes ongoing psychoacoustic studies that are examining aspects of hearing in two ice seal species.


Platelet-derived microRNA-223 attenuates TNF-α induced monocytes adhesion to arterial endothelium by targeting ICAM-1 in Kawasaki disease.
Kawasaki disease (KD) is an acute vasculitis that may result in permanent coronary artery damage with unknown etiology. Endothelial cell (EC) dysfunction and platelet hyperactivity are the hallmarks of KD. Platelets are involved in the development of endothelial dysfunction. MiR-223 transferred by platelet microparticles (PMPs) has been found to involve in the functional regulation of endothelial cells in sepsis. However, the role of platelet-derived miR-223 in endothelial dysfunction has not yet been investigated in KD. We seek to investigate the role of platelet-derived miR-223 in endothelial dysfunction of KD vasculopathy. Forty-five acute KD patients and 45 matched controls were randomly recruited in the study. When co-cultured with human coronary artery endothelial cells (HCAECs), KD platelets with higher levels of miR-223 were incorporated into HCAECs, resulting in the horizontal transfer of miR-223. Using KD platelets, PMPs, and platelet-releasate from the same amount of blood co-cultured with HCAECs, we found the increased expression of miR-223 in HCAECs was primarily derived from KD platelets, rather than PMPs or free miRNAs from platelet- releasate. KD platelet-derived miR-223 attenuated TNF-α induced intercellular cell adhesion molecule-1 (ICAM-1) expression in HCAECs. KD platelet-derived miR-223 also suppressed the monocyte adhesion to HCAECs. In vivo, platelet-specific miR-223 knockout (PF4-cre: miR-223flox/flox) C57BL/6 mice and miR-223flox/flox C57BL/6 mice were used. Using Lactobacillus casei cell wall extract (LCWE) to establish KD murine model, we showed that in LCWE-injected PF4-cre: miR-223flox/flox mice, deficiency of platelet-miR-223 exacerbates the medial thickening of the abdominal aorta, increased ICAM-1 expression with concomitant CD45+ inflammatory cells infiltration into the endothelium compared to LCWE-injected miR-223flox/flox mice. The horizontal transfer of platelet-derived miR-223 suppresses the expression of ICAM-1 in HCAECs, which at least in part attenuates leukocyte adhesion, thereby reducing endothelial damage in KD vasculitis.


Three dimensional shape reconstruction and finite element analysis of femur before and after the cementless type of total hip replacement.
Computerized tomography was used to reconstruct a shape, and stresses in three-dimensional objects were analysed. The human femur, which has a very irregular shape, was chosen as an object. CT image data of a cadaver femur were transferred to a computer, and an edge extraction program generated the cross-section of bone by specifying a range of CT values for each slice. Pixel data from the CT scan are converted into a vector of points (x, y, z) which can specify the boundaries of bone. Lateral surfaces are defined by stacking up the slices and making use of the vectorized data. Intermediate and oblique cross-sections can be obtained by an interpolation technique. The constructed model was used as input data for the finite element analysis. To understand the stress distributions before and after the cementless type of total hip replacement, a three-dimensional finite element stress analysis of the bone-implant system was carried out, assuming micromotions between the stem and the femur. The analysis was done for both frictionless and friction cases, modelling the contact point with a gap element having isotropic friction. The analysis shows that the stress is not concentrated on the femoral calcar when the friction coefficient is large.


Preparation of Immune and Synthetic VNAR Libraries as Sources of High-Affinity Binders.
The shark-derived autonomous variable antibody domains known as VNARs are attractive tools for therapeutic and diagnostic applications due to their favorable properties like small size (approximately 12 kDa), high thermal and chemical stability, and good tissue penetration. Currently, different techniques have been reported to generate VNAR domains against targets of therapeutic interest. Here, we describe methods for the preparation of an immune VNAR library based on bacteriophage display, and for the preparation of a synthetic library of VNAR domains using a modified protocol based on Kunkel mutagenesis. Finally, we describe procedures for in silico maturation of a VNAR using a bioinformatic approach to obtain higher affinity binders.


