Hydrophobic ion pairing: Key to highly payloaded self-emulsifying peptide drug delivery systems.
The aim of this study was the formation and characterization of various ion pairs of therapeutic peptides with different surfactants in order to reach a high payload in self-emulsifying drug delivering systems (SEDDS). Hydrophobic ion pairs (HIP) were formed between the anionic surfactants sodium docusate, dodecylsulfate and oleate and the peptides leuprorelin (LEU), insulin (INS) and desmopressin (DES). The efficiency of HIP formation was evaluated by quantifying the amount of formed complexes, log P value determination in n-octanol/water via HPLC and zeta potential measurements. Solvents and surfactants were screened regarding their complex solubilizing properties. Subsequently, peptide complexes were incorporated into SEDDS followed by payload and stability determination. Independent from the type of peptide, docusate showed the most efficient HIP properties followed by dodecylsulfate and oleate. Ratios of 2:1 for LEU, 6:1 for INS and 1.5:1 for DES led to the highest quantity of formed complexes with docusate and log P increased at least by 3 units. The more docusate was added to each peptide, the more negative became the zeta potential of the resulting complex. Incorporating these optimized complexes into novel SEDDS containing Capryol 90, Labrafil M 2125 CS, Labrasol ALF, Peceol, propylene glycol, tetraglycol, Transcutol HP and Tween 20 allowed payloads of the LEU, DES and INS complexes above 10%. Moreover, SEDDS exhibited high stability and constant negative zeta potential over a 4h incubation time. Following the procedure described herein payloads >10% can be achieved for peptide drugs in SEDDS.


A p53-independent pathway for activation of WAF1/CIP1 expression following oxidative stress.
Incubating human cells in diethylmaleate (DEM) depletes the intracellular pool of reduced glutathione (GSH) and increases the concentration of oxidative free radicals. We found that DEM-induced oxidative stress reduced the ability of p53 to bind its consensus recognition sequence and to activate transcription of a p53-specific reporter gene. Nevertheless, DEM treatment induced expression of WAF1/CIP1 but not GADD45 mRNA. The fact that N-acetylcysteine, a precursor of GSH that blocks oxidative stress, prevented WAF1/CIP1 induction by DEM suggests that WAF1/CIP1 induction probably was a consequence of the ability of DEM to reduce intracellular GSH levels. DEM induced WAF1/CIP1 expression in Saos-2 and T98G cells, both of which lack functional p53 protein. DEM treatment did not produce an increase in membrane-associated protein kinase C, but ERK2, a mitogen-activated protein kinase, was phosphorylated in a manner consistent with ERK2 activation. DEM treatment also produced a dose-dependent delay in cell cycle progression, which at low concentrations (0.25 mM) consisted of a G2/M arrest and at higher concentrations (1 mM) also involved G1 and S phase delays. Our results indicate that oxidative stress induces WAF1/CIP1 expression and arrests cell cycle progression through a mechanism that is independent of p53. This mechanism may provide for cell cycle checkpoint control under conditions that inactivate p53.


Comparing the effectiveness profile of pharmacological interventions used for orthodontic pain relief: an arm-based multilevel network meta-analysis of longitudinal data.
We compare the effectiveness profile of various analgesics used for orthodontic pain relief over a 1-week time period by conducting a longitudinal network meta-analysis (NMA). The MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases were searched till 31st December 2015 to identify the relevant studies. Additional studies were identified by hand searching journals and reference lists. Unpublished literature was also searched. Eligible studies were randomized-controlled trials (RCTs) evaluating the effectiveness of pharmacological interventions for pain relief after placement of separator or initial aligning arch wire. Pain intensity data at 2, 6, 12, 24, 36, 48, 72, 96, and 168 hours was collected. In addition, data were also extracted for potential covariates (age, sex, and procedure). A covariate-adjusted arm-based multilevel random coefficient model was used for evidence synthesis. Fifteen RCTs (1341 participants; male/females 595, 44.6%/746 55.4%; mean age 17.3 years, SD 4.1) were included. A total of 11 nodes (Acetaminophen, Aspirin, Etoricoxib, Flurbiprofen, Ibuprofen, Lumiracoxib, Meloxicam, Naproxen, Piroxicam, Placebo, and Control) were identified out of which five nodes (Placebo, Ibuprofen, Naproxen, Acetaminophen, and Aspirin) had subnodes (based on timing of administration). Compared to Control, Placebo, Flurbiprofen, Lumiracoxib, and Meloxicam were not significantly effective. Etoricoxib (most effective) and Piroxicam (second most effective) were effective over a long period which lasted up to 96 and 72 hours, respectively. Ibuprofen, Acetaminophen, Naproxen, and Aspirin were effective at 6, 12, and 24 hours. The effectiveness of these analgesics was significantly influenced by the timing of administration. Assessment of heterogeneity, transitivity, inconsistency, and publication bias revealed no major threat to the NMA derived estimates. Compared to the Control, Placebo was least effective whereas Etoricoxib was the most effective analgesic in reducing orthodontic pain. Administration timing has significant influence on the effectiveness profile of analgesics routinely used for managing orthodontic pain.


Bisphosphonate-associated Osteonecrosis of the jaws and endodontic treatment: two case reports.
Bisphosphonates are commonly used in the management of bone diseases, such as osteoporosis and Paget's disease, and to prevent bone complications and treat malignant hypercalcemia in certain types of cancer. Although this class of drugs has clear evidence of medical efficacy, there are an, increasing number of reports of bisphosphonate-associated osteonecrosis of the jaws that have substantial implications for the patient and for the treating dentist. This article reviews proposed possible mechanisms of bisphosphonate-associated osteonecrosis of the jaws and describes two case reports where non-surgical and surgical root canal treatment were precipitating factors. Recommendations for prevention and treatment of the disease follow. Thorough history-taking and timely consultation with the patient's oral surgeon and oncologist are emphasized.


Influence and influenceability: global directionality in directed complex networks.
Knowing which nodes are influential in a complex network and whether the network can be influenced by a small subset of nodes is a key part of network analysis. However, many traditional measures of importance focus on node level information without considering the global network architecture. We use the method of trophic analysis to study directed networks and show that both 'influence' and 'influenceability' in directed networks depend on the hierarchical structure and the global directionality, as measured by the trophic levels and trophic coherence, respectively. We show that in directed networks trophic hierarchy can explain: the nodes that can reach the most others; where the eigenvector centrality localizes; which nodes shape the behaviour in opinion or oscillator dynamics; and which strategies will be successful in generalized rock-paper-scissors games. We show, moreover, that these phenomena are mediated by the global directionality. We also highlight other structural properties of real networks related to influenceability, such as the pseudospectra, which depend on trophic coherence. These results apply to any directed network and the principles highlighted-that node hierarchy is essential for understanding network influence, mediated by global directionality-are applicable to many real-world dynamics.


[Prevention and management of postoperative complications in patients with inflammatory bowel disease].
The incidence of inflammatory bowel disease in China is rising on a yearly basis, followed by an increased number of patients who require surgery and those who suffer from maneuver postoperative complications. Surgical treatment is important in the management of patients with inflammatory bowel diseases. Management and prevention of postoperative complications is also a key factor to the success of surgical treatment if it is not more important than the surgical procedure itself. In this article, the most recent literatures in this field will be reviewed combined with our own clinical experiences. The types, risk factors, preoperative prevention strategies as well as postoperative management of surgical complications of patients with inflammatory bowel disease will be discussed.


Hemangiopericytoma of the infratemporal fossa: progression toward malignancy in a 30-year history.
Hemangiopericytoma is a rare vascular tumor first described by Stout and Murray in 1942 and characterized by a proliferation of Zimmermann's pericytes, smooth muscle cells arranged around blood vessels. This tumor presents as a slowly enlarging painless mass. Diagnosis with certainty is often a difficult one because of the close likeness with other spindle cell tumors; it requires the help of immunohistochemical techniques and sometimes ultrastructural techniques. Only 15% of hemangiopericytomas are localized in the cervicofacial region; in particular, occurrence in the infratemporal fossa is an exceptional occurrence. In this article, we report an unusual case of recidivate hemangiopericytoma of the infratemporal fossa that has progressively assumed features of malignancy over 30 years. The hemangiopericytoma relapse potentiality is elevated, even when the histologic characteristics of the tumor indicate a low aggressivity, and therefore every hemangiopericytoma must be considered to have malignant potential. In conclusion, the unpredictable behavior of hemangiopericytoma requires a radical primary treatment to avoid the risk of relapses that always are frequent and aggressive.


Understanding the clinical implications of minimal residual disease in childhood leukemia.
Improved laboratory techniques now allow a more sensitive detection of leukemia cells at designated intervals throughout therapy. Using flow cytometry and polymerase chain reaction, it is possible to detect 1 leukemic cell among 10(4) normal cells (1 leukemia cell in 10,000 normal cells), representing a 100-fold greater sensitivity than morphological examination in acute lymphoblastic leukemia (ALL). Recently, it has been shown that the molecular presence of persistent acute lymphoblastic leukemia at the end of remission therapy is a poor indicator of clinical outcome. Now similar studies are being performed in acute myeloid leukemia (AML). While the sensitivity using flow cytometry is less in AML than in ALL (able to detect 1 leukemic cell among 1000 normal cells in AML), persistent or minimal residual AML provides the clinician guidance with future treatment recommendations. Minimal residual disease (MRD) is now considered an important indicator response of disease response to treatment. As such, MRD once considered a research variable is now influencing treatment decisions. Therefore, it is imperative that the nurse have an understanding of the newer techniques to study residual leukemia and their clinical implications for patients and their families.


High short-term loosening rates with the Wagner Standard Cup.
The stability of prosthetic fixation is to a large extent dependent on component design. The purpose of this study is to analyze the short-term radiological results obtained with the Wagner Standard Cup in primary hip arthroplasty. An assessment was made of one hundred primary hip arthroplasties. The radiological evaluation revealed bone ingrowth in 37 of cases, fibrous integration in 49 and loosening in 14. In summary, osseointegration of the Wagner Standard Cup was unsuccessful in a high percentage of cases. This finding, which was unrelated to the type of stem or bearing surface used, bore a statistically significant relation (P<0.05) with an observed poor bone coverage of the acetabular component. Although insufficient bone coverage could arguably be attributable to a poor surgical technique, we would tend to agree with other authors that it is rather likely to result from a flawed implant design that impedes osseointegration.


