Chitosan oligosaccharide suppresses osteosarcoma malignancy by inhibiting CEMIP via the PI3K/AKT/mTOR pathway.
Osteosarcoma is a malignant bone tumor that is prone to metastasize early and primarily affects children and adolescents. Cell migration-inducing protein (CEMIP) plays a crucial role in the progression and malignancy of various tumor diseases, including osteosarcoma. Chitosan oligosaccharide (COS), an oligomer isolated from chitin, has been found to have significant anti-tumor activity in various cancers. This study investigates the effects of COS on CEMIP expression in osteosarcoma and explores the underlying mechanism. In present study, in vitro experiments were conducted to confirm the inhibitory activity of COS on human osteosarcoma cells. Our results demonstrate that COS possesses inhibitory effects against human osteosarcoma cells and significantly suppresses CEMIP expression in vitro. Next, we studied the inhibition of the expression of CEMIP by COS and then performed bioinformatics analysis to explore the potential inhibitory mechanism of COS against signaling pathways involved in regulating CEMIP expression. Bioinformatics analysis predicted a close association between the PI3K signaling pathway and CEMIP expression and that the inhibitory effect of COS on CEMIP expression may be related to PI3K signaling pathway regulation. The results of this study show that COS treatment significantly inhibits CEMIP expression and the PI3K/AKT/mTOR signaling pathway, as observed both in vitro and in vivo. This study demonstrates that COS could inhibit the expression of CEMIP, which is closely related to osteosarcoma malignancy. This inhibitory effect may be attributed to the inhibition of the PI3K/AKT/mTOR signaling pathway in vitro and in vivo.


Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism.
Knowledge of protein dynamics is fundamental to the understanding of biological processes, with NMR and 2D-IR spectroscopy being two of the principal methods for studying protein dynamics. Here, we combine these two methods to gain a new understanding of the complex mechanism of a cytokine:receptor interaction. The dynamic nature of many cytokines is now being recognised as a key property in the signalling mechanism. Interleukin-17s (IL-17) are proinflammatory cytokines which, if unregulated, are associated with serious autoimmune diseases such as psoriasis, and although there are several therapeutics on the market for these conditions, small molecule therapeutics remain elusive. Previous studies, exploiting crystallographic methods alone, have been unable to explain the dramatic differences in affinity observed between IL-17 dimers and their receptors, suggesting there are factors that cannot be fully explained by the analysis of static structures alone. Here, we show that the IL-17 family of cytokines have varying degrees of flexibility which directly correlates to their receptor affinities. Small molecule inhibitors of the cytokine:receptor interaction are usually thought to function by either causing steric clashes or structural changes. However, our results, supported by other biophysical methods, provide evidence for an alternate mechanism of inhibition, in which the small molecule rigidifies the protein, causing a reduction in receptor affinity. The results presented here indicate an induced fit model of cytokine:receptor binding, with the more flexible cytokines having a higher affinity. Our approach could be applied to other systems where the inhibition of a protein-protein interaction has proved intractable, for example due to the flat, featureless nature of the interface. Targeting allosteric sites which modulate protein dynamics, opens up new avenues for novel therapeutic development.


Use of licit and illicit drugs at the University of Alfenas.
This paper reports the study of drug consumption carried out within the population of undergraduate students from 2 colleges of Alfenas, in the state of Minas Gerais state. Both licit and illicit drugs were studied, including alcohol, tobacco, marijuana, cocaine, heroin, crack, inhalants, glue, tranquilizers, stimulants, and others. The research included a wide bibliographical search and the application of a questionnaire to approximately 23% of the students (total of 6500 students). A total of 1500 students participated in this investigation. The results demonstrated that there was a significant consumption of both licit and illicit drugs. The pattern of drug consumption in the research sample was similar to other investigations conducted in Brazil and in other countries. It was observed that 55% of the university students use drugs. However, the most surprising finding was that most of the students (88%) answered "yes" to the inquiry, "Have you already tried any type of drug, including alcohol and cigarettes?" The students revealed that they had taken drugs even prior to the admission to the university. The results suggest clearly that the university environment does not necessarily represent the starting point for student drug consumption.


[Revision consensus hemophilia: treatment and responsibility. Nederlandse Vereniging van Hemophilia Patients].
Haemophilia is an X-linked clotting disease occurring in 1400 men in the Netherlands. As the result of factor VIII or IX deficiency, haemophilia patients suffer from severe bleedings, spontaneous or caused by trauma. Bleedings mostly occur in major joints and muscles. Repeated bleedings can cause disability. Treatment of haemophilia consists of replacement therapy with factor VIII or IX. The first aim of treatment is to prevent bleedings (prophylaxis). The second aim is to limit joint damage in case of bleeding by timely and adequate substitution therapy. In addition, physical therapy and sports are used to keep patients in shape. Until the introduction of recombinant factor VIII in 1992 only plasma derived factor VIII and IX products were available. Substitution therapy has caused various side effects, such as allergic reactions. Since the introduction of ultra-pure concentrates, allergic reactions have grown rare. Viral infections like HIV and hepatitis C, which were transmitted through blood products, have not occurred in Dutch haemophilia patients since the introduction of adequate viral inactivation steps. In case of development of antibodies against factor VIII or IX, therapy with factor VIII or IX products is insufficient. Antibody formation is more often seen in haemophilia A (25%) than in haemophilia B (2%). In most cases antibodies disappear during so-called immune tolerance induction. This therapy consists of regular infusion with factor VIII or IX. Once an inhibitor has disappeared, patients can be treated normally once more. As haemophilia is a rare and complex disease patients should be treated in specialized centres, preferably by a comprehensive care team. This is even more justified because treatment of haemophilia is costly. Over the last 20 years haemophilia treatment has improved much. This has resulted in a decrease of the number and of the duration of hospitalization, and a decrease in days lost at school or work. This has led to great improvement of the social life of haemophilia patients.


Sulforaphane Ameliorates the Severity of Psoriasis and SLE by Modulating Effector Cells and Reducing Oxidative Stress.
Background: Sulforaphane, which is found in cruciferous vegetables, has been reported to have anti-inflammatory, antioxidant, and antitumour activities. However, whether sulforaphane has therapeutic effects on inflammatory or autoimmune skin diseases, including psoriasis and systemic lupus erythematosus (SLE), is unclear. Methods: The therapeutic effects of sulforaphane were analyzed in Imiquimod (IMQ)-induced psoriasis-like mice and lupus-prone MRL/lpr mice. In IMQ-induced psoriasis-like mice treated with sulforaphane (55.3 and 110.6 μmol/kg) or vehicle control, the pathological phenotypes were assessed by the psoriasis area and severity index (PASI) score, haematoxylin-eosin staining (H&E) and quantifying of acanthosis and dermal inflammatory cell infiltration. The proportions of T cell subsets in draining lymph nodes (dLNs) and spleens were examined by flow cytometry. In MRL/lpr mice treated with sulforaphane (82.9 μmol/kg) or vehicle control, mortality and proteinuria were observed, and the glomerular pathology was examined by H&E staining. C3 and IgG depositions in kidney sections were examined by immunofluorescence staining. The proportions of plasma cells, follicular helper T (Tfh) cells, neutrophils and dendritic cells in the dLNs and spleens were examined by flow cytometry. Finally, we examined the Malondialdehyde (MDA) concentration by thiobarbituric acid reactive substance assay and the expression of Prdx1, Nqo1, Hmox1, and Gss by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: Sulforaphane ameliorated the skin lesions in IMQ-induced psoriasis-like mice and the renal damage in lupus-prone MRL/lpr mice. In IMQ-induced psoriasis-like mice, sulforaphane reduced the proportions of Th1 and Th17 cells and increased the expression of antioxidant gene Prdx1. In lupus-prone MRL/lpr mice, sulforaphane increased the lifespan and the expression of Prdx1, and decreased the proportions of plasma cells, Tfh cells, neutrophils, and dendritic cells in the dLNs and spleens and the concentration of MDA. Conclusion: Sulforaphane has significant therapeutic effects on IMQ-induced psoriasis-like mice and lupus-like MRL/Lpr mice by reducing inflammatory and autoimmune-related cells and oxidative stress. These findings provide new evidence for developing natural products to treat inflammatory and autoimmune diseases.


Autoradiography of [3H]thymidine-labeled Chlamydia psittaci 6BC in mononuclear phagocytes.
Incorporation of tritiated [3H]thymidine by Chlamydia psittaci 6BC was achieved by growing the parasites in chick embryo yolk sac explants which were exposed to exogenous labeled thymidine. These labeled, purified chlamydiae were next observed by autoradiography within mouse peritoneal macrophages. The number of silver grains remained constant in the cytoplasm of macrophages throughout the developmental cycle of the parasite. The proliferation of labeled chlamydiae in macrophages was confirmed by Giemsa staining and immunofluorescence. Chlamydiae have never been successfully labeled with thymidine in earlier studies when assayed in cultured mammalian fibroblasts. It is suggested that a critical factor in the successful incorporation thymidine in chlamydiae may be the host-parasite system used.


Determination of genotypes of Toxoplasma gondii strains isolated from patients with toxoplasmosis.
To determine the genotypes of Toxoplasma gondii strains associated with human toxoplasmosis, we developed a sensitive approach for typing parasites grown from clinical samples by short-term in vitro culture. A newly described nested PCR assay was capable of amplifying genomic DNA from as few as five parasites in the presence of host tissues. Typing was based on DNA polymorphisms at the SAG2 locus, encoding tachyzoite surface antigen p22. Restriction fragment length polymorphisms in PCR-amplified SAG2 products were used to classify strains into one of the three major lineages of T. gondii. This approach was successfully used to determine the genotypes of 68 of 72 samples that had been previously isolated from patients with congenital, cerebral, and disseminated toxoplasmosis. Type II strains of T. gondii were found in a majority of the samples, accounting for 55 (81%) of the 68 toxoplasmosis cases. In contrast, type I and III strains were found in only 7 (10%) and 6 (9%) of the 68 cases, respectively. The results of this study support the previous finding that type II strains are most often associated with human toxoplasmosis. Nested PCR analysis at the SAG2 locus provides rapid assignment of T. gondii to a specific genotype that should be useful in analyzing a variety of clinical samples.


