Fetal hemoglobin in normal adults and beta-thalassemia heterozygotes.
A recently developed high performance liquid chromatographic (HPLC) procedure using a weak cation exchanger (PolyCAT) in columns of different sizes was used to quantify fetal hemoglobin (HbF) in blood of normal adults and beta-thalassemia (beta-thal) heterozygotes with ten different types of mutations. Preparative PolyCAT-HPLC greatly facilitated the characterization of isolated HbF, i.e., the determination of the relative quantities of the G gamma and A gamma chains. The method is accurate and allows quantitation of Hb F at the 0.5% level; preparative PolyCAT-HPLC allows isolation of (nearly) pure Hb F from blood samples with low (less than 1%) Hb F. Adult Hb F levels were determined in 69 normal adults (including 24 diabetics); Hb F levels fell below 1% except for subjects with abnormal -- G gamma -- G gamma -- arrangement and a C----T mutation at position -158 relative to the Cap site of both G gamma genes. The effect of the same mutation in the normal -- G gamma -- A gamma-arrangement was variable. Certain beta-thal mutations (namely, those at positions -29; -88; IVS-I-1; IVS-II-1) were associated with high Hb F levels in heterozygotes, while those at nucleotide (nt) positions IVS-I-6; IVS-I-110; codon 24; codon 39; codons 41/42; IVS-II-745 were not. G gamma values varied and often fell into two groups (high G gamma and low G gamma); high G gamma values were not associated with high Hb F values. The chromatographic procedure is ideally suited for Hb A2 quantitation. Average values of Hb A2 in beta-thal heterozygotes with any one of nine of the ten mutations were twice that of normals; the one exception was the beta-thal heterozygote with the IVS-I-6 (T----C) mutation with an average low Hb A2 value of 3.6%.


A stereoselective route toward polyhydoxylated piperidines. A total synthesis of (+/-)-deoxymannojirimycin.
[reaction: see text] A chemo- and stereoselective palladium-catalyzed amination of silylated butenediol dicarbonates has allowed for the introduction of a glycine moiety to obtain a desired functionalized epoxysilane. A stereoselective aldolization then delivered the piperidine ring which may be used as a precursor for the synthesis of a variety of polyhydroxylated azasugars. This efficient approach has been illustrated by the synthesis of 1-deoxymannojirimycin including a stereoselective reduction with LAH and a Tamao-Fleming oxidation of a C-SiMe(2)Ph bond.


Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma.
The discovery of the BRAFV600E mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients' deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms. Studies showed that receptor tyrosine kinases (RTK) such as PDGFRβ, IGF1R, EGFR and c-Met were overexpressed in melanoma cells. Along with increased secretion of growth factors such as HGF and TGF-α, this will trigger intracellular signalling cascades. This review discusses the role MAPK and Phosphatidylinositol-3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathways play in the mechanism of resistance of melanomas.


Risk factors for lymph node metastasis and evaluation of reasonable surgery for early gastric cancer.
To give the evidence for rationalizing surgical therapy for early gastric cancer with different lymph node status. A series of 322 early gastric cancer patients who underwent gastrectomy with more than 15 lymph nodes retrieved were reviewed in this study. The rate of lymph node metastasis was calculated. Univariate and multivariate analyses were performed to evaluate the independent factors for predicting lymph node metastasis. No metastasis was detected in No.5, 6 lymph nodes (LN) during proximal gastric cancer total gastrectomy, and in No.10, 11p, 11d during for combined resection of spleen and splenic artery and in No.15 LN during combined resection of transverse colon mesentery. No.11p, 12a, 14v LN were proved negative for metastasis. The global metastastic rate was 14.6% for LN, 5.9% for mucosa, and 22.4% for submucosa carcinoma, respectively. The metastasis in group II was almost limited in No.7, 8a LN. Multivariate analysis identified that the depth of invasion, histological type and lymphatic invasion were independent risk factors for LN metastasis. No metastasis from distal cancer (<or=1.0 cm in diameter) was detected in group II LN. The metastasis rate increased significantly when the diameter exceeded 3.0 cm. All tumors (<or=1.0 cm in diameter) with LN metastasis and mucosa invasion showed a depressed macroscopic type, and all protruded carcinomas were >3.0 cm in diameter. Segmental/subtotal gastrectomy plus D1/D1+No.7 should be performed for carcinoma (<or=1.0 cm in diameter, protruded type and mucosa invasion). Subtotal gastrectomy plus D2 or D2+No.7, 8a, 9 is the most rational operation, whereas No.11p, 12a, 14v lymphadenectomy should not be recommended routinely for poorly differentiated and depressed type of submucosa carcinoma (>3.0 cm in diameter). Total gastrectomy should not be performed in proximal, so does combined resection or D2+/D3 lymphadenectomy.


Management of traumatic pneumothorax.
In road accident trauma, pneumothorax can be 'open' (associated with a penetrating chest wound) or 'closed'; either can be associated with fractured ribs or development of intrapleural tension. Tension and open pneumothorax are recognised easily and their correction at the scene of the accident can be lifesaving. Any accompanying major intrathoracic and subcostal organ damage should be assessed.


Human Tissue-Engineered Model of Myocardial Ischemia-Reperfusion Injury.
Reducing ischemia-reperfusion injury would significantly improve patient survival. Current preclinical models are inadequate because they rely on animals, which do not emulate human physiology and the clinical setting. We developed a human tissue platform that allowed us to assess the human cardiac response, and demonstrated the platform's utility by measuring injury during ischemia-reperfusion and the effects of cardioprotective strategies. The model provides a foundation for future studies on how patient-specific backgrounds may affect response to therapeutic strategies. These steps will be necessary to help translate therapies into the clinical setting.


An examination of Australian newspaper coverage of the link between alcohol and cancer 2005 to 2013.
Alcohol is a Class-1 carcinogen but public awareness of the link between alcohol and cancer is low. The news media is a popular, readily-accessible source of health information and plays a key role in shaping public opinion and influencing policy-makers. Examination of how the link between alcohol and cancer is presented in Australian print media could inform public health advocacy efforts to raise awareness of this modifiable cancer risk factor. This study provides a summative qualitative content analysis of 1502 articles that included information about a link between alcohol and cancer, as reported within Australian newspaper media (2005-2013). We use descriptive statistics to examine the prominence of reports, the nature and content of claims regarding the link between alcohol and cancer, and the source of information noted in each article. Articles were distributed throughout newspapers, most appearing within the main (first) section. The link between alcohol and cancer tended not to appear early in articles, and rarely featured in headlines. 95% of articles included a claim that alcohol causes cancer, 5% that alcohol prevented or did not cause cancer, 1% included both. Generally, the amount of alcohol that would cause or prevent cancer was unspecified or open to subjective interpretation. Coverage increased over time, primarily within community/free papers. The claim that alcohol causes cancer often named a specific cancer, did not name a specific alcohol, was infrequently the focus of articles (typically subsumed within an article on general health issues), and cited various health-promoting (including advocacy) organisations as information sources. Articles that included the converse also tended not to focus on that point, often named a specific type of alcohol, and most cited research institutions or generic 'research' as sources. Half of all articles involved repetition of materials, and most confirmed that alcohol caused cancer. Information about a link between alcohol and cancer is available in the Australian newsprint media, but may be hidden within and thus overshadowed by other health-related stories. Strategic collaboration between health promoting organisations, and exploitation of 'churnalism' and journalists' preferences for ready-made 'copy' may facilitate increased presence and accuracy of the alcohol-cancer message.


Developmental impact of peripheral injury on neuroimmune signaling.
A peripheral injury drives neuroimmune interactions at the level of the injury and throughout the neuraxis. Understanding these systems will be beneficial in the pursuit to target persistent pain that involves both neural and immune components. In this review, we discuss the impact of injury on the development of neuroimmune signaling, along with data that suggest a possible cellular immune memory. We also discuss the parallel effects of injury in the nervous system and immune related areas including bone marrow, lymph node and central nervous system-related cells. Finally, we relate these findings to patient populations and current research that evaluates human tissue.


Localization and treatment of an oxidation-sensitive defect within the TCR-coupled signalling pathway that is associated with normal and premature immunologic aging.
The age-dependent decline in the ability of T-cells to mount a proliferative response both to mitogens and to receptor ligation is due to an age-related defect in signal transduction, since functional expression of receptors displayed by aged T-cells is not reduced. We show here that, although turnover of phosphatidylinositol is not diminished, total inositol-trisphosphate generation decreases after T-cell receptor (TCR) ligation, resulting in reduced flux of calcium. Defective inositol-trisphosphate generation may result from impaired activation of phospholipase C due to decreased tyrosine phosphorylation of this enzyme after ligation of CD3 in aged cells. Proliferation of aged T-cells, which is normally 10-30% of the level of young controls, was enhanced almost tenfold by glutathione or its precursor N-acetyl L-cysteine (NAC), reached levels of young controls and was accompanied by restoration of normal inositol-trisphosphate generation and calcium flux. These findings suggest that the T-cell antigen receptor is associated with at least two types of signal transduction modules. The first depends on synthesis and phosphorylation of phosphatidylinositol that is independent of sulphydryl groups and is not affected by senescence. The second transduction module includes tyrosine phosphorylation and activation of phospholipase C. This module is regulated by glutathione levels and is diminished in aged T-cells, that are deficient in reducing equivalents which support the PLC gamma-dependent generation of inositol-trisphosphate from phosphatidylinositol derivatives. This underlying biochemical defect also occurs earlier in strains which display premature aging due to differences in the H-2 region of MHC I.