Low-dose N-butyldeoxynojirimycin (OGT 918) for type I Gaucher disease.
The objective of this study was to evaluate the efficacy and safety of low-dose substrate balance therapy with OGT 918 for the treatment of adults with Gaucher disease. Eighteen patients with Gaucher disease from two centers were enrolled in an open-label 6-month study of OGT 918, 50 mg taken three times daily (TID), followed by an optional extended-use phase. Changes in liver and spleen volume at 6 and 12 months, as well as routine hematological and biochemical parameters on a monthly basis, were evaluated. During the extension, dosage was increased to 100 mg TID in patients in one center to improve the response. Seventeen patients completed 6 months; of 16 patients in the extension phase, 13 were evaluable at 12 months. Percentage changes in liver (-5.9%, P = 0.007) and spleen (-4.5%, P = 0.025) volumes and in chitotriosidase levels (-4.6%, P = 0.039) at 6 months were commensurately lower than those reported previously in an open-label trial using 100 mg TID; hemoglobin and platelet counts were not boosted. At 12 months there were further mean decreases from baseline in liver volume (-6.2%, P = 0.037), spleen volume (-10.1%, P < 0.05), and chitotriosidase levels (-15.3%, P < 0.05) as well as mean changes of +1.2 and +14.7% in hemoglobin and platelet concentrations, respectively [correction]. There were no serious adverse effects throughout the 6-month study period; common side effects were diarrhea (94%) and weight loss (67%), comparable to the incidence in the original trial. We conclude that OGT 918 was safe and effective at 50 mg TID, but shows dose dependency in ameliorating parameters of Gaucher disease relative to the results noted in the seminal trial; there was no improvement in the rate of hematological response and no reduction in side effects. Results from the extension wherein some patients were dose increased suggest that 100 mg TID should be the preferred starting regimen for patients with symptomatic type I Gaucher disease.


Identification of extractable growth factors from small intestinal submucosa.
When implanted as a biomaterial for tissue replacement, selected submucosal layers of porcine small intestine induce site-specific tissue remodeling. Small intestinal submucosa (SIS), as isolated, is primarily an acellular extracellular matrix material. In an attempt to discover the components of small intestinal submucosa which are able to induce this tissue remodeling, the material was extracted and extracts were tested for the ability to stimulate Swiss 3T3 fibroblasts to synthesize DNA and proliferate. Each of the four different extracts of small intestinal submucosa had measurable cell-stimulating activity when analyzed in both a whole cell proliferation assay (alamarBlue dye reduction) and a DNA synthesis assay ([3H]-thymidine incorporation). Proteins extracted from SIS with 2 M urea induced activity profiles in the two assays which were very similar to the activity profiles of basic fibroblast growth factor (FGF-2) in the assays. As well, the changes in cell morphology in response to the extracted proteins mimicked the changes induced by FGF-2. Neutralization experiments with specific antibodies to this growth factor confirmed the presence of FGF-2 and indicated that it was responsible for 60% of the fibroblast-stimulating activity of the urea extract of small intestinal submucosa. Western blot analysis with a monoclonal antibody specific for FGF-2 detected a reactive doublet at approximately 19 kDa and further confirmed the presence of FGF-2. Cell stimulating activity of proteins extracted from SIS with 4 M guanidine was neutralized by an antibody specific for transforming growth factor beta (TGF beta). Changes in the morphology of the fibroblasts exposed to this extract were nearly identical to changes induced by TGF beta. Although no reactive protein band was detected at 25 kDa in nonreduced western blot analysis, several bands were reactive at higher molecular weight. The identity of this TGF beta-related component of small intestinal submucosa is unknown. Identification of FGF-2 and TGF beta-related activities in SIS, two growth factors known to significantly affect critical processes of tissue development and differentiation, provides the opportunity to further elucidate the mechanisms by which this extracellular matrix biomaterial modulates wound healing and tissue remodeling.


Catalpol attenuates MPTP induced neuronal degeneration of nigral-striatal dopaminergic pathway in mice through elevating glial cell derived neurotrophic factor in striatum.
The protective effect of an iridoid catalpol extracted and purified from the traditional Chinese medicinal herb Rehmannia glutinosa on the neuronal degeneration of nigral-striatal dopaminergic pathway was studied in a chronic 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)/probenecid C57BL/6 mouse model and in 1-methyl-4-phenylpyridimium (MPP(+)) intoxicated cultured mesencephalic neurons. Rotarod performance revealed that the locomotor ability of mice was significantly impaired after completion of model production and maintained thereafter for at least 4 weeks. Catalpol orally administered for 8 weeks (starting from the second week of model production) dose dependently improved the locomotor ability. HPLC revealed that catalpol significantly elevated striatal dopamine levels without changing the metabolite/dopamine ratios. Nor did it bind to dopamine receptors. Therefore it is unlikely that catalpol resembles any of the known compounds for treating Parkinsonism. Instead, catalpol dose dependently raised the tyrosine hydroxylase (TH) neuron number in substantia nigra pars compacta (SNpc), the striatal dopamine transporter (DAT) density and the striatal glial cell derived neurotrophic factor (GDNF) protein level. Linear regression revealed that both the TH neuron number and DAT density were positively correlated to the GDNF level. In the cultured mesencephalic neurons, MPP(+) decreased the dopaminergic neuron number and shortened the neurite length, whereas catalpol showed protective effect dose dependently. Furthermore, the expression of GDNF mRNA was up-regulated by catalpol to a peak nearly double of normal control in neurons intoxicated with MPP(+) for 24 h but not in normal neurons. The GDNF receptor tyrosine kinase RET inhibitor 4-amino-5-(4-methyphenyl)-7-(t-butyl)-pyrazolo-[3,4-d]pyrimidine (PP1) abolished the protective effect of catalpol either partially (TH positive neuron number) or completely (neurite length). Taken together, catalpol improves locomotor ability by attenuating the neuronal degeneration of nigral-striatal dopaminergic pathway, and this attenuation is at least partially through elevating the striatal GDNF expression.


Effect of Ionic Liquid Modification on the ORR Performance and Degradation Mechanism of Trimetallic PtNiMo/C Catalysts.
Ionic liquids (ILs) modification, following the concept of "solid catalyst with ionic liquid layer (SCILL)", has been demonstrated to be an effective approach to improving both activity and stability of Pt-based catalysts for the oxygen reduction reaction. In this work, the SCILL concept has been applied to a trimetallic PtNiMo/C system, which has been documented recently to be significantly advantageous over the benchmark PtNi-based catalysts for oxygen reduction. To achieve this, two hydrophobic ILs ([BMIM][NTF2] and [MTBD][BETI]) were used to modify PtNiMo/C with four IL-loading amounts between 7 and 38 wt %. We found that the Pt mass activity (@0.9 V) could be improved by up to 50% with [BMIM][NTF2] and even 70% when [MTBD][BETI] is used. Exceeding a specific IL loading amount, however, leads to a mass transport related activity drop. Moreover, it is also disclosed that both ILs can effectively suppress the formation of nonreactive oxygenated species, while at the same time imposing little effect on the electrochemical active surface area. For a deeper understanding of the degradation mechanism of pristine and IL modified PtNiMo/C, we applied identical location transmission electron microscopy and in situ scanning flow cell coupled to inductively coupled plasma mass spectrometry techniques. It is disclosed that the presence of ILs has selectively accelerated the dissolution of Mo and eventually results in a more severe degradation of PtNiMo/C. This shows that future research needs to identify ILs that prevent the Mo dissolution to leverage the potential of the IL modification of PtNiMo catalysts.


Ontogenesis of the retinohypothalamic tract, vasoactive intestinal polypeptide- and peptide histidine isoleucine-containing neurons and melatonin binding in the hypothalamus of the mink.
The development of the retinohypothalamic tract (RHT) labeled with cholera toxin and of the vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) systems was studied in the hypothalamus of neonatal mink by using immunohistochemistry. Retinal fibers were observed in the suprachiasmatic nucleus (SCN) from birth and were adult-like by day 14. VIP and PHI immunoreactivity was also present from birth. Melatonin binding was studied by autoradiography using [125I]melatonin as a ligand. A specific binding was detected in near-term fetal and neonate brains in the olfactory epithelium, various thalamic nuclei, the pineal gland, and the pars tuberalis of the pituitary gland, but never in the SCN. These results are discussed in the context of the potential role of daylight cycles and/or melatonin in entraining circadian rhythms in neonate mink.


Prospective randomized comparison of two types of pressure therapy garments.
A prospective randomized study was undertaken to compare compliance efficacy and cost of the elastic nylon pressure garment (Jobst Institute, Inc., Toledo, Ohio) with the cotton elastic pressure garment (Tubigrip, SePro Healthcare Inc., Montgomeryville, Penn.). Of 110 patients enrolled, 54 received Jobst pressure garments and 56 received Tubigrip pressure garments. Time spent in pressure-therapy garments was the same for both groups. Comparable clinical results were achieved with either Tubigrip or Jobst garments. A significantly greater percentage of patients were compliant with Tubigrip pressure-garment therapy than with Jobst pressure-garment therapy. The cost of the Tubigrip garments was significantly lower than that of Jobst garments. These data suggest that the use of elasticized cotton pressure garments results in significantly better patient compliance, a lower cost, and equal therapeutic efficacy when compared with the elasticized nylon pressure garments.


A Randomized Controlled Trial to Determine the Effect of Inhaled Corticosteroid on Intraocular Pressure in Open-Angle Glaucoma and Ocular Hypertension: The ICOUGH Study.
The purpose of this study was to determine the risk of a steroid pressure response from inhaled corticosteroids. This randomized, double-masked, placebo-controlled trial included 22 adults with well-controlled open-angle glaucoma or ocular hypertension. Consenting participants were randomized to a 6-week course of twice-daily fluticasone propionate 250-μg metered-dose inhaler or saline placebo metered-dose inhaler. Biweekly clinic visits included masked Goldmann applanation tonometry and assessment to identify adverse effects. Primary outcome was mean intraocular pressure (IOP) at week 6. Secondary outcomes included IOP elevation of >20% at 2 consecutive visits, adherence, side effects, and logMAR visual acuity. A total of 10 patients in each arm completed the study. There were no statistically significant differences in IOP between groups at baseline (14.3±3.0 and 15.6±3.6 mm Hg in steroid and placebo groups, respectively, P=0.39) or at week 6 (14.7±2.4 and 14.8±3.8 mm Hg in steroid and placebo groups, respectively, P=0.92). Adherence was >80% for all participants. There were no statistically significant differences between groups in any secondary measures. One patient in the steroid group met the secondary end point of >20% elevation in IOP (IOP increased from baseline of 9 to 11 mm Hg at weeks 2 and 4). We found no clinically significant increase in mean IOP in patients with well-controlled open-angle glaucoma and ocular hypertension after 6 weeks of twice-daily inhaled fluticasone propionate compared with inhaled placebo. No participants exceeded their individualized target IOP. There were no differences in secondary outcomes.


