Overview of the Treatment of Congestion in Heart Failure.
Heart failure is a major problem in developed countries, leading to a high number of hospitalizations and healthcare costs. The most common symptom of heart failure is congestion, which is also the primary reason for hospitalization. Diuretics, particularly loop diuretics, are the cornerstone of the treatment of congestion. Likewise, there are other types of diuretics with different pathways of action, bioavailability profiles, adverse reactions, and effects on the cardiovascular and renal systems. Moreover, in recent years, new therapeutic alternatives have been proposed for challenging cases of diuretic resistance, such as ultrafiltration through peripheral access or peritoneal dialysis. The main objective of this article is to provide a step-guided approach to the management of congestion in patients with heart failure in order to guide the medical practice. Despite the significant amount of research published in recent years, there are no clear algorithms for managing acute heart failure. Diuretics remain the primary treatment of acute heart failure, and nephron blockade is key, but new therapies are emerging, and ongoing research is needed to develop better strategies for managing this condition.


The pharmacological rationale behind polypharmacy in heart failure.
The treatment of heart failure (HF) commonly requires a complex pharmacological regimen. Currently HF polypharmacy consists of drugs that target different factors for disease progression, such as altered hemodynamics and elevated neurohumoral factors. Even though a significant improvement of HF has been achieved by combination treatment with regard to morbidity and mortality rate, the increasing numbers and daily doses of drugs bare the risk of potential and sometimes unavoidable drug interactions. Furthermore, comorbidities can be a complication of polypharmacy treatment in HF patients. A pharmacological rationale behind polypharmacy in HF will be discussed on the basis of current treatment recommendations by the American Heart Association and the European Society of Cardiology. Finally, difficulties in polypharmacy regarding the major adverse drug effects and interactions will be outlined. Heart Fail Monitor 2008;6(1):20-27.


Effects of moderate and intensive training on the hypothalamo-pituitary-adrenal axis in rats.
The influence of the two distinct training programmes, moderate (M) and intensive (I), on hypothalamo-pituitary-adrenal (HPA) axis was investigated, in rats. Changes in plasma concentrations of adrenocorticotropin hormone (ACTH) and corticosterone were followed in response to (i) a 60-min acute running session performed on 2nd, 4th and 6th of the seven training weeks (ii) an acute restraint stress of 40 min applied after the final training programme. After 2nd, 4th and 6th week of the two training programmes, a 60-min running resulted in an enhanced secretion of ACTH and corticosterone, compared with both the baseline values (i.e. before running) and to the sedentary (S) group. However, on 4th and 6th weeks compared with 2nd week, ACTH and corticosterone remained elevated in intensive group when they are significantly reduced in moderate group. We could suggest that a moderate training resulted in an adapted hormonal response whereas a deadapted process occurred for the intensive programme. The day after the last training session, basal ACTH, corticosterone and corticosteroid-binding globulin (CBG) capacity were not affected by training. Hypothalamic corticotropin-releasing factor tissue-content (CRF) was increased significantly in the two trained groups. When compared with the sedentary group, the body weight of the rats in the two trained groups was significantly decreased with a total adrenal mass increasing but only in intensive group. The surimposed restraint stress resulted in significant increases in plasma ACTH and corticosterone both in trained and in sedentary animals. This result suggests that the adapted HPA axis response induced by both a moderate and intensive training do not prevent against the effects of a novel stress such as restraint stress.


Pathotype characterization of Plasmodiophora brassicae by European Clubroot Differential and Williams sets in China.
Clubroot disease caused by the soil-borne Plasmodiophora brassicae is devastating to Brassicaceae crops and spreading rapidly in China in recent years, resulting in great yield losses annually. Virulence of P. brassicae populations specializes and is in dynamic change in the fields. Information on the pathotypes and their distributions are crucial to control the clubroot disease. Presently, the pathotypes of P. brassicae prevalent in China, however, are not well determined. In this study, we used 16 Brassica hosts, including the European Clubroot Differentials (ECD) and Williams set, to designate the pathotypes of 33 P. brassicae populations from 13 provinces. The 33 P. brassicae populations could be divided into 26 pathotypes by the ECD set or 7 pathotypes by the Williams set, revealing ECD16/15/31 and ECD16/31/31 or P4 and P2 as the predominant pathotypes. We found the B. rapa differentials ECD01-04 showed stable and high levels of resistance to most pathotypes of P. brassicae in China, thereby providing the valuable resources for clubroot-resistance breeding of Brassicaceae crops. The ECD set exhibited much higher discernibility and further divided the isolates that belonged to the P4 pathotype into 10 ECD pathotypes. Isolates of ECD16/23/31 and ECD16/15/31 were strongly virulent on the Huashuang 5R-the first and widely used clubroot-resistant cultivar of oilseed rape in China. As we learn, 26 pathotypes are the most diverse populations of P. brassicae characterized by now in China. Our study provides new insights into virulence specialization of P. brassicae and their geographical distributions, contributing to exploitation of clubroot resistant resources and field layout of the present resistant Brassica crops in China.


Acetaldehyde exposure causes growth inhibition in a Chinese hamster ovary cell line that expresses alcohol dehydrogenase.
Chronic ethanol exposure causes many pathophysiological changes in cellular function due to ethanol itself and/or the effects of its metabolism (i.e., generation of acetaldehyde and redox equivalents). However, the role of each of these effects remains controversial. To address these questions, we have developed a cell line that expresses alcohol dehydrogenase. This cell line permits separate examination of the effects of ethanol and its metabolite acetaldehyde on cell function. An expression vector for the mouse liver alcohol dehydrogenase was constructed and transfected into Chinese hamster ovary cells. Cells expressing alcohol dehydrogenase were identified by screening with allyl alcohol, which is metabolized by alcohol dehydrogenase to the toxic aldehyde acrolein. A number of cell lines were identified that expressed alcohol dehydrogenase. A-10 cells were selected for further study because of their high sensitivity to allyl alcohol, suggesting a high level of alcohol dehydrogenase expression. These cells expressed a mRNA that hybridizes with the alcohol dehydrogenase cDNA and had an alcohol dehydrogenase activity comparable to murine liver. When cultures of these cells were exposed to ethanol, acetaldehyde was detected in both the medium and cells. The acetaldehyde concentration in the medium remained constant for at least 1 week in culture and was a function of the added ethanol concentration. Chronic exposure of A-10 cells to ethanol resulted in a dose-dependent reduction in the number of cells that accumulated over 7 days. Ethanol-treated cells remained viable, and growth inhibition was reversible. Growth inhibition was blocked by the alcohol dehydrogenase inhibitor 4-methylpyrazole, suggesting that acetaldehyde and not ethanol was responsible for growth inhibition in these cells.


The Stressors and Coping Strategies of Older Adults With Persistent Atrial Fibrillation Prior to and Following Direct Current Cardioversion.
The purpose of this study was to explore the stressors and coping strategies of older adults with persistent atrial fibrillation (AF) before and after direct current cardioversion. The study used a qualitative descriptive design. Sixteen patients were recruited through an AF clinic to participate in individual interviews prior to the cardioversion and at 6 and 12 weeks post procedure. Pre-cardioversion, older adults experienced symptom and health care-related stressors superimposed on existing non-AF stressors. They used a range of emotion and problem-focused coping. Non-AF stressors increased post procedure at the same time that participants perceived less need for coping strategies with a return to regular rhythm. There was a shift from AF to non-AF related stressors following the cardioversion but a decrease in coping strategies. Older adults with AF should be encouraged to maintain use of coping strategies to manage ongoing stress and reduce the risk of AF recurrence.


The long-term clinical and radiological outcomes in patients who suffer recurrent injuries to the anterior cruciate ligament after reconstruction.
The aim of this study was to investigate the long-term clinical and radiological outcome of patients who suffer recurrent injuries to the anterior cruciate ligament (ACL) after reconstruction and require revision surgery. From a consecutive series of 200 patients who underwent primary reconstruction following rupture of the ACL, we identified 36 who sustained a further rupture, 29 of whom underwent revision surgery. Patients were reviewed prospectively at one, two, seven, 15 and about 20 years after their original surgery. Primary outcome measures were the number of further ruptures, the posterior tibial slope (PTS), and functional and radiological outcomes. These were compared with a gender and age matched cohort of patients who underwent primary ACL reconstruction only. At a mean follow-up of 18.3 years (14.3 to 20.2), 29 patients had undergone revision surgery and within this revision group 11 had sustained more than three ruptures of the ACL (3 to 6). The mean age at the time of revision reconstruction was 26.4 years (14 to 54). The mean PTS was significantly higher in those patients who suffered a further injury to the ACL (11°) compared with the control group (9°) (p < 0.001). The mean PTS in those patients who sustained more than three ruptures was 12°. Patients who suffer recurrent injuries to the ACL after reconstruction have poorer functional and radiological outcomes than those who suffer a single injury. The causes of further injury are likely to be multifactorial but an increased PTS appears to have a significant association with recurrent ACL injuries. Cite this article: Bone Joint J 2017;99-B:337-43.


Treatment of a transorbital penetrating injury: a particular endovascular approach.
The management of craniocerebral penetrating injury currently represents a challenge for neurosurgeons and neuroradiologists and requires innovative planning. This report describes the case of a worker admitted to hospital with an intracranial piece of concrete-cutting saw stuck through the right eye. At the time of admission the patient was conscious and this fact influenced the choice of a particular approach. This patient escaped without neurological deficit or complications, except for the inevitable removal of an eye.


The pectoralis major myocutaneous flap revisited: a reliable technique for head and neck reconstruction.
The pectoralis major myocutaneous flap (PMMF) remains a useful flap for head and neck reconstruction. Although free-tissue transfer is often preferred, the benefits of the PMMF should not be overlooked. A retrospective chart review was performed on all PMMFs used at Emory for head and neck reconstruction from 1992 through 2008. A total of 139 PMMF were performed in 136 patients with an average age of 65 years. Eighty-six patients were males. All patients except one had a history of Head and Neck Cancer. A smoking history was present in 92% of the patients. Defect location included oral cavity (n = 59), pharyngeal/fistulae (n = 48), temporal bone and cheek (n = 24), oropharyngeal (n = 4), and esophageal (n = 2). The PMMF was used in 4 occasions as a salvage procedure. The survival of the flap was 99.2% (138/139). The PMMF provided definitive closure of the defect in 100% of the cases. The overall average follow-up was 10.5 months. Eighteen patients (13%) developed complications after the procedure. Patients who had radiation therapy had significantly higher complication rates. The PMMF flap remains a very versatile technique with proven reliability for soft tissue coverage of many head and neck defects.