A robust high-throughput fungal biosensor assay for the detection of estrogen activity.
Estrogenic active compounds are present in a variety of sources and may alter biological functions in vertebrates. Therefore, it is crucial to develop innovative analytical systems that allow us to screen a broad spectrum of matrices and deliver fast and reliable results. We present the adaptation and validation of a fungal biosensor for the detection of estrogen activity in cow derived samples and tested the clinical applicability for pregnancy diagnosis in 140 mares and 120 cows. As biosensor we used a previously engineered genetically modified strain of the filamentous fungus Aspergillus nidulans, which contains the human estrogen receptor alpha and a reporter construct, in which β-galactosidase gene expression is controlled by an estrogen-responsive-element. The estrogen response of the fungal biosensor was validated with blood, urine, feces, milk and saliva. All matrices were screened for estrogenic activity prior to and after chemical extraction and the results were compared to an enzyme immunoassay (EIA). The biosensor showed consistent results in milk, urine and feces, which were comparable to those of the EIA. In contrast to the EIA, no sample pre-treatment by chemical extraction was needed. For 17β-estradiol, the biosensor showed a limit of detection of 1ng/L. The validation of the biosensor for pregnancy diagnosis revealed a specificity of 100% and a sensitivity of more than 97%. In conclusion, we developed and validated a highly robust fungal biosensor for detection of estrogen activity, which is highly sensitive and economic as it allows analyzing in high-throughput formats without the necessity for organic solvents.


The specificity of in vivo tolerance to haptens in NZB and normal mice after exposure to hapten-modified syngeneic spleen cells.
We have evaluated hapten-specific hyporesponsiveness induced by in vivo administration of TNP-modified syngeneic spleen cells (TNP-SC). Pretreatment of non-autoimmune mice led to hyporesponsiveness to challenge with either TNP or the closely related hapten DNP coupled to Ficoll. There was also a significant reduction of the direct PFC response after challenge with TNP-HGG. In tolerized mice challenged with TNP-HGG, the IgM portion of the serum response was similarly suppressed; however, the total serum antibody as well as the indirect PFC response was not suppressed. There was no tolerance at all when the mice were challenged with DNP-HGG. Thus, exposure to TNP-SC results in an incomplete form of hapten-specific B cell tolerance. This tolerance is selective for the IgM isotype and does not extend to the cross-reactive hapten DNP on a thymic-dependent carrier, although it does extend to a DNP on a thymic-independent carrier. Autoimmune NZB mice were defective with regard to tolerance after injection of hapten-modified syngeneic spleen cells. They did manifest a reduced direct PFC response to the challenge with TNP-Ficoll, but failed to demonstrate cross-tolerance to DNP-Ficoll challenge. Moreover, they did not have suppression of the hapten-specific IgM response after challenge with TNP on the thymic-dependent carrier. These abnormalities in tolerance induction in NZB mice to modified self may help to explain the loss of self-tolerance that occurs spontaneously and is expressed as autoimmune disease.


Ultrastructural study of the neural microcircuits in the sensory epithelium of the paratympanic organ of the chicken.
The paratympanic organ (PTO) is a sensory organ located in the medial wall of the tympanic cavity of birds. The organ looks like a small tapering vesicle, and is equipped with a sensory epithelium formed by supporting cells (SCs) and Type II hair cells (Type II-HCs). The function of the PTO has not yet been precisely defined. The prevailing current hypothesis is that the PTO assesses the air pressure exerted on the external surface of the tympanic membrane. The PTO could may thus function as a barometer and, in flying birds, also as an altimeter. The afferent synapses of the PTO of chicken were described in detail in a previous paper. Reciprocal synapses between efferent nerve endings (ENEs) and the HCs were also observed, suggesting the existence of local microcircuits. The aim of this work was to provide a more detailed ultrastructural description of these microcircuits in the PTO of chicken. We observed for the first time: (1) reciprocal synapses between the HCs and the afferent nerve endings (ANEs); (2) presence of two distinct types of ENEs; (3) reciprocal synapses between the HCs and both types of ENEs. Overall, these results indicate that a complex processing of the incoming sensory signals may occur in the PTO. This thus suggests that the PTO may perform more complex functions than those supposed until now. We hypothesize that the PTO could have a role in the low-frequency sound perception.


Promoting quality improvement in French healthcare organisations: design and impact of a compendium of models and tools.
Relevant and user friendly information should be provided to professionals who wish to promote quality improvement in healthcare organisations (HCOs). In response to requests from French HCOs, we designed a compendium of methods and tools for use in quality improvement. Its contents were based on a critical review of the literature, face-to-face interviews with three industrial/business experts in quality, the views of 13 healthcare professionals knowledgeable in quality issues, and comments from over 40 potential users of the compendium. Overall, 14 methods and 20 tools relevant and applicable to the healthcare sector were identified. They were classified according to their main thrust, explained in detail, illustrated with specific cases from the literature or from personal experience, and published as a loose leaf compendium. The compendium was posted on the worldwide web and presented to healthcare managers in September 2000. It has become one of the most popular ANAES publications (approximately 5400 downloads over the first 6 months), partly because all French HCOs are legally bound to undergo accreditation which has been set up and is being implemented by ANAES.


Idiopathic spinal epidural lipomatosis: urgent decompression in an atypical case.
Symptomatic spinal epidural lipomatosis (SEL) is very rare and frequently associated to chronic exogenous steroid use, obesity and Cushing syndrome. The idiopathic cases where no identifiable association with SEL are found constitute only 17% of all cases. The usual clinical manifestations of this entity consist of dorsal or lumbar pain with paresthesias and weakness in lower limbs, but acute symptoms of myelopathy are exceptional. We report a case of acute paraparesis and urinary retention caused by thoracic SEL in a 55-year-old male who did not have any recognized predisposing factor for this condition. Urgent surgical decompression was performed in order to relieve the symptoms. Slow but progressive improvement was assessed after surgery. We consider this case to be exceptional due to the needing to perform an urgent decompressive laminectomy to treat a rapidly progressive myelopathy caused by idiopathic SEL.


Shaping the actin cytoskeleton using microtubule tips.
The microtubule cytoskeleton serves as a primary spatial regulator of cell shape. As part of their function, microtubules appear to activate or inhibit the actin cytoskeleton at specific locations at the cell cortex for cell polarization, cell migration and cytokinesis. Recent studies reveal molecular insights into these processes. Regulators of the actin cytoskeleton, such as activators of formin and Rho GTPases, are transported to specific sites on the cortex by riding on the plus ends of microtubules.


Elastographic versus x-ray CT imaging of radio frequency ablation coagulations: an in vitro study.
Techniques to image elasticity parameters (i.e., elastography) have recently become of great interest to researchers. In this paper we use conventional ultrasound elastography and x-ray CT to image radio frequency (RF) ablation sites of excised canine liver enclosed in gelatin. Thermal coagulations of different sizes were produced by applying the RF procedure for various times and end point temperatures. Dimensions, areas and volumes computed from CT and elastography were compared with those on whole mount pathology specimens. Ultrasound elastography exhibited high contrast for the thermal coagulations and performed better than CT. The correlation between pathology and elastography for this sample set of 40 thermal coagulations (r = 0.94 for volume estimation, r = 0.87 for area estimation) is better than the correlation between pathology and CT (r = 0.89 for volume estimation, r = 0.82 for area estimation).


Prevalence study of oral leukoplakia in a selected population of 1000 patients from The Netherlands.
A survey of a special population, the outpatients of a Department of Oral Surgery of a Teaching Hospital in Amsterdam, revealed a comparatively low prevalence rate for oral leukoplakia of 14/1000 patients (1.4%). No difference was found in the age distribution compared with similar investigations elsewhere in the world. However, in contrast with previous findings, which show a significant difference between prevalences of leukoplakia for men and women, leukoplakia was equally distributed between both sexes.


Influence of chelators and iron ions on the production and degradation of H2O2 by beta-amyloid-copper complexes.
beta-Amyloid peptide (Abeta) 1-42, involved in the pathogenesis of Alzheimer's disease, binds copper ions to form AbetaxCu(n) complexes that are able to generate H(2)O(2) in the presence of a reductant and O(2). The production of H(2)O(2) can be stopped with chelators. More reactive than H(2)O(2) itself, hydroxyl radicals HO() (generated when a reduced redox active metal complex interacts with H(2)O(2)) are also probably involved in the oxidative stress that creates brain damage during the disease. We report in the present work a method to monitor the effect of chelating agents on the production of hydrogen peroxide by metallo-amyloid peptides. The addition of H(2)O(2) associated to a pre-incubation step between ascorbate and AbetaxCu(n) allows to study the formation of H(2)O(2) but also, at the same time, its transformation by the copper complexes. AbetaxCu(n) peptides produce but do not efficiently degrade H(2)O(2). The reported analytic method, associated to precipitation experiments of copper-containing amyloid peptides, allows to study the inhibition of H(2)O(2) production by chelators. The action of a ligand such as EDTA is probably due to the removal of the copper ions from AbetaxCu(n), whereas bidentate ligands such as 8-hydroxyquinolines probably act via the formation of ternary complexes with AbetaxCu(n). The redox activity of these bidentate ligands can be modulated by the incorporation or the modification of substituents on the quinoline heterocycle.


An assessment of whether long-term global changes in waves and storm surges have impacted global coastlines.
A common inference in research studies of observed and projected changes in global ocean wave height and storm surge, is that such changes are potentially important for long-term coastal management. Despite numerous studies of the impacts of anthropogenic climate change on trends in global wind and waves, a clear link to impacts on sandy coastlines, at global scale, is yet to be demonstrated. This study presents a first-pass assessment of the potential link between historical trends in global wave and storm surge values and recession/progradation rates of sandy coastlines since the 1980s. Global datasets of waves, surge and shoreline change rate are used for this purpose. Over the past 30 + years, we show that there have been clear changes in waves and storm surge at global scale. The data, however, does not show an unequivocal linkage between trends in wave and storm surge climate and sandy shoreline recession/progradation. We conclude that these long-term changes in oceanographic parameters may still be too small to have a measurable impact on shoreline recession/progradation and that primary drivers such as ambient imbalances in the coastal sediment budget may be masking any such linkages.


Looking ahead: what long-term outcomes can we expect from spinal devices for degenerative disc disease.
Degenerative disc disease is one of the leading causes of pain and disability. Various surgical treatments are available, but the literature does not provide a comparative overview of their long-term outcomes. This article synthesizes the available long-term evidence on the treatment of degenerative disc disease. Fusion for degenerative disc disease has recently shown good long-term clinical outcomes, yet several studies strongly suggest that it may accelerate the degenerative process at adjacent levels. Arthroplasty shows at least equivalent long-term outcomes and is not expected to accelerate adjacent degeneration, but speculative concern remains about its safety, especially in regard to wear debris and facet joint arthrosis. Many other treatment devices are in various stages of development, but long-term studies are not yet available for most of them. When making treatment decisions, physicians and patients must consider the long-term outcomes, because the devices remain implanted indefinitely, and back pain could recur at any time if the degeneration progresses or the device fails. Before making a treatment decision, surgeons and patients should thoroughly discuss the long-term clinical prognosis, the safety of various procedures, the degrees of certainty in our currently available medical knowledge, and the patient's preferences. No one solution will be right for every patient, but we are entering a golden era of choices, where most patients with degenerative disc disease should be able to find a treatment that substantially improves their condition.


