Suppression of inflammatory and allergic responses by pharmacologically potent fungus Ganoderma lucidum.
Acute inflammation is the result of a complex signal transduction pathway that protects and heals our body and is necessary for our good health and normal wellbeing. Whereas, chronic inflammation can be correlated well with the onset of a plethora of autoimmune disorders; rheumatoid arthritis, systemic lupus and polymyalgia, rheumatic and other diseases like asthma, inflammatory bowel diseases, cardiovascular disorders, ulcerative colitis and Crohn's disease. Also, it has been reported to be associated with the onset of various cancers. An effective anti-inflammatory drug should be able to inhibit the development of chronic inflammation without interfering in normal homeostasis. A number of herbal drugs have been identified in the past that can target inflammatory cytokines. Among these, Ganoderma lucidum: a powerful medicinal mushroom has been found to possess immune-modulating and immune-potentiating capabilities and has been characterized as a wonder herb. This review mainly focuses on the molecular mechanism of anti-inflammatory and antiallergic action of this mushroom and also sheds light on various patent studies related to its pharmacological action.


Efficient 2D and 3D Facade Segmentation Using Auto-Context.
This paper introduces a fast and efficient segmentation technique for 2D images and 3D point clouds of building facades. Facades of buildings are highly structured and consequently most methods that have been proposed for this problem aim to make use of this strong prior information. Contrary to most prior work, we are describing a system that is almost domain independent and consists of standard segmentation methods. We train a sequence of boosted decision trees using auto-context features. This is learned using stacked generalization. We find that this technique performs better, or comparable with all previous published methods and present empirical results on all available 2D and 3D facade benchmark datasets. The proposed method is simple to implement, easy to extend, and very efficient at test-time inference.


Thrombocytopenia and bleeding in pediatric oncology patients.
Prophylactic platelet transfusions are the standard of care for patients with hypoproliferative thrombocytopenia after receiving chemotherapy or radiation for the treatment of malignancy, for BM replacement by leukemia or solid tumor, or in preparation for a hematopoietic stem cell transplantation.(1) During this time of thrombocytopenia, these patients may receive both prophylactic platelet transfusions, which are given to prevent potentially life-threatening bleeding when a patient's platelet count drops below a predetermined threshold, and therapeutic platelet transfusions, which are given to treat active or recurrent bleeding. In the 1950s, the invention of the plastic blood bag allowed for the production and storage of platelet concentrates,(2) and in the 1960s, it was recognized that prophylactic platelet transfusions effectively reduced hemorrhagic death in patients with newly diagnosed leukemia.(3,4) In 1962, Gaydos published the paper that is frequently credited with the inception of the 20 000/μL platelet transfusion threshold.(5) Despite a half-century of experience with prophylactic platelet transfusions, there are still insufficient data to provide clinicians with evidence-based guidelines specific to pediatric oncology and hematopoietic stem cell transplantation (HSCT) patients.


Comparison of the effectiveness of piezocision-aided canine retraction augmented with micro-osteoperforation: a randomized controlled trial.
To evaluate the effectiveness of micro-osteoperforation (MOP) on the rate of piezocision-aided canine retraction (CR). The split-mouth study included 25 participants at the stage of commencing CR. The participants received flapless piezocision bilaterally at T0 (0 months) and MOP only on one side at T3 (3 months). The quadrant that received MOP at T3 served as the intervention, whereas the other quadrant served as the control. The primary outcome was the rate of CR, assessed using digital models. The angular change (AC) of the canine and the change in the buccal cortical bone thickness (BCBT) from before to after CR were also assessed using cone beam computed tomography. The rate of CR was 0.82 ± 0.39 mm/month in the control quadrant vs 0.75 ± 0.44 mm/month in the intervention quadrant (P > .05). The AC of the canine was 2.00° ± 0.88° in the control quadrant vs 1.98° ± 0.86° in the intervention quadrant (P > .05). The crestal bone gain was 0.50 mm in the control quadrant vs 0.28 mm of bone loss in the intervention quadrant. The bone thickness at a 3-mm height was increased by 0.11 mm in the control quadrant vs a 0.29-mm decrease in the intervention quadrant. The bone thickness at a 6-mm height was decreased by 0.12 mm in the control quadrant vs a 0.15-mm decrease in the intervention quadrant. However, none of the changes or group differences in bone height or thickness were statistically significant (P > .05). The periodic activation of a piezocision-aided CR site using MOP had no significant positive effect on the rate of CR, angulation of the canine, or changes in BCBT.


H. pylori is related to NAFLD but only in female: A Cross-sectional Study.
Background: Recently, an increasing number of studies have focused on the extragastrointestinal effects of Helicobacter pylori (H. pylori), including metabolic syndrome, fatty liver, and rheumatic and skin diseases. Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease worldwide that conveys a heavy economic burden on patients and society. The aim of this study was to investigate the relationship between H. pylori and NAFLD and to identify potential influencing factors. Methods: We conducted a cross-sectional study of individuals who had undergone regular physical examinations at the Beijing Shijitan Hospital Health Examination Center from July to October 2018. We evaluated the associations between NAFLD and NAFLD with H. pylori infection and related serum markers using multiple linear regression and logistic regression. Results: There were significant relationships between H. pylori infection status and NAFLD in females (P=0.034) but not in males (P=0.795) according to Fisher's exact test. The association persisted after further adjustment for metabolic variables, gastrin factors, and liver enzymes. Waist-to-Hip Ratio, Body Mass Index, triglycerides, High-density lipoprotein cholesterol, glucose, uric acid, alkaline phosphatase, and Alanine aminotransferase are related to NAFLD after adjusting for age or interaction between biochemical indexes. Conclusion: H. pylori infection is related to NAFLD in female patients. The relationship between H. pylori and NAFLD may be mediated by markers of lipid metabolism and glycometabolism.


The relationship between long-term sunlight radiation and cognitive decline in the REGARDS cohort study.
Sunlight may be related to cognitive function through vitamin D metabolism or circadian rhythm regulation. The analysis presented here sought to test whether ground and satellite measures of solar radiation are associated with cognitive decline. The study used a 15-year residential history merged with satellite and ground monitor data to determine sunlight (solar radiation) and air temperature exposure for a cohort of 19,896 cognitively intact black and white participants aged 45+ from the 48 contiguous United States. Exposures of 15, 10, 5, 2, and 1-year were used to predict cognitive status at the most recent assessment in logistic regression models; 1-year insolation and maximum temperatures were chosen as exposure measures. Solar radiation interacted with temperature, age, and gender in its relationships with incident cognitive impairment. After adjustment for covariates, the odds ratio (OR) of cognitive decline for solar radiation exposure below the median vs above the median in the 3rd tertile of maximum temperatures was 1.88 (95 % CI: 1.24, 2.85), that in the 2nd tertile was 1.33 (95 % CI: 1.09, 1.62), and that in the 1st tertile was 1.22 (95 % CI: 0.92, 1.60). We also found that participants under 60 years old had an OR = 1.63 (95 % CI: 1.20, 2.22), those 60-80 years old had an OR = 1.18 (95 % CI: 1.02, 1.36), and those over 80 years old had an OR = 1.05 (0.80, 1.37). Lastly, we found that males had an OR = 1.43 (95 % CI: 1.22, 1.69), and females had an OR = 1.02 (0.87, 1.20). We found that lower levels of solar radiation were associated with increased odds of incident cognitive impairment.


[Risk factors of coronary disease].
Archival materials (medical histories, results of coronary angiography) of 307 patients with coronary artery disease (mean age 57.12 ± 10.04 years) were analyzed. Professional activity of 59 patients was associated with prolonged exposure to industrial hazard (xenobiotics). It was shown that proximal and middle parts of the major epicardial coronary arteries were most susceptible to atherosclerosis. In these segments complete chronic occlusion most often occurred. In one of five patients with coronary artery disease changes in the coronary arteries were not visualized by angiography. Percentage of unaffected coronary arteries was significantly higher in patients who were not in contact with technogenic xenobiotics. The degree of stenosis depended primarily on the effects of harmful occupational exposures, triglyceride, HDLP and LDLP cholesterol levels and hypertension. The number of damages to coronary blood vessels was determined mainly by the age of the patients and the presence of diabetes. The results show the importance of harmful work conditions as a risk factor for atherosclerotic changes in the coronary vessels.


Molecularly cloned mammalian glucosamine-6-phosphate deaminase localizes to transporting epithelium and lacks oscillin activity.
Glucosamine-6-phosphate deaminase (GNPDA) catalyzes the conversion of glucosamine-6-phosphate to fructose-6-phosphate, a reaction that under physiological conditions proceeds to the formation of fructose-6-phosphate. Though first identified in mammalian tissues in 1956, the enzyme has not previously been molecularly characterized in mammalian tissues, although a bacterial GNPDA has been cloned. Recently, a protein displaying similarity to bacterial GNPDA was purified and cloned from sperm extract. It was proposed that this protein was the factor, found in sperm extracts, that causes calcium oscillations in cells; thus, the protein was named 'oscillin.' We demonstrate that oscillin is the mammalian form of glucosamine 6-phosphate deaminase by showing that cloned oscillin has a robust GNPDA activity and can account for all such activity in mammalian tissues extracts. In situ hybridization and immunohistochemistry localize GNPDA selectively to tissues with high energy requirements such as the apical zone of transporting epithelia in the proximal convoluted tubules of the kidney and the small intestine; to neurons (but not glia) and especially to nerve terminals in the brain; and to motile sperm. Recombinant GNPDA and GNPDA purified to homogeneity from hamster sperm fail to elevate intracellular calcium when injected into mouse eggs over a wide range of concentrations under conditions in which sperm extracts elicit pronounced calcium oscillations. Thus, the calcium-releasing or oscillin activity of sperm extracts is due to a substance other than GNPDA. Since GNPDA is the sole enzyme linking hexosamine systems with glycolytic pathways, we propose that it provides a source of energy in the form of phosphosugar derived from the catabolism of hexosamines found in glycoproteins, glycolipids, and sialic acid-containing macromolecules. Evidence that GNPDA can regulate hexosamine stores comes from our observation that transfection of GNPDA into HEK-293 cells reduces cellular levels of sialic acid.