Preoperative prediction of outcome in patients with rectal and rectosigmoid cancer.
This study evaluated the possibility of dividing patients with primary rectal carcinoma into prognostic groups before surgery based on preoperative serum levels of carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), and an antigen defined by the monoclonal antibody C-50 (CA-50), as well as on some easily available clinical characteristics providing prognostic information. The evaluation was made both for patients who were "potentially curable" by surgery and, among those, for patients who were "potentially cured." Using the Cox regression model, the serum levels of the three tumor markers, together with the knowledge of whether or not the tumor was polypoid were combined to make up the set of variables that best predicted patient outcome. These variables and their associated regression coefficients were used to classify the patients according to prognosis. The cancer-specific mortality rate for the 24% of potentially curable patients with the best prognosis was 15%; for the 26% of potentially curable patients with the worst prognosis, the cancer-specific mortality rate was 57%. For potentially cured patients among those who were potentially curable, the cancer-specific mortality rates for patients with the best and worst prognoses were 14% and 47%, respectively. The information provided by these preoperatively available variables together was comparable with that given by Dukes' staging system, but the latter system was more informative. On the other hand, some of the preoperative variables provided information not provided by Dukes' staging system.


National Athletic Trainers' Association Releases New Guidelines for Exertional Heat Illnesses: What School Nurses Need to Know.
Exertional heat illnesses (EHI) occur in various populations and settings. Within a school setting, there are student athletes who take part in physical activity where the risk of EHI is increased. The National Athletic Trainers' Association (NATA) released an updated position statement on EHI in September of 2015. This article is a summary of the position statement. The sports medicine team, including school nurses and athletic trainers, provides quality health care to these physically active individuals. Thus, it is important for school nurses to understand the prevention, recognition, and treatment of EHI.


Thioredoxin reductase 1 inhibitor shikonin promotes cell necroptosis via SecTRAPs generation and oxygen-coupled redox cycling.
Shikonin, a naturally occurring naphthoquinone with potent anti-tumor activity, has been reported to induce cancer cell death via targeting selenoenzyme thioredoxin reductase 1 (TrxR1; TXNRD1). However, the interaction between shikonin and TrxR1 remains unclear, and the roles of the cellular antioxidant system in shikonin induced cell death are obscure. Here, we found that shikonin modified the Sec498 residue of TrxR1 to fully inhibit its antioxidant activity, however, the shikonin-modified TrxR1 still remained intrinsic NADPH oxidase activity, which promotes superoxide anions production. Besides, TrxR1 efficiently reduced shikonin in both selenocysteine dependent and selenocysteine independent manners, and the oxygen-coupled redox cycling of shikonin also generates excessive superoxide anions. The inhibitory effects and the redox cycling of shikonin towards TrxR1 caused cancer cell ROS-dependent necroptosis. Interestingly, as we evaluated, some cancer cell lines were insensitive to shikonin, especially kelch-like ECH associated protein 1 (KEAP1)-mutant non-small cell lung cancer (NSCLC) cells, which harbor constitutive activation of the nuclear factor-erythroid 2-related factor 2 (NRF2). NADPH bankruptcy caused by glucose starvation or glucose limitation (inhibiting glucose transporter 1 by BAY-876) could efficiently overcome the resistance of KEAP1-mutant NSCLC cells to shikonin. Glucose-6-phosphate dehydrogenase (G6PD), was known as a rate-limiting enzyme in the pentose phosphate pathway, however, the pharmacological inhibition of G6PD by 6-aminonicotinamide (6-AN), enhanced the shikonin-induced cytotoxicity but has no selectivity on KEAP1-mutant NSCLC cells. This study will be helpful in applying shikonin for potential chemotherapy, and in combinational treatment of KEAP1-mutant NSCLC.