Auxeticity of Concentric Auxetic-Conventional Foam Rods with High Modulus Interface Adhesive.
While the rule of mixture is applicable for addressing the overall Poisson's ratio of a concentrically aligned bi-layered rod under longitudinal loading, the same cannot be said for this rod under torsional loading due to the higher extent of deformation in the rod material further away from the torsional axis. In addition, the use of adhesives for attaching the solid inner rod to the hollow outer rod introduces an intermediate layer, thereby resulting in a tri-layered concentric rod if the adhesive layer is uniformly distributed. This paper investigates the effect of the adhesive properties on the overall auxeticity of a rod consisting of two concentrically aligned cylindrical isotropic foams with Poisson's ratio of opposite signs under torsional loads. An indirect way for obtaining Poisson's ratio of a concentrically tri-layered rod was obtained using a mechanics of materials approach. Results show that the auxeticity of such rods is influenced by the adhesive's stiffness, Poisson's ratio, thickness, and radius from the torsional axis.


Your theory of the evolution of morality depends upon your theory of morality.
Baumard et al. attribute to humans a sense of fairness. However, the properties of this sense are so underspecified that the evolutionary account offered is not well-motivated. We contrast this with the framework of Universal Moral Grammar, which has sought a descriptively adequate account of the structure of the moral domain as a precondition for understanding the evolution of morality.


Severe neurological manifestations in an Egyptian patient with a novel frameshift mutation in the Glutaryl-CoA dehydrogenase gene.
To characterize an Egyptian patient with glutaric acidemia type I (GA I) and to identify the causative mutation(s) that may be responsible for the disease phenotype. MRI was performed on the patient using the 1.5 T magnet, biochemical analysis was carried out using gas chromatography/mass spectrometry on the patient's dried blood spot, and the patient's organic acids were measured in dried blood and a urine sample using MS/MS and GC/MS, respectively. Total RNA was isolated from the patient's peripheral blood, and the synthesized cDNA was bi-directionally sequenced. The patient exhibited clinical features and MRI findings compatible with a diagnosis of GA I. The abnormal elevation of organic acids in the urine supported the presence of glutaryl-CoA dehydrogenase deficiency. Gene sequencing revealed a novel homozygous frameshift mutation, c.644_645insCTCG; p.(Pro217Leufs*14), in exon 8 of the GCDH gene. The present study revealed a novel frameshift mutation responsible for a severe GA I phenotype in an Egyptian patient. This novel mutation will ultimately contribute to a better understanding of the molecular pathology of the disease and shed light on the intricacies of the genotype-phenotype correlation of GA I disease.


Temperature dependence of sol-gel conversion kinetics in gelatin-water system.
The conversion kinetics of an aqueous gelatin solution to gel was studied by temperature modulated and regular DSC under isothermal and continuous cooling conditions. Isothermal runs revealed a decrease in the quasi-static heat capacity primarily associated with syneresis (phase separation) of the gel. Above 19 degrees C the isothermal process demonstrated negative effective activation energy that turned positive below 14 degrees C. Continuous cooling runs detected a reversing heat flow apparently related to the continuing formation and melting of new gel structures. Isoconversional kinetic analysis of continuous cooling measurements yielded negative activation energy for the whole range of conversions and temperatures suggesting that nucleation remained a rate controlling step throughout the whole gelation process.


Zeolite A synthesized from alkaline assisted pre-activated halloysite for efficient heavy metal removal in polluted river water and industrial wastewater.
High quality zeolite A was synthesized through a hydrothermal process using alkaline-assisted pre-activated halloysite mineral as the alumina and silica source. The synthesis conditions employed in this study were finely tuned by varying the activating temperature, sodium hydroxide content, water content and Si/Al ratio. The obtained zeolite A showed excellent adsorption properties for both single metal cation solutions and mixed cation solutions when the concentrations of the mixed cations were comparable with those in polluted natural river water and industrial wastewater. High adsorptive capacities for Ag+ (123.05mg/g) and Pb2+ (227.70mg/g) were achieved using the synthesized zeolite A. This observation indicates that the zeolite A synthesized from alkaline-assisted pre-activated halloysite can be used as a low-cost and relatively effective adsorbent to purify heavy metal cation polluted natural river water and industrial wastewater.


Diversity of navel microbiome in young adults.
Introduction. Human skin microbial communities represent a tremendous source of genetic diversity that evolves as a function of human age. Microbiota differs between regions of oily and moist skin, and appears to stabilize with age.Aim. We have a minimal understanding of the time frame required for the stabilization of skin microbiota, and the role played by gender. In the current study, we examined the microbiota present in the navel region of college-attending young adults in the age group of 18-25 years and investigated if diversity is associated with gender (male and female).Method. The study involved 16 female and six male subjects. Isolated DNA samples from navel swabs were processed using the Nextera XT library preparation kit and sequenced using the MiSeq platform. Data were analysed using QIIME and statistical analysis performed in R.Results. Microbiota of navel skin is dominated by Corynebacterium and Staphylococcus and includes opportunistic pathogens like Clostridium and Pseudomonas. Also present as the major component of the flora were the organisms normally associated with the gastrointestinal tract such as Acinetobacter, Campylobacter, Klebsiella and organisms from the Enterobacteriaceae and Moraxellaceae families. Comparison of alpha and beta diversity of the microbiota in the male and female navel regions suggests that the flora is not statistically different (P>0.05). However, pairwise comparison suggests that the abundance of 12 specific genera varied with gender, including higher abundance of Klebsiella and Enterobacter in females.Conclusion. Our findings indicate that the navel skin microbiota of young adults has a core microbiota of Corynebacterium and Staphylococcus. We also noted the presence of a significant number of opportunistic pathogens. A minor gender difference in the abundance of individual organisms was also observed.


Infected dermoid sinus tract mimicking recurrent sinusitis in an adolescent male.
Nasal dermoid sinus cysts are the most common congenital midline nasofrontal masses, but they can easily be confused with simple recurrent sinusitis upon clinical presentation. We report the case of a 14-year-old male who was initially diagnosed with frontal sinusitis and treated with antibiotics but, after multiple episodes of recurrence, was later sent for imaging. Computed tomography and magnetic resonance imaging showed an infected dermoid sinus tract. Subsequent surgery removed the mass and pathologic investigation proved the diagnosis.


Dynamics of BCR-ABL mRNA expression in first-line therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C.
We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 cases by real-time PCR, but in only four patients by nested PCR. Median best response in patients with relapse after CCR was 0.24% (n=3) as compared to 0.029% in patients with continuous remission (n=52, P=0.029). We conclude that (i) treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels; (ii) nested PCR may reveal residual BCR-ABL transcripts in samples that are negative by real-time PCR; (iii) BCR-ABL transcript levels parallel cytogenetic response, and (iv) imatinib is superior to IFN/Ara-C in terms of the speed and degree of molecular responses, but residual disease is rarely eliminated.


Hepatic artery thrombosis following pediatric liver transplantation: Assessment of blood flow measurement in allografts.
The purpose of this study was to define parameters which could be predictive of hepatic artery thrombosis, which continues to be a major complicating factor in pediatric liver transplantation. The hepatic blood flow of 14 pediatric liver patients (15 grafts) who weighed less than 15 kg was measured electromagnetically during orthotopic liver transplantation. The results of blood flow determination and the clinical data in 7 patients (8 grafts) who developed hepatic artery thrombosis were compared with those of 7 control patients. All patients with a hepatic arterial flow of less than 60 ml/min developed hepatic artery thrombosis (4/8 vs. 0/7; p < 0.05), and the patients with hepatic artery thrombosis exhibited higher total hepatic and portal vein flow per 100 gram of liver tissue (262 vs. 136 ml/min; p < 0.001 and 222 vs. 80 ml/min; p < 0.025, respectively) as well as longer cold preservation time (384 vs. 326 min; p < 0.025). The results of our study suggest that hepatic arterial flows of less than 60 ml/min are critical for the development of hepatic artery thrombosis, and that portal venous overflow and increased preservation times may contribute to the development of hepatic artery thrombosis.


Effects of supplementation with unsaturated fatty acids on plasma and membrane lipid composition and platelet function in patients with cirrhosis and defective aggregation.
Defective platelet aggregation and reduced platelet production of thromboxane A2, a metabolite of arachidonic acid, are common findings in patients with cirrhosis. We evaluated the effects of dietary supplementation with two combinations of unsaturated fatty acids on platelet function and plasma and membrane fatty acids in patients with liver cirrhosis. In a double-blind study, 15 patients with cirrhosis and defective aggregation were randomized to receive a 6-week supplementation with gamma-linolenic and linoleic acid (1 g/day of each fatty acid) or with oleic acid and linoleic acid (groups GLA and OA, respectively). Under baseline conditions, patients showed elevated concentrations of monounsaturated fatty acids and a reduction in polyunsaturated fatty acids. The product/precursor ratios for delta6 and delta5 desaturases, two key enzymes in the pathway leading to arachidonic acid, were significantly reduced in the group of patients. In the GLA group, a significant increase in the levels of dihomo-gamma-linolenic acid (20:3omega6) was observed in plasma and membranes, together with a parallel decrease in the 20:4/20:3omega6 ratio after supplementation. No significant changes were observed in the OA group. The levels of arachidonic acid did not change significantly in either group of patients. Platelet aggregation to collagen was unchanged in the GLA group, but significantly improved in the OA group. These results show that supplementation with precursors of arachidonic acid is ineffective in elevating plasma or membrane arachidonate levels and does not improve platelet aggregation, suggesting that synthesis of arachidonic acid through the delta5 desaturase cannot be correspondingly activated or that incorporation/retention of the produced fatty acid into lipids is impaired. The increased platelet aggregation in the OA group is likely to be explained by the effect of oleic acid contained in the diet, the effects of which may have been counteracted by the elevation in 20:3omega6, a source of anti-aggregatory prostanoids, in the GLA group.


The Relationship Between Acceptance Intention Toward a Smartphone Healthcare Application and Health-Promoting Behaviors Among Nursing Students.
The purpose of this study was to identify the relationship between acceptance intention toward a smartphone healthcare application and health-promoting behaviors among nursing students in order to propose a method to encourage nursing students' personal health management. Data were collected from June to July 2015 in two cities located in South Korea, targeting 450 nursing students. There was a weak positive relationship between acceptance intention toward a smartphone healthcare application and health-promoting behaviors (r = 0.281, P < .001). There were differences in health-promoting behaviors according to the level of acceptance intention toward a smartphone healthcare application: health-promoting behavior scores for the upper 50% of participants with higher intention scores (high-score group) were statistically higher than those for the lower 50% of participants (low-score group) (t = 4.247, P < .001). In the logistic regression, the high-score group had a greater likelihood of performing health-promoting behaviors (odds ratio, 2.260; P < .001, 95% confidence interval, 1.539-3.321). Health-promoting behaviors tended to increase among nursing students when the acceptance intention toward a smartphone healthcare application was high. To increase nursing students' intention to accept a smartphone healthcare application, it is necessary to develop applications featuring diverse, interesting health-related content suitable for their needs, so that they want to use these applications to promote health.