Protective Role of Orthokeratology in Reducing Risk of Rapid Axial Elongation: A Reanalysis of Data From the ROMIO and TO-SEE Studies.
To determine the relative risk of rapid progression and number needed to treat (NNT) in younger and older children using combined data from the retardation of myopia in orthokeratology (ROMIO) and toric orthokeratology-slowing eye elongation (TO-SEE) studies. Data from 136 subjects of two studies, ROMIO and TO-SEE, were retrieved (72 orthokeratology [ortho-k]: 37 ROMIO, 35 TO-SEE; 64 control: 41 ROMIO, 23 TO-SEE) and the myopia control effect on younger (6-8 years) and older (9-12 years) subjects evaluated. The rate of axial elongation was classified as not rapid (axial elongation = <0.36 mm/year) or rapid (axial elongation >0.36 mm/year). Cumulative frequency curves showed that the younger subjects in the control group had the greatest and most rapid axial elongation at the end of 24 months. In the younger subjects, ortho-k lens wear significantly reduced the risk of rapid progression by 88.8% (P = 0.002). The 2-year NNT for the younger ortho-k subgroup was 1.8, suggesting that treating just two younger subjects with ortho-k would prevent one subject from experiencing rapid progression over a 2-year period of treatment. The 2-year NNT for the older ortho-k subgroup was 11.8, which was statistically insignificant (P = 0.197). Orthokeratology significantly reduced risk of rapid progression in younger subjects. Treating just two 6- to 8-year-old subjects with ortho-k instead of single-vision spectacles could prevent one subject from developing rapidly progressing axial elongation during this critical 2-year period.


Laugier Hunziker syndrome.
Laugier Hunziker syndrome is a rare disorder that is characterized by adult-onset hyperpigmented macules of the lips, oral cavity, and fingertips. Longitudinal melanonychia is present in the majority of cases. We present a 45-year-old woman with adult-onset hyperpigmented macules of the oral cavity as well as linear melanonychia that involved multiple fingernails. The history, clinical examination, and paucity of laboratory abnormalities or systemic findings support a diagnosis of Laugier Hunziker syndrome.


Interleukin-4 and interferon-gamma interactions in the induction of intercellular adhesion molecule-1 and major histocompatibility complex class II antigen expression of normal human keratinocytes.
Interleukin-4 (IL-4) that may be produced by T-helper cells in atopic lesions has immunomodulatory activities on skin cells which are poorly known. Our study was aimed at determining whether the cytokine exerts some effects on keratinocyte activation and can either enhance or antagonize interferon-gamma (IFN-gamma)-induced ICAM-1 or HLA-DR antigen expression. Using normal keratinocytes cultured in defined medium and cytofluorography, we showed that treatments of the human cells with the cytokine IL-4 alone had no effect on the induction of ICAM-1 or HLA-DR molecules. However, a transient, but significant enhanced expression of ICAM-1 was observed by the combination of IFN-gamma and IL-4 after 24 h of stimulation, which was followed by a reduction at 48 and 72 h. Conversely, IL-4, when added during the IFN-gamma activation stage, had no effect on MHC class II antigen expression of keratinocytes; however, the cytokine reduced the expression of these antigens when added 24 h before the stimulation by IFN-gamma. These results suggest that IFN-gamma and IL-4 may interact to regulate ICAM-1 and HLA-DR expression on keratinocytes.


Treatments for primary aneurysmal bone cysts of the cervical spine: experience of 14 cases.
Aneurysmal bone cyst (ABC) is a benign lesion with the potential to be locally aggressive. The optimal treatment of cervical spine lesions remains controversial. This retrospective study was designed to evaluate the different treatments for primary ABCs of the cervical spine. This series included eight men and six women diagnosed between 2002 and 2012. A retrospective review of the hospital charts, operating room reports, office charts, and radiographs was performed. The data collected included patient age, sex, radiological features, pathology, treatment methods, outcomes, and complications from biopsies and treatments. The mean age at diagnosis was 17.5 years old with a range of 6-35 years. All patients had experienced local pain for a mean of 7.3 months (range, 0.5-18.0 months), and three patients had neurological deficits (one with radiculopathy and two with myelopathy). The Frankel classification before treatment was E in 12 cases, D in one case, and C in one case. Four patients received radiotherapy alone. Ten patients underwent surgery, including five total spondylectomies, two local resections, and three curettages. Three patients received preoperative selective arterial embolization, and four received adjuvant radiotherapy. The mean follow-up time was 44.5 months (range 12-96 months), and no recurrence was identified. Three patients with neurological deficits achieved complete recovery, as noted at the final follow-up examination. One patient received radiotherapy without appropriate immobilization as prescribed and developed C1-C2 subluxation with severe spinal cord compression but without myelopathy. He refused further treatment. The results can be achieved by different treatments (surgical resection/curettage, selective arterial embolization, and radiotherapy) for ABC of the cervical spine. Reconstruction of stability is also important for the treatment of cervical ABC.


Adrenal aldosterone-producing adenoma: use of colonic potential in diagnosis and subtraction scanning technique for localisation.
Primary hyperaldosteronism is a potentially curable cause of hypertension, and much interest has been shown in methods of diagnosing the associated hypokalaemic hypertension and localising the adrenal adenoma. In two patients the diagnosis of primary aldosteronism was confirmed by colonic potential measurement and the adenoma localised by a new subtraction technique for early adrenal imaging applied to the use of 131I-19-iodocholesterol. Both patients underwent adrenalectomy and in each case an adenoma was removed. Blood pressure and electrolyte levels returned to normal after operation. In one patient bilateral adrenal phlebography had failed to show the tumour, and sampling of aldosterone concentrations in the adrenal veins had been unsatisfactory.


Regional circulatory responses to hypocapnia and hypercapnia in bar-headed geese.
To investigate mechanisms that may allow birds to tolerate extreme high altitude (hypocapnic hypoxia), we examined the effects of severe hypocapnia and moderate hypercapnia on regional blood flow in bar-headed geese (Anser indicus), a species that flies at altitudes up to 9,000 m. Cerebral, coronary, and pectoral muscle blood flows were measured using radioactive microspheres, while arterial CO2 tension (PaCO2) was varied from 7 to 62 Torr in awake normoxic birds. Arterial blood pressure was not affected by hypocapnia but increased slightly during hypercapnia. Heart rate did not change during alterations in PaCO2. Severe hypocapnia did not significantly alter cerebral, coronary, or pectoral muscle blood flow. Hypercapnia markedly increased cerebral and coronary blood flow, but pectoral muscle blood flow was unaffected. The lack of a blood flow reduction during severe hypocapnia may represent an important adaptation in these birds, enabling them to increase O2 delivery to the heart and brain at extreme altitude despite the presence of a very low PaCO2.


Biologic therapy (TNF-alpha antagonists)-induced psoriasis: a cytokine imbalance between TNF-alpha and IFN-alpha?
We report 3 patients with psoriatic arthritis and 2 with rheumatoid arthritis who developed worsening, and/or de novo psoriasis, and/or psoriasiform rash, while on tumor necrosis factor antagonist therapy. All 5 patients initially presented with active skin, and/or joint inflammatory involvement, and exhibited significant clinical response to tumor necrosis factor antagonist therapy. Within approximately 6 months, however, psoriatic and/or psoriasiform rash developed de novo in 2 rheumatoid arthritis patient and exacerbated in the other 3 patients. Biopsy findings revealed histologic and immunohistochemical changes indistinguishable from psoriasis.Psoriatic rash improved after discontinuation of biologic therapy and/or initiation of a short course of oral prednisone. One patient with psoriatic arthritis was rechallenged with infliximab due to exacerbation of both psoriasis and psoriatic arthritis, and this was followed by prompt improvement of both conditions. At 6 months follow-up, this patient remains under excellent control. To date, there have been over 50 cases of this type of dermatologic complication described. Interferon alpha seems to play an important role in the pathogenesis of this complication. This type of complication has been described with all 3 available tumor necrosis factor inhibitors, and most patients improve after discontinuation of biologic therapy.


A Simple Biorefinery Concept to Produce 2G-Lactic Acid from Sugar Beet Pulp (SBP): A High-Value Target Approach to Valorize a Waste Stream.
Lactic acid is a high-value molecule with a vast number of applications. Its production in the biorefineries model is a possibility for this sector to aggregate value to its production chain. Thus, this investigation presents a biorefinery model based on the traditional sugar beet industry proposing an approach to produce lactic acid from a waste stream. Sugar beet is used to produce sugar and ethanol, and the remaining pulp is sent to animal feed. Using Bacillus coagulans in a continuous fermentation, 2781.01 g of lactic acid was produced from 3916.91 g of sugars from hydrolyzed sugar beet pulp, with a maximum productivity of 18.06 g L-1h-1. Without interfering in the sugar production, ethanol, or lactic acid, it is also possible to produce pectin and phenolic compounds in the biorefinery. The lactic acid produced was purified by a bipolar membrane electrodialysis and the recovery reached 788.80 g/L with 98% w/w purity.


[Effect of Electroacupuncture at Different Acupoints on Expression of NGF and TrkA in Cerebral Cortex in Rats with Myocardial Ischemia].
To compare the therapeutic effect of electroacupuncture (EA) of "Shenmen" (HT 7, Yuan point of the Heart Meridian), "Zhizheng" (SI 7, Luo point of the Small Intestine Meridian) and "Xinshu" (BL15, Back-shu point) on the expression of nerve growth factor (NGF) and its receptor, tyrosine kinase A (TrkA) in the cerebral cortex of myocardial ischemia (MI) rats. A total of 70 male SD rats were randomized into sham operation (sham, n=10), model, HT 7, SI 7, and BL15 groups (n=15 in each of the latter 4 groups). The MI model was established by ligation of the anterior descending branch of the left coronary artery. EA (1 mA, 2 Hz) was respectively applied to HT 7, SI 7 and BL15 for 15 min, once per day for 1 week. Immunohistochemistry and real-time fluorescent quantitative PCR were used to detect the expression of NGF and TrkA proteins and genes in the cerebral cortex. Compared with the sham group, no significant changes were found in the number of NGF immune-reaction (IR)-positive and TrkA IR-positive cells, and the expression levels of NGF mRNA and TrkA mRNA in the model group (P>0.05). After EA intervention, the number of NGF and TrkA IR-positive cells and the expression of NGF mRNA and TrkA mRNA in each of the 3 EA groups were significantly increased relevant to the model group (P<0.01, P<0.05). The effect of EA at BL 15 was significantly superior to that of EA at HT 7 and SI 7 in increasing the number of NGF and TrkA positive cells and up-regulating the expression of their mRNAs (P<0.01, P<0.05). EA at HT 7, SI 7 and BL 15 can increase the levels of expression of NGF and TrkA proteins and mRNAs in the cerebral cortex of subacute MI rats and the effects of EA-BL 15 are obviously superior to those of EA-HT 7 and EA-SI 7, suggesting a relative specificity of the effect of EA at different acupoints.