Natural history of achondroplasia: A retrospective review of longitudinal clinical data.
There are limited data on the longitudinal frequency and severity of the symptoms and complications of achondroplasia. We undertook a retrospective electronic chart review of 114 patients to develop a more thorough understanding of the lifetime impact of achondroplasia. Craniocervical stenosis (involving the foramen magnum with or without cervical vertebrae C1 and/or C2) was noted in nearly 50% of patients with craniovertebral junction imaging; however, corrective decompression surgery was only needed in 6% of patients. No children in our cohort died at 4 years of age or under. Kyphosis was present in most patients but usually resolved in early childhood. Cervical and lumbar stenosis were diagnosed in children and adults while, genu varum, elbow contractures, and radial head dislocations were identified during childhood. Central sleep apnea and obstructive sleep apnea were present in children, while the diagnosis of obstructive sleep apnea was shown to recur in adulthood. Cardiovascular risk factors were present in only 7% of patients. A range of mental health disorders were identified, with most diagnoses being made before 18 years of age. Our data show that achondroplasia has a significant impact on patients' physical health, and complications continue to be reported and require intervention throughout patients' lifetimes. This highlights the need for continuous support beyond pediatric care, by adult care clinicians experienced with managing the long-term complications of achondroplasia.


Determination of gossypol enantiomer ratio in cotton plants by chiral higher-performance liquid chromatography.
A celulose tris(3,5-dimethylphenylcarbamate) coated onto APS silica (Nucleosil, particle size, 7 microm; pore size, 500 A) was used under a reversed-phase condition to measure the enantiomeric ratios of gossypol enantiomers in cottonseeds, flowers, and roots in a number of cultivars samples of different Gossipium species. While unidimensional chromatography was used for measuring the enantiomeric ratio of all the samples of G. hirsutum, G. mustelinum, and in the seeds of G. barbadense, multidimensional chromatography was necessary for the analysis of samples of roots and flowers of G. barbadense. In the latter case, an ODS Hypersil column was used in the first dimension for sample clean up, and the enantiomers were resolved on the second dimension by the chiral column. As expected, all the seed samples of G. hirsutum and G. mustelinum showed the (P)-(+)-enantiomer in excess, whereas the seeds of G. barbadense showed the (M)-(-)-enantiomer. However, (P)-(+)-gossypol was found in enantiomeric excess in three samples examined of roots and in one of flower of G. barbadense. These results are discussed in this paper.


A green fluorescent protein kinase substrate allowing detection and localization of intracellular ERK/MAP kinase activity.
We describe a versatile intracellular reporter of ERK/MAP kinase activity: a cDNA construct, pGFP.MBP, encoding amino acids 85-144 of the human myelin basic protein fused to the C-terminus of an enhanced green fluorescent protein (GFP). The fused fragment of myelin basic protein contains a single consensus ERK/MAP kinase phosphorylation motif (PRTP, where the threonine is phosphorylated). Phosphorylation of the specific motif can be detected via immunoblotting or immunofluorescence with a commercially available phospho-specific monoclonal antibody. When expressed in mammalian cells by either transient or stable transfection, the fusion protein acts as a bona fide kinase substrate, as demonstrated by rapid serum-induced phosphorylation that is blocked by a specific MEK inhibitor. Moreover, the localization of the total substrate pool is easily visualized by GFP autofluorescence and the extent of its phosphorylation simultaneously detected within intact fixed cells by immunofluorescence using the commercially available phospho-specific antibody. The approach described should be generally applicable to the intracellular analysis of many specific protein kinase substrates for which phospho-specific antibodies have been produced.


Alcohol consumption and fruits and vegetable intake among older adults in Ghana: a cross-sectional survey based on WHO-SAGE Wave 2 data.
Alcohol consumption and inadequate fruits and vegetable (FnV) intake are major reasons for the shift from communicable to non-communicable diseases (NCDs) over the years. The older Ghanaian adult is at high risk of NCD and data on alcohol and FnV consumption are required to guide policy to mitigate its effect. This analysis aimed to determine the factors associated with alcohol consumption and assess the relationship between alcohol consumption and FnV intake among Ghanaians aged 50 years and older. This analysis used WHO Study on Global Ageing and Adult Health (SAGE) Wave 2, Ghana data set conducted between 2014 and 2015. Data on demographic characteristics, FnV intake, and alcohol consumption were collated and analysed. Multivariable Poisson, logistic and probit regression analyses were performed to assess the associations between alcohol consumption and inadequate FnV intake. A total of 3533 Ghanaians aged 50 years and older, 41.0% men and 59.0% women, were included in this study. The prevalence of lifetime alcohol consumption was 22.8% (95% CI 20.7% to 25.1%). Alcohol consumption was significantly associated with sex, age group, marital status, religion, place of residence and history of smoking. The prevalence of adequate FnV intake was 52.6% with a mean daily intake of 6.45 servings: 2.98 for fruits and 3.47 for vegetables. There was a significant positive correlation between inadequate FnV intake and alcohol consumption. Inadequate FnV consumption was significantly higher among lifetime alcohol consumers compared with non-alcohol consumers. (Poisson estimate; adjusted Prevalence Ratio (aPR) (95% CI)=1.35 (1.12 to 1.63), logistic estimate; adjusted Old Ratio (aOR) (95% CI)=1.13 (1.05 to 1.21) and probit estimate; adjusted normalized coefficient (aβ) (95% CI)=0.19 (0.07 to 0.31)). About a quarter and nearly half of older Ghanaian adults consume alcohol and inadequate FnV, respectively. Alcohol consumption is significantly associated with inadequate FnV intake. Interventions to address inadequate FnV intake among older adults in Ghana should also include policies that regulate the use of alcohol in this population.


Treatments to promote colonic hydration: enteral fluid therapy versus intravenous fluid therapy and magnesium sulphate.
Although large intestine impactions are commonly treated with i.v. fluids combined with the osmotic laxative MgSO4, enteral fluids are less expensive and also appear to be efficacious for impactions. Therefore, this study was conducted to compare the systemic and gastrointestinal effects of enteral fluids with the changes produced by i.v. fluids combined with MgSO4. Four horses with a fistula in the right dorsal colon alternately received both treatments in 2 periods one week apart. Sixty litres of fluids were administered continuously (10 l/h) through a venous catheter or a nasogastric tube. Magnesium sulphate (1 g/kg bwt) was administered via nasogastric tube before i.v. fluid therapy. Two horses had mild abdominal discomfort at the end of enteral fluid therapy. Pollakiuria, hypostenuria, increased bodyweight, increased faecal and ingesta hydration, and decreased PCV, plasma protein and plasma magnesium were produced by both treatments. Abdominal distention and more pronounced changes in bodyweight and ingesta hydration were seen with enteral fluids. Intravenous fluids plus MgSO4 produced hypocalcaemia and more pronounced changes in plasma protein. These results indicate that enteral fluid therapy is more effective in promoting ingesta hydration and produces less pronounced systemic effects than i.v. fluid therapy plus MgSO4.


Residual adrenal function in autoimmune Addison's disease: improvement after tetracosactide (ACTH1-24) treatment.
Despite lifelong steroid hormone replacement, there is excess morbidity and mortality associated with autoimmune Addison's disease. In health, adrenocortical cells undergo continuous self-renewal from a population of subcapsular progenitor cells, under the influence of ACTH, suggesting a therapeutic possibility. We aimed to determine whether tetracosactide (synthetic ACTH1-24) could revive adrenal steroidogenic function in autoimmune Addison's disease. Thirteen patients (aged 16-65 y) with established autoimmune Addison's disease for more than 1 year were recruited at the Newcastle University Clinical Research Facility. The intervention included a 20-week study of regular sc tetracosactide (ACTH1-24) therapy. Serum and urine corticosteroids were measured during medication withdrawal at baseline and every 5 weeks during the study. Serum cortisol levels remained less than 100 nmol/L in 11 of 13 participants throughout the study. However, two women achieved peak serum cortisol concentrations greater than 400 nmol/L after 10 and 29 weeks of tetracosactide therapy, respectively, allowing withdrawal of corticosteroid replacement. Concurrently, urine glucocorticoid and mineralocorticoid metabolite excretion increased from subnormal to above the median of healthy controls. One of these responders remains well with improving peak serum cortisol (672 nmol/L) 28 months after stopping all treatments. The other responder showed a gradual reduction in serum cortisol and aldosterone over time, and steroid therapy was recommenced after a 28-week period without glucocorticoid replacement. This is the first study to demonstrate that established autoimmune Addison's disease is amenable to a regenerative medicine therapy approach.


Vermamoeba vermiformis as etiological agent of a painful ulcer close to the eye.
In the present article, we report on the identification of Vermamoeba (Hartmannella) vermiformis as the etiological agent of a tissue infection close to the eye of a female patient. Laboratory examination revealed no involvement of any pathogenic bacteria or fungi in the tissue infection. V. vermiformis was identified by cultivation and morphology of trophozoites and cysts as well as phylogenetic analysis of nuclear 18S rDNA. The lesion improved in the course of 4 weeks by application of zinc paste.


Clinical effects of betamethasone and hyaluronan, and of defocalized carbon dioxide laser treatment on traumatic arthritis in the fetlock joints of horses.
The clinical effects of intra-articular betamethasone together with hyaluronan (betaM/HA) and treatment with a defocalized carbon dioxide laser on acute traumatic arthritis of the fetlock joint were assessed. The horses in these studies were selected using a thorough lameness examination, including intra-articular anaesthesia abolishing the lameness. This investigation comprised an observer-blind study, including 10 sport horses (10 joints), and a prospective study, including 180 sport horses (333 joints). In both studies, the material was divided into two groups treated with either betaM/HA or a carbon dioxide laser. The treatment doses were 12 mg of betaM, 20 mg of HA or 60 J/cm2 of treated area. Convalescence before training was 21 days for both groups in the observer-blind study. In the prospective study, convalescence in the betaM/HA group was 21 days but was only 7 days for the laser-treated group. In the observer-blind study, three of five treated joints recovered in both cohorts. In the prospective study, the groups had significantly different recovery rates--68% of the betaM/HA-treated joints and 80% of the carbon dioxide laser-treated joints. These results indicate that the defocalized carbon dioxide laser should be an applicable mode of treatment of acute traumatic synovitis in horses. However, the biochemical functions related to carbon dioxide laser treatment require further elucidation.