The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria.
The Silver-Russell syndrome (SRS) is characterised by severe intrauterine growth retardation, with a preserved head circumference, leading to a lean body habitus and short stature. Facial dysmorphism and asymmetry are considered typical features of the syndrome, although the range of phenotypic variance is unknown. Fifty seven subjects varying in age from 0.84 to 35.01 years, in whom the diagnosis of SRS had been considered definite or likely, were re-evaluated in a combined clinical and molecular study by a single observer (SMP). In 50 patients the clinical findings complied with a very broad definition of SRS. Notable additional findings included generalised camptodactyly seen in 11 (22%), many with distal arthrogryposis. Thirteen of the 25 males required genital surgery for conditions including hypospadias and inguinal hernia. Fourteen (36.8%) subjects above school age have received a statement of special educational needs. Molecular genetic analysis was performed in 42 subjects and has identified maternal uniparental disomy of chromosome 7 in four. The phenotype was generally milder with birth weights for one patient above and three below -2 SD from the mean. Two children had classical facial dysmorphic features, and two had a milder facial phenotype. Of relevance to the possible molecular mechanism underlying this condition, none of the four disomic patients had significant asymmetry.


Drastic morphological and molecular differences between lymph node micrometastatic tumors and macrometastatic tumors of lung adenocarcinoma.
The expansion of micrometastatic tumors to macrometastatic ones is thought to be tightly regulated by several microenvironmental factors. The aim of this study was to elucidate the morphological and phenotypical differences between micrometastatic and macrometastatic tumors. We first examined the morphological characteristics of 66 lymph node (LN) micrometastatic tumors (less than 2 mm in size) and 51 macrometastatic tumors (more than 10 mm in size) in 42 lung adenocarcinoma cases. Then, we evaluated the expression level of E-cadherin, S100A4, ALDH1, and Geminin in cancer cells and the number of smooth muscle actin (SMA), CD34, and CD204 (+) stromal cells in the primary tumors, matched micrometastatic tumors, and macrometastatic tumors (n = 34, each). Tumor budding reflects the process of EMT, and stromal reactions were observed more frequently in macrometastatic tumors (P < 0.001). E-cadherin staining score for the micrometastatic tumors was significantly higher than that for the primary tumors (P < 0.001). In contrast, the E-cadherin staining score for the macrometastatic tumors was significantly lower than that for the micrometastatic tumors (P = 0.017). As for the stromal cells, the numbers of SMA (+) fibroblasts, CD34 (+) microvessels, and CD204 (+) macrophages were significantly higher for the macrometastatic tumors and primary tumors than for the micrometastatic tumors (P < 0.001, all). The present study clearly showed that dynamic microenvironmental changes (e.g., EMT-related changes in cancer cells and structural changes in stromal cells) occur during the growth of micrometastases into macrometastases.


Eye-related visual hallucinations: consider 'Charles Bonnet syndrome'.
The Charles Bonnet Syndrome (CBS) is typically characterized by visual hallucinations in elderly people without cognitive defects. This article presents the case of an 80-year-old male patient with a one-year history of visual hallucinations, secondary to glaucoma, in both eyes. Neither a dopamine agonist nor cholinesterase inhibitor therapy improved his symptoms. In this case, the hallucinations were gradually improved after administration of a GABAergic drug, pregabalin, for diabetic polyneuropathy. Placebo-controlled clinical trials would be needed to support this effect of pregabalin, as suggested by this association.


An enzyme related to the high molecular weight multicatalytic proteinase, macropain, participates in a ubiquitin-mediated, ATP-stimulated proteolytic pathway in soluble extracts of BHK 21/C13 fibroblasts.
Soluble, cell-free extracts of BHK 21/C13 fibroblasts degraded a variety of exogenous proteins to acid-soluble peptides at pH 8.0. ATP stimulated the rates of proteolysis. Both the absolute rate of proteolysis and the magnitude of the ATP effect depended on the specific substrate. For example, casein was degraded approximately 10-fold faster than lysozyme, but lysozyme degradation was more highly stimulated by ATP than was casein degradation. Ubiquitin enhanced the ATP-stimulated proteolysis of each substrate in both postmicrosomal extracts and DEAE-cellulose fractionated extracts. In each extract, ubiquitin enhanced the ATP-stimulated degradation of lysozyme to a greater degree than that of casein. These results suggested that lysozyme was degraded by a pathway that was more dependent upon ubiquitin than was casein. Further evidence for this conclusion was obtained in studies using substrates whose amino groups were blocked by extensive methylation or carbamoylation. The high molecular weight proteinase, macropain, appears to be involved in the ATP-stimulated degradation of both substrates. Specific immunoprecipitation of macropain with polyclonal antibodies resulted in the inhibition of ATP-stimulated proteinase activity both in the absence and presence of ubiquitin. These results indicate that macropain plays a role in both ubiquitin-mediated and ubiquitin-independent ATP-stimulated proteolysis in BHK cell extracts.


Building filaments in the air: aerial morphogenesis in bacteria and fungi.
To disperse their spores to new sites, filamentous fungi and bacteria need to erect aerial filaments, which develop into fruiting bodies and spore-bearing structures. The first challenge to aerial development is breaking surface tension at an aqueous-air interface, and in both groups of microorganisms, surface-active proteins take part in the initiation of aerial morphogenesis. Comparative analysis of fungi and bacteria is providing new insights into the means by which aerial filamentation is accomplished.


Anti-obesity and anti-diabetic effects of fucoxanthin on diet-induced obesity conditions in a murine model.
Fucoxanthin, a characteristic carotenoid of brown algae, has been reported to exert an anti-diabetic effect in an obese murine model. Wakame (Undaria pinnatifida), an edible seaweed, is rich in fucoxanthin. This study examined the anti-obesity and anti-diabetic effects of fucoxanthin-rich wakame lipids (WLs) on high fat (HF) diet-induced obesity in mice. Mice were fed a high fat control (HFC) or normal fat control (NFC) diet for 10 weeks. The HF diet-fed group was administered a HF diet containing WLs for a further 5 weeks. Parameters related to diabetes and obesity conditions were evaluated and compared. The HF-WL diet, which was rich in fucoxanthin, significantly suppressed body weight and white adipose tissue (WAT) weight gain induced by the HF diet. Dietary administration of the HF diet resulted in hyperglycemia, hyperinsulinemia and hyperleptinemia in the mouse model. These perturbations were completely normalized in the HF-WL diet-fed group. Increased expression of monocyte chemoattractant protein-1 (MCP-1) mRNA expression was observed in HFC mice, but was normalized in the HF-WL groups. Moreover, the HF-WL diet promoted mRNA expression of β3-adrenergic receptor (Adrb3) in WAT and glucose transporter 4 (GLUT4) mRNA in skeletal muscle tissues. These results suggest that dietary WLs may ameliorate alterations in lipid metabolism and insulin resistance induced by a HF diet. There is therefore a biochemical and nutritional basis for the application of fucoxanthin-rich WLs as a functional food to prevent obesity and diabetes-related disorders.


Cell transplantation as future therapy for cardiovascular disease?: A workshop of the National Heart, Lung, and Blood Institute.
Despite the development of improved therapies and the significant advances in the understanding of the basis of disease pathogenesis, millions of Americans continue to live with life-threatening cardiovascular diseases. Recent breakthroughs suggest exciting directions that are likely to produce more effective therapies for the treatment of cardiovascular disease. One such area, cell transplantation (grafting of healthy cells into the diseased heart), holds enormous potential as an approach to cardiovascular pathophysiology. Once thought to be a scientific long shot, cell transplantation is becoming recognized as a viable strategy to strengthen weak hearts and limit infarct growth. The technology could also be used for the long-term delivery of beneficial recombinant proteins to the heart, which is a strategy to complement molecular biology advances and provide an alternative strategy for gene therapy. On August 24, 1998, the National Heart, Lung, and Blood Institute convened a workshop to discuss the current status of this fast-moving line of research and to explore its promise for treating cardiovascular disease. The participants included basic and clinical researchers, with representatives from academic and commercial research settings. The workshop was designed to establish the state-of-the-art and to equate current research with practical clinical application. The group recommended short- and long-term goals to assist in realizing, in the most expedient manner, the potential utility of cell transplantation for the treatment of cardiovascular disease. A summary of the meeting discussions and recommendations for future areas of research is presented.


Integrin receptor activation triggers converging regulation of Cav1.2 calcium channels by c-Src and protein kinase A pathways.
L-type, voltage-gated Ca2+ channels (CaL) play critical roles in brain and muscle cell excitability. Here we show that currents through heterologously expressed neuronal and smooth muscle CaL channel isoforms are acutely potentiated following alpha5beta1 integrin activation. Only the alpha1C pore-forming channel subunit is critical for this process. Truncation and site-directed mutagenesis strategies reveal that regulation of Cav1.2 by alpha5beta1 integrin requires phosphorylation of alpha1C C-terminal residues Ser1901 and Tyr2122. These sites are known to be phosphorylated by protein kinase A (PKA) and c-Src, respectively, and are conserved between rat neuronal (Cav1.2c) and smooth muscle (Cav1.2b) isoforms. Kinase assays are consistent with phosphorylation of these two residues by PKA and c-Src. Following alpha5beta1 integrin activation, native CaL channels in rat arteriolar smooth muscle exhibit potentiation that is completely blocked by combined PKA and Src inhibition. Our results demonstrate that integrin-ECM interactions are a common mechanism for the acute regulation of CaL channels in brain and muscle. These findings are consistent with the growing recognition of the importance of integrin-channel interactions in cellular responses to injury and the acute control of synaptic and blood vessel function.


Early versus Delayed Extracranial-Intracranial Bypass Surgery in Symptomatic Atherosclerotic Occlusion.
Clinical trials of extracranial-intracranial (EC-IC) bypass surgery studied patients in subacute and chronic stage after ischemic event. To investigate the short-term outcomes of EC-IC bypass in progressive acute ischemic stroke or recent transient ischemic attacks. The study was a retrospective review at a single tertiary referral center from 2008 to 2015. Inclusion criteria consisted of EC-IC bypass within 1 yr of last ischemic symptoms ipsilateral to atherosclerotic occlusion of internal carotid or middle cerebral artery. Early bypass group who underwent surgery within 7 d of last ischemic symptoms were compared to late bypass group who underwent surgery >7 d from last ischemic symptom. The primary endpoint was perioperative ischemic or hemorrhagic stroke or intracranial hemorrhage within 7 d of surgery. Of 126 patients who underwent EC-IC bypass during the period, 81 patients met inclusion criteria, 69 (85%) persons had carotid artery occlusion, 7 (9%) had proximal MCA occlusion, and 5 (6%) had both. Early surgery had a 31% (9/29) perioperative stroke rate compared to 11.5% (6/52) of patients undergoing late bypass (P = .04). Of patients with acute stroke within 7 d of surgery, 41% (7/17) had perioperative stroke within 7 d (P = .07). Six of nine patients (67%) with blood pressure dependent fluctuation of neurologic symptoms had perioperative stroke (P = .049). EC-IC bypass in setting of acute symptomatic stroke within 1 wk may confer higher risk of perioperative stroke. Patients undergoing expedited or urgent bypass for unstable or fluctuating stroke symptoms might be at highest risk for perioperative stroke.