Supplement to listing of accredited doctoral, internship, and postdoctoral training programs in health service psychology.
Provides an announcement from the Commission on Accreditation for the following status changes for accredited doctoral (clinical, counseling, school, or a combination there of and developed practice area), doctoral internship, and postdoctoral residency programs in health service psychology as of April 2, 2017. (PsycINFO Database Record


Cooperation of Adhesin Alleles in Salmonella-Host Tropism.
Allelic combinations and host specificities for three fimbrial adhesins, FimH, BcfD, and StfH, were compared for 262 strains of Salmonella enterica serovar Newport, a frequent human and livestock pathogen. Like FimH, BcfD had two major alleles (designated A and B), whereas StfH had two allelic groups, each with two alleles (subgroup A1 and A2 and subgroup B1 and B2). The most prevalent combinations of FimH/BcfD/StfH alleles in S. Newport were A/A/A1 and B/B/B1. The former set was most frequently found in bovine and porcine strains, whereas the latter combination was most frequently found in environmental and human isolates. Bacteria genetically engineered to express Fim, Bcf, or Stf fimbriae on their surface were tested with the different alleles for binding to human, porcine, and bovine intestinal epithelial cells. The major allelic combinations with bovine and porcine strains (A/A/A1) or with human isolates (B/B/B1) provided at least two alleles capable of binding significantly better than the other alleles to an intestinal epithelial cell line from the respective host(s). However, each combination of alleles kept at least one allele mediating binding to an intestinal epithelial cell from another host. These findings indicated that allelic variation in multiple adhesins of S. Newport contributes to bacterial adaptation to certain preferential hosts without losing the capacity to maintain a broad host range. IMPORTANCESalmonella enterica remains a leading foodborne bacterial pathogen in the United States; infected livestock serve often as the source of contaminated food products. A study estimated that over a billion Salmonella gastroenteritis cases and up to 33 million typhoid cases occur annually worldwide, with 3.5 million deaths. Although many Salmonella strains with a broad host range present preferential associations with certain host species, it is not clear what determines the various levels of host adaptation. Here, causal properties of host associations were determined with allelic variants of three colonization factors of S. enterica serovar Newport, a most frequent zoonotic serovar. This is the first study that related not only individual but also a small group of host-associated gene variants with functional properties that cooperate to determine the level of host-adapted virulence. The detected associations should help to identify sources of Salmonella infections in both humans and animals.


A factor analysis of body build in the rat.
Following a survey of the problems associated with the comparative study of measures of physique in domesticated and laboratory animals, techniques were developed for the measurement of body build in the adult albino laboratory rat (Rattus norvegicus). They involved anesthetisation of the animals and the use of calipers and a simple apparatus devised for the purpose. The 17 measures taken on 100 rats, 50 of each sex, are detailed and the reasons for excluding other given. Intercorrelations of all the measures and their reliability co-efficients, which were judged satisfactory, are presented. The tables of intercorrelations, one for each sex, were factor analysed separately, and rotations to simple structure performed. Two factors were identified, one having factor saturations on measures of body length and the other similarily defining body width. This pattern was similar for the two sexes and a single index of body build was therefore proposed in which the length of the rear foot is divided by the width of the shoulder girdle and multiplied by 100 to avoid decimals. The use of the index in other investigations is mentioned.


The efficacy of chlorine dioxide in controlling Salmonella contamination and its effect on product quality of chicken broiler carcasses.
A large spin-type chiller in an Ontario poultry processing plant was adapted so that the chill water could be treated with various levels of chlorine dioxide ( ClO2 ), increasing the concentration of ClO2 from 0 to 1.39 mg/liter resulting in reducing the bacteria count to the point where salmonellae could not be isolated from the chill water or the chilled broiler carcasses. In addition, coliform, psychrotroph , and aerobic plate counts were all greatly reduced (less than 1 log cycle) in chill water but were only slightly reduced (less than .5 log cycle) in macerated chicken broiler breast skin. Shelf-life was lengthened for broiler carcasses treated with 1.33 and 1.39 mg/liter ClO2 as compared to control carcasses. Sensory panelists reported no off flavors for any ClO2 concentration but rated broiler skin as being slightly lighter in color compared to control carcasses at all concentrations of ClO2 treatment.


Sphygmomanometry.
Hypertension is a major health problem in America today, affecting one in every six adults. The problem is that one-third of those with the disease do not know it. Optometry's role as a primary provider of health care must include screening procedures (sphygmomanometry) for hypertension.


Role of the primary infection in epidemics of HIV infection in gay cohorts.
A review of the data on infectivity per contact for transmission of the HIV suggests that the infectivity may be on the order of 0.1-0.3 per anal intercourse in the period of the initial infection, 10(-4) to 10(-3) in the long asymptomatic period, and 10(-3) to 10(-2) in the period leading into AIDS. The pattern of high contagiousness during the primary infection followed by a large drop in infectiousness may explain the pattern of epidemic spread seen in male homosexual cohorts in the early years of the epidemic. Simulations of cohorts of homosexual males, using that range of parameter values, indicate the following: (a) The initial fast rise and then more or less rapid flattening of the incidence curve of seropositives is primarily due to rapid initial spread, yielding a group of infecteds all of whom pass into the low infectivity asymptomatic period at close to the same time. All this occurs only if the basic reproduction number for the primary infection is > 1. (b) The behavioral changes that have been reported all started after the incidence of new infections began to fall, too late to have a major effect on the initial rise. The behavioral changes had a major effect in slowing down the subsequent rise in the number of seropositives. (c) High activity groups play an important role in the early rapid rise of the epidemic. However, it is not likely that the rapid decrease in rate of growth of seropositives is solely due to saturation of these very high activity groups. Although the evidence for this interpretation of the role of the primary infection is not conclusive, its implications for prevention and for vaccine trials are so markedly different from those of other interpretations that we consider it to be an important hypothesis for further testing.


Extravascular compared to Intravascular Femoral Closure is Associated with Less Bleeding and Similar MACE after Percutaneous Coronary Intervention.
Background: Various types of vascular closure devices (VCDs) are frequently utilized in patients undergoing percutaneous coronary intervention (PCI) in order to prevent arterial access site bleeding, which represents one of the most relevant complications associated with adverse clinical outcomes. This study aims to compare directly two mechanistically different types of femoral closure (FC) devices in patients undergoing PCI. Methods: This single-center, prospective, observational study includes consecutively patients either treated by the extravascular StarClose SE® (Abbott, Illinois, U.S.A.) or the intravascular AngioSeal™ FC (St. Jude Medical, Inc., St. Paul, MN, U.S.A.) after PCI. The primary endpoint was bleeding complications, the secondary endpoint was major adverse cardiac events (MACE) at 30 days of follow-up. Results: 200 patients in each group (StarClose SE® and AngioSeal™) were enrolled following PCI. The rates of overall and non-access site bleedings were significantly higher in the AngioSeal™ group (56%; 6%) compared to the StarClose SE® group (43.5%; 0.5%) (p = 0.012; 0.003). Additionally, complicated access site bleedings were also significantly higher in the AngioSeal™ group (p = 0.011). No significant differences of MACE were observed in both groups. However, there was a higher rate of unsuccessful implantation of the StarClose SE® (n=12, excluded from the study). Conclusions: In case of successful implantation, FC by the AngioSeal™ is associated with the higher rate of both access and non-access site bleedings, but similar rates of MACE at 30 days compared to the StarClose SE® device.


Hyperalimentation worksheet.
Parenteral hyperalimentation is an important means of nutritional support for critically ill patients. Calculating the amount of additives necessary for the appropriate compounding of hyperalimentations is a tedious process with many opportunities for error. A new computer program written in Pascal has been created to reduce pharmacy processing time. Menus and single-keystroke entry are implemented wherever practicable. A hard-copy printout and an individualized label are generated on command. Program testing has resulted in an 88% reduction of processing time.


DNAzyme-powered cascade DNA walkers for sensitive detection of uracil DNA glycosylase activity.
Uracil-DNA glycosylase (UDG) is a crucial repair enzyme, which is considered a reliable biomarker due to its abnormal expression associated with serious diseases. Herein, DNAzyme-powered cascade walkers were proposed for sensitive detection of UDG. The cascade walkers consisted of a fixed walker and a subsequently activated free walker. The fixed walker was constructed on 13 nm AuNPs by loading a fixed walking strand (WS1) and a track strand 1 (TS1). The WS1 contained a DNAzyme sequence, which was pre-locked by a locking strand (LS) with an uracil base. The TS1 inserted an RNA cleavage site and sealed the same DNAzyme. The free walker tracks were conjugated on 25 nm AuNPs by modifying a FAM-labeled track strand 2 (TS2) with an RNA cleavage site. When UDG specifically recognized the LS, the WS1 was released with the assistance of Endo·IV. Then the WS1 continuously cleaved TS1s to drive the fixed walker, thus releasing many sequences containing DNAzyme. The released sequences acted as free walking strands (WS2s) to repeatedly cleave TS2s to power the free walker, which led to fluorescence accumulation. The cascade walkers successfully detected UDG with a limit of 8.5 × 10-5 U mL-1. The cascade walkers offer a new method for sensitively analyzing glycosylase.