Unusual immunophenotype displayed by histiocytes in haemophagocytic lymphohistiocystosis.
Extensive immunophenotypic studies in a 2 1/2 month old girl with haemophagocytic lymphohistiocytosis were performed to characterise the proliferating histiocytes of the disease. The cells strongly expressed conventional macrophage antigens, but unexpectedly, there was a dissociated expression of the CD1a antigen (reacting with the monoclonal antibody NA1/34 but not with OKT6) and intracellular S-100 protein by the haemophagocytic lymphohistiocytosis histiocytes. These findings indicate that there is a "hybrid" phenotype between the two main arms of the mononuclear phagocyte system--namely, Langerhans' cells and phagocytic macrophages.


Incidence, predictors, and evolution of conduction disorders and atrial arrhythmias after contemporary mitral valve repair.
Conduction disorders (CD) and atrial arrhythmias (AA) in the postoperative period of cardiac surgery impede prompt clinical recovery and prolong hospitalization. Mitral valve repair (MVR) has become the treatment of choice for patients with significant valvular regurgitation, but information on CD and AA in this population is scarce. Records of consecutive patients undergoing MVR at a single center were reviewed. Patients with a preoperative pacemaker, CD, prior cardiac surgery or concomitant MVR were excluded. A total of 290 patients were included in the final analysis. Electrocardiograms pre andpost-operatively were analyzed for CD and AA. CD occurred in 69 (23.7%) patients: 47 (16.2%) had first degree atrio-ventricular block (AVB), 10 (3.4%) had Mobitz I, 3 (1.03%) had Mobitz II, and 9 (3.1%) complete AVB. Only 6 (2.0%) patients required pacemakers. Univariate predictors of AVB were age, preexisting right bundle branch block (RBBB), mitral valve ring size, and bypass time. The only multivariate predictors of AVB were bypass time and preexisting RBBB (OR 3.23 and 1.98, respectively). The most common AA was atrial fibrillation 13.1% (38 patients) followed by atrial flutter 2.7% (8 patients). Multivariate predictors of AA were age and left atrial size (OR 1.85 and 4.2, respectively). Length of stay in patients with CD or AA was prolonged 2.2 ± 2 days compared to controls (p < 0.05). In this large sample of patients undergoing MVR, we found that bypass time and preexisting RBBB were independent predictors of CD; age and left atrial size were independent predictors of AA.


[Evaluation of sensitivity and specificity of confirmatory assays for lupus anticoagulant (LA) detection].
To evaluate the sensitivity and specificity of confirmatory assays for LA detection, we performed the platelet neutralization procedure (PNP), diluted Russell's viper venom time (dRVVT) confirmatory assay (the ratio of LA-screen and LA-confirm:S/C), and specific hexagonal phase neutralization test (StaLA) on, plasma samples 43 LA-positive in either the ratio of dilute APTT and APTT(dAPTT/APTT) or dRVVT(LA-screen). The sensitivity and the specificity were evaluated by 4 different analyses based on, 1) maximal plasma dilution, 2) correlation between the screening assays and these confirmatory assays, 3) ratio of LA-positive in the confirmatory assays, and 4) receiver operation characteristic (ROC) method. All 4 analyses showed that sensitivity was in the order of PNP > S/C > Staclot-LA. However, the order of the specificity evaluated by the ROC method was Staclot-LA > S/C > PNP. The APTT-based confirmatory assay, PNP can detect LA of the plasma samples that were all positive in the dAPTT/APTT ratio, while the LA-positive plasma samples in dRVVT-confirm were all positive in the dRVVT-screen assay. Our findings suggest that confirmatory assays should be based on the method giving an abnormal screening assay. Accordingly, we recommend the following combinations of screening and confirmatory assays in terms of specificity; 1) dAPTT/APTT ratio and Staclot-LA as the APTT-based assay, and 2) LA-screen and LA-confirm as the dRVVT-based assay.


Different localization of SeqA-bound nascent DNA clusters and MukF-MukE-MukB complex in Escherichia coli cells.
MukF, MukE and MukB proteins form a complex that may participate in the organization of folded sister chromosomes in Escherichia coli. We have found that a MukB-GFPuv4 fusion protein is observed as discrete fluorescent foci, which are localized within cellular spaces occupied by nucleoids, but not at the constriction site of cell division in living cells. In contrast, MukB-GFPuv4 is distributed throughout the whole cell when either MukF or MukE is absent. Statistical analysis revealed that most newborn cells have two foci of mukB-gfpUV4 at one-quarter and three-quarter positions in the cell length and one focus of SeqA-bound nascent DNA at or near the middle of the cell. Subsequently, the single SeqA focus divides into two foci, and then these migrate to the one-quarter and three-quarter positions. Before cell division, most long cells have two SeqA foci and four MukB-GFPuv4 foci. In early stationary phase, SeqA foci disappear, but one or two foci of MukB-GFPuv4 remain. We discuss the reorganization and proper arrangement of folded sister chromosome in the cell quarter positions, which are performed after release from the long-time cohesion of sister chromosomes.


Interleukin-1beta induces MUC2 gene expression and mucin secretion via activation of PKC-MEK/ERK, and PI3K in human airway epithelial cells.
Interleukin 1beta(IL-1beta), a proinflammatory cytokine, is related with inflammatory diseases and it up-regulates MUC2 gene expression and mucin secretion. This study was designed to investigate the signal transduction pathway of the IL-1beta-mediated MUC2 gene expression and mucin secretion in human airway epithelial cells. In cultured human airway NCI-H292 epithelial cells, the steady state of the mRNA level of MUC2 gene expression and mucin secretion induced by IL-1beta were determined by reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunoblot analysis. To observe the signal pathway of the IL-1beta-mediated MUC2 gene expression and mucin secretion, we used several specific inhibitors. PD98059 (MEK/ERK inhibitor) suppressed IL-1beta-mediated MUC2 gene expression and mucin secretion, while SB203580 (p38 inhibitor) did not. Ro31-8220 (PKC inhibitor) inhibited IL-1beta-mediated MUC2 gene expression and mucin secretion. It inhibited ERK phosphorylation, but did not inhibit p38 phosphorylation. LY294002 (PI3K inhibitor) also suppressed MUC2 expression, but did not inhibit any MAPKs phosphorylation. These results suggest that the IL-1beta-mediated MUC2 gene expression and mucin secretion in NCI-H292 cells are regulated through activation of the PKC-MEK/ERK pathway, and that PI3K is also involved in the IL-1beta-mediated MUC2 gene expression and mucin secretion.


Role of Neural (N)-Cadherin in Breast Cancer Cell Stemness and Dormancy in the Bone Microenvironment.
Breast cancer cells that interact with spindle-shaped N-Cadherin+ Osteoblasts (SNOs) are recognised to become dormant through a Notch2-dependent mechanism. We found that Notch2High human BrCa MDA-MB231 (MDA) cells also expressed high level of N-Cadherin. This prompted us to hypothesize that N-Cadherin could have a role in MDA-SNO interaction. Of note, the expression of N-Cadherin in MDA cells reduced tumour incidence and bone osteolysis in BrCa mouse model. Moreover, similarly to Notch2High MDA cells, the N-CadherinHigh MDA cells revealed a high expression of the canonical Haematopoietic Stem cell (HSC) markers, suggesting an HSC mimicry, associated with higher ability to form mammospheres. Interestingly, N-CadherinHigh MDA cells showed greater capacity to adhere to SNOs, while the inhibition of SNO-mediating MDA cell proliferation was unremarkable. To investigate whether these features were shared by mouse BrCa, we used the 4T1 cell line in which N-Cadherin expression was abolished and then rescued. At variance with MDA cells, 4T1 cells expressing N-Cadherin revealed that the latter was associated with a lower expression of the HSC marker, Cxcr4, along with a lower capacity to form mammospheres. Furthermore, the rescue of N-Cadherin expression increased cell-cell adhesion and reduced proliferation of 4T1 cells when they were co-plated with SNOs. In conclusion, we demonstrated that: (i) N-CadherinHigh and Notch2High MDA cells showed similar HSC mimicry and dormancy features; (ii) N-Cadherin mediated BrCa-SNO adhesion; (iii) N-Cadherin had a positive Notch2-dependent role on SNO-induced dormancy and HSC mimicry in MDA cells, and a negative role in 4T1 cell stemness and HSC mimicry.


Capillary electrophoresis of conidia from cultivated microscopic filamentous fungi.
In immunocompromised people fungal agents are able to cause serious infections with high mortality rate. An early diagnosis can increase the chances of survival of the affected patients. Simultaneously, the fungi produce toxins and they are frequent cause of allergy. Currently, various methods are used for detection and identification of these pathogens. They use microscopic examination and growth characteristic of the fungi. New methods are based on the analysis of structural elements of the target microorganisms such as proteins, polysaccharides, glycoproteins, nucleic acids, etc. for the construction of antibodies, probes, and primers for detection. The above-mentioned methods are time-consuming and elaborate. Here hydrophobic conidia from the cultures of different strains of the filamentous fungi were focused and separated by capillary zone electrophoresis and capillary isoelectric focusing. The detection was optimized by dynamic modifying of conidia by the nonionogenic tenside on the basis of pyrenebutanoate. Down to 10 labeled conidia of the fungal strains were fluorometrically detected, and isoelectric points of conidia were determined. The observed isoelectric points were compared with those obtained from the separation of the cultured clinical samples, and they were found to be not host-specific.