Changes in serum potassium levels during hospitalization in patients with worsening heart failure and reduced ejection fraction (from the EVEREST trial).
Both hyperkalemia and hypokalemia may be related to heart failure (HF) therapy and are associated with adverse outcomes. Abnormalities in serum potassium levels in hospitalized patients with HF and reduced ejection fraction (EF) have not been previously investigated. A post hoc analysis was performed in 1,907 hospitalized patients with worsening HF and reduced EF in the placebo arm of the Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan (EVEREST) trial. Serum potassium was measured at randomization and at discharge or day 7. The co-primary end points were all-cause mortality (ACM) and cardiovascular mortality or the first HF hospitalization (CVM + HFH). The association between inhospital change in potassium levels and time to outcomes was evaluated using multivariate Cox regression models. Study participants had a mean age of 65.6 ± 12.0 years and were on optimal guideline-directed medical therapies, including β blockers (77%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (85%), and aldosterone antagonists (55%). Baseline potassium concentration was 4.3 ± 0.6 mEq/l, and hyperkalemia or hypokalemia was seen in 6.5% of the participants. On average, serum potassium level increased by 0.21 ± 0.66 mEq/l, p <0.0001, during hospitalization. Inhospital potassium change was not associated with either the primary or the secondary end point over a median follow-up of 9.9 months. In conclusion, in patients with reduced EF hospitalized for worsening HF, serum potassium abnormalities are common at baseline (within 48 hours of admission) and potassium levels increase during hospitalization, despite aggressive diuretic therapy. However, they are not associated with all-cause or CVM or HFH. Inhospital changes in potassium may limit the implementation of evidence-based therapies such as mineralocorticoid receptor antagonists.


Aberrations of the B-cell receptor B29 (CD79b) gene in chronic lymphocytic leukemia.
Leukemic B cells in chronic lymphocytic leukemia (B-CLL) typically exhibit low or undetectable surface Ig. Because the B29 (CD79b and Ig beta) and mb-1 (CD79a and Ig alpha) gene products are required for surface Ig display in the B-cell receptor complex (BCR), we analyzed the expression of these genes in B-CLL cells. The majority (83%) of the randomly selected B-CLL patient samples analyzed exhibited low or undetectable surface BCR measured by mu heavy chain and B29 expression. Levels of mb-1 mRNA in these B-CLL samples with low surface BCR were similar to those in normal B cells. Among those with decreased surface expression, B29 mRNA was not detected in half of these B-CLL samples. The remaining B-CLL samples with diminished surface BCR contained normal levels of B29 mRNA. Further analysis of cDNA clones from the majority of these latter samples contained point mutations, insertions, or deletions that were largely located in the B29 transmembrane and cytoplasmic domains. These results indicate the occurrence of somatic mutations predicted to affect B29 expression and/or function in the majority of B-CLL and suggest that these aberrations underlie the diminished surface BCR display and loss of BCR signaling characteristic of this leukemia.


Single-source-precursor synthesis of dense SiC/HfC(x)N(1-x)-based ultrahigh-temperature ceramic nanocomposites.
A novel single-source precursor was synthesized by the reaction of an allyl hydrido polycarbosilane (SMP10) and tetrakis(dimethylamido)hafnium(iv) (TDMAH) for the purpose of preparing dense monolithic SiC/HfC(x)N(1-x)-based ultrahigh temperature ceramic nanocomposites. The materials obtained at different stages of the synthesis process were characterized via Fourier transform infrared (FT-IR) as well as nuclear magnetic resonance (NMR) spectroscopy. The polymer-to-ceramic transformation was investigated by means of MAS NMR and FT-IR spectroscopy as well as thermogravimetric analysis (TGA) coupled with in situ mass spectrometry. Moreover, the microstructural evolution of the synthesized SiHfCN-based ceramics annealed at different temperatures ranging from 1300 °C to 1800 °C was characterized by elemental analysis, X-ray diffraction, Raman spectroscopy and transmission electron microscopy (TEM). Based on its high temperature behavior, the amorphous SiHfCN-based ceramic powder was used to prepare monolithic SiC/HfC(x)N(1-x)-based nanocomposites using the spark plasma sintering (SPS) technique. The results showed that dense monolithic SiC/HfC(x)N(1-x)-based nanocomposites with low open porosity (0.74 vol%) can be prepared successfully from single-source precursors. The average grain size of both HfC0.83N0.17 and SiC phases was found to be less than 100 nm after SPS processing owing to a unique microstructure: HfC0.83N0.17 grains were embedded homogeneously in a β-SiC matrix and encapsulated by in situ formed carbon layers which acted as a diffusion barrier to suppress grain growth. The segregated Hf-carbonitride grains significantly influenced the electrical conductivity of the SPS processed monolithic samples. While Hf-free polymer-derived SiC showed an electrical conductivity of ca. 1.8 S cm(-1), the electrical conductivity of the Hf-containing material was analyzed to be ca. 136.2 S cm(-1).


SOX2 promotes a cancer stem cell-like phenotype and local spreading in oral squamous cell carcinoma.
Emerging evidence shows that oral squamous cell carcinoma (OSCC) invasiveness can be attributed to a small subpopulation of cancer stem cells (CSCs) in the bulk of the tumor. However, the presence of CSCs in the OSCC close resection margins is still poorly unexplored. Here, we found that BMI1, CD44, SOX2, OCT4, UBE2C, CXCR4 CSCs marker genes are significantly upregulated, while IGF1-R, KLF4, ALDH1A1, CD133, FAM3C are downregulated in the tumor core vs healthy mucosa of 24 patients with OSCC. Among these, SOX2 appears also upregulated in the tumor close margin vs healthy mucosa and this significantly correlates with tumor size and lymph node compromise. In vitro analyses in CAL27 and SCC15 tongue squamous cell carcinoma cell lines, show that SOX2 transient knockdown i) promotes the mesenchymal-to-epithelial transition, ii) smooths the invasiveness, iii) attenuates the 3D tumor sphere-forming capacity, and iv) partially increases the sensitivity to cisplatin treatment. Overall, our study highlights that the OSCC close margins can retain CSC-specific markers. Notably, SOX2 may represent a useful CSCs marker to predict a more aggressive phenotype and a suitable target to prevent local invasiveness.


Sphingosine kinase 1 inhibition sensitizes hormone-resistant prostate cancer to docetaxel.
It has recently been shown that docetaxel chemotherapy is effective in prolonging life in patients with prostate cancer (PCa). We have investigated potential ways of increasing the effectiveness of chemotherapy in this disease. We have previously reported that sphingosine kinase 1 (SphK1) inhibition is a key step in docetaxel-induced apoptosis in the PC-3 PCa cell line and that pharmacologicalSphK1 inhibition is chemosensitizing in the docetaxel-resistant PCa LNCaP cell line. In this study we have addressed the mechanism of docetaxel-induced apoptosis of PC-3 cells and identified SphK1-dependent and -independent components. We have shown that SphK1 inhibition by docetaxel is a two-step process involving an initial loss of enzyme activity followed by a decrease in SphK1 gene expression. Using hormoneresistant PC-3 and DU145 PCa cells we have demonstrated that both pharmacological and siRNA-mediated SphK1 inhibition leads to a four-fold decrease in the docetaxel IC50 dose. This work points out to potential ways of increasing the effectiveness of chemotherapy for PCa by SphK1 inhibition.


Left atrial thrombus and dense spontaneous echocardiographic contrast in patients on continuous direct oral anticoagulant therapy undergoing catheter ablation of atrial fibrillation: Comparison of dabigatran, rivaroxaban, and apixaban.
Left atrial thrombus (LAT) and dense spontaneous echocardiographic contrast (SEC) detected by transesophageal echocardiography (TEE) in patients on continuous direct oral anticoagulants (DOAC) therapy before catheter ablation of atrial fibrillation (AF) or atrial flutter (AFL) have been described. We sought to compare rates of TEE-detected LAT and dense SEC among patients taking different DOACs. We evaluated 609 consecutive patients from 3 tertiary hospitals (median age 65 years; interquartile range 58-71 years; 436 (72%) men) who were on ≥4 weeks of continuous DOAC therapy (dabigatran, n = 166 [27%]; rivaroxaban, n = 257 [42%]; or apixaban, n = 186 [31%]) undergoing TEE before catheter ablation of AF/AFL. Demographic, clinical, and TEE data were collected for each patient. Despite ≥4 weeks of continuous DOAC therapy, 17 patients (2.8%) had LAT and 15 patients (2.5%) had dense SEC detected by TEE. The rates of LAT were 3.0%, 3.5%, and 1.6% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .482). The rates of dense SEC were 1.2%, 3.5%, and 2.2% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .299). Congestive heart failure (odds ratio 4.4; 95% confidence interval 1.6-12; P = .003) and moderate/severe left atrial enlargement (odds ratio 3.1; 95% confidence interval 1.1-8.6; P = .026) were independent predictors of LAT. In this study, ∼3% of patients on continuous DOAC therapy had LAT detected before catheter ablation of AF/AFL. Specific DOAC therapy did not significantly affect the rates of LAT detection.


Unani concept of drug substitution (therapeutic interchange) and its validation on scientific parameters.
Unani concept of therapeutic interchange, despite having immense practical aspect, has not been touched upon in a coherent way by most of the Unani scholars except Razi (Rhazes 865-925 AD), who took the concept plausibly and framed rules for alternate drug prescription at the time of unavailability of the drugs of choice. The Unani concept of therapeutic interchange is based on similarity in action, temperament and physical properties of drugs mainly botanicals, which are already established and need no further discussion; however, phytochemistry has not been considered a basis for substitution. Therefore, objective of this study was evaluation of the concept on phytochemical parameters as actions of most drugs are due to phytoconstituents. Classical Unani literature pertaining to therapeutic interchange and ethnobotanical literature for uses and phytoconstituents of three botanicals and their respective substitutes were reviewed. Ethnobotanical literature was collected from well known search engine viz., PubMed, Google Scholar, Scopus and Science direct. In view of exploring the concept on scientific basis, physicochemical, phytochemical and analytical (HPLC, GC-MS) studies were also conducted. The study exhibited similarity in phytoconstituents in main and substitute botanicals with insignificant differences. Direct relation between doses, actions, intensity of actions, temperament and chemical constituents of main and substitute botanicals was observed. The study, however, seemed to validate the concept on the basis of phytoconstituents, further pharmacological studies on the basis of properties and activities is required to strengthen the concept.