Efficiency and validity of commonly used substance abuse screening instruments in public psychiatric patients.
The more commonly used screening instruments for substance abuse were largely developed for addictive populations. We compared several alcohol and drug abuse scales to determine their efficiency and validity for psychiatric patients. The subjects were 100 consecutively admitted patients to a public psychiatric facility. DSM-III-R diagnoses, obtained from the alcohol and drug scales of the SCID-P, were the criterion measure. Methods of reliability included inter-rater agreement, estimates of internal consistency, and repeat test administration. Sensitivity, specificity and more infrequently used accuracy indices, such as likelihood ratios and Receiver Operating Characteristic (ROC) analysis, were utilized to assess scale validity. First, the reliability of all scales was high. Second, the instruments generally demonstrated highly acceptable levels of screening accuracy. Third, the intake evaluation was as reliable and valid as screening after admission on the unit. Finally, instruments were least discriminating for current problems (past 30 days). Lifetime measures were found to be reliable and valid for public psychiatric patients but further research is need on increasing the accuracy of screening for current substance abuse problems and the effectiveness of multiple screening approaches.


Environmental factors in HIV/AIDS epidemic development: new perspectives for gender equity and global protection against HIV transmission.
The HIV/AIDS epidemic is increasingly regarded as a socioeconomic problem. Among factors causing poverty, cultural aspects, including religion and traditions, appear to play an essential role in the rapid and global development of AIDS epidemic. AIDS is a pathologic syndrome caused by the human immunodeficiency virus (HIV). Scientific knowledge is required to prevent and treat AIDS. Although considerable progress has been made in antiretroviral therapy, neither actual cure of HIV infection, nor an efficient protection method, nor a vaccine are currently globally accessible. Consequently, the funding of scientific research is of utmost importance. On the basis of recent scientific findings, new perspectives for global protection and gender equity against HIV transmission are emerging. Progress is being made in developing microbicides or virucides, anti-infective medication formulated for topical self-administration, to protect against HIV and other sexually transmitted pathogens. Such developments need to be supported by extensive education campaigns geared to women to give them the possibility of protecting themselves and their children from HIV transmission. The level of funding for microbicide and vaccine development needs to be greatly increased. New possibilities have emerged for an efficient vaccine which would engage the mucosal immune system, first involved in the sexual transmission of HIV-1. The idea of vaccine production in edible tissues of transgenic crop plants has also gained momentum. The use of minimally processed, low-cost, orally delivered immunogens is especially valuable when raising mucosal antibodies is the object and when frequent boosting is anticipated, as is the case for mucosal immunity.


Epigenetic regulation and molecular characterization of C/EBPalpha in pancreatic cancer cells.
Molecular-targeted therapy is a hopeful approach for pancreatic cancer. Silencing of tumor suppressor genes can occur by histone deacetylation and/or DNA methylation in the promoter. Here, we identified epigenetically silenced genes in pancreatic cancer cells. Pancreatic cancer cell line, PANC-1 cells were treated either with or without 5Aza-dC (a DNA methyltransferase inhibitor) and suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor), and mRNA was isolated from these cells. Oligonucleotide microarray analysis revealed that 30 genes including UCHL1, C/EBPalpha, TIMP2 and IRF7 were up-regulated after treatment with 5Aza-dC and SAHA in PANC-1. The induction of these 4 genes was validated by real-time PCR in several pancreatic cancer cell lines. Interestingly, expression of C/EBPalpha was significantly restored in 6 of 6 pancreatic cancer cell lines. Chromatin immunoprecipitation assay revealed that histone H3 of the promoter region of C/EBPalpha was acetylated in PANC-1 treated with SAHA; and bisulfate sequencing showed methylation of its promoter region in several pancreatic cancer cell lines. Forced expression of C/EBPalpha markedly suppressed clonal proliferation of PANC-1 cells. Co-immunoprecipitation assay showed the interaction of C/EBPalpha and E2F1; and the interaction caused the inhibition of E2F1 transcriptional activity. Immunohistochemical analysis revealed that C/EBPalpha localized in the cytoplasm in pancreatic adenocarcinoma cells, whereas it localized predominantly in the nucleus in normal pancreatic cells. Our data demonstrated that aberrant silencing, as well as, inappropriate cytoplasmic localization of C/EBPalpha causes dysregulation of its function, suggesting that C/EBPalpha is a novel candidate tumor suppressor gene in pancreatic cancer cells.


MgATP-independent and MgATP-dependent exocytosis. Evidence that MgATP primes adrenal chromaffin cells to undergo exocytosis.
The MgATP dependency of secretion was investigated in digitonin-permeabilized adrenal chromaffin cells. Shortly after permeabilization there is a component of Ca2+-dependent secretion that occurs in the absence of MgATP in the medium. This secretion occurs from cells which are permeable to Ca2+/[ethylene-bis(oxyethylenenitrilo)]tetraacetic acid buffers, to nucleotides, and to proteins. It is prevented by treatment of cells with metabolic inhibitors to reduce cellular ATP prior to permeabilization. The rate of MgATP-independent secretion is rapid and terminates by approximately 2 min after introduction of Ca2+. MgATP-independent secretion is labile and is lost unless Ca2+ is introduced within 8 min of permeabilization. MgATP-dependent secretion occurs at a slower rate than MgATP-independent secretion and continues at a constant rate for 12 min. Preincubation of permeabilized cells with MgATP enhances Ca2+-dependent secretion during a subsequent incubation in the absence of MgATP. Similar MgATP sensitivities are observed when MgATP is present only prior to or only during stimulation with Ca2+ with half-maximal stimulation occurring at 0.4-0.5 and 0.6 mM MgATP, respectively. The data indicate that intact cells are primed by intracellular ATP so that immediately upon permeabilization, there is a component of secretion which is independent of medium MgATP. MgATP partially maintains the primed state after permeabilization by acting before Ca2+ in the secretory pathway.


3D Hierarchical, Pyramid-Based Cancer Cell Chip for the Detection of Anticancer Drug Effects.
In this study, we developed a novel three-dimensional (3D) cancer cell chip using a three-floor hierarchical 3D pyramid structure (3D pyramid) to simulate 3D tumor cell growth in vitro and to detect anticancer drugs. The proposed 3D pyramidbased cancer cell chip offered substantial advantages for the agglomerate formation of tumor cells, in which cells could be maintained as tumor spheroids for up to 3 weeks. Soon after HeLa tumor cells adhered to the micropatterned pillar sidewalls, they were suspended between the pillars based on scanning electron microscopy images. Treatment with the anticancer drug oleanolic acid resulted in 46.33% and 5.86% apoptotic cells on the 2D plate and 3D pyramid-based cell chip, respectively, compared with only 0.06% apoptotic cells in the control. The increase in chemoresistance to anticancer drugs in the 3D pyramid-based cell chip might be a result of cell confluence and hypoxia due to the spheroid formation of tumor cells in the 3D pyramid structure. These results indicated that the proposed cell chip could potentially be used for anticancer drug screening or can be incorporated into other models aimed at prolonging various cell functions in culture.


Effects of rice bran on performance, egg quality, oxidative status, yolk fatty acid composition, and fatty acid metabolism-related gene expression in laying ducks.
The study was designed to evaluate the effects of different dietary levels of rice bran (RB) in laying duck diets on performance, egg quality, oxidation status, egg yolk fatty acid composition, and hepatic expression of fatty acid metabolism-related genes. Longyan females (1080) with similar BW at 19 wk of age were randomly assigned to 6 dietary treatments, each consisting of 6 replicates of 30 birds. The basal diet (I) was a typical corn-soybean ration while the experimental diets (II to VI) substituted RB for corn and wheat bran and a small reduction of soybean meal. The level of substitution in diets (II to VI) was 6%, 12%, 18%, 24%, and 30%, respectively. The experiment lasted for 12 wks. Average egg weight and daily egg mass decreased linearly as the level of RB inclusion increased (P<0.001) and feed conversion ratio linearly increased (P<0.001). The proportions of C14:0 and C18:0 and total saturated fatty acids (SFA) in egg yolk linearly decreased with increasing RB, and many of the key polyunsaturated fatty acids (PUFA), like C18:2 n-6 and C18:3 n-3, linearly increased (P<0.001), but not those of C20:5 n-3 and C22:6 n-3. There were linear decreases (P<0.001) in hepatic abundance of FAS and SREBP1 transcripts, with a substantial reduction to about 30% those of ducks fed the control diet; there were no treatment effects on productive performance, eggshell thickness, strength, Haugh unit, antioxidation status, and egg yolk cholesterol or triglyceride content (P>0.05). In conclusion, the current study suggests that ducks from 19 to 31 wk could be fed diets with up to about 18% RB without effect on the number of eggs produced, egg quality, and oxidative status. Increasing amounts of RB linearly increased egg yolk concentrations of key fatty acids like C18:2 n-6 and C18:3 n-3 and decreased the hepatic abundance of FAS and SREBP-1 transcripts.


Malachite green induces genotoxic effect and biochemical disturbances in mice.
Malachite green (MG) is a triarylaminmethane dye used in the fish industry as an anti-fungal agent. Concern over MG is due to the potential for consumer exposure, suggestive evidence of tumor promotion in rodent liver, and suspicion of carcinogenicity based on structure-activity relationships. In order to evaluate the risks associated with exposure to MG, we examined the mutagenicity and biochemical effect of MG. For genotoxic effect we use the doses 27, 91, 272 and 543 mg/kg b.wt. for different period of time (7, 14, 21 and 28 days) to evaluate chromosomal aberrations in mouse somatic and germ cells as well as sister chromatid exchanges in bone marrow cells. For DNA fragmentation assay from mouse liver the same doses of MG were used for 28 days. For measuring biochemical parameters such as glycolysis and gluconeogenesis enzyme pathways, antioxidant indices, hepatic marker enzymes, total protein, glucose, glycogen levels and liver function enzyme activities were evaluated. Mice were treated orally up to 28 days with the two high doses of MG 272 and 543 mg/kg b.wt. Our results show that MG induce elevation in the percentage of SCE's and chromosomal aberrations (p < 0.01) after treatment with the high doses for long period of time. MG also induces DNA damage in mice liver in a dose dependent manner. Beside, MG treatment either in low or high doses causes biochemical disturbances in the major glucolytic-gluconeogenic pathways, hepatic marker enzymes, depleted glutathione and increased free radical as determined by increasing lipid peroxide. Histopathological observations revealed that MG induced sinusoidal, congestion, focal necrosis and degenerating in hepatic cells, hypertrophy and vacuolization followed by necrosis and cirrhosis.