N-acetylglucosamine-6-O sulfation on intestinal mucins prevents obesity and intestinal inflammation by regulating gut microbiota.
Intestinal mucins play an essential role in the defense against bacterial invasion and the maintenance of gut microbiota, which is instrumental in the regulation of host immune systems; hence, its dysregulation is a hallmark of metabolic disease and intestinal inflammation. However, the mechanism by which intestinal mucins control the gut microbiota as well as disease phenotypes remains nebulous. Herein, we report that N-acetylglucosamine (GlcNAc)-6-O sulfation of O-glycans on intestinal mucins performs a protective role against obesity and intestinal inflammation. Chst4-/- mice, lacking GlcNAc-6-O sulfation of the mucin O-glycans, showed significant weight gain and increased susceptibility to dextran sodium sulfate-induced colitis as well as colitis-associated cancer accompanied by significantly reduced immunoglobulin A (IgA) production caused by an impaired T follicular helper cell-mediated IgA response. Interestingly, the protective effects of GlcNAc-6-O sulfation against obesity and intestinal inflammation depend on the gut microbiota, evidenced by the modulation of the gut microbiota by cohousing or microbiota transplantation reversing disease phenotypes and IgA production. Collectively, our findings provide insight into the significance of host glycosylation, more specifically GlcNAc-6-O sulfation on intestinal mucins, in protecting against obesity and intestinal inflammation via regulation of the gut microbiota.


[Cryoglobulinemia type I and ischemic strokes].
Cryoglobulins are immunoglobulins that persist in the serum, precipitate at the cold temperature and resolubilise when rewarmed. There are three categories, the type I, II and III, with neurological symptoms. Those are dominated by peripheral neuropathy, the central nervous system is generally saved. We reported the case of a cryoglobulinemia of the type I having generated a ischemic cerebrovascular accident (CVA), a seldom described situation. A 62 years old man, without noteworthy past. He allowed for was occurred the functional impotence of the left hemicorp with a discrete left hemiparesis. The cerebral IRM has evoked subacute ischemic cerebrovascular accident. The cardiovascular check-up was normal. The Horton disease was isolated after biopsy of the left temporal artery. The biological check-up objectified indices in favor of a cryoglobulinemia, this one was identified and classified type I. A monoclonal gammopathy of undetermined significance (MGUS) was associated to him. The cutaneous, articular and renal manifestations are the most frequent complications of the cryoglobulinemia, the neurological complications are described, but with a less degree and are dominated by peripheral neuropathy. The attack of the central nervous system remains exceptional and is seen primarily with type I. Its correct assumption of responsibility requires to identify the cryoglobulinemic etiology. Association type I cryoglobulinemia and monoclonal gammapathy reinforced the chances for a central attack. In front of all CVA, it would be judicious to seek a cryoglobulin systematically. A hemopathy is often associated to type I, a electrophoretic exploration of serum proteins is not to be neglected to seek a possible origin of the cryoglobulinemia.


Effects of radiolysis on yttrium-90-labeled Lym-1 antibody preparations.
The physical half-life of 2.6 days and 2.2 MeV beta emissions of 90Y provide excellent properties for radioimmunotherapy applications. However, the clinically useful beta particles may be a source of radiation-induced damage of 90Y-labeled immunoconjugate radiopharmaceuticals during preparation or short-term storage. The stability of 90Y-labeled Lym-1 antibody was studied in standard radiopharmacy conditions to establish a formulation at which radiolysis is not a problem. Lym-1-21T-BAD immunoconjugate intermediate was prepared according to our standard procedure, then labeled with 90Y at 1, 2, 4 and 9.4 mCi/mg Lym-1 using 0.5 M tetramethylammonium acetate, pH 7, labeling buffer. Each mixture was challenged in diethylenetriaminepentaacetic acid to remove nonspecifically bound 90Y. The 90Y-21T-BAD-Lym-1 products were purified by centrifuged molecular sieving column chromatography. The radiochemical purity and immunoreactivity of each preparation was monitored daily by high-performance liquid chromatography (HPLC) and solid-phase radioimmunoassay, respectively, for 3 days. The preparation at 2 mCi/mg was also formulated in 4% (wt/vol) human serum albumin (HSA) overall and at 9.4 mCi/mg in five-fold water, 4 and 10% (wt/vol) HSA overall; all were monitored as above. The monomeric quality and purity profile of products at 1 and 2 mCi/mg were retained (> or = 80%) as was their immunoreactivity (> or = 75%) over 3 days. The radiochemical purity and immunoreactivity of the product at 4 mCi/mg declined to 65% and 28%, respectively, by 3 days after preparation and in just 48 hr, the product at 9.4 mCi/mg had degraded to 21% in radiochemical purity with only 3% immunoreactivity. The current HPLC data and earlier published chromatographic evidence did not support a compromised radiochemical integrity of 90Y-DOTA complexes by loss of 90Y from the DOTA chelate. Radiolysis of 90Y-labeled antibody preparations did not appear to be a problem at 90Y-21T-BAD-Lym-1 products < or = 2 mCi/mg. Human serum albumin proved to be an effective radioprotectant as the initial 100% immunoreactivity of the product at 2 mCi/mg was retained for 72 hr. The results underscore the need for appropriate formulations and dilutions of clinical doses of 90Y immunopharmaceuticals immediately after manufacture.


Small DNA fragments isolated from human T-cell clones are enriched in sequences involved in DNA bending.
IL-2 deprivation induces apoptosis in human IL-2-dependent T-cell clones. This process is characterized by typical cell morphology, changes in the cellular membranes and fragmentation of chromatin into units of single and multiple nucleosomes. We isolated apoptotic DNA of an IL-2-deprived T-cell clone and sequenced randomly selected fragments representing single and multiple nucleosomes.The frequency of phased adenosine tracts was markedly increased in the small apoptotic fragments as compared to oligonucleosomes. Our results thus indicate that chromatin fragmentation in human apoptotic T-cells is not random but preferentially involves DNA sequences with the capability to form bent DNA. Whether this indicates a colocalization of DNase cleavage sites and phased adenosine tracts on the chromosomes or a bias in selecting sites for apoptotic DNA fragmentation is discussed. Analysing the underlying mechanisms will shed new light on DNA degradation in apoptosis.


Comparison between three glass fiber post cementation techniques.
The aim of this experimental study was to compare the traditional cement systems with those of the latest generation, to assess if indeed these could represent of viable substitutes in the cementation of indirect restorations, and in the specific case of endodontic posts. The assessment of the validity of the cementing methods was performed according to the test of the push-out, conducted on sections obtained from the roots of treated teeth. The samples were divided into three groups. Group A (10 samples): etching for 30 seconds with 37% orthophosphoric acid (Superlux-Thixo-etch-DMG) combined with a dual-curing adhesive system (LuxaBond-Total Etch-DMG), dual-cured resin-composite cement (LuxaCore-DMG) and glass fiber posts (LuxaPost-DMG). Group B (10 samples): self-adhesive resin cement (Breeze-Pentron Clinical) and glass fiber posts (LuxaPost-DMG). Group C (10 samples): 3 steps light-curing, self-etching, self-conditioning bonding agent (Contax-Total-etch-DMG), dual-cured resin-composite cement (LuxaCore-DMG) and glass fiber posts (LuxaPost-DMG). The survey was conducted by examining the breaking resistance of the post-cement-tooth complex, subjected to a mechanical force. Statistical analysis was performed using SPSS Inc. ver. 13.0, Chicago, IL, USA. Group A values of bond strenth ranged from a minimum of 10.14 Mpa to a maximum value of 14.73 Mpa with a mean value of 12.58 Mpa. In Group B the highest value of bond strength was 6.54 Mpa and the minimum 5.55 Mpa. The mean value of the bond strength for the entire group was 6.58 Mpa. In Group C the highest bond strength was 6.59 Mpa whereas the lowest bond strength was 4.84 Mpa. Mean value of the bond strength of Group C was calculated at 5.7 Mpa. Etching with orthophosphoric acid combined with a dual-curing adhesive system and a dual-cured resin-composite cement was the technique that guaranteed the highest bond strength. Lowest bond strength values were obtained when dual self-adhesive cement was used.


Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19.
Recent advances in the pathophysiologic understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has indicated that patients with severe coronavirus disease 2019 (COVID-19) might experience cytokine release syndrome (CRS), characterized by increased interleukin (IL)-6, IL-2, IL-7, IL-10, etc. Therefore, the treatment of cytokine storm has been proposed as a critical part of rescuing severe COVID-19. Several of the cytokines involved in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs). JAK inhibition, therefore, presents an attractive therapeutic strategy for CRS, which is a common cause of adverse clinical outcomes in COVID-19. Below, we review the possibilities and challenges of targeting the pathway in COVID-19.


Fertility and contraception of 6 patients with ovarian pregnancy.
A series of 6 ovarian pregnancies out of 369 ectopic (1.65/100 tubal) were selected to evaluate the fertility and contraception of patients with this rare condition. Mean patients' age was 28.5 years, mean previous parity was 1.5 children and all but one were using some sort of contraception (four had an IUD inserted and one had a previous laparoscopic tubal ligation). Clinical features on admission were as reported for the ectopic pregnancy and surgical findings at laparotomy showed an otherwise intact tubes. Postoperative further contraception was used by four patients and the two non-users became pregnant easily within an 18 month period. We conclude that ovarian pregnancy is an accident which occurs in a rather fertile population with an intact genital tract and who were using intrauterine contraceptive devices. Postoperative reproduction performance shows a high fertility rate in those patients who were not using any contraceptives at all.


Usefulness of two-dimensional shear wave elastography in diagnosing hepatic veno-occlusive disease in pediatric patients undergoing hematopoietic stem cell transplantation.
This study aimed to evaluate the usefulness of two-dimensional shear wave elastography (2D-SWE) in diagnosing hepatic veno-occlusive disease (VOD) in pediatric patients. This study retrospectively included pediatric patients who underwent hematopoietic stem cell transplantation (HSCT) between November 2019 and January 2021. All 34 patients (8.7±5.0 years) were examined using 2D-SWE for an initial diagnosis. A subgroup analysis was performed using the data from follow-up examinations of patients diagnosed with VOD. The characteristics of the initial VOD diagnosis were compared with the longitudinal changes observed in VOD patients who underwent multiple ultrasound examinations. In total, 19 patients were diagnosed with VOD at 17.6±9.4 days after HSCT. All VOD patients showed hepatomegaly, ascites, and gallbladder wall thickening. Liver stiffness was higher in VOD patients than in non-VOD patients (12.4±1.1 vs. 6.3±0.8 kPa, P<0.001). Liver stiffness values above 7.2 kPa showed 84.2% sensitivity and 93.3% specificity in distinguishing VOD from non-VOD (area under the curve, 0.925; 95% confidence interval, 0.780 to 0.987; P<0.001). A subgroup analysis of 11 patients showed a linear decrease in liver stiffness values after VOD diagnosis with treatment (first, second, and third follow-ups; 13.5±1.7, 11.3±1.4, and 9.5±0.8 kPa, respectively), but without statistical significance in the pairwise analysis. Liver stiffness measured using 2D-SWE increased in pediatric patients who develop VOD after HSCT. Therefore, liver stiffness can be a predictive and quantitative parameter for diagnosing VOD.