Do Swiss community pharmacists address the risk of sexually transmitted infections during a consultation on emergency contraception? A simulated patient study.
Objectives: Since 2002, Swiss community pharmacists have dispensed emergency contraception (EC) as pharmacist-only medicine ideally using the official Swiss protocol. Our study aimed to determine pharmacists' resolution of an imaginary EC case, compliance with the protocol, and provision of information on the risk of sexually transmitted infections (STIs). Methods: We conducted a simulated patient study with 69 students who each visited a community pharmacy. The scenario started with the student requesting the 'morning after pill'. Current practice was assessed using an online evaluation form adapted from the Medication-Related Consultation Framework. Descriptive and statistical analyses were carried out. Results: All pharmacists correctly identified that the person needed EC. All pharmacists used an EC protocol and asked on average 10.9 (standard deviation 0.68) of 11 compulsory EC assessment questions. In total, 93% of pharmacists addressed EC counselling items and 56% addressed the risk of STIs, mainly by mentioning that condoms offered the best protection (76%). Conclusions: Community pharmacists correctly issued the EC, complied with the dispensing protocol and used their professional judgement to ensure optimal EC use. There is nevertheless room for improvement regarding pharmacists' STI counselling. Finally, the protocol's STI section could be enriched with specific information to guide counselling.


Mannitol causes compensatory cerebral vasoconstriction and vasodilation in response to blood viscosity changes.
There is no proof that osmotic agents such as mannitol lower intracranial pressure (ICP) by decreasing brain water content. An alternative mechanism might be a reduction in cerebral blood volume through vasoconstriction. Mannitol, by decreasing blood viscosity, would tend to enhance cerebral blood flow (CBF), but the cerebral vessels would constrict to keep CBF relatively constant, analogous to pressure autoregulation. The cranial window technique was used in this study to measure the pial arteriolar diameter in cats, together with blood viscosity and ICP changes after an intravenous bolus of 1 gm/kg of mannitol. Blood viscosity decreased immediately; the greatest decrease (23%) occurred at 10 minutes, and at 75 minutes there was a "rebound" increase of 10%. Vessel diameters decreased concomitantly, the largest decrease being 12% at 10 minutes, which is exactly the same as the 12% decrease in diameter associated with pronounced hyperventilation (PaCO2 30 to 19 mm Hg) in the same vessels; at 75 minutes vessel diameter increased by 12%. With hyperventilation, ICP was decreased by 26%; 10 minutes after mannitol was given, ICP decreased by 28%, and at 75 minutes it showed a rebound increase of 40%. The correlation between blood viscosity and vessel diameter and between vessel diameter and ICP was very high. An alternative explanation is offered for the effect of mannitol on ICP, the time course of ICP changes, "rebound effect," and the absence of influence on CBF, all with one mechanism.


Are sequential compression devices commonly associated with in-hospital falls? A myth-busters review using the patient safety net database.
Sequential compression devices (SCDs) help prevent deep venous thrombosis and pulmonary embolism in hospitalized patients; however, clinicians often decline to use this therapy because of a perceived increased risk for patient falls. There is limited information regarding the association between the use of SCDs and patient falls. In this study, we analyze if SCD use is a common risk factor for in-hospital falls. We used the Patient Safety Net event reporting system at our university-affiliated hospital to retrospectively quantify reports of SCD-related falls over a nearly 5-year period (July 1, 2004, through May 25, 2009). The primary outcome was to determine how often SCD-related falls occurred in relation to SCD patient days. Secondary aims of this study included an assessment of the severity of SCD-related falls, as well as potential risk factors for such falls. Three thousand five hundred sixty-two total falls were reported during our study period, 16 of which (0.45%) were SCD-related falls. There were 0.063 SCD-related falls per 1000 SCD patient days or 1 fall for every 15,774 SCD patient days. The mean age of patients was 57.8 ± 14.4 years, 69% were male subjects, 81% were on a surgical ward, and 69% occurred while attempting to toilet. Only 2 of the SCD-related falls caused temporary harm that required intervention. Sequential compression device use is rarely associated with in-hospital patient falls, and SCD-related falls are not more harmful than other types of falls.


Plug-technique for small incisional hernia.
The authors report their experience with a new prosthetic technique for the repair of incisional hernia defects smaller than 3 cm. From January 1995 to September 2002, 16 operations for small incisional hernias have been performed. Local anaesthesia was used in 12 out of 16 patients (75%). The repair was achieved by insertion of a polypropylene plug sutured to the margins of the hernial defect. All patients were discharged within 24 hours of surgery. Postoperative pain was mild and required hospital analgesia in 25% of cases. Back at home analgesia was needed in only 1 patient. During a follow-up ranging 3 to 91 months (mean 46), no recurrence has been recorded. The proposed technique allows a sound repair of small incisional hernias with minimal pain, quick rehabilitation and early return to unrestricted work.


Reliability and intersubject variability of the real ear unaided response.
Intratester test-retest reliability of the real ear unaided response (REUR) was determined on 49 ears using the Frye 6500 real ear analyzer. Results revealed mean differences of less than 1 dB for repeat measurements at seven test frequencies between 250 and 4000 Hz. The average peak resonant frequency of the repeated measure was within 16 Hz of the initial measure. In addition, the intersubject variability of the amplitude of REUR was quite large. A range of 7 dB was found at 250 to 500 Hz with the range expanding to 15 to 20 dB at 2000 to 4000 Hz. Also, the peak resonant frequency varied between 2100-4800 Hz. These results are discussed in terms of those dispensers who use the REUR to "custom" order hearing aids.


Do intradot electron-electron interactions induce dephasing?
We investigate the degree of coherence of electronic transport through a quantum dot (QD) in the presence of an intradot electron-electron interaction. By using an open multiterminal Aharonov-Bohm (AB) setup, we find that the intradot interaction does not induce any dephasing effect and the electron transport through the QD is fully coherent. We also observe that the asymmetric amplitude of the AB oscillation in the conductance through the two-terminal AB setup originates from the interplay between the confined structure and the electron-electron interaction. Thus, one cannot associate a dephasing process with this asymmetric amplitude, as has been done in previous studies.


Nucleotide and deduced amino acid sequence of equine retinal and pineal gland phosducin.
To determine the full-length complementary DNA (cDNA) sequence of equine retinal and pineal gland phosducin (PHD) and to clone these sequences. Samples of equine retinal RNA. A primer set was designed for use in identifying a fragment of the equine PHD nucleotide sequence, derived from retinal RNA samples, and subsequently for use to deduce specific primers for additional examination. The full-length cDNA was determined by the method of rapid amplification of cDNA ends (RACE). For full-length cDNA, newly designed primers were used. Nucleotide sequences were analyzed by use of computer software. The deduced amino acid sequence was compared with sequences of PHD reported for other species. In addition, the sequence of equine pineal PHD was cloned. The cDNA nucleotide sequence for equine PHD was 1,209 base pairs (bp) in length with an open-reading frame encoding a protein of 245 amino acids and a calculated molecular mass of 28.214 kd. Similarity with amino acid sequences of PHD from other species was 89 to 93%. Sequences of equine PHD from retina and pineal gland were identical. Equine PHD contained a peptide sequence with 100% homology to an uveitopathogenic peptide reported for rat PHD. Equine PHD is a highly conserved protein that has homology of immunologic interest with rat PHD. These results establish a basis for studying the role of PHD in ocular inflammation of horses.


Positive contrast MRI of prostate brachytherapy seeds by susceptibility mapping.
MRI can provide high-resolution images to assist physicians during intraoperative and post-operative phases of prostate brachytherapy. However, the brachytherapy seeds usually show as dark spots, i.e. negative contrast, on the MRI images. In this paper, we propose a new method to generate positive contrast seed images by mapping their susceptibility. The method is based on an improved kernel deconvolution algorithm using l1 regularization. Simulation results show the positive contrast seeds can be identified and differentiated using the proposed method.


A comparison of oral prednisolone given as single or multiple daily doses for active proctocolitis.
Forty mg has been shown to be the optimal daily dosage of prednisone for outpatients requiring oral steroids for active proctocolitis. Although daily doses of oral steroids are commonly divided, a single dose each morning causes less adrenal suppression and is more convenient to take. A randomized controlled trial has been performed on patients with proctocolitis, in which 23 received 40 mg prednisolone each morning as one dose, and 22 received 10 mg four times a day, over two weeks. Physicians unaware of the dosage schedule scored the disease activity and assessed the steroid side-effects when the patient entered the trial, at day 7 and at day 14. Of those taking the divided dose the disease improved in 17 and failed to improve in five. No side-effects were observed in ten patients. Of those receiving a once daily regimen, 17 improved and six did not. Nine patients had no side-effects. Further assessment showed no difference between the two groups either in response rate or side-effects produced. When oral steroids are indicated for active proctocolitis, 40 mg prednisolone, as a single dose each morning can be recommended.