Clinical perspectives on the combination of D-cycloserine and cognitive-behavioral therapy for the treatment of anxiety disorders.
In a particular success for translational research agendas, characterization of the neuronal circuits underlying fear extinction, and basic research in animal extinction paradigms, has led to intervention studies examining the use of D-cycloserine (DCS) to enhance therapeutic learning from exposure-based cognitive-behavioral therapy (CBT). In this article, we review these intervention studies, and discuss DCS augmentation of CBT relative to more traditional combination-treatment strategies in the treatment of anxiety disorders. We offer an accounting, based on evidence for internal context effects, of current limitations in the combination of antidepressant or benzodiazepine medications with CBT and discuss the advantages of isolated-dosing strategies with DCS relative to these limitations. This strategy is contrasted with the chronic-dosing applications of DCS for schizophrenia and Alzheimer's disease, and future directions for isolated-dosing strategies are discussed.


Fibronectin and asialoglyprotein receptor mediate hepatitis B surface antigen binding to the cell surface.
Both fibronectin and the asialoglycoprotein receptor (ASGPR) have been identified by some investigators as partners for hepatitis B virus (HBV) envelope proteins. Because fibronectin is a natural ligand for ASGPR, we speculated that HBV might attach to ASGPR expressed on the hepatocyte surface via fibronectin. To test this hypothesis, we first confirmed by co-immunoprecipitation that ASGPR, fibronectin and HBsAg bind to each other in HepG2.2.15 cells, and possible binding domains were identified by GST pull-down. In addition, by measuring binding of HBsAg to cells, we found that ASGPR and fibronectin enhanced the binding capability of HBsAg to HepG2 cells, and even to 293T and CHO cells, which normally do not bind HBV. In conclusion, our findings suggest that both fibronectin and ASGPR mediate HBsAg binding to the cell surface, which provides further evidence for the potential roles of these two proteins in mediating HBV binding to liver cells.


Advances in Extrusion 3D Bioprinting: A Focus on Multicomponent Hydrogel-Based Bioinks.
3D bioprinting involves the combination of 3D printing technologies with cells, growth factors and biomaterials, and has been considered as one of the most advanced tools for tissue engineering and regenerative medicine (TERM). However, despite multiple breakthroughs, it is evident that numerous challenges need to be overcome before 3D bioprinting will eventually become a clinical solution for a variety of TERM applications. To produce a 3D structure that is biologically functional, cell-laden bioinks must be optimized to meet certain key characteristics including rheological properties, physico-mechanical properties, and biofunctionality; a difficult task for a single component bioink especially for extrusion based bioprinting. As such, more recent research has been centred on multicomponent bioinks consisting of a combination of two or more biomaterials to improve printability, shape fidelity and biofunctionality. In this article, multicomponent hydrogel-based bioink systems are systemically reviewed based on the inherent nature of the bioink (natural or synthetic hydrogels), including the most current examples demonstrating properties and advances in application of multicomponent bioinks, specifically for extrusion based 3D bioprinting. This review article will assist researchers in the field in identifying the most suitable bioink based on their requirements, as well as pinpointing current unmet challenges in the field.


Brain Perfusion Imaging Under Acetazolamide Challenge for Detection of Impaired Cerebrovascular Reserve Capacity: Positive Findings with 15O-Water PET in Patients with Negative 99mTc-HMPAO SPECT Findings.
Cerebrovascular reserve capacity (CVRC) is an important parameter for treatment decisions in chronic cerebrovascular diseases. It can be assessed by measuring the acetazolamide-induced change in regional cerebral blood flow using SPECT with 99mTc-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) or PET with 15O-water. Methods: Our database was searched for patients with moyamoya vasculopathy or atherosclerotic cerebrovascular disease who had undergone 15O-water PET after normal 99mTc-HMPAO SPECT results with respect to CVRC. 15O-water PET was analyzed visually and quantitatively. Quantitative analysis was based on parametric CVRC maps generated by voxelwise image subtraction. Results: The search identified 18 patients (43 ± 15 y, 12 moyamoya vasculopathy). PET revealed impaired CVRC in 8 patients (44%). Quantitative analysis confirmed the positive visual findings in 15O-water PET and the negative findings in 99mTc-HMPAO SPECT. Conclusion:15O-water PET enables detection of impaired CVRC in a considerable fraction of symptomatic patients with stenoocclusion and negative 99mTc-HMPAO SPECT.


The significance of angiogenesis for predicting optimal therapeutic response in chronic myeloid leukaemia patients.
In this study the correlation and the prognostic value of the morphometric parameters of angiogenesis for optimal therapeutic response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukaemia (CML), i.e. complete cytogenetic response (CCgR) and major molecular response (MMoR), were investigated. Microvascular density (MVD) and a number of different size- and shape-related morphometric parameters of microvessels of bone marrow biopsy from 40 CML patients and 20 controls were examined. Microvessels of bone marrow were examined by using immunohistochemical staining for CD34 and quantified in the region of the most intense vascularisation by using image analysis. CML patients had significantly higher angiogenesis parameters when compared with controls. A statistically significant correlation was found between some parameters of angiogenesis and evaluated CCgR and MMoR. For achievement of CCgR, lower values of MVD, minor axis, area, circularity, and roundness and higher value of aspect ratio, while for achievement of MMoR only lower values of MVD have been identified as positive prognostic factors. Besides confirming increased angiogenesis in CML patients, this study also demonstrated prognostic significance of the degree of angiogenesis for the clinical outcome and identified angiogenic predictive factors for achieving optimal response on TKIs therapy.


[Pyomyositis in children: report of two cases].
Pyomyositis (PM) is an uncommon pyogenic infection of skeletal muscle and, when not properly treated, it can progress to a high-risk clinical situation with high mortality. Because it usually has a subacute presentation, diagnosis is often delayed. We present two cases of PM of the paraspinal muscles in healthy children and discuss the current state of knowledge of this disease.


Individual thorax geometry reduces position and size differences in reconstructed images of electrical impedance tomography.
Due to the ill-posed problem, the electrical impedance within the thorax cannot be exactly reconstructed. The aim of our study was to prove that reconstruction with individual thorax geometry improved the quality of EIT (electrical impedance tomography) images. Seven mechanically ventilated patients with acute respiratory distress syndrome were examined by EIT. The thorax contours were determined from routine computed tomography (CT) images based on automatic threshold filtering. EIT raw data was reconstructed offline with (1) back-projection with circular forward model; (2) GREIT reconstruction method with circular forward model and (3) GREIT with individual thorax geometry. The resulting EIT images were compared to rescaled CT images. The distance between the lung contour and the thorax contour was calculated for each method and the differences to that in CT were denoted as position differences. Shape differences was defined as the ratio of thorax (or lungs) size in EIT and that in rescaled CT. Method (3) has the smallest position differences (6.6 ± 2.8, 5.3 ± 3.3, 2.3 ± 1.4 in pixel, for each reconstruction method respectively; mean ± SD). The thorax and lungs sizes in the transformed CT images were 514 ± 73 and 177 ± 39. Shape differences of thorax were 1.81 ± 0.26, 1.81 ± 0.26, 1.10 ± 0.12 and that of lungs were 1.69 ± 0.45, 1.52 ± 0.45, 1.34 ± 0.35 for each method respectively. The reconstructed images using the GREIT method with individual thorax geometry were more realistic. Improvement of EIT image quality may foster the acceptance of EIT in routine clinical use.


Characterization of hemopexin and its interaction with heme by differential scanning calorimetry and circular dichroism.
Hemopexin is a plasma glycoprotein that has two structural domains (I and II) and binds and transports heme particularly to liver cells. Differential scanning calorimetry (DSC) studies show that hemopexin is largely stabilized by heme, which binds exclusively to domain I. The melting temperature (Tm) of heme-hemopexin is 66.4 +/- 0.7 degrees C as compared with 53.9 +/- 0.3 degrees C for apohemopexin, and this Tm increase is accompanied by a 100 kcal increase in molar enthalpy. Heme stabilizes hemopexin by stabilizing domain I. This is demonstrated by the 26 degrees C increase in Tm from 51.9 +/- 0.3 to 77.6 +/- 0.6 degrees C and the over 3-fold increase in molar enthalpy when domain I associates with heme. A moderate change in domain I secondary structure is indicated by an increase in negative molar ellipticity at 206 nm. However, there is no net effect on the secondary structure of holo-hemopexin caused by heme binding as indicated by both far-UV circular dichroism (CD) and Fourier-transform infrared spectra. The characteristic positive ellipticity of hemopexin at 233 nm, ascribed to tryptophan residues in domain II, is dramatically increased, suggesting a change in teritary structure for domain II of hemopexin. DSC and CD results show that isolated domain I and domain II interact both in the presence and absence of heme. Moreover, domain II destabilizes heme-domain I, which may be an important factor in facilitating heme release to the hemopexin receptor.(ABSTRACT TRUNCATED AT 250 WORDS)


Successful treatment of lichen amyloidosis with combined bath PUVA photochemotherapy and oral acitretin.
Lichen amyloidosis (LA) is a chronic, pruritic skin disorder characterized by brownish-grey papules on extensor surfaces of legs and rarely on the trunk. Thioflavin T-positive amyloid deposits are found in the papillary dermis of affected skin, which is the only organ involved. A variety of therapeutic regimens for lichen amyloidosis have been described; however, in many cases with only limited effect. We report on two patients with lichen amyloidosis with typical clinical symptoms not responding to local treatment. A combined regimen with bath psoralen ultraviolet A (PUVA) and oral acitretin was initiated, resulting in nearly complete resolution of the papules and impressive relief from the severe pruritus. The beneficial response has persisted for 8 months. The suggested combined therapy with bath PUVA photochemotherapy and oral acitretin represents an efficacious and practical treatment modality for lichen amyloidosis with long-lasting effects.


[Relationship between the expressions of glucocorticoid receptors α, β, γ, p and heat shock protein 90 mRNA in patients with primary immune thrombocytopenia resistant to the glucocorticoid].
To investigate the expressions of GRα, GRβ, GRγ, GRp and heat shock protein 90 (HSP90) in primary immune thrombocytopenia (ITP) patients and their correlations with glucocorticoid resistance. The expressions of glucocorticoid receptors (GRα, GRβ, GRγ, GRp) mRNA and HSP90 in peripheral blood mononuclear cells of 40 newly diagnosed ITP patients and 29 healthy volunteers were examined by real time PCR. Of them, 28 patients received glucocorticoid (GC) therapy divided into GC sensitive group (GCS) and GC resistant group (GCR) according to GC response. GRα, GRβ, GRγ, GRp, HSP90 mRNA and HSP90/GRα were analyzed in paired groups. The expression of HSP90 mRNA was significantly decreased in ITP patients \[0.91(0.48 - 2.21)\] than in normal subjects \[1.41(0.83 - 2.61)\] (P < 0.05). There were no significant differences in mRNA expressions of GRα, GRβ, GRγ, GRp and HSP90/GRα between ITP patients and normal controls. The expression of GRα mRNA in GCS patients was significant higher than in GCR patients (P < 0.05). Moreover, no significant differences in mRNA expressions of GRβ, GRγ, GRp and HSP90 and the ratio of HSP90 to GRα were observed between GCS and GCR patients. The expression of HSP90 mRNA decreased in adult ITP patients. GC resistance in adult ITP patients was associated with reduced expression of GRα. The very low expression of GRβ mRNA may be not involved in GC resistance in adult ITP.