The history of the discovery of blood circulation: unrecognized contributions of Ayurveda masters.
Ayurveda, the native healthcare system of India, is a rich resource of well-documented ancient medical knowledge. Although the roots of this knowledge date back to the Vedic and post-Vedic eras, it is generally believed that a dedicated branch for healthcare was gradually established approximately between 400 BCE and 200 CE. Probably because the language of documentation of these early textbooks is in Sanskrit, a language that is not in day-to-day use among the general population even in India, many significant contributions of Ayurveda have remained unrecognized in the literature related to the history of medicine. In this communication, the discovery of blood circulation has been taken up as a case, and a few important references from the representative Ayurveda compendia that hint at a preliminary understanding of the cardiovascular system as a "closed circuit" and the heart acting as a pump have been reviewed. The central argument of this review is that these contributions from Ayurveda too must be recorded and credited when reviewing the milestones in the history of medicine, as Ayurveda can still possibly guide various streams of the current sciences, if revisited with this spirit.


Analyzing the relationship between the personality traits of nursing students and their attitudes toward people with mental illnesses.
The aim is to analyze the relationship between the personality traits of nursing students and their attitudes toward people with mental illnesses. The cross-sectional study constituted of 281 students. The Community Attitudes toward the Mentally Ill Scale and the Ten-Item Personality Inventory were used. The students who have mental illnesses or in their families showed a higher goodwill score. The openness to experience subscale was correlated with conscientiousness, extraversion, emotional stability, and agreeableness. Organizing educational programs for nursing students focusing on developing a positive attitude toward people with mental illnesses is crucial.


Rapid, midline retroperitoneal exposure for four-level anterior lumbar interbody fusion-technical case atlas.
We describe a novel, rapid midline retroperitoneal operative technique in a patient, with multi-level degenerative scoliosis, who underwent an extensive L2-S1 anterior lumbar interbody fusion in addition to posterior instrumentation. Uniquely, our approach enables an essentially midline approach to the rectus muscle and uses the diminution of the transversalis fascia-to-peritoneum transition in the pelvis to provide expedited exposure-making it particularly helpful for ALIF exposure, retraction and intraoperative radiography. We minimize morbidity around the rectus sheath by dissecting only the medial rectus muscle and then gently, bluntly mobilizing the retroperitoneum from the deep pelvis cranially.


Structure of the Neisseria meningitidis outer membrane PilQ secretin complex at 12 A resolution.
The bacterial pathogen Neisseria meningitidis expresses long, thin, retractile fibers (called type IV pili) from its cell surface and uses these adhesive structures to mediate primary attachment to epithelial cells during host colonization and invasion. PilQ is an outer membrane protein complex that is essential for the translocation of these pili across the outer membrane. Here, we present the structure of the PilQ complex determined by cryoelectron microscopy to 12 A resolution. The dominant feature of the structure is a large central cavity, formed by four arm features that spiral upwards from a squared ring base and meet to form a prominent cap region. The cavity, running through the center of the complex, is continuous and is effectively sealed at both the top and bottom. Analysis of the complex using self-orientation and by examination of two-dimensional crystals indicates a strong C4 rotational symmetry, with a much weaker C12 rotational symmetry, consistent with PilQ possessing true C4 symmetry with C12 quasi-symmetry. We therefore suggest that the complex is a homododecamer, formed by association of 12 PilQ polypeptide chains into a tetramer of trimers. The structure of the PilQ complex, with its large and well defined central chamber, suggests that it may not function solely as a passive portal in the outer membrane, but could be actively involved in mediating pilus assembly or modification.


The bioequivalence of highly variable drugs and drug products.
'Highly variable drugs' have been defined as those drugs for which the within-subject variability (WSV) equals or exceeds 30% of the maximum concentration (Cmax) and/or the area under the concentration versus time curve (AUC). Despite the fact that highly variable drugs are generally safe with flat dose response curves, the bioequivalence of their formulations is a problem because the high variability means that large numbers of subjects are required to give adequate statistical power. Highly variable drug products are poor quality formulations where high within-formulation variability (e.g. tablet to tablet variability) poses a problem rather than high innate WSV of the drug itself. A further problem caused by high variability is that a subset of the population may respond differently to the two formulations producing a significant subject x formulation interaction. Practical examples are shown using replicate designs. The methods proposed to deal with the problems posed by highly variable drugs include: (i) Drug regulatory jurisdictions states that the 90% confidence interval (90% CI) around the test to reference geometric mean ratio (GMR) is required to fit with bioequivalence acceptance limits of 0.8 - 1.25 for both Cmax and AUC. The WSV for single point estimation of Cmax is often greater than that for AUC. One strategy therefore is not to require a 90% CI for Cmax of drugs that do not exhibit a toxicity associated with Cmax and merely require the GMR to fall within the acceptance limits. (ii) To arbitrarily broaden the bioequivalence acceptance limits. For example, to permit a sponsor to justify the use of wider limits e.g the 90% CI around the GMR of Cmax values might be required to fit within acceptance limits of 0.75 - 1.33 or even 0.70 - 1.42. (iii) A more systematic approach would be to broaden the acceptance limits by scaling to either the residual variance from a 2-period design or to the WSV of the reference product in a replicate design. Subsequent evaluations of scaling procedures have demonstrated that smaller numbers of subjects are required for bioequivalence studies on formulations of highly variable drugs. A disadvantage of scaling is that the method is less sensitive to differences between the means compared with unscaled treatment, such that the GMR may prove to be unacceptably low or high. This possibility has let to a suggestion that the GMR must fall within acceptance limits of 0.8 - 1.25 in scaled treatments. (iv) A similar method is to scale the metric rather than the acceptance limits. This method was proposed by the United States' Food and Drug Administration in the context of Individual bioequivalence, but may also be applied (v) to average bioequivalence. (vi) To carry out bioequivalence studies at steady state whenever a multiple dose regimen is ethically acceptable for healthy volunteers. This solution is based on the observation that high variability in a single dose study tends to be dampened at steady state, thus increasing statistical power. Drug regulators have not favored this approach on the grounds that bioequivalence testing should be based on the most discriminating test possible. (vii) Finally the use of metabolite data has been proposed since in many (but by no means all) cases, metabolite is less highly variable than that of the parent drug. This subject remains controversial except when the administered substance is a prodrug which converted by metabolism into the active drug.


[Indicators of oral fluid and their correction by means of hygiene in elderly people with general somatic diseases.]
The results of the study of oral fluid in older persons with somatic pathology, which was followed for 1 month, are presented. The acid-base state of the oral fluid was evaluated, and the viscosity of the oral fluid was determined. According to the results of the study of oral fluid and its correction by means of hygiene in older persons with somatic diseases, the dynamics of the indicators of the acid-base state of the oral fluid, its shift to the alkaline side and the positive dynamics of the effect of the viscosity of the oral fluid were noted. To ensure that the risk of adverse effects from changes in the state of the oral fluid is reduced, a joint approach involving all health professionals is needed, taking into account the determinants of health and ensuring the development of effective methods for the prevention of dental diseases in older persons.


Identification of a Torque Teno Mini Virus (TTMV) in Hodgkin's Lymphoma Patients.
At least 12% of human cancers are caused by virus infection. To understand whether other viruses are associated with human cancers, a viral metagenomics approach was used to analyze the composition of the viral communities of the serum of the patients with Hodgkin's lymphoma (HL) and non-Hodgkin lymphoma. In this report, a human anellovirus TTMV named TTMV-SH was discovered from three patients with HL. The complete genome of TTMV-SH is 2812nt in length. Phylogenetic analysis based on ORF1 indicated that TTMV-SH of the 11 isolates cluster with TTMV strain TLMV-CBD231 sharing only 60.3-62% sequence similarity, and the sequences divergence is 41.5-43.1%, which indicates that TTMV-SH is a novel species. The TTMV-SH prevalence in HL group, especially in nodular sclerosing Hodgkin's lymphomas (NSHL), was significantly higher than in the healthy group implicated that the TTMV-SH may be associated with HL, especially NSHL.


Elucidating the Molecular Basis of Sorafenib Resistance in HCC: Current Findings and Future Directions.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Sorafenib is the first multi-tyrosine kinase inhibitor approved for HCC and it has represented the standard of care for advanced HCC for almost 10 years, offering a survival benefit when compared to placebo. However, this benefit is limited, showing rare objective responses and a disease control rate approaching 50-60%, with most patients experiencing disease progression at 6 months. These scant results dictate the urgent need for strategies to overcome both primary and acquired resistance. Herein we report several mechanisms supporting resistance to sorafenib in HCC patients, including activation of oncogenic pathways. Among these, the AKT/mTOR pathway plays a crucial role being at the crossroad of multiple driving events. Autophagy, multidrug-resistant phenotype, hypoxia-related mechanisms and endoplasmic reticulum stress are gaining more and more relevance as crucial events driving the response to anticancer drugs, including sorafenib. Several HCC-specific miRNAs take part to the regulation of these cellular processes. Remarkably, molecularly targeted strategies able to overcome resistance in these settings have also been reported. So far, the vast majority of data has been derived from laboratory studies, which means the need for an extensive validation. Indeed, most of the possible drug associations displaying promising effects in improving sorafenib efficacy herein described derive from preclinical explorations. Notably, data obtained in animal models can be inconsistent with regard to the human disease for efficacy, safety, side effects, best formulation and pharmacokinetics. However, they represent the necessary preliminary step to improve the management of advanced HCC.