Lessons Learned from the Pandemic in the UAE: Children COVID-19 Vaccine Hesitancy and Its Impact on the Choice of Distance versus Face-to-Face Learning Modalities: An In-Depth Analysis of a National Study.
This study addresses the crucial aspect of childhood COVID-19 vaccination and its impact on parental decisions concerning learning modalities during the pandemic. This study aimed to gauge parental hesitancy towards vaccinating their children and its influence on choosing between distance and face-to-face learning options. Following STROBE guidelines for cross-sectional studies, this study surveyed 1973 parents in the United Arab Emirates using Google Forms during the COVID-19 pandemic. The results revealed that while more than half of the parents (51.6%) were willing to vaccinate their children if the COVID-19 vaccine was accessible and affordable, a significant majority (91.2%) expressed concerns about the rapid vaccine development process, which was the primary reason for vaccine rejection. Interestingly, a sizable portion (55.3%) had experienced online learning in the previous academic term, and, of those, 59.6% believed it negatively influenced their children's academic performance. Consequently, 66.4% expressed intent to shift their children back to face-to-face learning once feasible. Significantly, parents with medical backgrounds were more inclined (91.6%) to opt for face-to-face schooling compared to those without such backgrounds. Logistic regression analysis indicated associations between sociodemographic characteristics, educational level and background, and the decision to return children to face-to-face learning. Interestingly, when it comes to vaccine hesitancy, a noteworthy connection exists between the parents' reluctance to vaccinate their children and their preference for distance learning. In fact, parents who responded negatively to vaccinating their children against COVID-19, if the vaccine was available, showed a clear preference for the distance learning modality (p-value < 0.0001). This study underscores the complex interplay of factors and community perspectives shaping parental acceptance of childhood COVID-19 vaccination. The development pace of vaccines significantly influences parents' attitudes and beliefs about vaccination programs. Parents' medical backgrounds exhibit a clear correlation with their perceptions of sending children back to school safely. This highlights the potential impact of parental medical knowledge on decision making, emphasizing the need to consider parents' professional backgrounds when devising education- and vaccination-related policies.


Introducing high quality infection control in a hospital setting.
Hospital infection is a quality issue and as such has become an important topic in the current health care debate. Quality assurance and resource management are becoming integral to the measurement of nursing standards in clinical practice. Quality assurance is, in many ways, inseparable from effective infection control. This article outlines the development of such a high profile demonstration unit named Quality Infection Control (QIC) and discusses its strengths and weaknesses.


Common-path diffraction optical tomography for investigation of three-dimensional structures and dynamics of biological cells.
We present an optical holographic micro-tomographic technique for imaging both the three-dimensional structures and dynamics of biological cells. Optical light field images of a sample, illuminated by a plane wave with various illumination angles, are measured in a common-path interferometry, and thus both the three-dimensional refractive index tomogram and two-dimensional dynamics of live biological cells are measured with extremely high sensitivity. The applicability of the technique is demonstrated through quantitative and measurements of morphological, chemical, and mechanical parameters at the individual cell level.


Asymptomatic osteonecrosis: should it be treated?
Currently, there is no consensus regarding the treatment of precollapse osteonecrosis, particularly for asymptomatic osteonecrosis. With approximately 10,000 to 20,000 new cases of osteonecrosis a year, no single surgeon or center has the kind of experience that is able to address the most important questions concerning this disease. The literature strongly documents that symptoms of osteonecrosis will progress. Although the literature also supports the progression of asymptomatic osteonecrosis to symptomatic osteonecrosis on to collapse, that support is less convincing. Progression is proportional to lesion size, with small lesions (< 15% of femoral head involvement by volume) unlikely to progress. Although the results of core decompression have been somewhat controversial, the weight of the literature supports both the efficacy and safety of the procedure. The decision to treat osteonecrosis with core decompression is primarily based upon lesion size and stage of disease and does not necessarily depend on whether the patient is symptomatic. As large lesions (> 30% of the femoral head) are less likely to be successfully treated by core decompression and small lesions (< 15% of the femoral head) are less likely to progress, asymptomatic lesions within these ranges can be observed. The literature supports the position that moderately sized lesions (15-30% of the femoral head) should be treated by core decompression (with or without bone grafting).


Glucokinase gene locus transgenic mice are resistant to the development of obesity-induced type 2 diabetes.
Transgenic mice that overexpress the entire glucokinase (GK) gene locus have been previously shown to be mildly hypoglycemic and to have improved tolerance to glucose. To determine whether increased GK might also prevent or diminish diabetes in diet-induced obese animals, we examined the effect of feeding these mice a high-fat high-simple carbohydrate low-fiber diet (HF diet) for 30 weeks. In response to this diet, both normal and transgenic mice became obese and had similar BMIs (5.3 +/- 0.1 and 5.0 +/- 0.1 kg/m2 in transgenic and non-transgenic mice, respectively). The blood glucose concentration of the control mice increased linearly with time and reached 17.0 +/- 1.3 mmol/l at the 30th week. In contrast, the blood glucose of GK transgenic mice rose to only 9.7 +/- 1.2 mmol/l at the 15th week, after which it returned to 7.6 +/- 1.0 mmol/l by the 30th week. The plasma insulin concentration was also lower in the GK transgenic animals (232 +/- 79 pmol/l) than in the controls (595 +/- 77 pmol/l), but there was no difference in plasma glucagon concentrations. Together, these data indicate that increased GK levels dramatically lessen the development of both hyperglycemia and hyperinsulinemia associated with the feeding of an HF diet.


Vibrational study and spectra-structure correlations in ammonium saccharinate: comparison with the alkali saccharinates.
The FT IR spectra, at temperatures from liquid-nitrogen boiling (LNT) up to room temperature (RT), as well as the RT Raman solid-state spectra of protonated and deuterated ammonium saccharinate and of a series of alkali (Na, K, Rb, Cs) saccharinates are studied. The spectral assignments are aided with ab initio calculations on the free saccharinato anion at the HF/6-31 + + G(d,p) level. Attention is paid to the ND, CO and SO2 stretching regions. Correlation splitting is believed to be responsible for the presence of a v(CO) doublet. The averaged v(CO) frequency in (purely ionic) ammonium saccharinate is found to be the lowest in the so far studied saccharinates, along with the assumptions that the v(CO) frequency (or the corresponding averaged value) can have predictive value for the type of the metal-to-saccharinato ligand/ion bonding. The appreciably higher contribution of the dominating internal coordinate in the corresponding normal vibration in case of v(as)(SO2) than in v(s)(SO2) makes it suitable for spectra-structure correlations. Contrary to RT, even though no phase transitions were observed in the studied temperature range, some polycentered character is prescribed to the hydrogen bonds in which the ammonium ions of effective symmetry C8 participate at LNT. Certain structural predictions about the saccharinates of K, Rb and Cs are made.


The efficacy of attendance and semi-attendance group cognitive-behavioral therapy (CBT) on the anxiety disorders of adolescent girls.
Anxiety disorders are one of the most psychiatric disorders in children and adolescents that can cause long life functional disability. The first line treatment for this disorder is cognitive behavioral therapy that has primary, secondary and tertiary preventive effect, but is expensive and long time. Today there is some effort to find short term, group, semi-attendance and low cost therapies. Subjects were 42 girls (12- 17 y) with at least one anxiety disorder according to DSM-IV-TR with their parents who were divided into two groups randomly: group A which participated in 8 sessions and group B which participated in 4 sessions and the contents of sessions 3, 4, 6, and 7 were recorded on a CD for them. The tests used in this study were: SCARED, CATS, CAIS-C, CAIS-P, conducted before (T0), just after (T1) and three months after the treatment (T2). The collected data were analyzed by multivariate analysis of covariance test using SPSS software package, version 15.0. There was no significant difference between efficacy of semi-attendance group CBT and attendance group CBT in T0, T1 and T2 according to 4 tests (p = 0.311). The difference between the scores of these tests between T0 andT1 and T0 and T2 was significant in both groups (p < 0.001) but the difference between T1 and T2 was not significant. (p = 0.771). The efficacy of semi-attendance group CBT and attendance group CBT is similar and would sustain after 3 months.


Effect of an Educational Intervention Based on Bandura's Theory on Foot Care Self-Efficacy in Diabetes: A Prospective Quasi-Experimental Study.
The purpose of this study is to evaluate the foot care self-efficacy of diabetic foot patients and the effect of an educational intervention for improving it. This study was of a semi-experimental design and was conducted between January and December 2019 in a diabetic foot council of a university hospital. After power analysis to determine sample size, 33 participants meeting the inclusion criteria were included in the study. A Patient Identification Form and Diabetic Foot Care Self-Efficacy Scale (DFCSES) were used to collect data. Of the patients, 51.5% were male and the mean age was 54.91 ± 16.61 years. The mean score of DFCSES was 50.18 ± 20.88 before education and 72.67 ± 20.74 after education. The educational intervention has large effects on self-efficacy (d = 1.233), perceived knowledge level on diabetic foot (d = 1.102), perceived health status (d = 0.859), and perceived quality of life (d = 0.807). Educational intervention was found to be an effective way to improve foot care self-efficacy, perceived knowledge level on diabetic foot, perceived health status, and perceived quality of life.


Multi-level trophic cascades in a heavily exploited open marine ecosystem.
Anthropogenic disturbances intertwined with climatic changes can have a large impact on the upper trophic levels of marine ecosystems, which may cascade down the food web. So far it has been difficult to demonstrate multi-level trophic cascades in pelagic marine environments. Using field data collected during a 33-year period, we show for the first time a four-level community-wide trophic cascade in the open Baltic Sea. The dramatic reduction of the cod (Gadus morhua) population directly affected its main prey, the zooplanktivorous sprat (Sprattus sprattus), and indirectly the summer biomass of zooplankton and phytoplankton (top-down processes). Bottom-up processes and climate-hydrological forces had a weaker influence on sprat and zooplankton, whereas phytoplankton variation was explained solely by top-down mechanisms. Our results suggest that in order to dampen the occasionally harmful algal blooms of the Baltic, effort should be addressed not only to control anthropogenic nutrient inputs but also to preserve structure and functioning of higher trophic levels.


Evaluation of a Rapid Immunochromatographic Assay and Two Enzyme-Linked Immunosorbent Assays for Detection of IgM-Class Antibodies to Zika Virus.
There are currently five serologic assays available for detection of anti-Zika virus (ZIKV) IgM-class antibodies with U.S. Food and Drug Administration emergency use authorization. Among these are the Chembio DPP Zika IgM system (DPP Zika ICA; Chembio, Medford, NY), a rapid immunochromatographic assay (ICA), and the InBios ZIKV Detect 2.0 IgM antibody capture enzyme-linked immunosorbent assay (ZIKV 2.0 MAC-ELISA; InBios international, Inc., Seattle, WA), which has replaced the original InBios ZIKV Detect MAC-ELISA. We evaluated performance of these three serologic assays using 72 specimens characterized by plaque reduction neutralization testing (PRNT) for the presence or absence of neutralizing antibodies (NAbs) to ZIKV, dengue virus (DENV), and West Nile virus (WNV). The InBios ZIKV 2.0 MAC-ELISA was "presumptive Zika positive" in all 15 PRNT-confirmed ZIKV samples, while the Chembio DPP Zika ICA was nonreactive in three (20%) and the InBios ZIKV MAC-ELISA was negative in four (27%). The Chembio DPP Zika ICA and InBios ZIKV 2.0 MAC-ELISA showed >95% specificity in 22 ZIKV/DENV-seronegative specimens and in 13 samples positive for NAbs to non-ZIKV flaviviruses. Comparatively, the InBios ZIKV MAC-ELISA was "presumptive" or "possible Zika positive" in 8 of 12 WNV or DENV PRNT-positive samples and in 12 of 22 PRNT-seronegative sera. Our findings suggest that replacement of the InBios ZIKV MAC-ELISA with the InBios ZIKV 2.0 MAC-ELISA will lead to fewer samples requiring PRNT, minimizing unnecessary anxiety among patients ultimately determined to be seronegative for ZIKV and DENV by PRNT and alleviating some of the testing burden on laboratories performing PRNT.


Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression.
It is well known that most neurodegenerative diseases are associated with microglia-mediated inflammation. Our previous research demonstrates that the CD40 signaling is critically involved in microglia-related immune responses in the brain. For example, it is well known that the activation of the signal transducer and activator of transcription (STAT) signaling pathway plays a central role in interferon-gamma (IFN-gamma)-induced microglial CD40 expression. We and others have previously reported that microglial CD40 expression is significantly induced by IFN-gamma and amyloid-beta (A beta) peptide. Recent studies have shown that certain flavonoids possess anti-inflammatory and neuroprotective properties distinct from their well-known anti-oxidant effects. In particular, flavonoids, apigenin and luteolin have been found to be effective CD40 immunomodulators. Cultured microglia, both N9 and primary derived lines, were treated with flavonoids in the presence of IFN-gamma and/or CD40 ligation to assess any anti-inflammatory effects and/or mechanisms. CD40 expression on microglia was analyzed by fluorescence activated cell sorting (FACS). Anti-inflammatory effects and mechanisms were confirmed by ELISA for interleukin-6 (IL-6) and TNF-alpha, lactate dehydrogenase (LDH) assay, and STAT1 Western blotting. Apigenin and luteolin concentration-dependently suppressed IFN-gamma-induced CD40 expression. Apigenin and luteolin also suppressed microglial TNF-alpha and IL-6 production stimulated by IFN-gamma challenge in the presence of CD40 ligation. In addition, apigenin and luteolin markedly inhibited IFN-gamma-induced phosphorylation of STAT1 with little impact on cell survival. Our findings provide further support for apigenin and luteolin's anti-inflammatory effects and suggest that these flavonoids may have neuroprotective/disease-modifying properties in various neurodegenerative disorders, including Alzheimer's disease (AD).


Ultrasound perfusion imaging of the human brain.
Color-coded perfusion maps can be calculated from ultrasound harmonic gray-scale imaging data to analyze brain tissue perfusion. In 13 healthy volunteers, 2 doses (0.5 and 1.5 mL) of Optison, a perfluoropropane-containing ultrasound contrast agent, were injected intravenously, and they produced a strong increase in echo enhancement in the brain parenchyma. The contrast agent was injected twice for ultrasound examination of both hemispheres. A total of 24 hemispheres per dose was available for further analysis. We used harmonic imaging for quantification of echo enhancement. Color-coded perfusion maps were calculated from the ultrasound data. In 1 subject, magnetic resonance images were obtained parallel to the orientation of the ultrasound scans. After administration of both doses of Optison, it was possible to evaluate brain tissue perfusion in all 24 hemispheres. Subtraction of precontrast images and color coding enhanced the visualization of hemispheric perfusion. The epiphyseal gland, anterior interhemispheric fissure, third ventricle, and lateral fissure can be used as reliable anatomic landmarks. Artifacts caused by abrupt changes in thickness of the temporal bone are observed as signal-void streaks oriented from the ultrasound probe toward the cerebral midline. Harmonic gray-scale imaging with Optison shows strong echo enhancement in the brain parenchyma. By calculating color-coded perfusion maps, it is possible to visualize human brain tissue perfusion at the patient's bedside.


GCN2-dependent phosphorylation of eukaryotic translation initiation factor-2alpha in Arabidopsis.
The yeast regulatory protein kinase, general control non-derepressible-2 (GCN2) plays a key role in general amino acid control. GCN2 phosphorylates the alpha subunit of the trimeric eukaryotic translation initiation factor-2 (eIF2), bringing about a decrease in the general rate of protein synthesis but an increase in the synthesis of GCN4, a transcription factor that promotes the expression of genes encoding enzymes for amino acid biosynthesis. The present study concerned the phosphorylation of Arabidopsis eIF2alpha (AteIF2alpha) by the Arabidopsis homologue of GCN2, AtGCN2, and the role of AtGCN2 in regulating genes encoding enzymes of amino acid biosynthesis and responding to virus infection. A null mutant for AtGCN2 called GT8359 was obtained and western analysis confirmed that it lacked AtGCN2 protein. GT8359 was more sensitive than wild-type Arabidopsis to herbicides that affect amino acid biosynthesis. Phosphorylation of AteIF2alpha occurred in response to herbicide treatment but only in wild-type Arabidopsis, not GT8359, showing it to be AtGCN2-dependent. Expression analysis of genes encoding key enzymes for amino acid biosynthesis and nitrate assimilation revealed little effect of loss of AtGCN2 function in GT8359 except that expression of a nitrate reductase gene, NIA1, was decreased. Analysis of wild-type and GT8359 plants infected with Turnip yellow mosaic virus or Turnip crinkle virus showed that AteIF2alpha was not phosphorylated.


Dissecting firearm injury to the head and neck with non-linear bullet trajectory: a case report.
Firearm injuries to the head and neck have a potential for fatal complications caused by damage to neurovascular structures in the region. We herewith present a case of a missile injury to the face, caused by a bullet from a rifle with high muzzle energy that slackened while penetrating a vehicle before hitting the victim. The bullet advanced through the retrofacial spaces following a non-linear course and was retained within the opposite parapharyngeal region without injuring any vital structure. The resultant damage was a 'low-velocity injury'. However, it is noteworthy that the missile had still retained enough energy to penetrate the tissue and travel in a 'dissecting' fashion. It is likely that the blunting of the missile during vehicle penetration and the compactness of the anatomical structures bordering the head and neck spaces, such as fascia and tendons, forced the projectile to follow a non-linear inter-structural path. This case yet again demonstrates that the magnitude of firearm-related tissue damage may also depend upon the shape of the projectile and confirms that the head and neck spaces have anatomical integrity rather than just being arbitrarily designated topographical areas. It has also been confirmed that non-surgical approach with regular follow-ups is a viable option for uncomplicated head and neck injuries.


Rational design of K173A substitution enhances thermostability coupled with catalytic activity of Enterobacter sp. Bn12 lipase.
ELBn12 is a lipase isolated from Enterobacter sp. Bn12 with potential application in biotechnology. Homology modeling and rational design were applied to improve thermal stability of the lipase. K173A substitution introduced an AXXXA motif on the lipase model and it may have role in dimerization and thermostability of the protein. Site-directed mutagenesis was performed to construct the lipase variant. The mutated lipase was expressed in Escherichia coli pLysS and partially purified. Thermostability of the mutated lipase after 1 h of incubation at 70°C was twice that of wild-type lipase under the same conditions. Catalytic activity of the variant was about 1.5-fold towards tricaprylin at 60°C and pH 8.0; moreover, the lipase variant preserved its stability within the pH range of 7.0-11.0. Substitution of superficial hydrophilic Lys with hydrophobic Ala residue increased stability of the mutated lipase in the presence of nonionic surfactants, but this substitution caused lower stability towards polar solvents. Analysis of circular dichroism spectroscopy showed that the K173A mutation altered the secondary structure of the lipase into a more helical one. In conclusion, results of this study demonstrate the positive role of generation of a stabilizing protein motif through rational protein engineering that improves the enzyme characteristics.


Melatonin Increases the Sensitivity of Hepatocellular Carcinoma to Sorafenib through the PERK-ATF4-Beclin1 Pathway.
The mechanisms of resistance to the targeted drug sorafenib in the treatment of hepatocellular carcinoma (HCC) are poorly understood. The purpose of this study was to investigate the mechanism of sorafenib resistance and to elucidate the role of melatonin in overcoming sorafenib resistance. We first observed that sorafenib induced endoplasmic reticulum (ER) stress and activated autophagy in HCC, and the inhibition of ER stress and autophagy by specific inhibitors (PBA, TUDC and 3-MA) increased sorafenib-induced apoptosis, indicating that cells resist apoptosis by inducing ER stress and autophagy in the presence of sorafenib. Furthermore, specimens from patients with HCC revealed a close relationship between ER stress and autophagy, as demonstrated by the high correlation between expression of the autophagy-associated protein Beclin1 and expression of unfolded protein response (UPR) pathway proteins, especially PKR-like ER stress kinase (PERK); moreover, patients with combined expression of PERK and Beclin1 had more advanced disease (higher clinical stage) and a shorter overall survival time. ER stress inhibitors significantly blocked sorafenib-induced autophagy, selective knockdown of PERK and activating transcription factor 4 (ATF4) expression reduced sorafenib-induced autophagy activity compared with knockdown of the other two UPR pathways, and silencing ATF4 inhibited the expression of Beclin1. These results suggest that autophagy is downstream of ER stress and that the PERK-ATF4-Beclin1 pathway plays a role in ER stress-related autophagy. Interestingly, a low concentration of melatonin increased the sensitivity of HCC to sorafenib by inhibiting autophagy through the PERK-ATF4-Beclin1 pathway. Taken together, our findings suggest that cotreatment with sorafenib and melatonin is a potential therapy for HCC. Furthermore, ER stress-related autophagy plays key roles in apoptosis resistance. Therefore, targeting the PERK-ATF4-Beclin1 pathway may prove instrumental in HCC therapy.


Percutaneous First Metatarsophalangeal Joint Fusion.
The first metatarsophalangeal (MTP1) joint fusion is a very useful procedure in forefoot surgery and is still the gold standard for the treatment of severe and painful hallux rigidus. Normal walking and running are possible after MTP1 fusion, the first ray mobility being essentially in the interphalangeal (IP) joint with a compensatory hypermobility in dorsal flexion. Percutaneous MTP1 fusion is a simple procedure providing comparable results to fusions performed with open techniques. Postoperative cares are simplified with an immediate full weight bearing on rigid flat shoes and quick return to normal walking. Bone preparation is an important step and requires an experience in percutaneous forefoot surgery. Arthrodesis positioning and fixation with this percutaneous procedure are simple with possibility of clinical and radiological control. The indications for percutaneous MTP1 fusion are very large and only severe bone loss or osteoporosis represent the limits for this technique.