Age, physical impairment, and symptoms of anxiety: a test of mediating and moderating factors.
This study examines the processes linking physical impairment with symptoms of anxiety. Analyses are based on a representative sample of 967 physically disabled adults (ages 20 to 90) from ten counties of southwestern Ontario, Canada Several hypotheses test the intervening role of disability characteristics, perceived health care efficacy, personal attributes, and social stratification resources. Ordinary least squares (OLS) regression analyses included sets of those intervening variables entered sequentially. Adjustment produces a significant reduction in the association between symptoms of anxiety and impairment--confirming the intervening role of healthcare efficacy and mastery. Moreover, impairment and mastery have synergistic effects such that higher mastery buffers against the anxiety associated with higher impairment. Other findings raise important questions about age, impairment, and the sense of mastery in the contest of healthcare and gender.


Poly(glycolide) multi-arm star polymers: Improved solubility via limited arm length.
Due to the low solubility of poly(glycolic acid) (PGA), its use is generally limited to the synthesis of random copolyesters with other hydroxy acids, such as lactic acid, or to applications that permit direct processing from the polymer melt. Insolubility is generally observed for PGA when the degree of polymerization exceeds 20. Here we present a strategy that allows the preparation of PGA-based multi-arm structures which significantly exceed the molecular weight of processable oligomeric linear PGA (<1000 g/mol). This was achieved by the use of a multifunctional hyperbranched polyglycerol (PG) macroinitiator and the tin(II)-2-ethylhexanoate catalyzed ring-opening polymerization of glycolide in the melt. With this strategy it is possible to combine high molecular weight with good molecular weight control (up to 16,000 g/mol, PDI = 1.4-1.7), resulting in PGA multi-arm star block copolymers containing more than 90 wt % GA. The successful linkage of PGA arms and PG core via this core first/grafting from strategy was confirmed by detailed NMR and SEC characterization. Various PG/glycolide ratios were employed to vary the length of the PGA arms. Besides fluorinated solvents, the materials were soluble in DMF and DMSO up to an average arm length of 12 glycolic acid units. Reduction in the T(g) and the melting temperature compared to the homopolymer PGA should lead to simplified processing conditions. The findings contribute to broadening the range of biomedical applications of PGA.


Ligand interaction of human alpha 2-macroglobulin-alpha 2-macroglobulin receptor studied by partitioning in aqueous two-phase systems.
Alpha 2-macroglobulin (alpha 2-M) is a major proteinase inhibitor in human blood and tissue. Besides its antiproteolytic potential, alpha 2-M was found to modulate antigen- and mitogen-driven immune responses and cell growth by binding and transporting distinct cytokines, growth factors and hormones. The inhibitor is cleared from circulation by binding to a multifunctional cellular receptor present on different cell types. Alpha 2-M, as well as its receptor, are capable of binding a variety of ligands. In the present study we have applied aqueous two-phase systems to analyze the interaction of IL-1 beta and alpha 2-M receptor to different forms of alpha 2-M. The partition of IL-1 beta was changed by addition of transformed alpha 2-M to the two-phase systems rather than by the native inhibitor. The interaction between IL-1 beta and alpha 2-M was enhanced by divalent cations. In addition, the complex formation between 125I-labelled receptor and alpha 2-M could clearly be demonstrated by partitioning. In the presence of divalent cations, transformed alpha 2-M, in contrast to the native inhibitor, effectively changed the partition of the receptor. However, the observed alteration of the partition coefficient was found to be less compared with the values obtained by partitioning of the receptor in the presence of whole plasma containing the inhibitor in equivalent concentrations. The results indicate that other components of the plasma exist which competitively bind to the receptor but independent of Ca2+-ions.


Effect of alpha-lipoic acid on lipid profile in rats fed a high-fructose diet.
This study investigated the effect of administration of alpha-lipoic acid (LA) on lipid metabolism in high fructose-fed insulin-resistant rats. High-fructose feeding (60 g/100 g diet) to normal rats resulted in a significant increase in the concentrations of cholesterol, triglycerides (TGs), free fatty acids (FFAs), and phospholipids in plasma, liver, kidney, and skeletal muscle. Reduced activities of lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) and increased activity of the lipogenic enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase were observed in plasma and liver. High-density lipoprotein cholesterol (HDL-C) was significantly lowered and very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) were significantly elevated. Treatment with LA (35 mg/kg body weight intraperitoneal) reduced the effects of fructose. The rats showed near-normal levels of lipid components on plasma and tissues. Activities of key enzymes of lipid metabolism were also restored to normal values. Cholesterol distribution in the plasma lipoproteins was normalized, resulting in a favorable lipid profile. This study demonstrates that LA can alter lipid metabolism in fructose-fed insulin-resistant rats and may have implications in the treatment of insulin resistance.


Activity of long-wavelength cones under scotopic conditions in the cyprinid fish Danio aequipinnatus.
In carp (Cyprinus) and goldfish (Carassius), long-wavelength cones are reported to be active under scotopic conditions. Using the electroretinogram (ERG), we tested another cyprinid fish, Danio aequipinnatus, which contains A1-based visual pigments and for which we had previously measured the spectral sensitivities of individual cones. Dark adaptation curves show a rod/cone break at about 45 min. When thoroughly dark-adapted, the spectral sensitivity function is broader than can be accounted for by self-screening of rhodopsin, but it can be modeled by an additive combination of rods and the 560-nm cones. Dim, red background light causes adaptation of rods and a broadening of the spectral sensitivity function, which can be simulated by increasing the proportion of cones in the model. Brighter red backgrounds adapt the 560-nm cones. Because of the effect of red adapting lights, the ERG evidence for the participation of long-wavelength cones close to visual threshold appears to be different in Danio than in the goldfish Carassius.


Solvent selection for solid-to-solid synthesis.
Thermolysin catalyzed solid-to-solid synthesis of the model peptide Z-L-Phe-L-Leu-NH(2) is practically feasible in water and a range of organic solvents with different physicochemical properties. Excellent overall conversions were obtained in acetonitrile, ethyl acetate, n-hexane, methanol, 2-propanol, tert-amyl alcohol, tetrahydrofuran, toluene and water, while no product precipitation was observed in dichloromethane resulting in a much lower yield. In precipitation driven synthesis the product accumulates both in solution and in the solid phase. It was shown that the highest overall yields (yield in the liquid plus yield in the solid) can be expected in solvents where the substrate solubilities are minimized. The best yields of solid product can be expected in solvents where both product and substrate solubilities are lowest. This was in agreement with experimental observations and should be generally valid.


Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer.
MUC1 is a glycoprotein overexpressed in tumors as a hypoglycosylated form. A vaccine composed of a 100-amino acid peptide corresponding to five 20-amino acid long repeats, and SB-AS2 adjuvant, was tested in a phase I study for safety, toxicity, and ability to elicit or boost MUC1-specific immune responses. Patients with resected or locally advanced pancreatic cancer without prior chemotherapy or radiotherapy were eligible. Escalating doses of the peptide (100, 300, 1,000, and 3,000 mug) were admixed with SB-AS2 and administered intramuscularly every 3 weeks for three doses, in cohorts of four patients. Sixteen patients were enrolled. Common adverse effects were grade 1 flu-like symptoms, tenderness, and erythema at the injection site. Delayed-type hypersensitivity (DTH) sites showed few or no T cells prevaccination (Pre V), but increased T-cell infiltration postvaccination (Post V). There was an increase in the percentage of CD8(+) T cells in the peripheral blood Post V. An increase in total MUC1-specific antibody was seen in some patients, and several patients developed IgG antibody. Two of 15 resected pancreatic cancer patients are alive and disease free at follow-up of 32 and 61 months. MUC1 100mer peptide with SB-AS2 adjuvant is a safe vaccine that induces low but detectable mucin-specific humoral and T-cell responses in some patients. No difference was seen between different peptide doses. Further evaluation is warranted to examine the effect on disease-free survival and overall survival, especially in early disease and in the absence of immunosuppressive standard therapy.


A higher-order generalized singular value decomposition for comparison of global mRNA expression from multiple organisms.
The number of high-dimensional datasets recording multiple aspects of a single phenomenon is increasing in many areas of science, accompanied by a need for mathematical frameworks that can compare multiple large-scale matrices with different row dimensions. The only such framework to date, the generalized singular value decomposition (GSVD), is limited to two matrices. We mathematically define a higher-order GSVD (HO GSVD) for N≥2 matrices D(i)∈R(m(i) × n), each with full column rank. Each matrix is exactly factored as D(i)=U(i)Σ(i)V(T), where V, identical in all factorizations, is obtained from the eigensystem SV=VΛ of the arithmetic mean S of all pairwise quotients A(i)A(j)(-1) of the matrices A(i)=D(i)(T)D(i), i≠j. We prove that this decomposition extends to higher orders almost all of the mathematical properties of the GSVD. The matrix S is nondefective with V and Λ real. Its eigenvalues satisfy λ(k)≥1. Equality holds if and only if the corresponding eigenvector v(k) is a right basis vector of equal significance in all matrices D(i) and D(j), that is σ(i,k)/σ(j,k)=1 for all i and j, and the corresponding left basis vector u(i,k) is orthogonal to all other vectors in U(i) for all i. The eigenvalues λ(k)=1, therefore, define the "common HO GSVD subspace." We illustrate the HO GSVD with a comparison of genome-scale cell-cycle mRNA expression from S. pombe, S. cerevisiae and human. Unlike existing algorithms, a mapping among the genes of these disparate organisms is not required. We find that the approximately common HO GSVD subspace represents the cell-cycle mRNA expression oscillations, which are similar among the datasets. Simultaneous reconstruction in the common subspace, therefore, removes the experimental artifacts, which are dissimilar, from the datasets. In the simultaneous sequence-independent classification of the genes of the three organisms in this common subspace, genes of highly conserved sequences but significantly different cell-cycle peak times are correctly classified.


Evaluating a revised self-efficacy scale for preoperative patients.
Nurses conduct preoperative teaching to help patients cope with the adversities of surgery. Self-efficacy can predict an individual's behavior in aversive situations (eg, surgery); therefore, assessing patients' self-efficacy is one way perioperative nurses can plan patient care and help patients through the surgical experience. This study expands on the results of a previous evaluation of a preoperative self-efficacy scale. The content and face validity of the revised 15-item scale used in this study were assessed before the instrument was administered to preoperative patients. Evidence supports the validity of the multidimensional instrument. Internal consistency estimates > or = .84 support the subscales' reliability.