Extra-Axial Chordoma of the Hand.
Chordomas are low-grade malignant tumors that are locally aggressive and have the potential to metastasize. They most often occur in the sacrococcygeal and spheno-occipital portions of the vertebral column. Morphologically similar tumors have been found outside the axial skeleton and are referred to as extra-axial chordomas. Several case reports have described the radiologic, microscopic, and immunologic profiles of these tumors and their similarities to axial chordomas. The authors report a 24-year-old man who presented with a mass in his left hand and underwent surgical excision. Specimens stained positive for pancytokeratin, S100, and brachyury. Brachyury is a protein that is present during embryogenesis and is expressed by chordomas. This is the first report of an extra-axial chordoma within the interosseous muscle compartment of the hand in a young patient.


Plants utilise ancient conserved peptide upstream open reading frames in stress-responsive translational regulation.
The regulation of protein synthesis plays an important role in the growth and development of all organisms. Upstream open reading frames (uORFs) are commonly found in eukaryotic messenger RNA transcripts and typically attenuate the translation of associated downstream main ORFs (mORFs). Conserved peptide uORFs (CPuORFs) are a rare subset of uORFs, some of which have been shown to conditionally regulate translation by ribosome stalling. Here, we show that Arabidopsis CPuORF19, CPuORF46 and CPuORF47, which are ancient in origin, regulate translation of any downstream ORF, in response to the agriculturally significant environmental signals, heat stress and water limitation. Consequently, these CPuORFs represent a versatile toolkit for inducible gene expression with broad applications. Finally, we note that different classes of CPuORFs may operate during distinct phases of translation, which has implications for the bioengineering of these regulatory factors.


Microbial fermentation technology for degradation of saponins from peony seed meal.
Peony seed meal is a very important feed protein raw material with a high potential for development; however, the presence of some anti-nutritional factors, such as saponins, reduces its reusability. This study aimed to establish ideal microbial fermentation conditions for the degradation of saponins in peony seed meal for its subsequent use in poultry feed. First, saponins were extracted via two methods: ethanol extraction and reflux. Then, response surface methodology and orthogonal array testing were used to establish the optimal conditions for the degradation of saponins by (a) liquid fermentation of single bacteria, (b) liquid fermentation of compound bacteria, and (c) solid-state fermentation. The degradation efficiencies were 40.21% (±1.62), 59.82% (±1.54), and 69.31% (±2.95), respectively. The maximum degradation was obtained via solid-state fermentation, and the soluble protein content for this fermentation product was found to be 14% higher than that of unfermented peony seed meal.


Two-Photon Intravital Fluorescence Lifetime Imaging of the Kidney Reveals Cell-Type Specific Metabolic Signatures.
In the live animal, tissue autofluorescence arises from a number of biologically important metabolites, such as the reduced form of nicotinamide adenine dinucleotide. Because autofluorescence changes with metabolic state, it can be harnessed as a label-free imaging tool with which to study metabolism in vivo Here, we used the combination of intravital two-photon microscopy and frequency-domain fluorescence lifetime imaging microscopy (FLIM) to map cell-specific metabolic signatures in the kidneys of live animals. The FLIM images are analyzed using the phasor approach, which requires no prior knowledge of metabolite species and can provide unbiased metabolic fingerprints for each pixel of the lifetime image. Intravital FLIM revealed the metabolic signatures of S1 and S2 proximal tubules to be distinct and resolvable at the subcellular level. Notably, S1 and distal tubules exhibited similar metabolic profiles despite apparent differences in morphology and autofluorescence emission with traditional two-photon microscopy. Time-lapse imaging revealed dynamic changes in the metabolic profiles of the interstitium, urinary lumen, and glomerulus-areas that are not resolved by traditional intensity-based two-photon microscopy. Finally, using a model of endotoxemia, we present examples of the way in which intravital FLIM can be applied to study kidney diseases and metabolism. In conclusion, intravital FLIM of intrinsic metabolites is a bias-free approach with which to characterize and monitor metabolism in vivo, and offers the unique opportunity to uncover dynamic metabolic changes in living animals with subcellular resolution.


New Insights into the Role of an Interlayer for the Fabrication of Highly Selective and Permeable Thin-Film Composite Nanofiltration Membrane.
A triple-layered TFC nanofiltration (NF) membrane consisting of a polyamide (PA) top layer covered on a poly(ether sulfone) microfiltration membrane with a carbon nanotube (CNT) interlayer was fabricated via interfacial polymerization. The structure and properties of the PA active layer could be finely tailored by tuning the interfacial properties and pore structure of the CNT interlayer, including its surface pore size and thickness, thus improving its NF performance. This TFC NF membrane exhibited a high divalent salt rejection (the rejection of Na2SO4 and MgSO4 solution >98.3%) and dye rejection (the rejection of methyl violet (MV) >99.5%) with a high pure water flux of around 21 L m-2 h-1 bar-1. Excitingly, this membrane also showed excellent selectivity to both mono/divalent salt ion (the selectivity of Cl-/SO42- is as high as 85.5) and NaCl/dye solution (the selectivity of NaCl/MV is more than 123.5), which are much higher than most of other commercial and reported NF membranes. Moreover, this membrane also showed a good separation performance and long-term stability during a continuous NF process for a salt/dye mixture solution. This triple-layered TFC NF membrane showed a great promise for applications in both wastewater treatment and dyes recycling.


[A case of primary leiomyosarcoma of the inferior vena cava treated by surgical resection and reconstruction with synthetic graft replacement].
Leimyosarcoma of the inferior vena cava (IVC) is a rare tumor, with about 200 cases reported in the world literature. There were 5 cases reported in Korea. We report a case of primary leiomyosarcoma of the inferior vena cava in a 50 year-old woman who presented with a heterogenous enhancing mass within IVC on CT scan and MRI scan. The tumor expanded the IVC with displacement of the adjacent structures. The patient underwent ultrasound guided percutaneous biopsy which was consistent with leiomyosarcoma. The patient was treated by surgical resection and synthetic graft replacement of the inferior vena cava and postoperative external beam radiation therapy. We report the case of leiomyosarcoma of the inferior vena cava with a review of relevant literatures.


Therapeutic approaches in pelvic bleeding of neoplastic origin.
The aim of this study is to present the main - surgical and non-surgical - therapeutic approaches (or methods) used in the treatment of pelvic bleeding of neoplastic origin. analysis of the materials found in the literature on this subject. Among the surgical methods used, hypogastric artery ligation is the oldest therapeutic approach in cervical bleedings of neoplastic origin. Due to the frequent recurrence of haemorrhages, mere ligation has been proven not to be sufficient, but necessitating the concomitant ligation of the lumbo-ovarian, round and uterosacral ligaments. In the case of severe bleedings, difficult to control, direct embolization of the hypogastric artery below the level of ligation is usually practiced. As for the non-surgical methods used, we chose to present uterine artery embolization and the application of haemostatic Mohs' paste. Uterine artery embolization consists in the permanent occlusion of the uterine arteries in neoplastic abundant haemorrhages, when the intervention includes the use of permanent embolic material. Stopping the bleeding within the first 24 hours from the embolization means that the intervention has been a success, and provides the patient with the possibility to continue the therapy protocol according to her stadialization. Recent studies of the Japanese researchers have indicated the possibility to use the Mohs' paste for haemostatic purposes on patients with cervical bleedings of medium intensity, in cases of advanced cervical cancer. With severe haemorrhages - occurring spontaneously or during surgery - the emergency haemostatic intervention consists in the bilateral hypogastric artery ligation. With long-lasting haemorrhages of medium intensity, we usually resort to uterine artery embolization, since this is a minimally invasive method and may also be performed with abundant bleeding under emergency pressure. The application of the Mohs' paste for haemostatic purposes is a new therapeutic method, whose efficiency cannot be yet estimated.


A health profile of adults in a Northern Territory aboriginal community, with an emphasis on preventable morbidities.
We conducted a brief health survey of adults in an isolated Northern Territory Aboriginal community, whose standardised mortality rates are the second highest in Australia. The screen revealed high rates of smoking and excessive drinking, of preventable infections and their sequelae, and of hypertension, insulin resistance, diabetes and renal disease. The infectious morbidities were more pronounced and the life-style morbidities almost entirely new since a health screen in 1957. Most morbidities were strongly associated with identifiable risk factors, such as overweight, smoking, excessive drinking, skin sores and scabies, all of which which are amenable to modification. Problems with food supply and pricing, poor food choices and diversion of money to cigarettes, beer and gambling all contributed to poor nutrition. Low birthweight probably compounds the risk for serious adult disease associated with these environmental influences. This profile highlights the failure of current systems to deal with health needs. Improvements in infrastructure, education and employment, and reinvigoration of preventive and primary health care programs, assumption of responsibility for health by the community and by individuals themselves, and better management of existing morbidities are essential to rectifying this shameful situation.


Aggression from Patients or Next of Kin and Exposure to Bullying Behaviors: A Conglomerate Experience?
Although workplace violence and aggression have been identified as important stressors in the nursing profession, studies simultaneously comparing patient-initiated aggression and exposure to bullying behaviors at work are rather scarce. The aim of this study was to compare aggression from patients or next of kin and exposure to bullying behaviors in terms of prevalence, health-related quality of life outcomes, and potential overlap in those targeted. In the period of 2008-2009, data were collected among 2059 members of the Norwegian Nurses Organization. Latent class (LC) analysis and a multivariate analysis of variance (MANOVA) were used to investigate the proposed relationships. The results showed that aggression from patients or next of kin and exposure to bullying behaviors were perceived as separate and independent stressors. Although aggression from patients or next of kin was more frequent than workplace bullying, the latter was the only significant stressor related to health-related quality of life in terms of reduced mental health functioning. Although being a rather infrequent experience, exposure to bullying behaviors seems to have more severe health-related outcomes for nurses than aggression from patients or next of kin. Hence, the results of the study strengthen previous findings and suggest that managers must aim to maintain a positive psychosocial work environment with zero-tolerance for bullying.