Comparative Study of Phytochemistry, Antioxidant and Biological Activities of Berberis libanotica Fruit and Leaf Extracts.
Berberis libanotica Ehrenb. ex C.K. Schneider of the Berberidaceae family is an endemic Lebanese plant and is widely used in folk medicine. This study highlights the phytochemical composition and biological activities (in vitro) of fruit and leaf extracts. The two organs were extracted by cold maceration with four solvents of increasing polarity: cyclohexane, dichloromethane, ethyl acetate and methanol. The extracts were screened for their chemical composition by HPLC-DAD to identify and quantify the phenolic compounds. Volatile compounds were detected by GC-MS. The antioxidant capacity through DPPH inhibition was tested. The anti-acetylcholinesterase, antibacterial and anti-proliferative activities were evaluated. Thirteen compounds, including 12 phenolics, were detected in the fruits, whereas 8 phenolic compounds were identified in the leaves. A total of 137 volatile compounds were identified in both organs. At 50 μg/mL, the methanolic leaf extract presented the highest antioxidant capacity, with an inhibition percentage of 54.9%. The dichloromethane fruit extract reduced the acetylcholinesterase activity by 65.3%. The cyclohexane leaf extract reduced the proliferation of the HCT-116 cells by 54.8%, while the dichloromethane fruit extract exhibited the best inhibition against the Caco-2 cells (54%). Interestingly, the minimum inhibitory concentration (MIC) value of the cyclohexane fruit extract against Salmonella enterica serovar Kentucky was 2.4 μg/mL, and the MIC value of the cyclohexane leaf extract against E. coli was 9.7 μg/mL.


[Formation of an actin cytoskeleton and adhesive structures during the spreading of cultured cells].
Fibroblast spreading was studied using immunofluorescent method that provided visualization of actin structures and adhesion contacts in the same cell. Four stages of actin system formation were observed. 1. Actin concentration in ruffles at the cell periphery. Formation of numerous dot-like contacts along the whole perimeter of the cell. 2. Formation of a circumferential actin bundle. Focal contacts are located at the outer edge of the bundle. 3. Gradual transformation of the circumferential bundle into actin network with triangular meshes. Peripheral (rather than internal) filaments of the network are associated with the focal contacts. 4. Appearance of the system of long straight actin bundles (stress fibers) associated with dash-like focal contacts. The stress fibers are supposed to arise from the triangular actin network which in its turn arises from the circumferential bundle. It is suggested that the formation of actin cytoskeleton is a process driven by the development of tensions in actin structures attached to the focal contacts at the cell periphery.


Current Status of the Pharmacokinetics and Pharmacodynamics of HIV-1 Entry Inhibitors and HIV Therapy.
Human Immunodeficiency Virus (HIV) entry inhibitors target the first step of the HIV life cycle and efficiently inhibit HIV from infecting the immune cells which is a key prerequisite for viral spread. Because of their unique mechanism of action on cell-cell transmission, they may provide a promising perspective for the treatment of AIDS. Maraviroc (MVC) and Enfuvirtide (ENF) have been approved by the FDA for the treatment of HIV-1 infection. Attachment inhibitors (BMS-663068 and TNX-355) and co-receptor inhibitors (PRO-140 and cenicriviroc (CVC)) have reached phase II or III clinical trials. These entry inhibitors show beneficial pharmacokinetics and substantial reductions of plasma HIV-1 RNA load in HIV infected patients. Most entry inhibitors are generally safe, without serious Adverse Event (AE) or AE leading to discontinuation. The pharmacokinetics of MVC, CVC and BMS-663068 was affected by CYP3A4 inhibitors or inducers. The FDA has proposed that the dosage of MVC (300 mg, BID, orally) be adjusted to half or two-fold for patients if it is combined with a major CYP3A4 inhibitor or inducer, respectively. Researchers suggested that the dosage of CVC (50-75 mg, QD, orally) may also need adjustment but the dosage of BMS-663068 (600 mg, BID, orally) does not. The standard, recommended ENF dosage is 90 mg BID, injected subcutaneously for adults, and 2 mg/kg BID, up to a maximum dose of 90 mg, injected subcutaneously for pediatric patients. TNX-355 (10-15 mg/kg, BID, intravenously) and PRO-140(5-10 mg/kg, BID, intravenously; 324 mg, biweekly, subcutaneously) are administered by intravenous infusion or subcutaneous injection.


A single dose of oral vitamin K effectively reverses oral anticoagulation with phenprocoumon during heart catheterisation.
To investigate the effectiveness of a single adjusted dose of oral vitamin K to temporarily reverse oral anticoagulation with phenprocoumon (Marcoumar) for heart catheterisation. Patients under stable oral anticoagulation with phenprocoumon routinely scheduled for heart catheterizstion were given a single adjusted dose of oral vitamin K a day prior to the intervention. The customary anticoagulation scheme was kept unchanged with the exception of taking the double usual dose of phenprocoumon the evening after the intervention. The primary outcome was the achieved international normalised ratio (INR) immediately before the intervention. Secondary outcomes were the INR after one and four weeks, changes in phenprocoumon and coagulation factors II and VII and adverse events. 38 patients at a median age of 71 (63-74) years scheduled for heart catheterisation were included. The median INR changed from 2.2 (1.9-2.6) the day before to 1.5 (1.4-1.7) immediately before the intervention. An INR < or =1.5 respectively < or =1.8 was achieved in 61% and 95% of the patients. The INR values after one respectively four weeks were comparable to preintervention values. No thromboembolic or bleeding adverse events occurred during the study. A single adjusted oral dose of vitamin K given a day prior to heart catheterisation combined with a doubled phenprocoumon dose on the procedure day seems to be an easy applicable, safe and effective way to temporary reverse oral anticoagulation with phenprocoumon.


Analgesic Effects of Intravenous Acetaminophen vs Placebo for Endoscopic Sinus Surgery and Postoperative Pain: A Randomized Clinical Trial.
Intravenous acetaminophen is a commonly prescribed analgesic for the prevention and treatment of postsurgical pain. Its efficacy in the context of endoscopic sinus surgery (ESS) has yielded mixed results. To compare the efficacy of perioperative intravenous acetaminophen (IVAPAP) with that of placebo in improving early postoperative pain after endoscopic sinus surgery (ESS). A prospective, randomized clinical trial including 62 patients undergoing ESS for chronic rhinosinusitis in a single tertiary referral hospital. Participants were randomized to receive 1 g of IVAPAP or 100 mL of placebo consisting of saline infusions immediately before the start of surgery and 4 hours after the initial dose. The primary outcome was postoperative pain measured by visual analog scale (VAS) scores up to 24 hours after surgery by blinded observers. Secondary endpoints included postoperative opioid (intravenous and oral) use and adverse events in the 24-hour postoperative period. Of the 62 enrolled adult participants, 60 were randomized (31 to IVAPAP intervention and 29 to placebo). The mean (SD) age of participants was 53.7 (14.7) years and 35 (58%) of the participants were men and 25 (42%) were women. Within the first hour, mean pain scores were reduced in the IVAPAP group compared with the control group, reaching a maximum difference of 7.7 mm on a VAS scale favoring the treatment group with a true difference possibly as high as 22 mm, and the data are compatible with a clinically meaningful difference. At 12- and 24-hours, average pain scores were less in the placebo group and the data are compatible with a clinically meaningful difference of 5.8 (-5.2 to 16.8) and 8.2 (-1.9 to 18.4), respectively, favoring the placebo group. However, at all time points the CIs included the null value and were wide, thus preventing definitive conclusions. Inspection of the secondary outcomes favored IVAPAP, but the wide range of the CIs and inclusion of the null value prevent definitive conclusions. The results of this study are inconclusive. The data suggest that perioperative intravenous acetaminophen may reduce immediate postoperative pain and opioid requirements compared with placebo and these differences could be clinically meaningful. Unfortunately, the imprecision of the estimates prevents definitive conclusion. Use of IVAPAP does not seem to increase adverse events. clinicaltrials.gov Identifier: NCT01608308.


Employment status changes of workers after referral to an occupational disease clinic.
Occupational diseases (OD) are among the most significant issues of work life, with economic, medical, social, and ethical aspects. The majority of studies concerning OD focus on the causes or medical outcomes of OD. There are a limited number of studies investigating the social and economic impacts of being diagnosed with an OD. One of the important social aspects of OD is the employability of workers after an OD diagnosis. The aim of this study is to evaluate the changes in employment status after the OD diagnosis process. This is a cross sectional study. There were 204 eligible cases, and 198 (97%) completed the study. The study data were obtained from patient files, including OD Committee reports and questionnaires applied via telephone interview. Among the 198 applicants, 170 (85.9%) were male and 146 (73.7%) were diagnosed with an OD. Of these workers, 106 (53.5%) had quit their current jobs. Of those workers, 89 out of 106 were in the OD group, and 17 were in the non-OD group. Diagnosis with OD (OR: 3.1 CI: 1.4-6.8) and non-union membership (OR: 11.1 CI: 5.2-23.5) increased the likelihood of quitting the job after an OD diagnosis. The short-term prognosis of OD was relatively poor. OD diagnosis or even referral to an outpatient clinic may cause quitting the job. Policies should account for the risk of unemployment after an OD diagnosis, and OD surveillance systems should obtain data on the employment status of workers following diagnosis.


Measurement of plasma methoxyamines for the diagnosis of pheochromocytoma.
Urinary methoxyamine determination is considered as the most sensitive and specific parameter for the diagnosis of pheochromocytoma. Since blood sampling is easier to perform, we developed a new HPLC method to assay metanephrine (MN) and normetanephrine (NMN) in plasma. We now report the results for total (free and conjugated) MN and NMN in 22 cases of pheochromocytoma compared to 26 healthy subjects, 33 patients with essential hypertension, 14 with miscellaneous diseases and 4 patients with renal failure. The mean normal values (mean +/- SD) were 0.40 +/- 0.10 ng/ml for MN and 0.85 +/- 0.25 ng/ml for NMN. The sum of MN+NMN was 1.25 +/- 0.28 and the range 0.9-1.9. In essential hypertension, the range of NMN+MN was 1.2-6.0. In the 4 renal failures, both MN and NMN were drastically increased. In 49 samples drawn from 22 pheochromocytomas, MN was elevated over the hypertensive range in 34 samples and NMN in 47 samples. The total MN+NMN ranged from 6.2 to 436 ng/ml; this figure was observed whatever the clinical presentation even in silent tumors or in paroxysmal forms between the crisis. After tumor removal, the values dropped rapidly. In conclusion, plasma determination of MN and NMN provides a highly sensitive and specific biological pointer for the diagnosis of pheochromocytoma in patients without renal failure.