A lung recruitment maneuver immediately before rescue surfactant therapy does not affect the lung mechanical response in immature lambs with respiratory distress syndrome.
In animals with acquired surfactant-deficiency, a recruitment maneuver by increased tidal volumes enhances the effect of exogenous surfactant. In contrast, in the preterm lamb model, hyperinflation early after birth impairs the effect of surfactant prophylaxis. Here we examined whether a lung recruitment maneuver just before surfactant would affect the response to rescue treatment in immature lambs with established respiratory distress syndrome (RDS). Five pairs of preterm twin lambs with gestational age 127 days were delivered by cesarean section and supported by pressure-limited mechanical ventilation for 4 h. At 30 min of age, when all the lambs were in severe respiratory failure, they were treated with porcine surfactant, 200 mg x kg-1. One lamb in each pair was subjected to a lung recruitment maneuver consisting of five sustained inflations of 20 ml x kg-1 just before surfactant instillation. At 10 min after surfactant treatment, all the lambs showed a large improvement in oxygenation and an increase in inspiratory capacity and static compliance. Except for a transiently better oxygenation after surfactant therapy in the recruitment group (P < 0.05), there was no significant between-group differences in gas exchange or lung mechanics at any time point during the study. There was no difference in post mortem intrapulmonary air volume or alveolar expansion in histologic lung sections between groups. This small study does not show any positive or negative effect of a lung recruitment maneuver on the response to rescue surfactant therapy in immature animals with RDS.


Melanoma genetics and therapeutic approaches in the 21st century: moving from the benchside to the bedside.
Metastatic melanoma is notoriously one of the most difficult cancers to treat. Although many therapeutic regimens have been tested, very few achieve response rates greater than 25%. Given the rising incidence of melanoma and the paucity of effective treatments, there is much hope and excitement in leveraging recent genetic and molecular insights for therapeutic advantage. Over the past 30 years, elegant studies by many groups have helped decipher the complex genetic networks involved in melanoma proliferation, progression and survival, as well as several genes involved in melanocyte development and survival. Many of these oncogenic loci and pathways have become crucial targets for pharmacological development. In this article we review: (1) our current understanding of melanoma genetics within the context of signaling networks; (2) targeted therapies, including an extensive discussion of promising agents that act in the Bcl-2 signaling network; (3) future areas of research.


Design, synthesis, cytotoxicity screening and molecular docking of new 3-cyanopyridines as survivin inhibitors and apoptosis inducers.
Recently, targeting survivin proved to be an attractive strategy for developing anticancer agents. Survivin overexpression is highly correlated with cancer aggressiveness, recurrence and resistance to chemotherapeutic treatment and radiotherapy. Additionally, survivin is overexpressed selectively in most cancer types with a very little expression in completely differentiated cells, which encouraged us to design and synthesize a novel series of 3-cyanopyridine derivatives targeting survivin. The newly synthesized compounds were evaluated for their cytotoxic activities against three cancer cell lines; PC-3, HepG2 and MDA-MB-231. Compounds 4a, 4b, 5c and 6c showed significant cytotoxic activities that were more potent than the reference drug, 5-FU. Hence, these compounds were selected to be further studied regarding their apoptotic potential in PC-3 cells. Interestingly, they decreased the level of Bcl-2 by 1.9-3.8 folds and increased the level of Bax by 6.1-8.8 folds compared to the control. Moreover, they elevated the level of active caspase-3 by 7.1-8.5 folds in comparison to the control. In order to estimate the cytotoxicity level of these compounds in non-tumorigenic cells, WI38 cells were treated with these compounds. They showed high IC50 values (148.57-193.64 µM), indicating selective cytotoxicity to the tumor cells, and much less toxic effect to the normal ones. Additional studies on the mechanism of 4a, the most active compound, revealed that it induced cell cycle arrest at the G2/M phase in addition to an increase in the percentage of pre-G1 apoptotic cells. Furthermore, western blotting was carried out using different concentrations of 4a. Results showed that 4a markedly suppressed survivin expression in PC-3 cells and caused a decrease in the caspase-7/cleaved caspase-7 ratio and in Bcl-2/Bax ratio, in addition to an increase in the level of the cleaved PARP. Finally, docking study of the most active compound in the active site (dimerization site) of survivin was in agreement with the in vitro survivin inhibitory activity.