[Intra-arterial infusion treatment with prostaglandin E1 in patients with intermittent claudication].
In a double-blind, placebo-controlled study 50 patients with peripheral arterial occlusive disease stage IIb were given daily or intra-arterial infusion of either 1 ampoule of Prostavasin (20 micrograms PGE 1) or 1 ampoule of placebo (646.7 micrograms alpha-cyclodextrin), each dissolved in 50 ml saline, over 60-120 min. Weekends excepted, the therapy was continued for three weeks. Under PGE 1 therapy the maximum ergometric walking distance increased by 146% (mean: from 109 m to 268 m), as opposed to 40% in the placebo group (mean: from 101.5 m to 142 m). Furthermore, significant improvements were seen with regard to painfree walking capacity (PGE 1: + 170%; placebo: + 49%). Free maximum and pain-free walking distances were increased as well (PGE 1: + 131% and 48%; placebo: + 26% and 27%). Haemorrheological parameters, e.g. plasma and whole blood viscosity, haematocrit and erythrocyte aggregation decreased (p less than 0.01) after PGE 1, whereas a significant increase (p less than 0.01) in acral digital temperature, blood flow and ultrasonic Doppler values was seen. No side-effects were observed.


Secure telemonitoring system for delivering telerehabilitation therapy to enhance children's communication function to home.
A secure telemonitoring system was developed to transform CosmoBot system, a stand-alone speech-language therapy software, into a telerehabilitation system. The CosmoBot system is a motivating, computer-based play character designed to enhance children's communication skills and stimulate verbal interaction during the remediation of speech and language disorders. The CosmoBot system consists of the Mission Control human interface device and Cosmo's Play and Learn software featuring a robot character named Cosmo that targets educational goals for children aged 3-5 years. The secure telemonitoring infrastructure links a distant speech-language therapist and child/parents at home or school settings. The result is a telerehabilitation system that allows a speech-language therapist to monitor children's activities at home while providing feedback and therapy materials remotely. We have developed the means for telerehabilitation of communication skills that can be implemented in children's home settings. The architecture allows the therapist to remotely monitor the children after completion of the therapy session and to provide feedback for the following session.


Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care.
Surgical intensive care unit (ICU) stay of longer than 10 days is often described by the experienced intensivist as a "complicated clinical course" and is frequently attributed to persistent immune dysfunction. "Systemic inflammatory response syndrome" (SIRS) followed by "compensatory anti-inflammatory response syndrome" (CARS) is a conceptual framework to explain the immunologic trajectory that ICU patients with severe sepsis, trauma, or emergency surgery for abdominal infection often traverse, but the causes, mechanisms, and reasons for persistent immune dysfunction remain unexplained. Often involving multiple-organ failure (MOF) and death, improvements in surgical intensive care have altered its incidence, phenotype, and frequency and have increased the number of patients who survive initial sepsis or surgical events and progress to a persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Often observed, but rarely reversible, these patients may survive to transfer to a long-term care facility only to return to the ICU, but rarely to self-sufficiency. We propose that PICS is the dominant pathophysiology and phenotype that has replaced late MOF and prolongs surgical ICU stay, usually with poor outcome. This review details the evolving epidemiology of MOF, the clinical presentation of PICS, and our understanding of how persistent inflammation and immunosuppression define the pathobiology of prolonged intensive care. Therapy for PICS will involve innovative interventions for immune system rebalance and nutritional support to regain physical function and well-being.


Use new poly (ε-caprolactone/collagen/NBG) nerve conduits along with NGF for promoting peripheral (sciatic) nerve regeneration in a rat.
Regeneration of peripheral nerve defects remained a remarkable clinical challenge. Engineered nerve conduits represent a promising strategy to improve functional recovery in peripheral nerve injury repair. However, nerve conduits require additional factors such as neurotrophic factors to create a more conducive microenvironment for nerve regeneration. Neurotrophic factors have well-demonstrated abilities to improve neurite outgrowth, making them great candidates for repairing of defected nerves. To this end, we examined the beneficial effects of repairing the transected rat sciatic nerve by loading of nerve growth factor (NGF) in nerve conduits. The PCL/Collagen/NBG conduits were interposed into the 10 mm right sciatic nerve defects. Twenty-four rats were randomly allocated into four groups: 1- nerve autograft group, 2- a nongrafted group with gap 10-mm, 3- conduit group and 4- the conduits loaded with NGF. Motor and sensory functional recovery, the evoked muscle action potential, and motor distal latency showed significant improvement in rats treated with NGF. The histology and immunohistochemistry studies revealed less fibrosis and a high level of expression of CD31 and NF-200 protein at the crush site in the Conduit + NGF group. In conclusion, the PCL/Collagen/NBG conduit loaded with NGF, which exhibited nanometer-scale features, neurotrophic activity, favorable mechanical properties and biocompatibility could improve sciatic nerve regeneration in rats.


Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline.
Age-related declines in cognitive fitness are associated with a reduction in autophagy, an intracellular lysosomal catabolic process that regulates protein homeostasis and organelle turnover. However, the functional significance of autophagy in regulating cognitive function and its decline during aging remains largely elusive. Here, we show that stimulating memory upregulates autophagy in the hippocampus. Using hippocampal injections of genetic and pharmacological modulators of autophagy, we find that inducing autophagy in hippocampal neurons is required to form novel memory by promoting activity-dependent structural and functional synaptic plasticity, including dendritic spine formation, neuronal facilitation, and long-term potentiation. We show that hippocampal autophagy activity is reduced during aging and that restoring its levels is sufficient to reverse age-related memory deficits. Moreover, we demonstrate that systemic administration of young plasma into aged mice rejuvenates memory in an autophagy-dependent manner, suggesting a prominent role for autophagy to favor the communication between systemic factors and neurons in fostering cognition. Among these youthful factors, we identify osteocalcin, a bone-derived molecule, as a direct hormonal inducer of hippocampal autophagy. Our results reveal that inducing autophagy in hippocampal neurons is a necessary mechanism to enhance the integration of novel stimulations of memory and to promote the influence of systemic factors on cognitive fitness. We also demonstrate the potential therapeutic benefits of modulating autophagy in the aged brain to counteract age-related cognitive impairments.


Minimally invasive esophagectomy and its current role in esophageal cancer.
The incidence of esophageal cancer has increased over the previous 4 decades. In 2014 alone, it is estimated that there will be 18,000 patients diagnosed with esophageal cancer, and 15,000 deaths from the disease.Esophagectomy, most commonly with adjuvant chemotherapy and radiation to treat locoregional spread, is the primary vehicle to offer patients cure. Open approaches (transthoracic Ivor Lewis, transhiatal, left thoracoabdominal, and 'three phase' McKeown esophagectomy) have been the most common, and are associated with significant morbidity and mortality.With this morbidity in mind, minimally invasive esophagectomy (MIE) has gained enthusiasm from the surgical community as an approach to minimize post-operative morbidity without sacrificing long-term outcomes. In this article, we review the basic steps of the three major approaches to MIE. We also review the recent data which supports the surgical field's growing enthusiasm for this approach to esophageal cancer. Based on our review of current data, we conclude that patients undergoing MIE have improved short-term outcomes with regard to morbidity and quality of life, with no adverse effects of the quality of oncologic resection.


Vascular endothelial growth factor levels in childhood acute lymphoblastic and myeloblastic leukemia.
Angiogenesis has been associated with the growth, dissemination and metastasis and has been shown to be a prognostic. Although there are some data suggesting that angiogenesis may have a role in the pathophysiology of leukemia, its role in patient prognosis is yet to be defined. We analyzed the expression level of vascular endothelial growth factor (VEGF), an angiogenesis promoter and its possible- prognostic value in bone marrow samples at the time of diagnosis and remission of acute childhood leukemia patients. Besides 46 patients diagnosed as ALL or AML, 16 children were also included as a control group in the study. Our data have demonstrated that VEGF levels of AML patients were found higher than the control group statistically (P = 0.022). However we could not find any significant difference between VEGF levels of diagnosis and remission in both AML and ALL groups by blastic VEGF expression (P > 0.05). In this study the higher levels of VEGF in AML patients is one of the main findings although we were not able to assess any role of VEGF in predicting prognosis in pediatric leukemia patients by evaluating blastic cell VEGF expression. These results have demonstrated that the relationship between angiogenesis or angiogenesis promoters and hematological malignancies is not clear and simple as different methods or different cells beside different angiogenesis promotors are involved to these studies. So that not only tumor cells and their cytokines but also surrounding cells and their cytokines must be taken into consideration with the standardized study methods in the further studies to obtain a promising treatment approach.


Expression of baculovirus anti-apoptotic p35 gene in tobacco enhances tolerance to abiotic stress.
Expression of baculovirus anti-apoptotic p35 gene in plants on biotic stress responses has been well studied but its function on abiotic stress has not been documented. In the present study, the p35 gene from Autographa californica multiple nucleopolyhedrovirus (AcMNPV) was expressed in tobacco. A detached leaf assay was used to test tolerance of p35 transgenic plants to various abiotic stress responses. Expression of p35 gene in tobacco gave tolerance to treatment with methanol and H2O2 and also delayed leaf senescence under starvation in the dark. Germination of T(0) seeds on NaCl-containing medium also demonstrated to increase salt tolerance.


Methodology in subliminal psychodynamic activation: basic questions remain unanswered.
Birgegard and Sohlberg recently implied that the interchange between them and Fudin in 1999 to 2000 resolved methodological issues in subliminal psychodynamic activation research. There remain, however, unresolved problems, both logical and empirical, which impair interpretations of findings in this area. These issues include questions concerning the value of the presentation of partial vs complete messages and the parameters involved in the information processing of such stimuli. The pursuit of solutions to these problems would be most efficacious if such research were brought more in line with experimental principles and established procedures used in the presentation of subliminal stimuli. In the absence of these efforts, research in subliminal psychodynamic activation will probably continue to tend toward circular reasoning and the production of ambiguous results that will never reach a wide audience.