Measuring Speech Intelligibility and Hearing-Aid Benefit Using Everyday Conversational Sentences in Real-World Environments.
Laboratory and clinical-based assessments of speech intelligibility must evolve to better predict real-world speech intelligibility. One way of approaching this goal is to develop speech intelligibility tasks that are more representative of everyday speech communication outside the laboratory. Here, we evaluate speech intelligibility using both a standard sentence recall task based on clear, read speech (BKB sentences), and a sentence recall task consisting of spontaneously produced speech excised from conversations which took place in realistic background noises (ECO-SiN sentences). The sentences were embedded at natural speaking levels in six realistic background noises that differed in their overall level, which resulted in a range of fixed signal-to-noise ratios. Ten young, normal hearing participants took part in the study, along with 20 older participants with a range of levels of hearing loss who were tested with and without hearing-aid amplification. We found that scores were driven by hearing loss and the characteristics of the background noise, as expected, but also strongly by the speech materials. Scores obtained with the more realistic sentences were generally lower than those obtained with the standard sentences, which reduced ceiling effects for the majority of environments/listeners (but introduced floor effects in some cases). Because ceiling and floor effects limit the potential for observing changes in performance, benefits of amplification were highly dependent on the speech materials for a given background noise and participant group. Overall, the more realistic speech task offered a better dynamic range for capturing individual performance and hearing-aid benefit across the range of real-world environments we examined.


Integrated parabolic nanolenses on MicroLED color pixels.
A parabolic nanolens array coupled to the emission of a nanopillar micro-light emitting diode (LED) color pixel is shown to reduce the far field divergence. For a blue wavelength LED, the total emission is 95% collimated within a 0.5 numerical aperture zone, a 3.5x improvement over the same LED without a lens structure. This corresponds to a half-width at half-maximum (HWHM) line width reduction of 2.85 times. Using a resist reflow and etchback procedure, the nanolens array dimensions and parabolic shape are formed. Experimental measurement of the far field emission shows a HWHM linewidth reduction by a factor of 2x, reducing the divergence over the original LED.


Dengue virus-infected human monocytes trigger late activation of caspase-1, which mediates pro-inflammatory IL-1β secretion and pyroptosis.
Dengue virus (DENV) infection affects millions of people annually and has the potential to cause fatal haemorrhagic fever and shock. Although the underlying pathogenesis of severe dengue illness is still unclear, current evidence suggests that severe disease progression has an immunological basis. In this study, we investigated the role of caspase-1 during host-pathogen interactions within DENV-infected human monocytes. Using DENV-infected primary monocytes, we examined caspase-1 at various levels of gene expression and probed for potential immune consequences mediated by caspase-1 such as secretion of pro-inflammatory IL-1β and pyroptotic cell death. We report that DENV-infected monocytes upregulated functional caspase-1 mRNA and pro-caspase-1 activation as a late response to infection. In addition, we found that caspase-1 is responsible for IL-1β secretion and pyroptosis of DENV-infected monocytes. Together, our results show that late caspase-1 activation within DENV-infected monocytes can contribute to pro-inflammatory outcomes that might play a role in dengue immunopathogenesis.


[Anxiety and Polymorphism Val66Met of BDNF gene Predictors of Depression Severity in Ischemic Heart Disease].
In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular- genetic factors (polymorphism of brain-derived neirotrophic factor - BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-Item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It was shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression.


Estrus response and fertility of Menz and crossbred ewes to single prostaglandin injection protocol.
Natural lambing in sheep in Ethiopia occurs throughout the year in a scattered manner negatively affecting survival and growth rates of the lambs born during the unfavorable season of the year. Thus, controlling the time of mating artificially using exogenous source of hormones is considered as one of the ways to mitigated problems related to haphazard lambing. To this end, an experiment was conducted to evaluate efficacy of prostaglandin-based estrus synchronization protocol in local and crossbred ewes. A total of 160 ewes (80 local and 80 crossbreds) which lambed at least once and aged 3-5 years were used. Lutalyse® (dinoprost tromethamine sterile solution equivalent to 5 mg dinoprost per ml) and its analog, Synchromate® (cloprostenol sodium equivalent to 0.250 mg cloprostenol per ml), were tested at different doses. The treatments used were intramuscular injection of (1) 2.50 ml of Lutalyse® (12.5 mg dinoprost tromethamine), (2) 2 ml of Lutalyse® (10.0 mg dinoprost tromethamine), (3) 1 ml of Synchromate® (0.25 mg of cloprostenol Sodium), and (4) 0.8 ml of Synchromate® (0.20 mg of cloprostenol Sodium). Forty ewes (20 local and 20 crossbreds) were allocated per treatment. Following injection of the respective hormones, rams of known fertility were introduced into the flock for the duration of 96 h at the ratio of one ram to 10 ewes. All estrus synchronization protocols except treatment 4 (0.8 ml of Synchromate®) induced estrus (heat) in majority (55-65%) of local and crossbred ewes within 96 h post-hormone injection. The time interval from hormone administration to onset of estrus was also more or less similar for all treatment groups except for treatment group 4 which showed heat quicker. The highest lambing rate was recorded in local ewes (84.62% (11/13) treated with 2.5 ml of Lutalyse®, whereas the least was obtained in crossbreds (33.33% (3/9) treated with 0.8 ml Synchromate®. In conclusion, even though 2.5 ml and 2 ml of Lutalyse® or 1 ml of Synchromate® were able to induce heat in majority of local and crossbred ewes, the highest lambing percentage was obtained from ewes treated with 2.5 ml of Lutalyse®. Therefore, the use of 2.5 ml Lutalyse® is recommended to synchronize estrus in local and crossbred ewes under Ethiopian smallholder sheep production system for the benefit of improved lambing rate.


Proliferative activity of Echinacea angustifolia root extracts on cancer cells: Interference with doxorubicin cytotoxicity.
Doxorubicin is an anticancer drug that causes apoptosis in cells, but cardiotoxicity limits the cumulative dose that can remain in the blood. Echinacea extracts have been prescribed to supplement cancer chemotherapy. In a recent study, it was reported that Echinacea purpurea extracts protected noncancerous cells from apoptosis. Our study aimed to determine interference with doxorubicin chemotherapy, and if fractions and compounds from Echinacea angustifolia roots protected the cells. Cervical and breast cancer cells were treated with the Echinacea samples and doxorubicin. At 0.05 and 0.5 microM doxorubicin concentration, cynarine increased HeLa cell growth by 48-125% and 29-101%, respectively (p<0.01). At 0.05 microM doxorubicin concentration, chicoric acid increased cell growth by 23-100% (p<0.01). When MCF-7 cells were treated with Echinacea and doxorubicin, the ethyl acetate fraction increased cell growth by 20-25%, and chicoric acid increased cell growth by 10-15%. Cynarine showed proliferative activity on HeLa cells, but showed antiproliferative activity on MCF-7 cells. Results indicate that phenolic compounds are responsible for proliferative activity. Studies with individual compounds show that chicoric acid and cynarine interfered with cells treated with 0.5 microM doxorubicin. The results of this study show that Echinacea herbal medicines affect cell proliferation despite cancer treatment, and that herbal medicines require further study with respect to anticancer drugs.


[Cystosarcoma phyllodes of the lacteal glands].
Thirty-three cases of phyllode cystosarcoma were diagnosed in the course of 21 years at the Tumour Department of the Berlin School of Medicine (Charité). Ten of them were found to be in sarcomatous degeneration. Metastasation was positively established in four of these ten cases, and locally delimited recurrences were recorded from two. Metastasation in cases of phyllode cystosarcoma has been found to occur rarely through regional lymph nodes. Therefore, routine removal of those lymph nodes is not considered necessary.


Infection Masquerading As Spontaneous Tumor Lysis Syndrome.
Tumor lysis syndrome (TLS) is a life-threatening condition due to malignant tumor cell lysis resulting in severe metabolic derangements that require prompt recognition and management to prevent progression to end-organ damage and death. This case describes a patient presenting with clinical and laboratory abnormalities complicated by multi-organ dysfunction concerning spontaneous TLS from a suspected undiagnosed malignancy. The patient had an unremarkable malignancy workup and was ultimately diagnosed with endocarditis, which improved with treatment of the infection. Therefore, this case demonstrates that systemic infections may rarely present with metabolic abnormalities and multi-organ dysfunction resembling spontaneous TLS.


Down-regulation of pro-apoptotic genes is an early event in the progression of malignant melanoma.
Down-regulation of apoptosis genes has been implicated in the development and progression of malignant melanoma. We used cDNA microarray to evaluate pro-apoptotic gene expression comparing normal skin to melanoma (thin and thick), nodal disease and distant metastases. Twenty-eight specimens including skin (n = 1), thin melanoma (n = 6), thick melanoma (n = 7), nodal disease (n = 6), and distant metastases (n = 8), were harvested at the time of resection from 16 individuals. RNA was isolated and microarray analysis utilizing the Affymetrix GeneChip (54,000 genetic elements, U133A+B... levels) was performed. Mean level of expression was calculated for each gene within a sample group. Expression profiles were then compared between tissue groups. Student's t-test was used to determine variance in expression between groups. We reviewed the expression of 54,000 genetic elements, of which 2,015 were found to have significantly altered expression. This represents 1,602 genes. Twenty-two pro-apoptotic genes were found to be down-regulated when compared to normal skin. Overall reduction was evaluated comparing normal skin to metastases with a range of 3.31-64.04-fold-decrease. When comparing the tissue types sequentially, the greatest fold-decrease in gene expression occurred when comparing skin to all melanomas (thin and thick) (p = 0.011). Subset analysis comparing normal skin to thin melanoma or thick melanoma, revealed the greatest component of overall reduction at the transition from thin to thick lesions (p = 0.003). Sequential down-regulation of pro-apoptotic genes is associated with the progression of malignant melanoma. The greatest fold-decrease occurs in the transformation from thin to thick lesions.