Intercycle variability of day 3 follicle-stimulating hormone levels and its effect on stimulation quality in in vitro fertilization.
Prior studies have demonstrated that gonadotropin stimulation quality and pregnancy rates are better in in vitro fertilization (IVF) patients with low basal cycle day 3 follicle-stimulating hormone (FSH) levels. The records of 81 patients who had undergone three or more IVF attempts during a 2-year period were studied to determine the degree and potential impact of intercycle variability in basal FSH concentrations. The mean of the individual standard deviations for all 81 patients was 4.2 +/- 0.4 mIU/mL. However, the patients with a mean basal FSH of less than 15 mIU/mL had a mean deviation of only 2.6 +/- 0.2 mIU/mL, whereas those with a mean basal FSH of greater than or equal to 15 mIU/mL had a mean deviation of 7.3 +/- 0.7 mIU/mL. Intercycle variability in basal FSH values did not predict changes in ovarian response to gonadotropin stimulation and thus may not be used to select an optimal cycle in which to stimulate an individual patient. Furthermore, patients with large intercycle variation responded poorly to gonadotropin stimulation independent of their basal FSH concentration. This information allows more precise counseling of patients regarding their appropriateness for assisted reproduction.


So you think you can jump? A novel long jump assessment to detect deficits in stroked mice.
Stroke survivors suffer from persistent disability, as well as severe sensorimotor and cognitive deficits. The preclinical assessment of such deficits is important for the development of novel interventions and therapeutics. The aim of this study was to develop a quantitative behavioral measure of hindlimb functionality in rodents, which could be used to assess deficits after a neural injury, such as stroke. Here we introduce a test to measure long jump behavior in mice. Using this test we first showed that while male and female mice exhibited no differences in jump success rate, the female mice showed lower baseline jumping latencies. Next we demonstrated that the induction of a cerebral stroke via middle cerebral artery occlusion (MCAO) for 45min did not affect the jump success rate in either group; however, it did significantly increase jump latencies in both male and female mice. Finally, we used therapeutic interventions to explore mechanisms that may be involved in producing this increase in jump latency by administering the anti-depressant fluoxetine prior to the long jump assay, and also tested for potential changes in anxiety levels after stroke. Other methods to assess hindlimb functionality are not specific, because they measure behaviors that rely not only on hindlimbs, but also on forelimbs and tail. This study introduces a novel assay that can be used to measure a stroke induced behavioral deficit with great sensitivity, and raises interesting questions about potential mechanisms regulating this effect.


A practical approach to pediatric patients referred with an abnormal coagulation profile.
Workup for prolonged prothrombin time (PT) and activated partial thromboplastin time (PTT) is a frequent referral to a Hematology and Coagulation Laboratory. Although the workup should be performed in a timely and cost-effective manner, the complete laboratory assessment of the coagulation state has not been standardized. To determine which clinical and laboratory data are most predictive of a coagulopathy and to formulate the most efficient strategy to reach a diagnosis in patients referred for abnormal coagulation profiles. Retrospective case review. Medical records of 251 patients referred for prolonged PT and/or PTT to our Hematology Service between June 1995 and December 2002 were reviewed. The study included 135 males and 116 females with a mean age of 7.0 years. A personal history of bleeding was reported in 137 patients, and a family history of bleeding was reported in 116 patients. Fifty-one patients (20%) had a coagulopathy (ie, a bleeding risk). Factors predictive of a bleeding risk were a positive family history of bleeding (P < .001) and a positive personal history of bleeding (P = .001). Of 170 patients with findings of normal PT and PTT values on repeat testing, 14 were subsequently diagnosed with a coagulopathy. Two of these patients reported no positive personal or family history of bleeding. Coagulopathy was identified in 20% of the children referred for abnormal PT and/or PTT. In the absence of a personal or family history of bleeding, a normal PT and/or PTT on repeat testing has a negative predictive value of more than 95%.