The geometry of the eternal triangle.
Jealousy is often imputed to psychopathology in the protagonist. Psychodynamically, it can be attributed to an ego-deficiency, chronic insecurity, or a deflected libidinal drive. We propose that, when a primary love relationship is threatened, jealousy is best understood from a systems perspective. Three individuals create the experience of jealousy in one of them, which results in a pathogenic "eternal triangle" composed of: the jealous partner who seeks to woo and/or punish an errant mate; the architect of the triangle who takes a lover to supplement the marriage or supplant the mate; and a third person who intrudes across the boundaries of the couple. Therapists must be aware of the role of each agent in order to deal with the volatile, yet highly enduring configuration of the triangle.


Novel spiroimidazopyridine derivative SAK3 improves methimazole-induced cognitive deficits in mice.
Methimazole (MMI) is a first-line therapy used to manage hyperthyroidism and Graves' disease. Despite its therapeutic benefit, chronic MMI administration can lead to hypothyroidism and perturb brain homeostasis in patients, resulting in neuropsychiatric disorders such as depression and cognitive dysfunction. We recently developed the spiroimidazopyridine derivative SAK3 as cognitive enhancer; however, mechanisms underlying its activity remained unclear. Here, we show that SAK3 potentially improves cognitive impairment seen following MMI-induced hypothyroidism. Twenty-four hours after MMI (75 mg/kg, i.p.) treatment, we administered SAK3 (0.1, 0.5 and 1 mg/kg, p.o.) to mice daily for 7 days. MMI treatment alone disrupted olfactory bulb (OB) glomerular structure, as assessed by staining with the olfactory marker protein (OMP), reduced the number of choline acetyl transferase (ChAT)-immunoreactive neurons in medial septum (MS), and significantly impaired cognition. SAK3 (0.5 and 1 mg/kg, p.o.) administration significantly restored the number of cholinergic MS neurons in MMI-treated mice, and SAK3 treatment at a higher dose significantly improved cognitive deficits seen in MMI-treated control mice. Overall, our study suggests that SAK3 treatment could antagonize such impairment in patients with hypothyroidism.


Detection of allele specific differences in IFNL3 (IL28B) mRNA expression.
Variants of the interferon-lambda3 (IFNL3) gene have been associated with both spontaneous and treatment induced clearance of HCV infection. Attempts to link polymorphisms of the IFNL3 gene with variation in the level of IFNL3 expression have been inconclusive. This is partially due to the difficulty to design assays distinguishing IFNL3 from IFNL2. In this study an allele specific real-time PCR (RT-PCR) assay was developed which allows the relative quantification of the two IFNL3 transcripts in cells heterozygous for SNP IFNL3.rs4803217 in the 3'UTR of the IFNL3 gene. This SNP is in strong linkage disequilibrium (LD) with the predictive marker rs12979860. Raji cells showed two-fold increased levels of IFNL3.rs4803217 C-allele expression. In peripheral blood mononuclear cells (PBMCs) of eight uninfected donors, two donors showed increased IFNL3.rs4803217 C-allele expression. This indicates that allele specific differences in IFNL3 expression vary between individuals and might contribute to the variety of outcomes in HCV infected patients.


Sulfur dioxide absorption cross-section measurements from 290 nm to 317 nm.
Accurate measurements of the SO(2) absorption cross section between 290 and 317 nm have been made using a frequency-doubled dye-laser source with a 0.05-nm linewidth. The spectrum is applicable to the differential absorption method of detecting SO(2) and offers greatly extended wavelength coverage compared with previous measurements.


Cell-targeted vaccines: implications for adaptive immunity.
Recent advancements in immunology and chemistry have facilitated advancements in targeted vaccine technology. Targeting specific cell types, tissue locations, or receptors can allow for modulation of the adaptive immune response to vaccines. This review provides an overview of cellular targets of vaccines, suggests methods of targeting and downstream effects on immune responses, and summarizes general trends in the literature. Understanding the relationships between vaccine targets and subsequent adaptive immune responses is critical for effective vaccine design. This knowledge could facilitate design of more effective, disease-specialized vaccines.


Coronary artery ectasia with annuloaortic ectasia.
A 50-year-old Japanese woman with annuloaortic ectasia was found to have total coronary artery ectasia without evident atherosclerosis. The coronary ectasia may have been secondary to or of similar etiology to the annuloaortic ectasia. There was neither stigmata of Marfan's syndrome nor any sign of dissection of the ascending aorta or coronary arteries. Furthermore, the patient was not elderly, and had no hyperlipidemia, diabetes mellitus, or history of smoking. There was a marked blood pressure difference between the arms, and linear calcification was present in the aortic wall. A stenotic lesion was present in the right mid-subclavian artery. Although it is impossible to rule out atherosclerosis as the etiology of these findings, the possibility that they may be a manifestation of Takayasu's arteritis is discussed.


Effect of iron fortification of nursery complementary food on iron status of infants in the DPRKorea.
The aim of this study was to determine the iron status of infants who consumed porridge cooked in water with added ferrous sulphate. A total of 234 infants, aged 6-12 months, were recruited from 36 nurseries in the Democratic Peoples Republic of Korea (DPRK North Korea) and randomly divided into iron (Fe) and placebo groups. At baseline, almost half the children had Hb<110 g/L and no significant differences between the two groups were found with regard to hemoglobin concentration and anemia prevalence. The Fe group received rice porridge fortified with 10 mg of iron (as ferrous sulfate) per day, added to the water in which the rice was cooked and the placebo group non-fortified cereal for 6 months. After which, the hemoglobin (Hb), serum ferritin (SF) and packed cell volume (PCV) were measured and it was found that the proportion of children with anemia (Hb<110 g/L) was lower (24.3% v 48.1% p<0.01), the Hb levels (117.6 g/L v 109.8 g/L p<0.001) and serum ferritin were higher (40.7 v 26.8 mcg/L p<0.001); and iron deficiency anemia (Hb<110 g/L, SF<12 mcg/L) was lower in the Fe group (3% v 22% p<0.001) when compared to the placebo group. Ferrous sulphate, added to the water in which rice was cooked, lowered the prevalence of iron deficiency anemia of infants in the DPRK with no adverse reactions. This simple fortification would be suitable as a nationwide program in the DPRK and other countries with large infant nurseries.


Multiple endocrine neoplasia type 1 and the search for the genetic trigger.
Multiple endocrine neoplasia type 1 (MEN-1) is characterized by primary hyperparathyroidism, endocrine pancreatic-duodenal and anterior pituitary tumors. The diagnosis is challenging and involves the exclusion of other endocrine neoplasia syndromes with overlapping features. The predisposing genetic defect was assigned to chromosomal region 11q13 based on linkage analysis. Combined tumor and pedigree genotype analysis showed that allele losses in pancreatic, parathyroid and pituitary tumors eliminated the wild-type allele at the 11q13 loci, suggesting inactivation of a tumor suppressor gene in this region. A 5-Mb integrated map of the region has been established by the European consortium on MEN-1. Based on this mapping the critical interval was restricted to 2 Mb, a region within which eight candidate genes are located.


Experimental treatment of benign prostatic hyperplasia with transurethral balloon dilation of the prostate: preliminary study in 73 humans.
A prospective noncontrolled study of the safety and potential efficacy of transurethral balloon catheter dilation of the prostate (TUDP) in the treatment of benign prostatic hyperplasia (BPH) was performed in 73 subjects with moderate to severe symptoms and signs of prostatism who were selected on the basis of a quantitative symptom score (SS), uroflowmetry measurements, and residual urine volume. Seven patients had urinary retention. Mean age was 69.6 years (range, 59-95 years). TUDP was successfully accomplished in 70 patients (96%). There were no significant complications. Mean follow-up was 16.2 months (range, 6-36 months). Forty-six patients (66%) showed improved SS at the most recent follow-up. In 24 patients (34%) SS was unimproved, necessitating prostatectomy in 17 subjects (24%). Reduction in mean residual urine volume was not statistically significant. Only 38% of patients with median lobe enlargement showed improvement in SS, compared with 74% for the others. The authors conclude that TUDP is safe and shows promising effectiveness and that the ultimate demonstration of effectiveness requires a controlled clinical trial.


Single-cell RNA sequencing identifies critical transcription factors of tumor cell invasion induced by hypoxia microenvironment in glioblastoma.
Rationale: Glioblastoma (GBM) is an aggressive malignant primary brain cancer with poor survival. Hypoxia is a hallmark of GBM, which promotes tumor cells spreading (invasion) into the healthy brain tissue. Methods: To better elucidate the influence of hypoxia on GBM invasion, we proposed a data-driven modeling framework for predicting cellular hypoxia (CHPF) by integrating single cell transcriptome profiling and hypoxia gene signatures. Results: We characterized the hypoxia status landscape of GBM cells and observed that hypoxic cells were only present in the tumor core. Then, by investigating the cell-cell communication between immune cells and tumor cells, we discovered significant interaction between macrophages and tumor cells in hypoxic microenvironment. Notably, we dissected the functional heterogeneity of tumor cells and identified a hypoxic subpopulation that had highly invasive potential. By constructing cell status specific gene regulatory networks, we further identified 14 critical regulators of tumor invasion induced by hypoxic microenvironment. Finally, we confirmed that knocking down two critical regulators CEBPD and FOSL1 could reduce the invasive ability of GBM under hypoxic conditions. Additionally, we revealed the therapeutic effect of Axitinib and Entinostat through the mice model. Conclusion: Our work revealed the critical regulators in hypoxic subpopulation with high invasive potential in GBM, which may have practical implications for clinical targeted-hypoxia cancer drug therapy.


The effect of stress inoculation training on anxiety and performance.
Stress inoculation training is an intervention that has shown considerable promise; however, many questions arise regarding the application of this clinically based approach to more applied workplace settings. A meta-analysis was conducted to determine the overall effectiveness of stress inoculation training and to identify conditions that may moderate the effectiveness of this approach. The analysis was based on a total of 37 studies with 70 separate hypothesis tests, representing the behavior of 1,837 participants. Results indicated that stress inoculation training was an effective means for reducing performance anxiety, reducing state anxiety, and enhancing performance under stress. Furthermore, the examination of moderators such as the experience of the trainer, the type of setting in which training was implemented, and the type of trainee population revealed no significant limitations on the application of stress inoculation training to applied training environments.