Selective inhibition of platelet macroaggregate formation by a recombinant heparin-binding domain of human thrombospondin.
Thrombospondin (TSP) is a platelet alpha-granule adhesive protein that plays a critical role in the stabilization of thrombus by promoting the formation of platelet macroaggregates. We have recently shown that a monoclonal antibody (mAb) to the NH2-terminal heparin-binding domain of TSP, MAII, inhibits platelet aggregation induced by thrombin in a dose-dependent manner. In this study, we have expressed in Escherichia coli two recombinant proteins comprising residues 1 to 174 (TSP18) and 1 to 242 (TSP28) of TSP. After purification, both proteins reacted equally well with mAb MAII, whereas the reactivity of TSP18 for heparin was lower than that of TSP28 or native TSP. At micromolar concentrations, TSP18 and TSP28 inhibited the second wave of platelet aggregation and the concomitant release of [14C]5-hydroxytryptamine induced by ADP in citrated platelet-rich plasma as well as aggregation and secretion induced by a low concentration of thrombin in washed platelet suspensions. The proteins did not inhibit surface expression of endogenous TSP on activated platelets, as measured by the binding of radiolabeled mAb 5G11, indicating that they did not interfere with the primary binding of TSP to the plasma membrane. In contrast, in a solid-phase binding assay, the proteins inhibited in a dose-dependent manner (IC50, 0.1 and 0.06 mumol/L for TSP18 and TSP28, respectively) the binding of radiolabeled TSP to surface-adsorbed fibrinogen. Furthermore, specific and saturable binding of the proteins to immobilized fibrinogen was demonstrated by enzyme-linked immunosorbent assay. The results suggest that interaction between the heparin-binding domain of TSP and membrane-bound fibrinogen may be critical in the platelet aggregation/secretion process.


Gastrografin administration in the treatment of postoperative delayed gastric emptying.
Five cases of delayed gastric emptying (DGE) are reported. Three patients had pancreatic head carcinoma and underwent a Whipple operation during which truncal vagotomy and gastrectomy were performed. The remaining two patients underwent vagotomy and gastrectomy because of benign peptic ulcer. In one of the pancreatectomy cases, the pylorus was at first preserved, but after DGE developed, a gastrectomy was carried out, which did not result in any improvement. The duration of DGE was 16-72 days, during which time the patients were under total parenteral or enteral nutrition. There were no other major complications. The patients received prokinetic agents (metoclopramide, erythromycin) but without any improvement. Finally, all patients were treated with Gastrografin, 40 ml every two hours, via a nasogastric tube. In all cases, gastric motility was restored within 20-36 hours.


Approach to febrile neutropenia in the general paediatric setting.
Febrile neutropenia is common in children with cancer and can also occur outside of the oncology setting. The present article provides an overview of febrile neutropenia from the general paediatric perspective.In cancer patients, the principles of febrile neutropenia management have remained relatively constant. For neutropenic children with cancer, empirical antibiotics should be initiated at the onset of fever. There is insufficient evidence at this point to recommend exclusively outpatient management of the child with cancer-related febrile neutropenia.Far less is known about febrile neutropenia in the noncancer setting. The approach to this condition should be influenced by the underlying condition and its associated risk of invasive infection and serious outcome in the absence of hospitalization and empirical antibiotic therapy.


Immunobiology of acute graft-versus-host disease.
Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). The immunobiology of acute GVHD is complex and can be conceptualized to be a three-step process. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to the damage and activation of host tissues and induces the secretion of inflammatory cytokines TNF-alpha and IL-1. As a consequence expression of MHC antigens and adhesion molecules is increased, thus enhancing the recognition of host alloantigens by donor T cells. Donor T-cell activation in step 2 is characterized by donor T-cell interaction with host APCs and subsequent proliferation, differentiation, and secretion of cytokines. Cytokines such as IL-2 and IFN-gamma enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses, and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. These inflammatory cytokines in turn stimulate production of inflammatory chemokines, thus recruiting effector cells into target organs. In step 3, effector functions of mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharide (LPS) that leaks through the intestinal mucosa damaged during step 1. This mechanism may result in the amplification of local tissue injury and further promotion of an inflammatory response, which, together with the CTL and NK components, leads to target tissue destruction in the transplant host.


A hospital-level analysis of the work environment and workforce health indicators for registered nurses in Ontario's acute-care hospitals.
The purpose of this study was to explore the relationship between hospital-level indicators of the work environment and aggregated indicators of health and well-being amongst registered nurses working in acute-care hospitals in Ontario, Canada. This ecological analysis used data from a self-reported survey instrument randomly allocated to nurses using a stratified sampling approach. Multivariable linear regression models were used to examine hospital-level associations for burnout, musculoskeletal pain, self-rated general health, and absence due to illness. The unit of analysis was the hospital (n = 160), with individual nurse responses (n = 6,609) aggregated within hospitals. After controlling for basic differences in nurse workforces, including mean age and education, higher (better) work-environment scores were found to be generally associated with higher health-indicator scores, while a larger proportion of full-time than part-time nurses was found to be associated with lower (poorer) health scores. This study may provide direction for policy-makers in coping with the recruitment and retention of nursing staff in light of the current nursing shortage.


PIM kinases 1, 2 and 3 in intracellular LIF signaling, proliferation and apoptosis in trophoblastic cells.
Proviral insertion in murine (PIM) lymphoma proteins are mainly regulated by the Janus Kinase/Signal Transducer Activator of Transcription (JAK/STAT) signaling pathway, which can be activated by members of the Interleukin-6 (IL-6) family, including Leukemia Inhibitory Factor (LIF). Aim of the study was to compare PIM1, PIM2 and PIM3 expression and potential cellular functions in human first and third trimester trophoblast cells, the immortalized first trimester extravillous trophoblast cell line HTR8/SVneo and the choriocarcinoma cell line JEG-3. Expression was analyzed by qPCR and immunochemical staining. Functions were evaluated by PIM inhibition followed by analysis of kinetics of cell viability as assessed by MTS assay, proliferation by BrdU assay, and apoptosis by Western blotting for BAD, BCL-XL, (cleaved) PARP, CASP3 and c-MYC. Apoptosis and necrosis were tested by flow cytometry (annexin V/propidium iodide staining). All analyzed PIM kinases are expressed in primary trophoblast cells and both cell lines and are regulated upon stimulation with LIF. Inhibition of PIM kinases significantly reduces viability and proliferation and induces apoptosis. Simultaneously, phosphorylation of c-MYC was reduced. These results demonstrate the involvement of PIM kinases in LIF-induced regulation in different trophoblastic cell lines which may indicate similar functions in primary cells.


Overproduction of S-adenosylmethionine decarboxylase in ethylglyoxal-bis(guanylhydrazone)-resistant mouse FM3A cells.
A variant cell line, termed SAM-1, which overproduced S-adenosylmethionine decarboxylase (AdoMetDC), was isolated by treatment of mouse FM3A cells with N-methyl-N'-nitro-N-nitrosoguanidine and subsequent incubation with ethylglyoxal bis(guanylhydrazone), an inhibitor of the enzyme. The cells were resistant to ethylglyoxal bis(guanylhydrazone), and showed AdoMetDC activity approximately five-times higher than control cells. The rate of AdoMetDC synthesis and the amount of AdoMetDC existing in SAM-1 cells were about five-times those in control cells. The amount of AdoMetDC mRNA existing in SAM-1 cells was five-times more than that in control cells. The amount of 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine, an irreversible inhibitor of AdoMetDC, necessary to inhibit cell growth was also five-times more in SAM-1 cells than in control cells. However, the following were the same in both SAM-1 and control cells; the amount of genomic DNA for AdoMetDC, the size and nucleotide sequence of 5' untranslated region of AdoMetDC mRNA, the deduced amino acid sequence (334 residues) from the nucleotide sequence of AdoMetDC cDNA and the degradation rate (t1/2 = about 4 h) of AdoMetDC. In addition, AdoMetDC mRNA in control cells was slightly more stable than that in SAM-1 cells. The results indicate that the overproduction of AdoMetDC in SAM-1 cells was caused by the increase of AdoMetDC mRNA. The variant cell line is convenient for studying the regulation of AdoMetDC and the physiological function of polyamines.


Detection of human T cell leukemia virus type I and human immunodeficiency virus in cultured lymphocytes of a Zairian man with AIDS.
We report the detection of human T cell leukemia virus type I (HTLV-I) and human immunodeficiency virus (HIV) in the cultured lymphocytes of a 45-year-old Zairian man with AIDS. HIV was successfully isolated and analyzed by SDS-PAGE and competition radioimmunoassay. However, by the culture techniques used, HTLV-I could not be separated from the HIV. Western blot analysis of the patient's serum showed the presence of both HTLV-I- and HIV-specific antibodies. The finding of this dual infection may explain reports that greater than or equal to 30% of patients with AIDS are positive for antibodies to HTLV-I.


Cytotoxicity and anti-hepatitis B virus activities of saikosaponins from Bupleurum species.
Saikosaponins, the main active constituents of Bupleurum spp., have been shown to possess immunomodulatory, hepatoprotective, anti-tumor and anti-viral activities. In this study, saikosaponins a, c and d were evaluated for cytotoxicity and anti-hepatitis B virus ( HBV) activities. Results showed that, with the exception of saikosaponins a and d, HBV-transfected human hepatoma cells (2.2.15 cells) cultured with saikosaponin c showed a significantly lower level of HBeAg in culture medium. Saikosaponin c also possessed activity in inhibiting HBV DNA replication; this inhibitory effect was not due to the cytotoxicity of saikosaponin c or its effect on 2.2.15 cell proliferation. Although saikosaponin d exhibited cytotoxicity on 2.2.15 cells, it failed to inhibit HBV multiplication. The cytotoxicity of saikosaponin d against HepG2 human hepatocellular carcinoma cells was due to the induction of apoptosis through the activation of caspases 3 and 7, which subsequently resulted in poly-ADP-ribose-polymerase (PARP) cleavage. DNA fragmentation was clearly noted at more than 6 h after HepG2 cells exposure to saikosaponin d. The present study concludes that saikosaponin c exhibits anti-HBV activity and saikosaponin d possesses potent cytotoxicity against human hepatocellular carcinoma cells.


Stereoselective [3+2] Carbocyclization of Indole-Derived Imines and Electron-Rich Alkenes: A Divergent Synthesis of Cyclopenta[b]indole or Tetrahydroquinoline Derivatives.
An unprecedented stereoselective [3+2] carbocyclization reaction of indole-2-carboxaldehydes, anilines, and electron-rich alkenes to obtain cyclopenta[b]indoles is disclosed. This pathway is different from the well-established Povarov reaction: the formal [4+2] cycloaddition involving the same components, which affords tetrahydroquinolines. Moreover, by simply changing the Brønsted acid catalyst, this multicomponent coupling process could be divergently directed towards the conventional Povarov pathway to produce tetrahydroquinolines or to the new pathway (anti-Povarov) to generate cyclopenta[b]indoles. Supported by computational studies, a stepwise Mannich/Friedel-Crafts cascade is proposed for the new anti-Povarov reaction, whereas a concerted [4+2] cycloaddition mechanism is proposed for the Povarov reaction.