Rapid Discovery of Potential Drugs for Osteonecrosis of Femoral Head Based on Gene Expression Omnibus Database and Connectivity Map.
To use Gene Expression Omnibus (GEO) database coupled with Connectivity Map (CMap) databases to screen potential therapeutic drugs for osteonecrosis of femoral head (ONFH) rapidly. Raw genetic data with accession number GSE74089 that contained eight hip articular cartilage specimens from four ONFH patients and four healthy controls were obtained from the Gene Expression Omnibus (GEO) database and were then integrated using R to identify differentially expressed genes (DEGs). Subsequently, to identify several potential small molecular compounds that were most strongly negatively correlated with ONFH, a search query of DEGs was explored by using CMap. Filtering revealed 1937 DEGs with log (fold-change) ≥1 and adjust P value < 0.001. Finally, a network of candidate targets for ONFH with 135 nodes and 660 edges was constructed through network topology analysis, including 96 up-regulated genes and 39 down-regulated genes. Several significant gene functions and signaling pathways associated with pathological processes of ONFH were identified via gene enrichment analysis. Based on the CMap database, some potential small molecular components that may be possible to counteract the effects of molecular signal imbalance for ONFH were identified. Neostigmine bromide with low CMap score and P value and specificity score was predicted to be the most candidate compound, involved in the "positive regulation of stem cell proliferation," "regulation of protein autophosphorylation," "VEGF signaling pathway," and "ECM-receptor interaction." The GEO and CMap databases can be effectively used in understanding the molecular changes in ONFH and provide a systematic manner to identify potential drugs for ONFH prevention and treatment. However, additional clinical and experimental research of the candidate compound is warranted.


Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest.
In hematopoietic cells, the Bcr/Abl tyrosine kinase that is encoded by the Philadelphia chromosome translocation both stimulates proliferation and activates an anti-apoptotic program that is associated with a G2/M delay upon exposure to various apoptotic stimuli. We recently reported that the monocyclic monoterpene, perillyl alcohol (POH) selectively induces in Bcr/Abl transformed cells, G0/G1 arrest and apoptosis. Therefore, POH activates anti-proliferative and apoptotic pathways against which the Bcr/Abl kinase does not protect. In this report, we show that in Bcr/Abl-transformed cells, POH induces cytoplasmic acidification, redistribution of phosphatidylserine in the plasma membrane along with DNA fragmentation, all of which can be prevented by the phorbol ester, TPA. The ability of TPA to protect against POH-induced cytotoxicity was blocked by inhibitors of protein kinase C (PKC) and the Na(+)/H(+) antiport. In contrast, TPA does not protect the cells from POH-mediated G0/G1 arrest. While POH inhibits a distal step in the mevalonate biosynthesis pathway, lovastatin, also a potential anticancer agent, inhibits the initial step in this pathway. Not surprisingly, lovastatin also induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed cells, however, TPA protects cells from both apoptosis and G0/G1 arrest caused by lovastatin. Thus, in Bcr/Abl-transformed cells, POH and lovastatin cause growth arrest by different mechanisms. Together, these observations demonstrate that POH-mediated cell cycle arrest precedes apoptosis and raises the possibility that that the primary effect of POH is to induce G0/G1 arrest with apoptosis being a consequence of the growth arrest.