[Systematization of the angioarchitectonics of the colon in adult man].
The systematization of the angioarchitecture of the human colon was studied in 25 colons, the vascular system of which was injected with gelatinous indian ink. The arterial vascularization of the colonic wall is organized in two morphologically very different types of networks. The first type forms the distributional networks which consist of the subserosal, intermuscular and submucosal networks distributing harmoniously the blood running from the straight arteries. The second type forms the functional networks which consist of the muscular and mucosal networks related to the supply of the essential structure of the colonic wall. These consist essentially of pre- and postcapillary vessels. The venous vascularization of the colonic wall is organized according to a similar pattern. It also consists of three venous networks: the submucosal, intermuscular and subserosal networks which are tributaries of the straight veins and which receive the mucosal and muscular veins.


Differential ventral septal vasopressin release is associated with sexual dimorphism in PGE2 fever.
The vasopressinergic innervation of the ventral septal area (VSA) has been shown to be implicated in antipyresis. Because this system is less well developed in female rats, we hypothesized that female rats would display exaggerated febrile responses. We therefore examined the temperature responses of conscious and urethan-anesthetized rats of both sexes to centrally administered prostaglandin E2 (PGE2) and correlated these responses with the release and action of endogenous arginine vasopressin (AVP) in the VSA. Both conscious [25 ng/5 microliters PGE2 intracerebroventricularly (i.c.v.)] and anesthetized (VSA microdialyzed, 50 ng/5 microliters PGE2 i.c.v.) female rats had higher fevers than did males. Infusion of an AVP V1a receptor antagonist {1 nmol [d(CH2)5Tyr(Me)]AVP} plus PGE2 gave rise to higher fevers in males but not in females. Measurements of AVP in microdialysates of the VSA showed that the release of endogenous AVP was increased in response to PGE2 in males only. Baseline AVP release in both sexes was similar. The results suggest that there is a sex-related difference in PGE2 fever, which may be accounted for by the differential AVP release in the VSA.


[Clinical and epidemiological characteristics of an influenza outbreak in military personnel-Trujillo, Peru, 2008].
We describe an acute febrile respiratory infection outbreak in a military unit in Trujillo, Peru. Cases were identified using the influenza like illness (ILI) definition of the Ministry of Health. Nasal swab samples used for a rapid influenza test (RIT) and pharyngeal swab samples for viral isolation were taken. For influenza A, genotyping of a partial sequence of the hemagglutinin region was performed. The rate attack was 82.9%. Fifty-nine cases appeared between April 1 and 8, 2008; 58 came from the military unit (MU) #1 and one from the MU #2. The RIT identified 40 cases of influenza A and 43 cases were confirmed through cell culture. Isolations were genetically similar to the A H1N1 Brisbane strain. Early detection of outbreaks in confined locations such as military bases permits immediate action in preventing disease propagation.


Reproductive traits of ewe lambs representing eight genetic types born in winter, spring, summer and fall.
Crossbred ewe lambs of eight genetic types (Dorset X 3/4 Dorset, DD; Dorset X 3/4 Finn, DF; Finn X 3/4 Dorset, FD; Finn X 3/4 Finn, FF; Romanov X 3/4 Dorset, RD; Romanov X 3/4 Finn, RF; Romanov X Western, RW; and Western X Western, WW) were used to determine age and weight at conception, conception rate, ovulation rate, litter size and prenatal mortality. Each cross was represented in five different lamb crops born in winter, spring, summer and fall. High conception rates (greater than 88%) were obtained in all crops of ewe lambs, even in those born in June and exposed to rams the same year. Only Western ewe lambs born in June and exposed to rams in year of birth achieved low conception (59%). Ewe lambs born in October and missing the breeding season in the year of birth were more than 100 d older than ewe lambs born earlier in the calendar year and bred the same year. Prenatal mortalities varied widely (8 to 18%) among lamb crops, with management suspected to be a factor. Additive genetic effects in ovulation rate and litter size of the Romanov were similar to that of Finn. Romanov crosses (RF, RD, RW) conceived at the youngest age (226, 227, 231 d), demonstrating that Romanov is an early-maturing breed.


Filamentous network mechanics and active contractility determine cell and tissue shape.
For both cells and tissues, shape is closely correlated with function presumably via geometry-dependent distribution of tension. In this study, we identify common shape determinants spanning cell and tissue scales. For cells whose sites of adhesion are restricted to small adhesive islands on a micropatterned substrate, shape resembles a sequence of inward-curved circular arcs. The same shape is observed for fibroblast-populated collagen gels that are pinned to a flat substrate. Quantitative image analysis reveals that, in both cases, arc radii increase with the spanning distance between the pinning points. Although the Laplace law for interfaces under tension predicts circular arcs, it cannot explain the observed dependence on the spanning distance. Computer simulations and theoretical modeling demonstrate that filamentous network mechanics and contractility give rise to a modified Laplace law that quantitatively explains our experimental findings on both cell and tissue scales. Our model in conjunction with actomyosin inhibition experiments further suggests that cell shape is regulated by two different control modes related to motor contractility and structural changes in the actin cytoskeleton.


Acid-stable serine proteinase inhibitors in the urine of Alzheimer disease subjects.
A comparative study of the levels of acid-stable proteinase inhibitors (kallikrein and trypsin inhibitors) in the urine of healthy and Alzheimer subjects, of both sexes, has been performed. A preliminary characterization of the purified inhibitors indicates that the urinary antitryptic activity is accounted for by the presence of the well known Urinary Trypsin Inhibitor (UTI) while an apparently new molecule appears to be responsible for the antikallikrein activity. The urinary levels of kallikrein inhibitors are very similar in healthy and sick subjects while the levels of trypsin inhibitors appear significatively increased in Alzheimer subjects of both sexes. The data presented here support the hypothesis that unpaired proteolytic processes could be involved in the pathogenesis of Alzheimer's disease and suggest that the levels of urinary acid-stable inhibitors may prove to be useful markers of the disease.


Exclusion of pregnant women from industry-sponsored clinical trials.
The lack of human data available to inform evidence-based treatment for illness during pregnancy has led to calls for greater inclusion of pregnant women in research, but the extent of their current representation is poorly characterized. Our objective was to measure the current exclusion of pregnant women from industry-sponsored clinical trials as a baseline for future comparison. We compiled data from studies enrolling women of childbearing potential posted on www.ClinicalTrials.gov between 1 October 2011 and 31 January 2012. The review was limited to open United States-based phase IV interventional studies sponsored by the pharmaceutical industry evaluating treatment of conditions that may be experienced by but are not limited to pregnant women and did not involve a medication classified as potentially teratogenic. If there was no mention of pregnancy in the inclusion or exclusion criteria, we contacted a study representative to confirm that pregnant women could be enrolled. Of 558 qualifying industry-sponsored studies, five (1%) were designed specifically for pregnant women. Of 367 phase IV clinical trials with verified inclusion and exclusion criteria, 348 (95%) excluded pregnant women and 19 (5%) did not. We found the exclusion of pregnant women from industry-sponsored clinical trials to be common practice. Moving beyond reflexive exclusion and developing thoughtful criteria for inclusion of pregnant women in clinical research would likely advance the evidence base to inform treatment decisions during pregnancy and lead to better health outcomes for women and children.


Prevalence and predictors of unsatisfactory anal cytology tests in a cohort of gay and bisexual men in Sydney, Australia: baseline findings from the Study of the Prevention of Anal Cancer (SPANC).
Anal cytology has been suggested as a screening test for the anal cancer precursor high-grade squamous intraepithelial lesion (HSIL). We aimed to assess the prevalence and predictors of initial unsatisfactory anal cytology tests ('unsats'). The Study of the Prevention of Anal Cancer is a natural history study of anal human papillomavirus (HPV) and precancerous lesions among gay and bisexual men (GBM) of at least 35 years in Sydney, Australia. At each study visit, an anal swab is collected for cytological testing. Unsats are defined as slides with fewer than 2000 nucleated squamous cells and no abnormal cells. Among 617 GBM enrolled, the median age was 49 (range: 35-79) years and 220 (35.7%) were HIV positive. Initial unsats occurred in 61 (9.9%, 95% confidence interval: 7.6-12.5%), and 29 (4.7%, 95% confidence interval: 3.2-6.7%) remained unsatisfactory on repeat cytology. Initial unsats were associated with fewer lifetime anal-receptive partners with a condom (P=0.007); fewer recent anal-receptive sexual partners without a condom (P=0.005); never having had anal chlamydia (P=0.023) or gonorrhea (P=0.003); HIV-negative status (P=0.002); fewer total (P=0.002), low-risk (P=0.005), and high-risk (P=0.015) HPV types detected; lack of anal HPV18 detection (P=0.001); never having anally douched (P<0.001); and douching with soapy water (P=0.009) among those who douched. Unsats were less common among those with histologic HSIL (P=0.008) and nonsignificantly less common among those with fewer anal canal octants affected by HSIL (P=0.080), but were more common among those who felt more nervous (P=0.020) during the examination. Our findings suggest that unsats are more common among GBM with less receptive anal sexual experience. Avoiding douching with soapy water and strategies to aid patient relaxation during sampling may reduce the unsat rate.


Integrating multiple lines of evidence into historical biogeography hypothesis testing: a Bison bison case study.
One of the grand goals of historical biogeography is to understand how and why species' population sizes and distributions change over time. Multiple types of data drawn from disparate fields, combined into a single modelling framework, are necessary to document changes in a species's demography and distribution, and to determine the drivers responsible for change. Yet truly integrated approaches are challenging and rarely performed. Here, we discuss a modelling framework that integrates spatio-temporal fossil data, ancient DNA, palaeoclimatological reconstructions, bioclimatic envelope modelling and coalescence models in order to statistically test alternative hypotheses of demographic and potential distributional changes for the iconic American bison (Bison bison). Using different assumptions about the evolution of the bioclimatic niche, we generate hypothetical distributional and demographic histories of the species. We then test these demographic models by comparing the genetic signature predicted by serial coalescence against sequence data derived from subfossils and modern populations. Our results supported demographic models that include both climate and human-associated drivers of population declines. This synthetic approach, integrating palaeoclimatology, bioclimatic envelopes, serial coalescence, spatio-temporal fossil data and heterochronous DNA sequences, improves understanding of species' historical biogeography by allowing consideration of both abiotic and biotic interactions at the population level.