Design, synthesis and pharmaco-toxicological assessment of 5-mercapto-1,2,4-triazole derivatives with antibacterial and antiproliferative activity.
The extensive biochemical research of multiple types of cancer has revealed important enzymatic signaling pathways responsible for tumor occurrence and progression, thus compelling the need for the discovery of new means with which to block these signaling cascades. The phosphoinositide 3-kinase/ protein kinase B (PI3K/AKT) pathway, which plays an important role in maintaining relevant cellular functions, exhibits various alterations in common human cancers, thus representing a suitable target in cancer treatment. Molecules bearing the 1,2,4-triazole moiety are known to possess multiple biological activities, including anticancer activity. The current study used molecular docking in the design of 5-mercapto-1,2,4-triazole derivatives with antiproliferative activity targeting the PI3K/AKT pathway. Three structures emerged as the result of this method, which indicated for these a highly favorable accommodation within the active binding site of PI3K protein, thus acting as potential PI3K inhibitors, and hence interfering with the above-mentioned pathway. The molecules were synthesized and their chemical structure was confirmed. The antiproliferative activity of these compounds was tested on 4 cancer cell lines (A375, B164A5, MDA-MB-231 and A549) and on normal human keratinocytes (HaCaT) by in vitro alamarBlue assay. The 3 compounds revealed antitumor activity against the breast cancer cell line (MDA-MB-231) and reduced toxicity on the normal cell line. The antibacterial activity of the compounds was also tested in vitro on Gram-positive and Gram-negative bacterial strains, revealing moderate activity.


Defining a clinically meaningful effect for the design and interpretation of randomized controlled trials.
This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents. Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials. The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them. The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD. The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects. There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials.


Transformation of context-dependent sensory dynamics into motor behavior.
The intrinsic dynamics of sensory networks play an important role in the sensory-motor transformation. In this paper we use conductance based models and electrophysiological recordings to address the study of the dual role of a sensory network to organize two behavioral context-dependent motor programs in the mollusk Clione limacina. We show that: (i) a winner take-all dynamics in the gravimetric sensory network model drives the typical repetitive rhythm in the wing central pattern generator (CPG) during routine swimming; (ii) the winnerless competition dynamics of the same sensory network organizes the irregular pattern observed in the wing CPG during hunting behavior. Our model also shows that although the timing of the activity is irregular, the sequence of the switching among the sensory cells is preserved whenever the same set of neurons are activated in a given time window. These activation phase locks in the sensory signals are transformed into specific events in the motor activity. The activation phase locks can play an important role in motor coordination driven by the intrinsic dynamics of a multifunctional sensory organ.


MtABCG20 is an ABA exporter influencing root morphology and seed germination of Medicago truncatula.
Abscisic acid (ABA) integrates internal and external signals to coordinate plant development, growth and architecture. It plays a central role in stomatal closure, and prevents germination of freshly produced seeds and germination of non-dormant seeds under unfavorable circumstances. Here, we describe a Medicago truncatula ATP-binding cassette (ABC) transporter, MtABCG20, as an ABA exporter present in roots and germinating seeds. In seeds, MtABCG20 was found in the hypocotyl-radicle transition zone of the embryonic axis. Seeds of mtabcg20 plants were more sensitive to ABA upon germination, due to the fact that ABA translocation within mtabcg20 embryos was impaired. Additionally, the mtabcg20 produced fewer lateral roots and formed more nodules compared with wild-type plants in conditions mimicking drought stress. Heterologous expression in Arabidopsis thaliana provided evidence that MtABCG20 is a plasma membrane protein that is likely to form homodimers. Moreover, export of ABA from Nicotiana tabacum BY2 cells expressing MtABCG20 was faster than in the BY2 without MtABCG20. Our results have implications both in legume crop research and determination of the fundamental molecular processes involved in drought response and germination.


Reversible avascular necrosis of the femoral head in tumor-induced osteomalacia.
To document the course and reversal of avascular necrosis of the femoral heads (ANFH) in a 27-year-old woman with tumor-induced osteomalacia (TIO). We describe clinical, biochemical, and magnetic resonance imaging changes in a patient who sought medical assistance because of pain in her back, hips, and knees and an enlarging mass on her right thigh. The patient proved to have TIO, an unusual condition characterized by humorally controlled renal phosphate wasting, low to undetectable levels of 1,25-dihydroxyvitamin D(3), and osteomalacia. Eleven months after removal of a small spindle cell tumor of the right thigh and without other treatment, complete clinical and biochemical remission was observed, and the magnetic resonance images revealed resolution of the ANFH. Prompt treatment of ANFH in TIO can lead to complete radiologic and clinical remission.


Treatment of liver trauma in the Lebanon War, 1982.
During the Lebanon War, 1982, 37 laparotomies were performed in our ward, mostly for penetrating abdominal trauma. The liver was injured in 11 of these patients and was bleeding at the time of laparotomy in all cases. Liver sutures were restricted to superficial wounds only. In deep lacerations, all devitalized liver tissue was removed by anatomic segmentectomy or lobectomy. Patients who had segmentectomies had a rapid and uneventful recovery, with the exception of one who developed jaundice but later recovered. In one case, the intrahepatic left main branch of the portal vein was repaired. Two soldiers died during surgery. We report our experience in liver surgery during the Lebanon War.


Evaluation of cutaneous melanoma thickness by digital dermoscopy analysis: a retrospective study.
Digital dermoscopy analysis (DDA) exploits computerized analysis of digital images and offers the possibility of parametric analysis of morphological aspects of pigmented skin lesions by means of integration with dedicated software. We conducted a study by DDA in 141 melanomas, with the aim assessing whether the numerical variables extrapolated by univariate logistic analysis could be used in a system of multivariate analysis to predict melanoma thickness before surgery. Melanoma images were evaluated for 49 DDA parameters. Logistic analysis was conducted to identify statistically significant variables. The leave-one-out method was used to evaluate the predictive representations of rules for stepwise logistic classification. The percentage of correctly classified cases was calculated by a classification matrix. Melanomas less than 1 mm had a smaller area, faded borders and were more symmetrical than melanomas greater than 1 mm. The latter had a bluer colour and more random disposition of elements. The accuracy was 86.5%. Specifically, 97 of 108 thin melanomas (specificity 89.8%) and 25 of 33 thick melanomas (sensitivity 75.7%) were correctly classified. In conclusion, the predictive value of DDA for melanoma thickness was quite good. Moreover, DDA allowed us to know objectively those dermoscopic features important in the differentiation between thick and thin melanoma. However, further studies should be performed in a prospective setting before the clinical application.


Coronary atherosclerosis in Mangalore--a random post mortem study.
A study was undertaken in Mangalore, South Kanara District of Karnataka, India to evaluate the rising prevalence of coronary artery diseases in our country. Seventy hearts were analysed, at post-mortem, between December 1996 and December 1997. The coronary arteries and the myocardium were examined, both grossly and histologically, to relate them with regard to the age and gender of the deceased. Fifty five hearts were from males and 15 were from females. Forty eight (68.59%) hearts were proven to be afflicted with coronary atherosclerosis. Twenty seven of these had three or four vessel disease. A total of 192 sections from the four major epicardial arteries of the 48 hearts were examined. Of these, 124 showed atherosclerosis (with 37 in advanced stages), of which 103 were occlusive lesions while the remaining 21 were fatty streaks. Severe stenosis (grade III or IV) was commonest in the left anterior descending artery. Twenty one (30%) of the 70 hearts showed histological evidence of myocardial ischaemia. Of these 6 were from females and 15 were males. Myocardial ischaemia was found to have no correlation to the severity of stenosis.


Cold reacting antilymphocyte antibodies in type I (insulin dependent) diabetes.
Non HLA antilymphocyte antibodies have been detected in numerous auto-immune illnesses and notably in type I (insulin dependent) diabetes. In order to ascertain their role in this illness, the actual frequency of this phenomenon has been estimated. The privileged cellular target has been determined. Finally correlations with the other immunogenetic markers of diabetes have been investigated. Non HLA antilymphocyte antibodies are frequent, above all at the beginning of the illness (32.4% before 6 months, 10% after 5 years). The cellular target is mainly composed of B lymphocytes. B lymphocyte enrichment of cellular suspensions leads to better method sensitivity (70.3% positive reactions at the beginning of the illness). No correlation was found with presence of anti islet cell antibodies or anti coxsackie B virus antibodies (IgM). Association with the HLA DR3 phenotype is relatively frequent but does not attain statistical significance.


An unusual source of apparent mitochondrial heteroplasmy: duplicate mitochondrial control regions in Thalassarche albatrosses.
Molecular ecologists, in search of suitable molecular markers, frequently PCR-amplify regions of mitochondrial DNA from total DNA extracts. This approach, although common, is prone to the co-amplification of nuclear copies of transposed DNA sequences (numts), which can then generate apparent mitochondrial sequence heteroplasmy. In this study we describe the discovery of apparent mitochondrial sequence heteroplasmy in Thalassarche albatrosses but eliminate the possibility of true sequence heteroplasmy and numts and instead reveal the source of the apparent heteroplasmy to be a duplicated control region. The two control regions align easily but are not identical in sequence or in length. Comparisons of functionally significant conserved sequence blocks do not provide evidence of degeneration in either duplicate. Phylogenetic analyses of domain I of both control region copies in five Thalassarche species indicate that they are largely evolving in concert; however, a short section within them is clearly evolving independently. To our knowledge this is the first time contrasting evolutionary patterns have been reported for duplicate control regions. Available evidence suggests that this duplication may be taxonomically widespread, so the results presented here should be considered in future evolutionary studies targeting the control region of all Procellariiformes and potentially other closely related avian groups.


Vascularised fibula osteocutaneous flap for cervical spinal and posterior pharyngeal wall reconstruction.
We report a case of vascularised fibula osteocutaneous flap used for composite cervical spinal and posterior pharyngeal wall reconstruction, in a patient with recurrent skull base chordoma, resected by an anterior approach via median labio-mandibular glossotomy approach. Bone stability and pharyngeal wall integrity were simultaneously restored.