SEC23B is required for pancreatic acinar cell function in adult mice.
Mice with germline absence of SEC23B die perinatally, exhibiting massive pancreatic degeneration. We generated mice with tamoxifen-inducible, pancreatic acinar cell-specific Sec23b deletion. Inactivation of Sec23b exclusively in the pancreatic acinar cells of adult mice results in decreased overall pancreatic weights from pancreatic cell loss (decreased pancreatic DNA, RNA, and total protein content), as well as degeneration of exocrine cells, decreased zymogen granules, and alterations in the endoplasmic reticulum (ER), ranging from vesicular ER to markedly expanded cisternae with accumulation of moderate-density content or intracisternal granules. Acinar Sec23b deletion results in induction of ER stress and increased apoptosis in the pancreas, potentially explaining the loss of pancreatic cells and decreased pancreatic weight. These findings demonstrate that SEC23B is required for normal function of pancreatic acinar cells in adult mice.


Divalent metal ion coordination by residue T118 of anthrax toxin receptor 2 is not essential for protective antigen binding.
The protective antigen (PA) subunit of anthrax toxin interacts with the integrin-like I domains of either of two cellular receptors, ANTXR1 or ANTXR2. These I domains contain a metal ion-dependent adhesion site (MIDAS) made up of five non-consecutive amino acid residues that coordinate a divalent metal ion that is important for PA-binding. The MIDAS residues of integrin I domains shift depending upon whether the domain exists in a closed (ligand-unbound) or open (ligand-bound) conformation. Of relevance to this study, the MIDAS threonine residue coordinates the metal ion only in the open I domain conformation. Previously it was shown that the MIDAS threonine is essential for PA interaction with ANTXR1, a result consistent with the requirement that the I domain of that receptor adopts an open conformation for PA-binding. Here we have tested the requirement for the MIDAS threonine of ANTXR2 for PA-binding. We show that the toxin can bind to a mutant receptor lacking the MIDAS threonine and that it can use that mutant receptor to intoxicate cultured cells. These findings suggest that an open-like configuration of the ANTXR2 MIDAS is not essential for the interaction with PA.


The use of patient-specific measurement instruments in the process of goal-setting: a systematic review of available instruments and their feasibility.
The aim of this study was to identify the currently available patient-specific measurement instruments used in the process of goal-setting and to assess their feasibility. After a systematic search in PubMed, EMBASE, CINAHL, PsychINFO and REHABDATA, patient-specific instruments were included, structured in a goal-setting practice framework and subjected to a qualitative thematic analysis of feasibility. A total of 25 patient-specific instruments were identified and 11 were included. These instruments can be used for goal negotiation, goal-setting and evaluation. Each instrument has its own strengths and weaknesses during the different phases of the goal-setting process. Objective feasibility data were revealed for all instruments such as administration time, instruction, training and availability. Subjective feasibility could only be analysed for the Canadian Occupational Performance Measure, Goal Attainment Scaling, Self-Identified Goal Assessment and Talking Mats. Relevant themes were that Canadian Occupational Performance Measure and Goal Attainment Scaling were time consuming and difficult for patients with cognitive problems, but they facilitated goal-setting in a client-centred approach. Talking Mats was especially feasible for patients with cognitive and communication impairments. A total of 11 instruments were identified, and although some had strong points, there is no single good instrument that can be recommended specifically. Applying a combination of the strengths of the available instruments within a goal-setting framework can improve goal setting and tailor it to individual patients.


Signal transduction of erbB receptors in trastuzumab (Herceptin) sensitive and resistant cell lines: local stimulation using magnetic microspheres as assessed by quantitative digital microscopy.
ErbB2 (HER-2), a member of the epidermal growth factor (EGF) receptor family, is a class I transmembrane receptor tyrosine kinase. Although erbB2 has no known physiologic ligand, it can form complexes with other members of the family and undergo transactivation of its very potent kinase activity, thereby initiating downstream signaling and cell proliferation. ErbB2 is a frequent pathologic marker in ductal invasive breast carcinomas and is targeted by using a specific humanized monoclonal antibody, trastuzumab (Herceptin). The antibody is effective in only 20% to 50% of erbB2-positive tumors, and this resistance, as yet poorly understood, constitutes a major therapeutic challenge. Magnetic microspheres coated with ligands or antibodies are widely used for separation of proteins and cells and allow localized, high intensity, and precisely timed stimulation of cells. We used EGF- and trastuzumab-covered paramagnetic microspheres, quantitative confocal laser scanning microscopy, and digital image processing to investigate the (trans)activation of and local signal propagation from erbB1 and erbB2 on trastuzumab sensitive and resistant carcinoma cell lines expressing these receptors at high levels. On A431 cells expressing high levels of endogenous erbB1 and transfected erbB2-mYFP (A4-erbB2-mYFP F4 cell line), EGF-coupled-microspheres activated erbB1 and transactivated erbB2-mYFP. In two other cell lines with comparable erbB2 expression but lower levels of erbB1, EGF microspheres transactivated erbB2 less efficiently. Trastuzumab in solution activated erbB2 on A4-erbB2-mYFP and the trastuzumab sensitive SKBR-3 cells, but only negligibly on the resistant JIMT-1 cells that showed a 10 times higher K(d) for the antibody. Nevertheless, pronounced erbB2 activation and tyrosine phosphorylation could be detected after stimulation with trastuzumab-coupled microspheres in all cell lines, although transactivation of erbB1 was negligible. Receptor phosphorylation was restricted to the immediate proximity of the microspheres, i.e., receptor clusters external to these locations remained inactive. ErbB1 ligand and erbB2 specific antibody attached to magnetic microspheres are efficient tools in assessing erbB activation, localized signal propagation, and erbB heterodimer formation. Trastuzumab coupled to microspheres is more efficient at accessing erbB2 and activating it than trastuzumab in solution.


Calcitonin Gene-Related Peptide Improves Hypoxia-Induced Inflammation and Apoptosis via Nitric Oxide in H9c2 Cardiomyoblast Cells.
The aim of this work was to investigate whether calcitonin gene-related peptide (CGRP) plays a protective role in cardiomyocytes against hypoxia-induced inflammation and apoptosis via an NO-mediated pathway. H9c2 cardiac cells were exposed to hypoxia for 2 h to establish a model of myocardial hypoxic-ischemic injury. The cells were pretreated with either CGRP or nitric oxide synthase (NOS) inhibitor (L-NAME) before being exposed to hypoxia for 30 min. Cell viability was analyzed using a cell counter kit 8 (CCK-8). The levels of IL-6 and TNF-α were determined by the corresponding enzyme-linked immunosorbent assay. The expression levels of several apoptosis proteins (p53, caspase-3, cytochrome C) and NOS were detected by Western blot assays. An NO kit was used to evaluate the production of NO. Pretreatment of H9c2 cardiac cells with CGRP for 30 min prior to exposure to hypoxia markedly improved cell viability (83.57 ± 3.21 vs. 62.83 ± 8.30%, p < 0.001); the same effect was observed following pretreatment with the NOS inhibitor L-NAME (89.34 ± 5.95 vs. 75.01 ± 5.61%, p < 0.01). Pretreatment with CGRP also significantly attenuated the inflammatory responses induced by hypoxia, as evidenced by decreases of the levels of both IL-6 (193.21 ± 13.54 vs. 293.38 ± 56.49%, p < 0.001) and TNF-α (207.71 ± 44.27 vs. 281.46 ± 64.88%, p < 0.001). Additionally, CGRP significantly decreased the hypoxia-induced overexpression of the apoptotic proteins (p53: 0.27 ± 0.10 vs. 0.87 ± 0.30, p < 0.001; caspase-3: 0.65 ± 0.15 vs. 0.98 ± 0.26, p < 0.001; cytochrome C: 1.51 ± 0.39 vs. 2.80 ± 0.69, p < 0.001) and enhanced the expression of both endothelial NOS (eNOS; 0.59 ± 0.24 vs. 0.37 ± 0.14, p < 0.05) and phosphorylated eNOS (0.60 ± 0.13 vs. 0.40 ± 0.07, p < 0.05). Furthermore, the application of both L-NAME and CGRP attenuated the hypoxia-induced expression of inducible NOS (iNOS; p < 0.05) and enhanced a hypoxia-mediated decrease in NO (p < 0.01). Interestingly, the expression levels of cell apoptosis (p < 0.05), iNOS and eNOS (p < 0.05) were decreased with L-NAME and CGRP cotreatment following 2 h of acute hypoxia, but the apoptotic factors (p < 0.05) were increased compared with only CGRP pretreatment. CGRP protects cardiomyocytes from hypoxia-induced inflammation and apoptosis by modulating NO production.


Stability of benefits of mime therapy in sequelae of facial nerve paresis during a 1-year period.
To assess the stability of benefits of mime therapy, a modality of physiotherapy for patients with facial nerve paresis, during a period of 1 year. A prospective follow-up build on a randomized clinical trial in which a treatment group is compared with a control group. Physiotherapy outpatient department. Forty-eight patients with a history of a facial nerve paresis of 9 months or more. Mime therapy. Sequelae of facial nerve paresis were measured using the same measurement instruments as in the randomized clinical trial--the Sunnybrook and the House-Brackmann (HB) Facial Grading Systems, the lip length and pout indices, a stiffness scale, and the Facial Disability Index. Stability of outcome level and of interpatient differences is analyzed. Of the 46 patients who completed the follow-ups, repeated-measures analyses of covariance revealed no significant differences in the average scores nor significant trends of the posttherapy measurements, except for the pout index and the Facial Disability Index-social. For six sequelae (except HB), 95% of patient-sequel combinations showed immediate improvement after mime therapy, for HB grades this was 74%. Where sequelae improved, the posttherapy individual courses (T2-T3-T4) showed, also for HB, in majority absence of deterioration; benefits obtained were stable. Mime therapy is effective in patients with facial nerve paresis and benefits are stable 1 year after therapy.


Design of compact Marx module with square pulse output.
Compact pulsed power system based on compact Marx generator is widely used in terms of drive resistance and capacitive loads. This system usually adopts high performance components such as high energy density capacitors, compact switches, and integrated structure. Traditional compact Marx generator can only output double-exponential pulse profile. In this paper a compact, low-impedance Marx module which can output rectangular pulse profile is design and tested. This module has multiple circuits of different discharge frequencies in parallel to generate quasi-rectangular pulse. Discharge characteristic of an ideal module with infinite branches is calculated theoretically. A module with two branches has been designed and tested. Test results show that the impedance of the module is 1.2 Ω. When charging voltage is 100.6 kV and load resistance is 1 Ω, the peak output pulse is 45.2 kV voltage, the peak power is about 2 GW, the pulse width is about 130 ns, and the rise time is about 35 ns. The energy density and power density of the module are 15 kJ/m(3) and 140 GW/m(3), respectively.