Evidence for fine-scale genetic structure and estuarine colonisation in a potential high gene flow marine goby (Pomatoschistus minutus).
Marine fish seem to experience evolutionary processes that are expected to produce genetically homogeneous populations. We have assessed genetic diversity and differentiation in 15 samples of the sand goby Pomatoschistus minutus (Pallas, 1770) (Gobiidae, Teleostei) from four major habitats within the Southern Bight of the North Sea, using seven microsatellite and 13 allozyme loci. Despite its high dispersal potential, microsatellite loci revealed a moderate level of differentiation (overall F(ST)=0.026; overall R(ST)=0.058). Both hierarchical analysis of molecular variance and multivariate analysis revealed significant differentiation (P<0.01) between estuarine, coastal and marine samples with microsatellites, but not with allozymes. Comparison among the different estimators of differentiation (F(ST) and R(ST)) pointed to possible historical events and contemporary habitat fragmentation. Samples were assigned to two breeding units in the estuary and coastal region. Despite this classification, there were indications of a complex and dynamic spatiotemporal structure, which is, most likely, determined by historical events and local oceanic currents.


Improving countershock success prediction during cardiopulmonary resuscitation using ventricular fibrillation features from higher ECG frequency bands.
Countershock outcome prediction using ventricular fibrillation (VF) feature analysis needs undisturbed electrocardiogram (ECG) signals and therefore requires interruption of cardiopulmonary resuscitation (CPR). Features that originate from higher frequency bands of the VF power spectrum may be less affected by CPR artefacts and as such reduce cumulative hands-off intervals. From 192 patients with in-hospital and out-of-hospital cardiac arrest, four countershock outcome prediction features (peak-peak amplitude, mean slope, median slope, power spectrum analysis) were analysed in 550 short time ECG records, each including a CPR corrupted and a subsequent undisturbed sequence. ECG features calculated from the main frequency band (0-26Hz) and from bandpass-filtered subbands (>10-26Hz) were compared using the similarity level method and differences in shock advice numbers. The feature similarity between ECG periods with and without CPR artefacts was higher in bandpass-filtered (Sim=0.79, 0.8, 0.78, 0.66) than in unfiltered ECG traces (Sim=0.58, 0.69, 0.68, 0.47). For the features evaluated, the difference in number of shock advices between subsequent traces with and without CPR artefact was significantly reduced using VF analysis from higher frequency bands. The accuracy of shock outcome prediction during CPR could be increased by using filtered ECG features from higher ECG subbands instead of features derived from the main ECG spectrum.


ABC proteins: key molecules for lipid homeostasis.
Forty-nine ABC protein genes exist on human chromosomes. Eukaryotic ABC proteins were originally recognized as drug efflux pumps involved in the multidrug resistance of cancer cells. However, it is now realized that one of their major physiological roles is cellular lipid transport and homeostasis, and their dysfunction is often associated with human diseases. ABCA1 and ABCA7 mediate the apolipoprotein-dependent formation of a high-density lipoprotein-cholesterol complex. ABCA3 is indispensable for pulmonary surfactant secretion. ABCG5 and ABCG8 are involved in the secretion of plant sterols and cholesterol into bile. However, the primary substrates and mechanism of action of these ABC proteins have not been precisely defined. In this review article, we first describe the general structure and functions of eukaryotic ABC proteins. The current model of ABCA1 functionality is then explained based on studies on a topological model, subcellular localization, apoA-I dependence of HDL formation, functional defects of Tangier disease mutants, and ATP hydrolysis of purified ABCA1. ABCA1 is supposed to function as a transporter of lipids as well as a receptor for apoA-I. ABCA3 is likely involved in accumulating phospholipids and cholesterol in lamellar bodies and in generating multivesicular structures.


What else are psychotherapy trainees learning? A qualitative model of students' personal experiences based on two populations.
After an introductory course in experiential-integrative psychotherapy, 21 graduate students provided personal narratives of their experiences, which were analyzed using the grounded theory method. Results produced 37 hierarchically organized experiences, revealing that students perceived multiple changes in both professional (i.e., skill acquisition and learning related to the therapeutic process) and personal (i.e., self growth in a more private sphere) domains. Analysis also highlighted key areas of difficulties in training. By adding the personal accounts of graduate trainees, this study enriches and extends Pascual-Leone et al.'s (2012) findings on undergraduates' experiences, raising the number of cases represented in the model to 45. Findings confirm the model of novice trainee experiences while highlighting the unique experiences of undergraduate vs. graduate trainees.