Role of human GABA(A) receptor beta3 subunit in insecticide toxicity.
The gamma-aminobutyric acid type A (GABA(A)) receptor is the target for the major insecticides alpha-endosulfan, lindane, and fipronil and for many analogs. Their action as chloride channel blockers is directly measured by binding studies with [(3)H]ethynylbicycloorthobenzoate ([(3)H]EBOB). This study tests the hypothesis that GABA(A) receptor subunit composition determines the sensitivity and selectivity of insecticide toxicity. Human receptor subtypes were expressed individually (alpha1, alpha6, beta1, beta3, and gamma2) and in combination in insect Sf9 cells. Binding parameters were similar for [(3)H]EBOB in the beta3 homooligomer, alpha1beta3gamma2 heterooligomer, and native brain membranes, but toxicological profiles were very different. Surprisingly, alpha-endosulfan, lindane, and fipronil were all remarkably potent on the recombinant beta3 homooligomeric receptor (IC50 values of 0.5-2.4 nM), whereas they were similar in potency on the alpha1beta3gamma2 subtype (IC50 values of 16-33 nM) and highly selective on the native receptor (IC50 values of 7.3, 306, and 2470 nM, respectively). The selectivity order for 29 insecticides and convulsants as IC50 ratios for native/beta3 or alpha1beta3gamma2/beta3 was as follows: fipronil > lindane > 19 other insecticides including alpha-endosulfan and picrotoxinin > 4 trioxabicyclooctanes and dithianes (almost nonselective) > tetramethylenedisulfotetramine, 4-chlorophenylsilatrane, or alpha-thujone. Specificity between mammals and insects at the target site (fipronil > lindane > alpha-endosulfan) paralleled that for toxicity. Potency at the native receptor is more predictive for inhibition of GABA-stimulated chloride uptake than that at the beta3 or alpha1beta3gamma2 receptors. Therefore, the beta3 subunit contains the insecticide target and other subunits differentially modulate the binding to confer compound-dependent specificity and selective toxicity.


Activation of the tobacco SIP kinase by both a cell wall-derived carbohydrate elicitor and purified proteinaceous elicitins from Phytophthora spp.
Two purified proteinaceous fungal elicitors, parasiticein (an alpha elicitin) and cryptogein (a beta elicitin), as well as a fungal cell wall-derived carbohydrate elicitor all rapidly activated a 48-kD kinase in tobacco suspension cells. The maximum activation of this kinase paralleled or preceded medium alkalization and activation of the defense gene phenylalanine ammonia-lyase (PAL). In addition, the two elicitins, which also induced hypersensitive cell death, activated a 44- and a 40-kD kinase with delayed kinetics. By contrast, the cell wall-derived elicitor only weakly activated the 44-kD kinase and failed to activate the 40-kD kinase. The size and substrate preference of the 48-kD kinase are reminiscent of the recently purified and cloned salicylic acid-induced protein (SIP) kinase, which is a member of the mitogen-activated protein kinase family. Antibodies raised against a peptide corresponding to the unique N terminus of SIP kinase immunoreacted with the 48-kD kinase activated by all three elicitors from Phytophthora spp. In addition, the cell wall elicitor and the salicylic acid-activated 48-kD kinase copurified through several chromatography steps and comigrated on two-dimensional gels. Based on these results, all three fungal elicitors appear to activate the SIP kinase. In addition, inhibition of SIP kinase activation by kinase inhibitors correlated with the suppression of cell wall elicitor-induced medium alkalization and PAL gene activation, suggesting a regulatory function for the SIP kinase in these defense responses.


Decreased theta event-related synchronization during working memory activation is associated with progressive mild cognitive impairment.
Among the different quantitative electroencephalographic markers, theta activity is known to reflect neural resources involved in memory processes and directed attention. Previous studies suggested that synchronization likelihood analysis in theta-band frequency might be a sensitive method to identify early alterations of neuronal networks in mild cognitive impairment (MCI). We report here a longitudinal study of 24 MCI patients with theta event-related synchronization (ERS) analysis during the n-back working memory task and neuropsychological follow-up after 1 year. Statistical analysis included analysis of variance and logistic regression to assess the relationship between cognitive decline and theta ERS. Upon follow-up, 13 MCI patients showed progressive MCI and 11 remained stable. In both groups, the phasic increase in theta amplitude after stimulus presentation did not depend on working memory load and electrode sites. Progressive MCI cases displayed significantly lower theta ERS power over all electrode sites compared to stable MCI cases. Theta ERS was significantly related to the cognitive outcome explaining 15.5% of its variability. In terms of MCI classification, the best combination of sensitivity and specificity was 0.87 and 0.60, respectively, with an area under the corresponding receiver operating characteristic curve reaching 76%. The present data indicate that a decrease in the early phasic theta ERS power during working memory activation may predict cognitive decline in MCI. This phenomenon is not related to working memory load but may reflect the presence of early deficits in directed attention-related neural circuits in MCI.


Changes of diagnosis to manic-depressive illness.
In a cohort of patients with an operationally confirmed diagnosis of mania, half of the patients had received a previous diagnosis of schizophrenia, and over one third of the patients had received a diagnosis of personality disorder. Retrospective analysis of case-notes, using operational criteria based on DSM-III, found that manic-depressive illness was more likely to have been the correct previous diagnosis.


Expression of brain-derived neurotrophic factor is not modulated by chronic mild stress in the rat hippocampus and amygdala.
Accumulating evidence supports a role for brain-derived neurotrophic factor (BDNF) in depression. However, most of these studies have been performed in animal models that have a low face validity with regard to the human disease. Here, we examined the regulation of BDNF expression in the hippocampus and amygdala of rats subjected to the chronic mild stress (CMS) model of depression, a paradigm that induces anhedonia, a core symptom of depression. We found that exposure of rats to the CMS paradigm did not modulate BDNF mRNA expression in the hippocampus and amygdala. In addition, chronic administration of imipramine, which reversed CMS-induced anhedonia, did not alter BDNF mRNA expression in these limbic structures.


Mortality of nickel workers: experience of men working with metallic nickel.
The mortality of men employed in a plant manufacturing nickel alloys from metallic nickel and other metals has been examined. The plant has operated since May 1953, and 1925 men were identified who had been employed in the operating areas at the plant, other than as members of the staff, for a total of five or more years, excluding breaks. Analysis of samples of air obtained from personal samplers showed that since 1975 most of the men are likely to have been exposed to average concentrations of nickel of between 0.5 and 0.9 mg Ni/m3. All but 22 (1.1%) of the men were successfully traced to 1 April 1978 or until they died or emigrated. One hundred and seventeen had died. The numbers of deaths observed from cancers of respiratory and other sites, other respiratory disease, ischaemic heart disease, and other causes of death were compared with the numbers expected from national and local mortality rates. No evidence of the existence of any occupational hazard was obtained. The number of deaths from lung cancer (15) in men employed for five years or more is small. At 98% of the number expected at local rates it is statistically compatible with risks of between 0.5 and 2.2 times "normal."


β-arrestin1-mediated acetylation of Gli1 regulates Hedgehog/Gli signaling and modulates self-renewal of SHH medulloblastoma cancer stem cells.
Aberrant Sonic Hedgehog/Gli (Hh/Gli) signaling pathway is a critical regulator of Sonic hedgehog medulloblastoma (SHH-MB). Cancer stem cells (CSCs), thought to be largely responsible for tumor initiation, maintenance, dissemination and relapse, have been identified in SHH-MB. Since we previously demonstrated that Hh/Gli signaling controls CSCs features in SHH-MB and that in these tumors miR-326 is down regulated, here we investigated whether there is a functional link between Hh/Gli signaling and miR-326. We evaluated β-arrestin1 (Arrb1) and its intragenic miR-326 levels in CSCs derived from SHH-MB. Subsequently, we modulated the expression of Arrb1 and miR-326 in CSCs in order to gain insight into their biological role. We also analyzed the mechanism by which Arrb1 and miR-326 control Hh/Gli signaling and self-renewal, using luciferase and protein immunoprecipitation assays. Low levels of Arrb1 and miR-326 represent a feature of CSCs derived from SHH-MB. We observed that re-expression of Arrb1 and miR-326 inhibits Hh/Gli signaling pathway at multiple levels, which cause impaired proliferation and self-renewal, accompanied by down regulation of Nanog levels. In detail, miR-326 negatively regulates two components of the Hh/Gli pathway the receptor Smoothened (Smo) and the transcription factor Gli2, whereas Arrb1 suppresses the transcriptional activity of Gli1, by potentiating its p300-mediated acetylation. Our results identify a new molecular mechanism involving miR-326 and Arrb1 as regulators of SHH-MB CSCs. Specifically, low levels of Arrb1 and miR-326 trigger and maintain Hh/Gli signaling and self-renewal.


Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension.
Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies.NEW & NOTEWORTHY Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.


Word-Object Learning via Visual Exploration in Space (WOLVES): A neural process model of cross-situational word learning.
Infants, children, and adults have been shown to track co-occurrence across ambiguous naming situations to infer the referents of new words. The extensive literature on this cross-situational word learning (CSWL) ability has produced support for two theoretical accounts-associative learning (AL) and hypothesis testing (HT)-but no comprehensive model of the behavior. We propose Word-Object Learning via Visual Exploration in Space (WOLVES), an implementation-level account of CSWL grounded in real-time psychological processes of memory and attention that explicitly models the dynamics of looking at a moment-to-moment scale and learning across trials. We use WOLVES to capture data from 12 studies of CSWL with adults and children, thereby providing a comprehensive account of data purported to support both AL and HT accounts. Direct model comparison shows that WOLVES performs well relative to two competitor models. In particular, WOLVES captures more data than the competitor models (132 vs. 69 data values) and fits the data better than the competitor models (e.g., lower percent error scores for 12 of 17 conditions). Moreover, WOLVES generalizes more accurately to three "held-out" experiments, although a model by Kachergis et al. (2012) fares better on another metric of generalization (Akaike Information Criterion [AIC]/Bayesian Information Criterion [BIC]). Critically, we offer the first developmental account of CSWL, providing insights into how memory processes change from infancy through adulthood. WOLVES shows that visual exploration and selective attention in CSWL are both dependent on and indicative of learning within a task-specific context. Furthermore, learning is driven by real-time synchrony of words and gaze and constrained by memory processes over multiple timescales. (PsycInfo Database Record (c) 2022 APA, all rights reserved).