Binding of monosodium urate crystals with idiotype protein efficiently promote dendritic cells to induce cytotoxic T cells.
Monosodium urate (MSU) crystals have been reported to evoke specific cell immunity and to work as an adjuvant in a mouse model. The crystals also have another unique characteristic to bind with positively charged proteins, which could help to deliver some antigens into human dendritic cells (DC). We focused on the application of MSU crystals as not only an adjuvant but also as a carrier of positively charged antigenic protein to induce human cytotoxic T cells (CTL) efficiently in vitro. We selected human leukocyte antigen (HLA)-A2 expressing the multiple myeloma IM-9 cell line and its product idiotype (Id) protein as one of the best pairs of target cells and positively charged tumor-specific antigen, respectively. Following the sensitization of DC derived from HLA-A2-positive volunteers pulsed with tumor-specific monoclonal immunoglobulin G-Fab fragments (IM-9 Fab) attached to MSU crystals, the DC-stimulated CD8(+) T cells killed significantly more target cells (40.1 +/- 1.7%) than those stimulated by DC pulsed with MSU crystals alone (6.2 +/- 8.6%, P < 0.01) or IM-9 Fab alone (4.7 +/- 8.1%, P < 0.01). These cytotoxic effects of the DC-stimulated CD8(+) cells were reduced when MSU crystals were precoated with fetal bovine serum. In addition, we confirmed that MSU crystals facilitated human DC to express the maturation marker, CD83 and deliver (Fab')(2), attaching to the crystals by flow cytometer analysis. MSU crystals have distinct advantages of a protein carrier binding with positively charged proteins and delivering antigenic protein into DC, as well as an adjuvant promoting DC maturation and inducing CTL.


Corticosterone increases FGF-2 (bFGF) immunoreactivity in the substantia nigra of the rat.
The effects of acute and subchronic (7 days) administrations of the adrenocortical hormone corticosterone on basic fibroblast growth factor (bFGF, FGF-2) immunoreactivity were studied in the substantia nigra of the rat by semiquantitative immunocytochemistry coupled with image analysis. Corticosterone was able to increase FGF-2 immunoreactivity in different nigral subregions and cell types (astrocytes and neurones) depending on the duration of the treatment. These results open up the possibility that stress hormones can modulate the trophic state of the substantia nigra through an action on FGF-2.


Radiographic changes of chronic recurrent multifocal osteomyelitis that persisted into adulthood.
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare non-infectious autoinflammatory disorder typically seen in young women. We describe the case of a young man who presented at 13 years of age with pain in the tibia, humerus, clavicle and hip. Worsening of the condition through clinical presentation and radiographic imaging was observed over 10 years. Radiographic imaging initially showed some sclerotic changes, but worsened to osteolytic lesions of the proximal tibia, elevation of the lateral cortex and thickening of the anterior cortex. Bone biopsy of his right anterior proximal tibia showed no infection or neoplasia. But, laboratory results showed elevation of inflammatory markers such as erythrocyte sedimentation rate or C-reactive protein. The patient was diagnosed with CRMO and treated with antibiotics for suspicion of chronic bacterial osteomyelitis. Chronic bone pain, abnormal imaging and elevation of inflammatory markers suggesting that chronic bacterial osteomyelitis can lead to difficulties with the diagnosis of CRMO.


The importance of residential dusk and dawn light exposure for sleep quality, health, and well-being.
Light exposure during twilight plays a critical role in the entrainment of the human circadian system. People are most often at home during dusk and dawn, and light exposure at home - either natural or from electric light - may therefore contribute substantially to sleep and well-being. However, very little research has focused on the effects of home lighting on sleep and well-being, and even less research has investigated the effects of light exposure during twilight. Therefore, a literature study was performed to collect studies on light exposure at home during dusk and dawn. Studies looking at light exposure during dusk and dawn have focused on either electric light intervention (i.e., dusk and dawn simulation) at home or in the laboratory or daylight exposure in the bedroom (i.e., the presence and type of curtains in the bedroom). Most research has focused on dawn simulation during the darker months of the year, often using sunrise alarms. In general, study results pointed to the importance of twilight light exposure at home for sleep and well-being. These results may depend on the characteristics of the user, such as age or chronotype.


The pre-Columbian introduction and dispersal of Algarrobo (Prosopis, Section Algarobia) in the Atacama Desert of northern Chile.
Archaeological and palaeoecological studies throughout the Americas have documented widespread landscape and environmental transformation during the pre-Columbian era. The highly dynamic Formative (or Neolithic) period in northern Chile (ca. 3700-1550 yr BP) brought about the local establishment of agriculture, introduction of new crops (maize, quinoa, manioc, beans, etc.) along with a major population increase, new emergent villages and technological innovations. Even trees such as the Algarrobos (Prosopis section Algarobia) may have been part of this transformation. Here, we provide evidence that these species were not native to the Atacama Desert of Chile (18-27°S), appearing only in the late Holocene and most likely due to human actions. We assembled a database composed of 41 taxon specific AMS radiocarbon dates from archaeobotanical and palaeoecological records (rodent middens, leaf litter deposits), as well an extensive bibliographical review comprising archaeobotanical, paleoecological, phylogenetic and taxonomic data to evaluate the chronology of introduction and dispersal of these trees. Although Algarrobos could have appeared as early as 4200 yr BP in northernmost Chile, they only became common throughout the Atacama over a thousand years later, during and after the Formative period. Cultural and natural factors likely contributed to its spread and consolidation as a major silvicultural resource.


Multiple Beau's lines due to dysmenorrhoea?
Four young women who complained of nail ridging, were found to have several evenly spaced Beau's lines. The lines appear to be related to their menstrual cycles and each one had severe dysmenorrhoea. Linear nail growth was not impaired.


Oxygen delivery to the heart and brain during hypoxia: Pekin duck vs. bar-headed goose.
To investigate mechanisms that may allow birds to tolerate extreme high altitude, we acutely exposed unanesthetized bar-headed geese (Anser indicus) and Pekin ducks (Anas platyrhynchos) to 0.21, 0.10, and 0.05 inspired fractional concentrations of O2 (FIO2). In both birds, arterial O2 partial pressure (PaO2) was about 95 Torr at 0.21 FIO2, 45 Torr at 0.10 FIO2, and 28 Torr at 0.05 FIO2. Hyperventilation occurred at both levels of hypoxia, with PaCO2 decreasing to about 7 Torr at 28 Torr PaO2. At 28 Torr PaO2, arterial O2 content (CaO2) in geese (10.4 vol%) was significantly higher than in ducks (4.1 vol%). As PaO2 declined from about 95 to 28 Torr, both cerebral and coronary blood flow (determined by using the radioactive microsphere method) increased more than fivefold in ducks but less than threefold in geese. At both levels of hypoxia, O2 delivery (flow X CaO2) to the heart and brain of geese was the same as or higher than that of ducks. The unique control of cerebral and coronary O2 delivery exhibited by both species of birds may be related to their remarkable tolerance to severe hypocapnic hypoxia.


β-Amyrin oxidation by oat CYP51H10 expressed heterologously in yeast cells: the first example of CYP51-dependent metabolism other than the 14-demethylation of sterol precursors.
CYP51 has been recognized as a unique CYP family that consists of one isolated molecular species, a sterol 14-demethylase essential for sterol biosynthesis. However, another CYP51 gene classified as the CYP51H subfamily has been identified in higher plants, in addition to a sterol 14-demethylase gene, CYP51G1. To shed light on the function of this "second CYP51", oat CYP51H10 was introduced into the β-amyrin-producing yeast cells, and the effect of the expressed CYP51H10 on β-amyrin metabolism in the host cells was examined. In the CYP51H10-introduced cells, β-amyrin was converted to a metabolite with 12,13-epoxy and one additional hydroxyl group. Since the 12,13-epoxy group introduced into β-amyrin ring is an essential structure of avenacin A-1, a triterpene glycoside produced in oat from β-amyrin, the present findings indicate the contribution of CYP51H10 to avenacin A-1 biosynthesis from β-amyrin. This is the first study showing a second function of the CYP51 family.


Effect of consecutive intragastric balloon (BIB®) plus diet versus single BIB® plus diet on eating disorders not otherwise specified (EDNOS) in obese patients.
Eating disorders are a group of conditions characterised by abnormal eating habits. Greater than 50 % of patients with eating disorders have an 'eating disorder not otherwise specified' (EDNOS). No specific tools exist to evaluate EDNOS, and patients are identified only with a diagnosis of exclusion from the other eating disorders. The BioEnterics® Intragastric Balloon (BIB®) is used worldwide as a short-term treatment option in obese patients. A new frequency score was used to evaluate the influence of double consecutive BIB® treatment compared with single BIB® treatment followed by diet on four categories of EDNOS (grazing, emotional eating, sweet-eating and after-dinner grazing). A prospective study allocated 50 obese patients (age range 25-35, BMI range 40.0-44.9) into two groups: BIB® (6 months) followed by diet therapy (7 months; group A (N = 25)) and BIB® placement for 6 months followed by another BIB® for 6 months, with a 1-month interval between placement (group B (N = 25)). Baseline demographics were similar across both groups. At the time of removal of the first BIB® device, EDNOS scores in both groups were not significantly different, but decreased significantly from baseline. By the end of the study, all EDNOS scores were significantly lower in patients undergoing consecutive BIB®, compared with single BIB® followed by diet therapy. The placement of an intragastric balloon in obese patients allows for a reduction in the intensity of grazing, emotional eating, sweet-eating and after-dinner grazing. A more significant reduction in the EDNOS score was observed with two consecutive BIBs®.