Is pH paper an acceptable, low-cost alternative to the blood gas analyzer for determining pleural fluid pH?
Our laboratory uses pH paper rather than a blood gas analyzer to measure pleural fluid pH to decrease cost and avoid analyzer malfunction due to viscous fluids. To compare these two methods of determining pleural fluid pH, 42 patients undergoing diagnostic or therapeutic thoracentesis had two 1-mL aliquots of pleural fluid anaerobically collected in a heparinized syringe and placed on ice. pH measurements were made using litmus paper (pHydron Vivid 6-8 brand litmus paper; MicroEssential Labs; Brooklyn, NY) and the model 995-Hb blood gas analyzer (AVL Instruments; Roswell, GA) within 1 h of collection. Agreement analysis was performed in three ways: on the entire group; in subcategories of complicated or uncomplicated parapneumonic effusions (<7.1, 7.1 to 7.3, >7.3); and in subcategories of poor prognosis or better prognosis malignant effusions(<7.3, >7.3). pH measured with pH paper was significantly more variable (SD=0.55, coefficient of variation [CV]=7.5%) than was pH measured with the blood gas analyzer (SD=0.11, CV=1.5%). There was no significant correlation between values obtained with the two techniques (r=-0.26, SD of the differences=0.59). Using the pH subcategories, there was 72% discordance in classification between litmus paper and arterial blood gas (ABG) determinations for patients with parapneumonic effusions. In patients with malignant effusions, there was 30% discordance. The pH values obtained by the ABG analyzer predicted tube thoracostomy 72% of the time, whereas the pH values obtained using pH paper were consistent only 36% of the time. Determination of pleural fluid pH using pH paper is unreliable and should not be considered an acceptable alternative to the blood gas analyzer. There is no need to determine pH on purulent samples. Hospital laboratories will be more likely to allow the use of the ABG analyzer on fluids other than blood if clinicians keep this in mind.


[Efficacy of first- or second-line latanoprost on intraocular pressure and ocular symptoms in patients with open-angle glaucoma or ocular hypertension].
The aim of this study was to assess the changes in intraocular pressure (IOP) and ophthalmic symptoms with the Glaucoma Symptom Scale in patients suffering from open-angle glaucoma (OAG) or ocular hypertension (OHT) after 3 months of treatment with latanoprost. This multicentric open study was carried out in adult patients suffering from OAG or simple OHT (naive or previously treated with monotherapy) and needing a change or initiation of anti-glaucomatous treatment. One drop of latanoprost 0.005% was instilled every evening for 12 weeks in each affected eye. Efficacy was assessed by the variation in IOP and ophthalmic symptomatology at the end of treatment. Prognosis factors associated with a relative IOP reduction of at least 30% were sought (using a logistic regression model). A total of 920 patients suffering from OAG (54%) or OHT (44%), either previously treated (69%) or naive (31%), were included. The male:female ratio was 0.78 and the mean age was 63+/-13 years. At inclusion, the mean IOP was 22.1+/-3.8 mmHg. After treatment, IOP was significantly decreased by 5.1+/-4 mmHg, corresponding to a 22% reduction. IOP reduction was 7.1+/-4 mmHg, corresponding to 29% in naive patients and 4.2+/-4 mmHg, corresponding to 19% in previously treated patients. A relative IOP reduction of at least 30% was reached by 47% of naive patients and 21% of previously treated patients. In previously treated patients, a relative IOP reduction of at least 30% had a greater chance of being reached in men with previous ophthalmic history and high IOP at inclusion (above 21 mmHg). IOP reduction was similar in patients with OAG and OHT. A significant improvement in ophthalmic symptoms was observed after treatment in previously treated patients. A total of 7% of the patients presented an adverse event affecting the visual system: eye irritation (2%), eye pain (2%), or eye hyperemia (1%). Compliance was good for 94% of the patients. Latanoprost given as first or second-line treatment at the recommended dose effectively decreases IOP in patients with OAG or OHT. This treatment also improves visual and nonvisual symptoms in previously treated patients and presents a good safety profile.


Probing the structure of the crystalline core of field-aligned, monodisperse, cylindrical polyisoprene-block-polyferrocenylsilane micelles in solution using synchrotron small- and wide-angle X-ray scattering.
The self-assembly of block copolymers in selective solvents represents a powerful approach to functional core-shell nanoparticles. Crystallization of the core can play a critical role in directing self-assembly toward desirable, nonspherical morphologies with low mean interfacial curvature. Moreover, epitaxial growth processes have been implicated in recent advances that permit access to monodisperse cylinders, cylindrical block comicelles with segmented cores and/or coronas, and complex hierarchical architectures. However, how the core-forming block crystallizes in an inherently curved nanoscopic environment has not been resolved. Herein we report the results of synchrotron small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS) studies of well-defined, monodisperse crystalline-coil polyisoprene-block-polyferrocenylsilane cylindrical micelles aligned in an electric field. WAXS studies of the aligned cylinders have provided key structural information on the nature of the PFS micelle core together with insight into the role of polymer crystallinity in the self-assembly of these and potentially related crystalline-coil block copolymers.


[Malignant carcinoid of the duodenum with polymorphism of the neuroendocrine granules].
In a man of 67, malignant multihormonal carcinoid of the duodenum 1 or 2 cm in size with deep penetration into the intestinal wall and multiple metastases into the lymph nodes became a cause of a secondary biliary liver cirrhosis and fatal intestinal haemorrhage. There was a difference between the cell population of a primary tumour in which D-cells dominated and EC-cells were also present and metastasis where a higher level of serotonin and its analogs was detected and where EC-cells dominated and ECL-cells were found as well. This observation confirms the opinion that the malignancy of carcinoid is determined by the degree of its invasiveness. Polymorphism of secretory granules in the cells of the same tumour supports the concept of the unique precursor of APUD-cells.


Ruthenium-Catalyzed C(sp2)-H Bond Bisallylation with Imidazopyridines as Directing Groups.
A Ru(II)-catalyzed bisallylation of imidazopyridines with vinylcyclopropanes or vinyl cyclic carbonate has been successfully realized. Notably, pharmacophore imidazopyridine was utilized as an intrinsic directing group, which gave access to value-added bisallylated products in high yields via double tandem C-H and C-C/C-O activation. The current methodology was featured with broad substrate scope, good functional group compatibility, and operational simplicity.


Ethnic variations in ulcerative colitis: Experience of an international hospital in Thailand.
To investigate the clinical characteristics, treatment, medication use, and treatment response in patients with ulcerative colitis (UC) across ethnic groups. This study retrospectively analyzed medical records of all 268465 patients who visited the Bumrungrad International Digestive Disease Center during 2005-2010. The demographics, clinical characteristics, medication use, results of investigations, and medical and surgical management for patients with UC were evaluated. Evaluation included sigmoidoscopy and colonoscopy performed in compliance with the American Society of Gastrointestinal Endoscopy practice guidelines. Patient ethnicities were categorized into seven groups: Thai, Oriental, South Asian (SA), Middle Eastern (ME), Caucasian, African, and Hispanic. UC pathological severity was classified into inactive, mild, moderate, and severe. Associations between categorical variables were analyzed using the χ(2) or Fischer's exact test. Associations between categorical and interval variables were analyzed using Student's t-test and/or analysis of covariance. UC was diagnosed in 371 of the 268465 patients: male 56.33%; ME 42%, Caucasian 23%, and Thai 19%. Annual incidence of UC was 82 cases per 100000 with wide ethnic variation, ranging from 29 to 206 cases per 100000 in Oriental and ME patients, respectively. Of the patients with UC, 16.71% had severe UC with highest incidence among the patients from ME (20.39%) and lowest among the Caucasian population (11.90%). ME had highest proportion of pancolitis (52.90%), followed by Caucasian (45.35%) and Asian (34.40%). Only 20.93% of Caucasian patients received steroid, compared with 26.40% and 27.10% of Asian and Middle Eastern, respectively (P = 0.732). Overall, 13.72% of UC patients did not respond to steroid therapy, with non-significantly higher proportions of non-responders among Asian and Middle Eastern patients (15.22% and 15.04%, respectively) (P = 0.781). On average, 5.93% underwent surgical management with ethnic variation, ranging from 0% in African to 18% in SA. Cancer was found in three (Thai, ME, and African) cases (0.82 institution-specific incidence). Incidence, symptom duration, pathological severity, clinical manifestations, medication use, treatment response, need for surgical consultation, and cancer incidence of patients with UC potentially vary by ethnicity.


Expedited placement to maximize utilization of marginal organs.
Deceased donation represents the largest supply of organs for transplant in the United States. Organs with suboptimal characteristics related to donor disease or recovery-related issues are increasingly discarded at the time of recovery, prompting late allocation to candidates later in the match sequence. Late allocation contributes to organ injury by prolonging cold ischemia, which may further lead to the risk of organ discard, despite the potential to provide benefit to certain transplant candidates. Expedited placement of marginal organs has emerged as a strategy to address the growing problem of organ discard of marginal organs that have been declined late after recovery. In this review, we describe the basis for expedited organ placement, and approaches to facilitating placement of these grafts, drawing examples from kidney and liver donation and transplantation globally. There is significant global variation in practice related to late allocation. Multiple policy mechanisms exist to facilitate expedited placement, including simultaneous offers to multiple centers, predesignation of aggressive centers, and increasing organ procurement organization autonomy in late allocation. Optimizing late allocation of deceased donor organs holds significant promise to increase the number of transplants.


Primary hyperparathyroidism revisited in menopausal women with serum calcium in the upper normal range at population-based screening 8 years ago.
Population-based screening showed 2.1% prevalence of primary hyperparathyroidism (pHPT) in postmenopausal women. Individuals with total serum (s)-calcium levels of 2.55 mmol/L or more at screening were diagnosed with pHPT when subsequent analysis supported inappropriately elevated intact parathormone (PTH) levels in relation to even normal s-calcium levels. The arbitrary diagnostic criteria were validated by parathyroidectomy. Herein we reinvestigated biochemical signs of pHPT in women not diagnosed with pHPT due to s-calcium 2.50 to 2.54 mmol/L (group A, n = 160) at screening or due to appropriate PTH levels on two occasions after screening (group B, n = 70). Altogether, 99 women in group A and 47 in group B underwent reinvestigation 8.8 years after screening when they were 65 to 84 years old. The s-calcium levels averaged 2.56 mmol/L and had increased in group A (mean 0.04 mmol/L) and decreased in group B (mean 0.05 mmol/L). A total of 48 and 18 females (48%, 38%), respectively, met the previously validated criteria of pHPT. Altogether 21% of them were hypercalcemic (range 2.60-3.12 mmol/L). Subgroup analysis showed that PTH had not increased with time (n = 47) and that atherogenic blood lipids, but not glucose levels, were similar in pHPT patients and matched controls (n = 37). Assuming the existence of pHPT already at screening, the prevalence of pHPT could be adjusted to 3.4%. Even the most liberal diagnostic criteria utilized at pHPT screening seemed to underdiagnose the disease by inefficient cutoff limits for s-calcium and PTH. Because one-fifth of the women with pHPT progressed to hypercalcemia, long-term follow-up is advocated for those with s-calcium in the upper normal range.