Antagonistic Evaluation of Chromobacterium sp. JH7 for Biological Control of Ginseng Root Rot Caused by Cylindrocarpon destructans.
Cylindrocarpon destructans is an ascomycete soil-borne pathogen that causes ginseng root rot. To identify effective biocontrol agents, we isolated several bacteria from ginseng cultivation soil and evaluated their antifungal activity. Among the isolated bacteria, one isolate (named JH7) was selected for its high antibiotic activity and was further examined for antagonism against fungal pathogens. Strain JH7 was identified as a Chromobacterium sp. using phylogenetic analysis based on 16S rRNA gene sequences. This strain was shown to produce antimicrobial molecules, including chitinases and proteases, but not cellulases. Additionally, the ability of JH7 to produce siderophore and solubilize insoluble phosphate supports its antagonistic and beneficial traits for plant growth. The JH7 strain suppressed the conidiation, conidial germination, and chlamydospore formation of C. destructans. Furthermore, the JH7 strain inhibited other plant pathogenic fungi. Thus, it provides a basis for developing a biocontrol agent for ginseng cultivation.


Inhibition of Src family kinases blocks epidermal growth factor (EGF)-induced activation of Akt, phosphorylation of c-Cbl, and ubiquitination of the EGF receptor.
Stimulation of T47D cells with epidermal growth factor (EGF) results in the activation of the intrinsic tyrosine kinases of the receptor and the phosphorylation of multiple cellular proteins including the receptor, scaffold molecules such as c-Cbl, adapter molecules such as Shc, and the serine/threonine protein kinase Akt. We demonstrate that EGF stimulation of T47D cells results in the activation of the Src protein-tyrosine kinase and that the Src kinase inhibitor PP1 blocks the EGF-induced phosphorylation of c-Cbl but not the activation/phosphorylation of the EGF receptor itself. PP1 also blocks EGF-induced ubiquitination of the EGF receptor, which is presumably mediated by phosphorylated c-Cbl. Src is associated with c-Cbl, and we have previously demonstrated that the Src-like kinase Fyn can phosphorylate c-Cbl at a preferred binding site for the p85 subunit of phosphatidylinositol 3'-kinase. PP1 treatment blocks EGF-induced activation of the anti-apoptotic protein kinase Akt suggesting that Src may regulate activation of Akt, perhaps by a Src --> c-Cbl --> phosphatidylinositol 3'-kinase --> Akt pathway.


[Freud's letters considered as a historical source].
Freud's epistolary activity shows him to have been extraordinarily productive in this genre throughout his life. His letters, even more than his works, bear witness to his mastery of style. They have been extensively published in biographical, historical and scientific accounts because of the historical evidence they contain, but they have rarely been the object of a proper methodological analysis. This essay presents the project of a "concordance of the letters to and by Freud" which should facilitate the approach by historians of this extremely scattered epistolary work. 3200 letters of which Freud was the author have already been published since his death, and almost 1,200 letters that were addressed to him. This article also includes a discussion of the methodological principles that must be taken into consideration when using these letters as so many historical sources.


MeClas: An online tool for hazard identification and classification of complex inorganic metal-containing materials.
MeClas is a web-based tool to generate (eco)toxicity hazard categories and corresponding classification & labelling information of inorganic metal-containing complex materials such as ores, concentrates, intermediates or alloys for which the manual application of the GHS/CLP rules is very complex and requires a high level of consistency. The tool comprises several tiers, aimed at the progressive refinement of classification through recognition of specific mineral content, speciation/mineralogy up to bio-availability corrections. Where relevant in a regional jurisdiction (EU and US), mandatory classification references are used complementary to high quality (eco)toxicity reference values (ERV/TRV) and self-classifications. MeClas addresses the GHS human health and environmental hazard endpoints, is based on an unambiguous algorithm defined under GHS/CLP, has a well defined domain of applicability and robust predictability. MeClas allows a consistent approach across companies in line with GHS ruling (and regional implementations), considering the metal specificities and related classification GHS/CLP Guidance, and the most up to date (eco)-toxicological hazard information on self-classifications and ERV/TRV.


Genetic and structural analyses reveal the low potential of the SARS-CoV-2 EG.5 variant.
The severe acute respiratory syndrome coronavirus 2 EG.5 lineage is the latest variant under monitoring, and it is generating significant concern due to its recent upward trend in prevalence. Our aim was to gain insights into this emerging lineage and offer insights into its actual level of threat. Both genetic and structural data indicate that this novel variant presently lacks substantial evidence of having a high capacity for widespread transmission. Their viral population sizes expanded following a very mild curve and peaked several months after the earliest detected sample. Currently, neither the viral population size of EG.5 nor that of its first descendant is increasing. The genetic variability appear to be flattened, as evidenced by its relatively modest evolutionary rate (9.05 × 10-4 subs/site/year). As has been observed with numerous prior variants, attributes that might theoretically provide advantages seem to stem from genetic drift, enabling the virus to continually adjust to its host, albeit without a clear association with enhanced dangerousness. These findings further underscore the necessity for ongoing genome-based monitoring, ensuring preparedness and a well-documented understanding of the unfolding situation.


Recovery (passive vs. active) during interval training and plasma catecholamine responses.
The effect of recovery mode (Active [AR] vs. Passive [PR]) on plasma catecholamine (Adrenaline [A] and Noradrenaline [NA]) responses to maximal exercise (Exemax) was studied during interval training (IT). 24 male subjects (21.1±1.1 years) were randomly assigned to a control group (CG, n=6), AR training group (ARG, n=9) or PR group (PRG, n=9). ARG and PRG participated in an IT program 3 times a week for 7 weeks. Before and after training, maximal oxygen uptake (VO2max) and maximal aerobic velocity (MAV) were measured. Plasma A and NA were determined at rest, at the end of Exemax and after 10 and 30 min of recovery. Training induced significant changes only in ARG: an increase of VO2max and MAV along with a significant increase of A and NA at the end of Exemax (2.82±0.15 vs. 1.03±0.15 nmol/l and 7.22±0.36 vs. 6.65±0.57 nmol/l, respectively p<0.05). The ratio A/NA measured at the end of Exemax also increased significantly after training (0.41±0.11 vs. 0.16±0.08, P>0.05). The present results show that IT with AR induces a significant increase of A and NA concentrations in response to maximal exercise. The study furthermore shows that IT program with AR may induce more stress than the same program with PR.


Human intestinal spirochaetosis in northern Japan.
A histological diagnosis of human intestinal spirochaetosis (HIS) was made in 114 patients during the period 1994-2007. All patients lived in three prefectures in the northern part of Honshu, Japan. Most patients were elderly and male. Twenty-nine patients complained of abdominal pain, bloody stools, diarrhoea or bowel symptoms, but most patients showed no direct symptoms of bowel disease, and occult faecal blood detected at medical check-up was the main reason for colonoscopic examination. There were no homosexual patients and no immunosuppressed patients. HIS was evenly distributed throughout the whole colorectum. PCR analysis of Brachyspira aalborgi and Brachyspira pilosicoli revealed that more patients were infected with B. aalborgi. Follow-up PCR studies confirmed that infestation with B. aalborgi could be repeatedly detected over a 6 year period. This study, involving over 100 patients, identified the characteristic features of HIS in northern Japan. The results suggest that these spirochaetes may be harmless commensals that cause no obvious pathological alterations in infected individuals.


Sunscreens suppress cutaneous vitamin D3 synthesis.
Sunscreens block the cutaneous absorption of UV-B radiation and prevent sunburning, premature aging, and cancer of the skin. Inasmuch as UV-B radiation is also responsible for the photosynthesis of vitamin D3, we investigated the effect of sunscreens on the cutaneous formation of vitamin D3 in vivo and in vitro. Eight normal subjects, four of whom had been protected with the sunscreen para-aminobenzoic acid (sun protection factor 8), were exposed to one minimal erythema dose of UV radiation. The mean serum vitamin D3 concentration increased from 1.5 +/- 1.0 (+/- SEM) to 25.6 +/- 6.7 ng/mL in unprotected subjects, whereas it was 5.6 +/- 3.0 and 4.4 +/- 2.4 ng/mL at these times in the subjects who were protected with para-aminobenzoic acid. Para-aminobenzoic acid also prevented the photoisomerization of 7-dehydrocholesterol to previtamin D3 in human skin slices in vitro. These results indicate that the sunscreen interferred with the cutaneous production of vitamin D3.


Inhibition of C(2)-H/D exchange of a bis(imidazolium) dication upon complexation with cucubit[7]uril.
Inclusion of the alpha,alpha'-bis(3-(1-methylimidazolium))-p-xylene dication in cucurbit[7]uril (CB[7], K(CB[7]) = (4.3 x 10(9) M(-1)), with C-H...O=C hydrogen bonding between the guest C(2)-protons and the carbonyl oxygens of the host portals, inhibits the H/D exchange for the C(2)-proton with k(OD) (25 degrees C, D2O) decreasing from 1.2 x 10(3) M(-1) s(-1) (pKa = 22.3) in the absence of CB[7] to 0.9 M(-1) s(-1) (pKa = 25.4) in the presence of 1.1 equiv. CB[7].


Evidence of hepatitis A infection in immature rhesus monkeys.
Forty immature (less than 2 years old) rhesus monkeys (Macaca mulatta) with marked increases in aspartate and alanine aminotransferase activities were examined. Serological and histopathological evaluations were done to determine if affected animals were infected with hepatitis A virus. Although no clinical signs of illness were noted in any of the monkeys, an excellent correlation was found between the increased serum aminotransferase values and seropositivity with the acute phase (IgM) HAVAB-M antibody. Histopathological evaluations of livers of selected animals revealed hepatic lesions consistent with those in chimpanzees and marmosets infected with hepatitis A virus: generalized activation of sinusoidal lining cells, focal hepatocellular necrosis with occasional acidophilic bodies, and cuffs of mononuclear cells in the portal areas. Although no animals were seropositive for HAVAB upon receipt from the breeding colony, a total of ten of 18 animals for which serological data were available had seroconverted to HAVAB positivity during the 4-month observation period. These results are consistent with hepatitis A infection in immature rhesus monkeys and indicate the potential significance of serological testing in animals in which hepatic function is being evaluated.