Long-chain polyunsaturated fatty acids in the sn-2 position of phosphatidylcholine decrease the stability of recombinant high density lipoprotein apolipoprotein A-I and the activation energy of the lecithin:cholesterol acyltransferase reaction.
The lecithin:cholesterol acyltransferase (LCAT) kinetics and activation energy and the stability of apolipoprotein A-I (apoA-I) were investigated using recombinant HDL (rHDL) containing phosphatidylcholine (PC), [3H]cholesterol, and apo A-I. The PC component of the rHDL contained sn-1 16:0 and sn-2 18:1 (POPC), 20:4 (PAPC), 20:5 n-3 (PEPC), or 22:6 n-3 (PDPC) or 10% of the respective PC species and 90% sn-1 18:1, sn-2 16:0 PC ether (OPPC ether). The appVmax of the rHDL containing 100% PC varied 10-fold and was ordered POPC > PEPC > PAPC > PDPC, whereas the appKm values varied 19-43 microns PC. The ether-containing rHDL had appVmax values 17-40% of their respective 100% PC rHDL, but maintained the same rank order. The activation energy of LCAT was lower for rHDL containing long chain polyunsaturated fatty acids (PUFA) compared to rHDL containing 100% POPC or 10% PC/90% OPPC ether. The concentration of guanidine HCl (D1/2) required to denature one-half of the apoA-I on rHDL containing long chain PUFA was reduced (1.2-16 M) compared to those containing 100% POPC or 10% PC/90% OPPC (2.2-2.4 M) and there was a strong correlation (r = 0.71) between LCAT activation energy and the stability of apoA-I (i.e., D1/2). We conclude that long chain PUFA in the sn-2 position of PC decreases the catalytic efficiency of LCAT, the activation energy of the LCAT reaction and the stability of apoA-I on the rHDL particles. The strong association between rHDL apoA-I stability and LCAT activation energy suggests that the temperature-dependent step of the LCAT reaction may be sensitive to the strength of the interaction of apoA-I with rHDL PC.


The challenge of using experimental infectivity data in risk assessment for Ebola virus: why ecology may be important.
Analysis of published data shows that experimental passaging of Zaire ebolavirus (EBOV) in guinea pigs changes the risk of infection per plaque-forming unit (PFU), increasing infectivity to some species while decreasing infectivity to others. Thus, a PFU of monkey-adapted EBOV is 10(7) -fold more lethal to mice than a PFU adapted to guinea pigs. The first conclusion is that the infectivity of EBOV to humans may depend on the identity of the donor species itself and, on the basis of limited epidemiological data, the question is raised as to whether bat-adapted EBOV is less infectious to humans than nonhuman primate (NHP)-adapted EBOV. Wildlife species such as bats, duikers and NHPs are naturally infected by EBOV through different species giving rise to EBOV with different wildlife species-passage histories (heritages). Based on the ecology of these wildlife species, three broad 'types' of EBOV-infected bushmeat are postulated reflecting differences in the number of passages within a given species, and hence the degree of adaptation of the EBOV present. The second conclusion is that the prior species-transmission chain may affect the infectivity to humans per PFU for EBOV from individuals of the same species. This is supported by the finding that the related Marburg marburgvirus requires ten passages in mice to fully adapt. It is even possible that the evolutionary trajectory of EBOV could vary in individuals of the same species giving rise to variants which are more or less virulent to humans and that the probability of a given trajectory is related to the heritage. Overall the ecology of the donor species (e.g. dog or bushmeat species) at the level of the individual animal itself may determine the risk of infection per PFU to humans reflecting the heritage of the virus and may contribute to the sporadic nature of EBOV outbreaks.


Outcome following ECT for primary unipolar depression: a test of newly proposed response predictors.
This study considered dexamethasone suppression test (DST) results, Winokur 's familial subtyping, and the presence or absence of melancholia according to DSM-III criteria as potential predictors of response to ECT. Familial subtype and DST results independently predicted outcome after ECT, but melancholia did not. Relationships between outcome and several other traditional items tested for comparison generally agreed with those in earlier studies. The pattern of significant predictors varied considerably depending on outcome measure--Hamilton depression score at discharge, global rating at discharge, or symptom score during a 6-month follow-up--which may explain some of the discrepancies between results of earlier predictor studies.


Prognostic significance of pretreatment serum levels of albumin, LDH and total bilirubin in patients with non-metastatic breast cancer.
Liver function tests (LFTs) have been reported as independent predictors of non-liver disease-related morbidity and mortality in general population and cancer patients. In this study, we evaluated the relationship between pretreatment serum LFTs and overall survival (OS) in non-metastatic Caucasian breast cancer patients. Seven LFTs, including albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase (LDH), total bilirubin and total protein, were measured in pretreatment serum from 2425 female Caucasian patients with newly diagnosed, histologically confirmed non-metastatic invasive breast cancer. Multivariate Cox model was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for the association of individual LFTs with 5-year OS while adjusting for age, smoking status, pathological characteristics and treatment regimen. We found that serum albumin, LDH and total bilirubin were significantly associated with 5-year OS in multivariate Cox analyses. Patients with higher albumin level exhibited 45% reduced risk of death (HR = 0.55, 95% CI: 0.40-0.75) compared with those with lower albumin level. Patients with higher total bilirubin level had a nearly 40% reduction in the risk of death (HR = 0.62, 95% CI: 0.45-0.85) and patients with higher LDH levels had a 1.42-fold increased risk of death (HR = 1.42, 95% CI: 1.08-1.88). Furthermore, cumulative analysis showed a significant dose-response trend of significantly increasing risk of death with increasing number of unfavorable LFT levels. Our result highlighted the potential of using pretreatment serum levels of albumin, LDH and total bilirubin as prognostic factors for OS in patients with non-metastatic breast cancer.


MR imaging of cardiac tumors.
Magnetic resonance (MR) imaging is an important tool in the evaluation of cardiac neoplasms. T1-weighted, T2-weighted, and gadolinium-enhanced sequences are used for anatomic definition and tissue characterization, whereas cine gradient-echo imaging is used to assess functional effects. Recent improvements in pulse sequences for cardiac MR imaging have led to superior image quality, with reduced motion artifact and improved signal-to-noise ratio and tissue contrast. Although there is some overlap in the MR imaging appearances of cardiac tumors, particularly of primary malignancies, differences in characteristic locations and features should allow confident differentiation between benign and malignant tumors. Indicators of malignancy at MR imaging are invasive behavior, involvement of the right side of the heart or the pericardium, tissue inhomogeneity, diameter greater than 5 cm, and enhancement after administration of gadolinium contrast material (as a result of higher tissue vascularity). Concomitant pericardial or pleural effusions are rare in benign processes but occur in about 50% of cases of malignant tumors. MR imaging offers improved resolution, a larger field of view, and superior soft-tissue contrast compared with those of echocardiography, suggesting that knowledge of the MR imaging features of cardiac neoplasms is important for accurate diagnosis and management.


Macrophages and microcirculation in regressed and partially regressed irradiated choroidal and ciliary body melanomas.
To investigate how tumour-infiltrating macrophages and microcirculation attributes of uveal melanomas regressed after brachytherapy and whether primarily enucleated melanomas differ. A case-control analysis of 34 matched pairs of irradiated and nonirradiated choroidal and ciliary body melanomas with main outcome variables being area of necrosis, extravascular matrix loops and networks, tumour-infiltrating macrophages in nonnecrotic areas identified with mAb PG-M1 to the CD68 epitope, and microvascular density (MVD) determined by mAb QBEND/10 to the CD34 epitope. Comparison of primarily enucleated eyes to eyes with irradiated, secondarily enucleated melanomas revealed significantly more necrosis (median difference, +9%, P = 0.0012) and lower MVD (median difference, -10 counts/0.313 mm(2), P = 0.011) in the latter. In eyes managed with brachytherapy, loops and networks tended to be less frequent (P = 0.077). Number and type of macrophages were similarly distributed, being moderate to high in about 95% (P = 0.67) of the matched pairs, and intermediate to dendritic in 79% (P = 0.90). In the irradiated eyes, presence of epithelioid cells and the number and type of macrophages showed no association with microcirculation attributes, whereas in the primarily enucleated tumours, high number of macrophages was associated with high MVD (P < 0.001). This study suggests that regression after brachytherapy reduces MVD. The difference cannot be attributed to different numbers of tumour-infiltrating macrophages and different cell type in nonnecrotic areas of the tumour.


[Neovascularization after ischemic stroke].
After ischemic stroke, there is neovascularization around the infarcted area, which is called penumbra. Angiogenesis and arteriogenesis are responsible for the new vessel formation. Until recently, vasculogenesis has been proved to involve mechanisms in postischemic neovascularization, which was thought to be restricted to embryonic development. New blood vessels' formation is a complex pathologic process after ischemic stroke, in which many factors are properly involved. There are factors stimulating neovascularization, such as vascular endothelial growth factor, platelet-derived growth factor, basic fibroblast growth factor and angiopoietin; there are also factors inhibiting neovascularization, such as thrombospondin. Functional recovery was found after stroke, which may contribute to angiogensis in the periinfarct tissue. Thus, therapeutic angiogenesis has been initially studied in animal models, but there is still a long way to go for therapeutic angiogenesis to be used in the treatment of stroke patient.


Comparison of the Modified Transtibial Technique, Anteromedial Portal Technique and Outside-in Technique in ACL Reconstruction.
To compare clinical and radiographic results of anterior cruciate ligament (ACL) reconstruction using modified transtibial technique (mTT), anteromedial (AM) portal technique and outside-in (OI) technique. From March 2007 to December 2012, ACL reconstruction was performed using the mTT, AM portal technique and OI technique in 20 patients each. Anteroposterior and rotational stability were assessed using the GNRB arthrometer and pivot-shift test. Femoral tunnel obliquity was measured on the anteroposterior and lateral radiographs. Tegner score, Lysholm score, International Knee Documentation Committee score, pivot-shift test were improved at final follow-up in all three groups. However, statistical difference was not shown. Side-to-side difference in GNRB arthrometer was average of 1.4 mm, 1.0 mm and 0.9 mm in mTT, AM and OI group, showing the signicant difference between mTT and AM/OI groups (p<0.001). The mean femoral tunnel obliquity was 56.4° in the mTT group, 39.4° in the AM group and 33.6° in the OI group, showing significant intergroup difference (p<0.001). It showed the significant difference among three groups (p<0.001). Clinical results were improved in all three groups. Femoral tunnel obliquity in AM and OI were more horizontal on the coronal plane. They are thought to have more benefits in oblique positioning of the grafted ACL in rotational stability; however, there was no significant difference among three techniques in pivot-shift test to assess the rotational stability in this study.


Detection of bcl-2 rearrangement in mucosa-associated lymphoid tissue lymphomas from patients with hepatitis C virus infection.
It has been shown that t(14;18)(q32;q21) involving fusion of IGH with MALT1 occurs frequently in mucosa-associated lymphoid tissue (MALT) lymphomas. Results of the present study indicate that the classical form of t(14;18)(q32;q21) involving fusion of IGH with bcl-2 can be detectable in a subset of MALT lymphomas in patients with hepatitis C virus (HCV) infection.