Linking coordinated hydraulic traits to drought and recovery responses in a tropical montane cloud forest.
Understanding plant hydraulic functioning and water balance during drought has become key in predicting species survival and recovery. However, there are few insightful studies that couple physiological and morphological attributes for many ecosystems, such as the vulnerable Tropical Montane Cloud Forests (TMCF). In this study, we evaluated drought resistance and recovery for saplings for five tree species spanning deciduous to evergreen habits from a Mexican TMCF. In drought simulations, water was withheld until plants reached species-specific P50 or P88 values (pressures required to induce a 50 or 88% loss in hydraulic conductivity), then they were rewatered. Drought resistance was considered within the isohydric-anisohydric framework and compared to leaf gas exchange, water status, pressure-volume curves, specific leaf area, and stomatal density. The TMCF species closed stomata well before significant losses in hydraulic conductivity (isohydric). Yet, despite the coordination of these traits, the traits were not useful for predicting the time needed for the species to reach critical hydraulic thresholds. Instead, maximum photosynthetic rates explained these times, reinforcing the linkage between hydraulic and carbon dynamics. Despite their varying hydraulic conductivities, stomatal responses, and times to hydraulic thresholds, 58 of the 60 study plants recovered after the rewatering. The recovery of photosynthesis and stomatal conductance can be explained by the P50 values and isohydry. This study raises new questions surrounding drought management strategies, recovery processes, and how lethal thresholds are defined. Further studies need to consider the role of water and carbon balance in allowing for both survival and recovery from drought.


Non-albicans Candida infections in patients with hematologic malignancies.
The epidemiology of invasive Candida infections is characterized by a recent decline in Candida albicans and C. tropicalis with a concomitant increase in the incidence of non-albicans Candida species such as C. glabrata and C. krusei, a phenomenon at least partly ascribed to triazole use. Of particular concern is the recognition that these organisms are multiresistant, adding a new dimension to the challenge of management. C. lusitaniae, though uncommon, mainly presents as breakthrough fungemias in patients on antifungal therapy. C. parapsilosis, an organism of relatively low virulence, plays an increasing role because of its ability to cause intravenous line and hyperalimentation fluid colonization. Emergence of azole-resistant (relative or absolute) Candida species is being met by a new class of antifungal agents namely the echinocandins and a new generation of broad-spectrum triazole agents. This article addresses the biology, epidemiology, prognostic factors, and management of an emerging group of pathogens such as non-albicans Candida.


Protective effects of voluntary exercise during the postinitiation phase of pancreatic carcinogenesis in the rat.
Studies were undertaken to evaluate the effects of exercise on the development of pancreatic cancer. Exercise is one life-style factor that has received little attention with regard to its role in the etiology of cancer. Male Lewis and female F344 rats were initiated with azaserine during the suckling period and weaned to the experimental protocols. Food and water were available ad libitum. A purified diet of 20% unsaturated fat was fed to both the sedentary and exercise groups. Rats of the exercise group had free access to voluntary exercise wheels. At approximately 2 and 4 months postinitiation, pancreases were evaluated for the number and size of azaserine-induced putative preneoplastic foci by quantitative stereology. Voluntary exercise activity peaked at approximately 2 months postinitiation with a gradual decline in activity there-after. Male Lewis rats averaged 0.95 +/- 0.13 km/day (SE) and female F344 rats averaged 2.73 +/- 0.26 km/day of voluntary wheel running. Compared with the sedentary groups, male Lewis and female F344 rats with access to the running wheels had significantly smaller foci at 4 months postinitiation. Azaserine-induced foci were evaluated in the male Lewis rats at both 2 and 4 months postinitiation. At 4 months postinitiation, the size and growth rate (as measured by [3H]thymidine autoradiography) of foci were less in the rats with access to the exercise wheels. No differences were observed at 2 months postinitiation. Access to voluntary exercise reduced the growth rate of azaserine-induced pancreatic foci. The effect occurred late in the postinitiation phase and was not directly related to the extent of running activity early in the postinitiation phase.


The Impact of Frailty on Morbidity and Mortality following Open Emergent Colectomies.
Elderly and frail patients undergo open emergency colectomies and are at greater risk for complications. The relationship between frailty and open emergent colectomies is yet unexplored. The purpose of this study was to evaluate the relationship between frailty and outcomes after open emergent colorectal surgery. Using the American College of Surgeons National Quality Improvement Program database, a validated modified frailty index was used, along with logistic regression, to assess the relationship between frailty and outcomes. Outcomes included mortality (primary), Clavien-Dindo Complication Grade >3, reintubation, ventilator >48 hours, and reoperation (secondary). The rates for 30-day mortality, Clavien-Dindo Grade >3, reintubation, ventilator > 48 hours, and reoperation in our cohort were 16.6%, 36.9%, 8.6%, 23.9%, and 15.0%, respectively. There was a statistically significant increase in prevalence of all outcomes with increasing frailty. A causal relationship between frailty and complications cannot be established in a retrospective analysis. Also, extrapolation of our data to reflect outcomes beyond 30 days must be done with caution. Frailty is a statistically significant predictor of mortality and morbidity after open emergent colectomies and can be used in an acute care setting.


Salmonellosis in captive black rhinoceroses (Diceros bicornis).
Salmonellosis caused by Salmonella enterica subspecies arizonae (formerly known as Salmonella arizonae) was diagnosed in three of five captive black rhinoceroses (Diceros bicornis) at the Denver Zoological Gardens. Two of the three animals died despite supportive treatment. The other two rhinoceroses remained asymptomatic and were negative for Salmonella spp. after serial fecal cultures. The source for the salmonellosis was never identified.


Clinical characteristics of Nocardia infection in patients with rheumatic diseases.
Although Nocardiosis has considerable recurrence and mortality rates, characteristics and risk factors of Nocardia infection have not been assessed in patients with rheumatic diseases. Here, we examined the characteristics and risk factors of Nocardia infection in rheumatic disease patients in our hospital. Ten rheumatic disease patients who developed Nocardia infection were identified by retrospectively reviewing the medical records. Possible predisposing factors for Nocardia infection were high-dose glucocorticoid treatment, concomitant use of immunosuppressants, preexisting pulmonary diseases, and diabetes mellitus. All patients had pulmonary Nocardiosis, and six of them had disseminated Nocardiosis when their pulmonary lesions were identified.


Selective dephasing of OH and NH proton magnetization based on (1)H chemical-shift anisotropy recoupling.
A method for selectively suppressing the signals of OH and NH protons in (1)H combined rotation and multiple-pulse spectroscopy (CRAMPS) and in (1)H-(13)C heteronuclear correlation (HETCOR) solid-state NMR spectra is presented. It permits distinction of overlapping CH and OH/NH proton signals, based on the selective dephasing of the magnetization of OH and NH protons by their relatively large (1)H chemical-shift anisotropies. For NH protons, the (14)N-(1)H dipolar coupling also contributes significantly to this dephasing. The dephasing is achieved by a new combination of heteronuclear recoupling of these anisotropies with (1)H homonuclear dipolar decoupling. Since the 180 degrees pulses traditionally used for heteronuclear dipolar and chemical-shift anisotropy recoupling would result in undesirable homonuclear dephasing of proton magnetization, instead the necessary inversion of the chemical-shift Hamiltonian every half rotation period is achieved by inverting the phases of all the pulses in the HW8 multiple-pulse sequence. In the HETCOR experiments, carefully timed (13)C 180 degrees pulses remove the strong dipolar coupling to the nearby (13)C spin. The suppression of NH and OH peaks is demonstrated on crystalline model compounds. The technique in combination with HETCOR NMR is applied to identify the CONH and NH-CH groups in chitin and to distinguish NH and aromatic proton peaks in a peat humin.


Legal aspects of open disclosure: a review of Australian law.
Health professionals worry that information about adverse events conveyed to patients in open disclosure (OD) may be used against them in medicolegal proceedings. Whether and how strongly state and federal laws in Australia protect against such uses is unclear. Our analysis concludes that existing laws do not prohibit the sharing of most types of information on adverse events with patients. However, none of these laws was enacted with OD in mind and, in general, the protections they provide are quite weak. If policymakers want OD to become a routine part of medical practice, law reform may be needed in the form of stronger protections directed specifically at the contents of OD communications.


Concentrations of Trace Elements in Hemodialysis Patients: A Prospective Cohort Study.
Low concentrations and excessive concentrations of trace elements have been commonly reported in hemodialysis patients, but available studies have several important limitations. Random sample of patients drawn from a prospective cohort. 198 incident hemodialysis patients treated in 3 Canadian centers. We used mass spectrometry to measure plasma concentrations of the 25 elements at baseline, 6 months, 1 year, and 2 years following enrollment in the cohort. We focused on low concentrations of zinc, selenium, and manganese and excessive concentrations of lead, arsenic, and mercury; low and excessive concentrations of the other 19 trace elements were treated as exploratory analyses. Low and excessive concentrations were based on the 5th and 95th percentile plasma concentrations from healthy reference populations. At all 4 occasions, low zinc, selenium, and manganese concentrations were uncommon in study participants (≤5.1%, ≤1.8%, and ≤0.9% for zinc, selenium, and manganese, respectively) and a substantial proportion of participants had concentrations that exceeded the 95th percentile (≥65.2%, ≥74.2%, and ≥19.7%, respectively). Almost all participants had plasma lead concentrations above the 95th percentile at all time points. The proportion of participants with plasma arsenic concentrations exceeding the 95th percentile was relatively constant over time (9.1%-9.8%); the proportion with plasma mercury concentrations that exceeded the 95th percentile varied between 15.2% and 29.3%. Low arsenic, platinum, tungsten, and beryllium concentrations were common (>50%), as were excessive cobalt, manganese, zinc, vanadium, cadmium, selenium, barium, antimony, nickel, molybdenum, lead, and chromium concentrations. There was no evidence that low zinc, selenium, or manganese concentrations exist in most contemporary Canadian hemodialysis patients. Some patients have excessive plasma arsenic and mercury concentrations, and excessive lead concentrations were common. These findings require further investigation.