Psychotherapy research in the 1980s: defining areas of consensus and controversy.
Psychotherapy research is characterized by slowly accumulated findings, not by dramatic breakthroughs. In this review of psychotherapy research methodology, the author identifies eight areas of relative consensus--such as the use of clinical trials, random assignment to treatment conditions, investigation of interaction effects, high statistical power, and integration of process and outcome--as well as areas of controversy. The latter mainly concern disagreements about the usefulness of meta-analysis, the distinction between specific and nonspecific factors, and the choice of comparison groups. Taken together, the areas of consensus, along with the methodological suggestions the literature offers for future research, signal a shift toward studies that are more relevant to clinicians. However, implementation of such studies depends very much on the collaboration of clinicians and researchers.


Distinguishing the strength of electronic coupling for Mo2 -containing mixed-valence compounds within the Class III regime.
Two, symmetrical, mixed-valence (MV), complex cations-{[Mo2 (DAniF)3 ]2 (μ-oxamidate)}(+) (1(+) ) and {Mo2 (DAniF)3 ]2 (μ-dithiooxamidate)}(+) (2(+) ; DAniF=N,N'-di(p-anisyl)formamidinate)-are significantly differentiated in terms of electronic coupling between the two [Mo2 ] units. For 1(+) the intervalence (IV) charge-transfer band in the near-IR spectrum is truncated in half on the low-energy side as predicted for MV compounds at the Class II-III limit (2Hab /λ=1; for which Hab =electronic coupling matrix element and λ=reorganization energy). In contrast, the very strongly coupled analogue 2(+) , as indicated by 2Hab /λ=3.5 (> >1), exhibits a higher energy and more symmetrical IV band. As rare examples, this pair of MV species shows distinct optical behaviors for MV systems crossing the Class III region. Optical analysis and DFT calculations are carried out to elucidate the transformation from vibronic to electronic vertical transition.


Isotopic Composition of Atmospheric Mercury in China: New Evidence for Sources and Transformation Processes in Air and in Vegetation.
The isotopic composition of atmospheric total gaseous mercury (TGM) and particle-bound mercury (PBM) and mercury (Hg) in litterfall samples have been determined at urban/industrialized and rural sites distributed over mainland China for identifying Hg sources and transformation processes. TGM and PBM near anthropogenic emission sources display negative δ(202)Hg and near-zero Δ(199)Hg in contrast to relatively positive δ(202)Hg and negative Δ(199)Hg observed in remote regions, suggesting that different sources and atmospheric processes force the mass-dependent fractionation (MDF) and mass-independent fractionation (MIF) in the air samples. Both MDF and MIF occur during the uptake of atmospheric Hg by plants, resulting in negative δ(202)Hg and Δ(199)Hg observed in litter-bound Hg. The linear regression resulting from the scatter plot relating the δ(202)Hg to Δ(199)Hg data in the TGM samples indicates distinct anthropogenic or natural influences at the three study sites. A similar trend was also observed for Hg accumulated in broadleaved deciduous forest foliage grown in areas influenced by anthropogenic emissions. The relatively negative MIF in litter-bound Hg compared to TGM is likely a result of the photochemical reactions of Hg(2+) in foliage. This study demonstrates the diagnostic stable Hg isotopic composition characteristics for separating atmospheric Hg of different source origins in China and provides the isotopic fractionation clues for the study of Hg bioaccumulation.


Staged Delayed Sternal Closure Using a Binder Clip After Pediatric Cardiac Surgery.
After pediatric cardiac surgery, patients who undergo delayed sternal closure may become hemodynamically unstable. We performed a staged sternal closure technique using a binder clip in 31 consecutive patients to minimize cardiopulmonary instability. Only one patient (3.2%) died of mediastinitis. Thus, our technique may be safe and minimize cardiopulmonary instability. doi: 10.1111/jocs.12767 (J Card Surg 2016;31:464-466).


Abrogated Cell Contact Guidance on Amino-Functionalized Microgrooves.
Topographical and chemical features of biomaterial surfaces affect the cell physiology at the interface and are promising tools for the improvement of implants. The dominance of the surface topography on cell behavior is often accentuated. Striated surfaces induce an alignment of cells and their intracellular adhesion-mediated components. Recently, it could be demonstrated that a chemical modification via plasma polymerized allylamine was not only able to boost osteoblast cell adhesion and spreading but also override the cell alignment on stochastically machined titanium. In order to discern what kind of chemical surface modifications let the cell forget the underlying surface structure, we used an approach on geometric microgrooves produced by deep reactive ion etching (DRIE). In this study, we systematically investigated the surface modification by (i) methyl-, carboxyl-, and amino functionalization created via plasma polymerization processes, (ii) coating with the extracellular matrix protein collagen-I or immobilization of the integrin adhesion peptide sequence Arg-Gly-Asp (RGD), and (iii) treatment with an atmospheric pressure plasma jet operating with argon/oxygen gas (Ar/O2). Interestingly, only the amino functionalization, which presented positive charges at the surface, was able to chemically disguise the microgrooves and therefore to interrupt the microtopography induced contact guidance of the osteoblastic cells MG-63. However, the RGD peptide coating revealed enhanced cell spreading as well, with fine, actin-containing protrusions. The Ar/O2-functionalization demonstrated the best topography handling, e.g. cells closely attached even to features such as the sidewalls of the groove steps. In the end, the amino functionalization is unique in abrogating the cell contact guidance.


Critical friends: A way to develop preceptor competence?
Preceptorship entails for nurses to create a supportive learning and working climate where students or newcomers are given opportunities to develop professional competence. However, being a skilled and experienced nurse does not automatically turn the professional into a skilled educator as teaching of a subject is a whole different story. Preceptors need to continuously and critically reflect on their practices in order to facilitate the development of professional pedagogical competence. Critical friends are colleagues with comparable educational background evaluating the work of each other. The relationship should rely on friendship and mutual trust, adding new dimensions to the reflective process. Being engaged in a critical friendship allows the "friends" to become aware of their own shortcomings which can then be reflected on in relation to clinical as well as pedagogical practices. Being and having a critical friend might be one promising way forward for preceptors to develop pedagogical and professional competence.


New species of many-plumed moths (Lepidoptera: Alucitidae) from Tanzania.
Basing on the examination of new material on many-plumed moths from Tanzania, four new species have been discovered: Alucita agassizi Ustjuzhanin Kovtunovich sp. nov., A. iringiensis Ustjuzhanin Kovtunovich sp. nov., A. snezhinka Ustjuzhanin Kovtunovich sp. nov. and A. tanzanica Ustjuzhanin Kovtunovich sp. nov. They are described and compared with the closest species. The diagnostic characters for each new taxon are specified. The genitalia are described and illustrated, images of the adults are provided. Data on many-plumed moths previously unknown for Tanzania are given. Two species, A. seychellensis (Fletcher 1910) and A. malawica (Ustjuzhanin Kovtunovich, 2016) are reported from Tanzania for the first time.


A standardized pomegranate fruit extract ameliorates thioacetamide-induced liver fibrosis in rats via AGE-RAGE-ROS signaling.
This work aimed to investigate a possible mechanism that may mediate the hepatoprotective effects of pomegranate fruit extract (PFE) against thioacetamide (THIO)-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly allocated into four groups (n = 8 each): control; PFE (150 mg/kg/day, orally); THIO (200 mg/kg, i.p, 3 times a week); and THIO and PFE-treated groups. Oral PFE treatment decreased liver/body weight ratio by 12.4%, diminished serum function levels of ALT, AST, ALP, LDH, and total bilirubin, increased serum albumin, boosted hepatic GSH (by 35.6%) and SOD (by 17.5%), and significantly reduced hepatic levels of ROS, MDA, 4-HNE, AGEs, and RAGE in THIO-fibrotic rats relative to untreated THIO group. Moreover, PFE administration downregulated the hepatic levels of profibrotic TGF-β1 (by 23.0%, P < 0.001) and TIMP-1 (by 41.5%, P < 0.001), attenuated α-SMA protein expression, decreased serum HA levels (by 41.3%), and reduced the hepatic levels of the fibrosis markers hydroxyproline (by 26.0%, P < 0.001), collagen type IV (by 44.3%, P < 0.001) and laminin (by 43.4%, P < 0.001) compared to the untreated THIO group. The histopathological examination has corroborated these findings, where PFE decreased hepatic nodule incidence, attenuated portal necroinflammation and reduced extent of fibrosis. These findings may suggest that oral PFE administration could slow the progression of hepatic fibrogenesis via reducing hepatic levels of AGEs, RAGE, ROS, TGF-β1, and TIMP-1.


Frontotemporal dementia: a review.
This review summarizes the clinical, imaging, and pathological features of frontotemporal dementia (FTD). Clinicians have become increasingly sensitive to FTD in the differential diagnosis of Alzheimer's disease. Clinical subgroups of FTD patients have been recognized, including patients with progressive non-fluent aphasia, semantic dementia, and behavioral disorder with executive difficulty. The clinical, neuroimaging and neuropathological profiles associated with these clinically defined subgroups are examined.


Dominant mutation for ethionine resistance in Saccharomyces cerevisae.
An ethionine-resistant mutant of Saccharomyces cerevisiae has been investigated whose mutation (et(r2)) confers resistance to the heterozygous diploid also containing the sensitive allele, et(s). The mutation is apparently specific for reversal of ethionine inhibition. The principal difference between the sensitive et(s) strain and the mutant was the latter's inability to concentrate large intracellular quantities of adenosylethionine. Reduced incorporation of ethyl groups or ethionine in other cellular fractions of the mutant was also detected. The data show that the mutant has not lost the ability to form adenosylethionine. It is suggested that the mutant has an increased ability to hydrolyze this sulfonium compound after it has been synthesized. It is possible that some of the ethionine is detoxified before it can participate in protein or adenosylethionine synthesis. No mutant alteration in accumulation of ethionine from the medium was detected. In the presence of ethionine, the parental strain accumulated 25 times more adenosylethionine than did the mutant. However, with methionine, only twice as much adenosylmethionine was accumulated by the parental strain as by the mutant.