Effects of Polymethoxyflavonoids on Bone Loss Induced by Estrogen Deficiency and by LPS-Dependent Inflammation in Mice.
Polymethoxyflavonoids (PMFs) are a family of the natural compounds that mainly compise nobiletin, tangeretin, heptamethoxyflavone (HMF), and tetramethoxyflavone (TMF) in citrus fruits. PMFs have shown various biological functions, including anti-oxidative effects. We previously showed that nobiletin, tangeretin, and HMF all inhibited interleukin (IL)-1-mediated osteoclast differentiation via the inhibition of prostaglandin E2 synthesis. In this study, we created an original mixture of PMFs (nobiletin, tangeretin, HMF, and TMF) and examined whether or not PMFs exhibit co-operative inhibitory effects on osteoclastogenesis and bone resorption. In a coculture of bone marrow cells and osteoblasts, PMFs dose-dependently inhibited IL-1-induced osteoclast differentiation and bone resorption. The optimum concentration of PMFs was lower than that of nobiletin alone in the suppression of osteoclast differentiation, suggesting that the potency of PMFs was stronger than that of nobiletin in vitro. The oral administration of PMFs recovered the femoral bone loss induced by estrogen deficiency in ovariectomized mice. We further tested the effects of PMFs on lipopolysaccharide-induced bone resorption in mouse alveolar bone. In an ex vivo experimental model for periodontitis, PMFs significantly suppressed the bone-resorbing activity in organ cultures of mouse alveolar bone. These results indicate that a mixture of purified nobiletin, tangeretin, HMF, and TMF exhibits a co-operative inhibitory effect for the protection against bone loss in a mouse model of bone disease, suggesting that PMFs may be potential candidates for the prevention of bone resorption diseases, such as osteoporosis and periodontitis.


Deoxygenation of polyhydroxybenzenes: an alternative strategy for the benzene-free synthesis of aromatic chemicals.
New synthetic connections have been established between glucose and aromatic chemicals such as pyrogallol, hydroquinone, and resorcinol. The centerpiece of this approach is the removal of one oxygen atom from 1,2,3,4-tetrahydroxybenzene, hydroxyhydroquinone, and phloroglucinol methyl ether to form pyrogallol, hydroquinone, and resorcinol, respectively. Deoxygenations are accomplished by Rh-catalyzed hydrogenation of the starting polyhydroxybenzenes followed by acid-catalyzed dehydration of putative dihydro intermediates. Pyrogallol synthesis consists of converting glucose into myo-inositol, oxidation to myo-2-inosose, dehydration to 1,2,3,4-tetrahydroxybenzene, and deoxygenation to form pyrogallol. Synthesis of pyrogallol via myo-2-inosose requires 4 enzyme-catalyzed and 2 chemical steps. For comparison, synthesis of pyrogallol from glucose via gallic acid intermediacy and the shikimate pathway requires at least 20 enzyme-catalyzed steps. A new benzene-free synthesis of hydroquinone employs conversion of glucose into 2-deoxy-scyllo-inosose, dehydration of this inosose to hydroxyhydroquinone, and subsequent deoxygenation to form hydroquinone. Synthesis of hydroquinone via 2-deoxy-scyllo-inosose requires 2 enzyme-catalyzed and 2 chemical steps. By contrast, synthesis of hydroquinone using the shikimate pathway and intermediacy of quinic acid requires 18 enzyme-catalyzed steps and 1 chemical step. Methylation of triacetic acid lactone, cyclization, and regioselective deoxygenation of phloroglucinol methyl ether affords resorcinol. Given the ability to synthesize triacetic acid lactone from glucose, this constitutes the first benzene-free route for the synthesis of resorcinol.


Effects of dietary supplementation of herbal active ingredients promoting insulin-like growth factor-1 secretion on production performance, egg quality, blood hematology, and excreta gas emission in laying hens.
The purpose of this study was to evaluate the effects of supplementing herbal active ingredients (YGF251) which can promote the secretion of insulin-like growth factor-1 (IGF-1) in the diet on production performance, egg quality, blood hematology, and excreta gas emission in laying hens. A total of 288 ISA Brown (41-week-old) laying hens with an initial body weight of 1.83±0.68 kg were randomly assigned to 1 of 4 dietary treatments in a randomized block design based on body weight. Each treatment had 12 replicate cages having 6 adjacent cages per replicate (hens are kept in cages alone). The experimental period was 35 days. Dietary treatments were based on the corn-soybean meal-wheat-based basal diet and supplemented with 0.00%, 0.05%, 0.10%, or 0.15% YGF251. There was a linear increased egg weight in weeks 1 to 5 (p<0.05), egg mass in week 1 (p<0.05) and weeks 1 to 5 (p<0.05), egg strength on day 7 (p<0.05), 21 (p<0.01), and 35 (p<0.01), eggshell thickness on day 21 (p<0.05) and 35 (p<0.01), haugh unit on day 21 (p< 0.01) and 35 (p<0.05), serum IGF-1 concentration on day 21 (p<0.05) and 35 (p<0.01), and serum total protein concentration on day 35 (p<0.05) were observed with the supplementing YGF251 increased in the diet, while feed conversion ratio in weeks 1 to 5 (p<0.05) and excreta ammonia emission (p<0.01) decreased linearly with the dose of YGF251 increased. Dietary supplementation of YGF251 positively affected the production performance and egg quality of laying hens through increasing serum IGF-1 concentration in a dose-dependent manner. Moreover, YGF251 supplementation improved barn environment by reducing excreta noxious gas emission.


Neurologists for patient safety: where we stand, time to deliver.
Neurologists have a professional opportunity, an ethical responsibility, and sound clinical and economic reasons for engaging in efforts to improve patient safety. Better communication with patients and other providers, closer follow-up of consultation cases, and more focused supervision of trainees will help to reduce current patterns of error and misunderstanding. Patient education with attention to health literacy should improve adherence to management plans and help to bridge transitions of care across providers and sites. Through teaching and by example, neurologists can profoundly influence successive generations of clinicians to adopt safer practices, a culture of openness, and enhanced professionalism. The federal Safety and Quality Improvement Act of 2005, once implemented, should increase the evidence basis for safer care through voluntary, legally protected reporting of errors and adverse events within the framework of patient safety organizations.


[Non-A non-B hepatitis virus: demonstration of a double antigenic and structural kinship with hepatitis B virus].
Major antigenic identity has been demonstrated by immunodiffusion between the Ag described by Shirachi and confirmed by us (NANB/e) in the serum on non A non B hepatitis and the HBe/3 specificity of hepatitis B virus (HBV). A second Ag (NANB/c) linked to the core of a new virion morphologically similar to HBV and also associated with ADN polymerase activity as recently described, has been identified and purified from an infected liver. This NANB/c Ag also cross reacts with HBc Ag. These results confirm that HBV and the NANB virus defined here belong to the same new class of DNA viruses.


Comparison of two different techniques used for the maintenance of peri-implant soft tissue health: a pilot randomized clinical trial.
The aim of this pilot study was to compare the effectiveness of two different methods of debridement on maintaining and improving peri-implant soft tissue health over a period of 12 months. Twenty adult patients (25 implants) were enrolled in a randomized, single-blinded, parallel group clinical trial. All implants included showed no signs of pathologic bone loss. Patients were scheduled to be reviewed every 3 months over a 12 months period. Nine patients (15 implants) were randomly allocated to a test group and treated with a low abrasive air polishing powder (Air-Flow® Perio, EMS) (AFP) and another nine (10 implants) to a control group and treated with titanium curettes (TC). Peri-implant crevicular fluid samples were analyzed to quantitatively measure the concentration of six interleukins (IL-6, IL-8, IL-1β, TNF, IL-10 and IL-12). A multilevel analysis was used to test the comparison between the two treatments. The same analysis was used to study the relationship between clinical parameters and cytokines while controlling for confounding factors. There was no significant difference in bleeding on probing (BOP) between the two treatment methods (p = .35). Both debridement techniques resulted in a similar reduction of BOP (40.04% and 39.93%). IL-6 was the only cytokine of the six investigated that demonstrated a correlation with a clinical parameter (BOP) (p = .05). Both treatment methods were proven to be effective in reducing peri-implant inflammation and preventing further disease progression. Some cytokines may act as markers for peri-implant disease as the present study showed a significant relationship between IL-6 and BOP.


When and how is job embeddedness predictive of turnover? a meta-analytic investigation.
The present meta-analytic study introduces an overall model of the relationships between job embeddedness and turnover outcomes. Drawing on 65 independent samples (N = 42,907), we found that on-the-job and off-the-job embeddedness negatively related to turnover intentions and actual turnover, after controlling for job satisfaction, affective commitment, and job alternatives. In addition, the negative relationships between on-the-job embeddedness (off-the-job embeddedness) and turnover criteria were stronger in female-dominated samples and public organizations (collectivistic countries). Finally, turnover intentions, job search behavior, and job performance fully (partially) mediated the effect of on-the-job embeddedness (off-the-job embeddedness) on actual turnover. The research and practical implications of our findings are noted, in light of study limitations and future research needs.


Microbial diversity and colonization patterns of two step-down care units from a tertiary care hospital.
Nosocomial surfaces are potential pathogen reservoirs. Our aim was to describe the microbial diversity and analyze microbial patterns of healthcare-associated pathogens in two step-down-care-units at a tertiary care hospital. We monitored infected patients over 45 days to describe microbial diversity and colonization patterns. A total of 2762 isolates were recovered from the sampled sites, coagulase-negative staphylococci represented 44.64% (1233/2762) of the isolates. The most frequently recovered ESKAPE species (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae) were A. baumannii (7.53%; 208/2762 isolates) and E. faecium/Enterococcus faecalis (5.18%; 143/2762). We recovered a high diversity of species, including potential pathogens. A. baumannii was detected more frequently on diverse surfaces and persisted in patients' nostrils during the hospital stay.


Induction of heat shock gene expression in RAT1 primary fibroblast cells by ELF electric fields.
Recent studies have demonstrated that the Ku70 gene fragment can be placed in the anti-sense orientation under the control of a heat-inducible heat shock protein 70 (HSP70) promoter and activated through heat shock exposure. This results in attenuation of the Ku70 protein expression, inhibiting cellular repair processes, and sensitizing the transfected cells to exposures such as the ionizing radiation exposures used clinically. However, achieving the tissue temperatures necessary to thermally induce the HSP70 response presents significant limitations to the clinical application of this strategy. Previous findings suggest an alternative approach to inducing a heat shock response, specifically through the use of extremely low frequency (ELF) electrical field stimulation. To further pursue this approach, we investigated HSP70 responses in transfected rat primary fibroblast (RAT1) cells exposed to 10 Hz electric fields at intensities of 20-500 V/m. We confirmed that low frequency electric fields can induce HSP70 heat shock expression, with peak responses obtained at 8 h following a 2 h field exposure. However, the approximate threefold increase in expression is substantially lower than that obtained using thermal stimulation, raising questions of the clinical utility of the response.