Low pH-Based Method to Increase the Yield of Plant-Derived Nanoparticles from Fresh Ginger Rhizomes.
Plant-derived nanoparticles (PDNPs) are naturally occurring exosome-like nanovesicles derived from dietary plants containing key plant bioactives. Ginger-derived PDNPs have a therapeutic effect on alcohol-induced liver injury, inflammatory bowel disease, and colon cancer. PDNPs are conventionally purified by differential ultracentrifugation, a technique not amenable for scale up. We have recently developed a polyethylene glycol (PEG) 6000-based method for cost-effective purification of ginger PDNPs, with comparable efficiency to differential ultracentrifugation (Sci. Rep. 2020, 10 (1), 4456.). Herein, we report a 4-5-fold higher ginger PDNP recovery when PEG precipitation was carried out in low pH conditions (pH 4 and 5). Low pH-derived ginger PDNPs were smaller in size without an overt change in zeta potential. The spontaneous intracellular entry and protection against oxidative stress in A431 cells were similar between ginger PDNPs purified under low, neutral, and alkaline pH. Low-pH purified ginger PDNPs had higher levels of total polyphenolic content compared to PDNPs purified under neutral and alkaline pH. Recently, ginger PDNP-derived microRNAs have been shown to exhibit cross-kingdom regulation by targeting human, gut microbiome, and viral transcripts. Using qRT-PCR, we also verified the presence of miRNAs that were predicted to target SARS-CoV-2 in ginger PDNPs purified under low pH. Thus, we have developed a method to purify ginger PDNPs in high yields by using low-pH conditions without affecting the major bioactive contents of PDNPs.


Interpreting observational studies: why empirical calibration is needed to correct p-values.
Often the literature makes assertions of medical product effects on the basis of ' p < 0.05'. The underlying premise is that at this threshold, there is only a 5% probability that the observed effect would be seen by chance when in reality there is no effect. In observational studies, much more than in randomized trials, bias and confounding may undermine this premise. To test this premise, we selected three exemplar drug safety studies from literature, representing a case-control, a cohort, and a self-controlled case series design. We attempted to replicate these studies as best we could for the drugs studied in the original articles. Next, we applied the same three designs to sets of negative controls: drugs that are not believed to cause the outcome of interest. We observed how often p < 0.05 when the null hypothesis is true, and we fitted distributions to the effect estimates. Using these distributions, we compute calibrated p-values that reflect the probability of observing the effect estimate under the null hypothesis, taking both random and systematic error into account. An automated analysis of scientific literature was performed to evaluate the potential impact of such a calibration. Our experiment provides evidence that the majority of observational studies would declare statistical significance when no effect is present. Empirical calibration was found to reduce spurious results to the desired 5% level. Applying these adjustments to literature suggests that at least 54% of findings with p < 0.05 are not actually statistically significant and should be reevaluated.


The road less traveled: emerging principles of kinesin motor utilization.
Proteins of the kinesin superfamily utilize a conserved catalytic motor domain to generate movements in a wide variety of cellular processes. In this review, we discuss the rapid expansion in our understanding of how eukaryotic cells take advantage of these proteins to generate force and movement in diverse functional contexts. We summarize several recent examples revealing that the simplest view of a kinesin motor protein binding to and translocating a cargo along a microtubule track is inadequate. In fact, this paradigm captures only a small subset of the many ways in which cells harness force production of the generation of intracellular movements and functions. We also highlight several situations where the catalytic kinesin motor domain may not be used to generate movement, but instead may be used in other biochemical and functional contexts. Finally, we review some recent ideas about kinesin motor regulation, redundancy, and cargo attachment strategies.


Effect of surface treatment of CAD/CAM resin composites on the shear bond strength of self-adhesive resin cement.
This study examined the effects of sandblasting, hydrofluoric acid etching and priming on the shear bond strength of self-adhesive resin cement between seven different CAD/CAM resin composites and a resin composite core material at 24-h after cement mixing. Five surface treatments [control (C), sandblasting (S), priming (P), sandblasting with priming (SP), and 9% HF etching with priming (HFP)] were performed respectively for disc specimens of CAD/CAM blocks. There were no significant differences in bond strength among the C, S, and P, except for one block (p>0.05). SP showed a greater bond strength than S. Weibull moduli were not changed significantly among all treatments for all blocks, whereas the strengths with 5% and 95% failure probability of SP and HFP showed greater values than the others. The bond strengths of HFP were comparable to those of SP. Priming after sandblasting or HF etching could be effective to increase the bond strength of CAD/CAM blocks.


Agrobacterium tumefaciens AK-6b gene modulates phenolic compound metabolism in tobacco.
The 6b gene (AK-6b) of Agrobacterium tumefaciens AKE10 can substitute for the requirement of tobacco tissues for auxin and cytokinin to maintain callus growth in the culture medium. To identify compounds that might be involved in this process we analyzed phenolic metabolites in transgenic tobacco tissues expressing the AK-6b gene. On medium containing both cytokinin and auxin (SH medium), transgenic calli accumulated higher levels of chlorogenic acid, caffeoyl putrescine, rutin and kaempferol-3-rutinoside, than did wild-type tissues. In contrast, the levels of scopolin and its aglycone, scopoletin were lower in transgenic tissues. On hormone-free medium, these phenolic compounds showed neither significant levels nor an apparent relationship with AK-6b transcript levels, except for the negatively correlated levels of scopoletin and AK-6b transcripts. Apparently, the AK-6b gene acts, in SH medium, to redirect the synthesis of scopolin in tobacco tissues towards the preferential synthesis of caffeic acid derivatives and flavonoids.


[Causes of divorce].
Results are presented from a 1991 survey on causes of divorce in Poland. "From the women's point of view, alcohol abuse by husband, infidelity, a lack of interest in family life and lack of responsibility were the most frequent causes of the divorces. For men, the most important causes were...a lack of understanding between spouses, infidelity and the influence of other people (mainly parents)." (SUMMARY IN ENG)


Local Rather than Global H3K27me3 Dynamics Are Associated with Differential Gene Expression in Verticillium dahliae.
Differential growth conditions typically trigger global transcriptional responses in filamentous fungi. Such fungal responses to environmental cues involve epigenetic regulation, including chemical histone modifications. It has been proposed that conditionally expressed genes, such as those that encode secondary metabolites but also effectors in pathogenic species, are often associated with a specific histone modification, lysine27 methylation of H3 (H3K27me3). However, thus far, no analyses on the global H3K27me3 profiles have been reported under differential growth conditions in order to assess if H3K27me3 dynamics govern differential transcription. Using chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing data from the plant-pathogenic fungus Verticillium dahliae grown in three in vitro cultivation media, we now show that a substantial number of the identified H3K27me3 domains globally display stable profiles among these growth conditions. However, we observe local quantitative differences in H3K27me3 ChIP-seq signals that are associated with a subset of differentially transcribed genes between media. Comparing the in vitro results to expression during plant infection suggests that in planta-induced genes may require chromatin remodeling to achieve expression. Overall, our results demonstrate that some loci display H3K27me3 dynamics associated with concomitant transcriptional variation, but many differentially expressed genes are associated with stable H3K27me3 domains. Thus, we conclude that while H3K27me3 is required for transcriptional repression, it does not appear that transcriptional activation requires the global erasure of H3K27me3. We propose that the H3K27me3 domains that do not undergo dynamic methylation may contribute to transcription through other mechanisms or may serve additional genomic regulatory functions. IMPORTANCE In many organisms, including filamentous fungi, epigenetic mechanisms that involve chemical and physical modifications of DNA without changing the genetic sequence have been implicated in transcriptional responses upon developmental or environmental cues. In fungi, facultative heterochromatin that can decondense to allow transcription in response to developmental changes or environmental stimuli is characterized by the trimethylation of lysine 27 on histone H3 (H3K27me3), and H3K27me3 has been implicated in transcriptional regulation, although the precise mechanisms and functions remain enigmatic. Based on ChIP and RNA sequencing data, we show for the soilborne broad-host-range vascular wilt plant-pathogenic fungus Verticillium dahliae that although some loci display H3K27me3 dynamics that can contribute to transcriptional variation, other loci do not show such a dependence. Thus, although we recognize that H3K27me3 is required for transcriptional repression, we also conclude that this mark is not a conditionally responsive global regulator of differential transcription upon responses to environmental cues.


Benefits and problems of electronic information exchange as perceived by health care professionals: an interview study.
Various countries are currently implementing a national electronic patient record (n-EPR). Despite the assumed positive effects of n-EPRs, their overall adoption remains low and meets resistance from health care providers. This study aims to increase our understanding of health care providers' attitude towards the n-EPR, by investigating their perceptions of the benefits and problems of electronic information exchange in health care and the n-EPR in particular. The study was conducted in three Dutch health care settings: acute care, diabetes care, and ambulatory mental health care. Two health care organisations were included per setting. Between January and June 2010, interviews were conducted with 17 stakeholders working in these organisations. Relevant themes were deduced by means of thematic qualitative analysis. Health care providers perceived electronic information exchange to promote the efficiency and quality of care. The problems they perceived in electronic information exchange mainly concerned the confidentiality and safety of information exchange and the reliability and quality of patient data. Many problems perceived by health care providers did not specifically apply to the n-EPR, but to electronic information exchange in general. The implementation of the Dutch n-EPR has mainly followed a top-down approach, thereby neglecting the fact that the perceptions and preferences of its users (health care providers) need to be addressed in order to achieve successful implementation. The results of this study provide valuable suggestions about how to promote health care providers' willingness to adopt electronic information exchange, which can be useful for other countries currently implementing an n-EPR. Apart from providing information about the benefits and usefulness of electronic information exchange, efforts should be focused on minimising the problems as perceived by health care providers. The safety and confidentiality of electronic information exchange can be improved by developing tools to evaluate the legitimacy of access to electronic records, by increasing health care providers' awareness of the need to be careful when using patient data, and by measures to limit access to sensitive patient data. Improving health care providers' recording behaviour is important to improve the reliability and quality of electronically exchanged patient data.


Limitations of a mouse model of sickle cell anemia.
We aimed to use an established murine model of sickle cell anemia to develop an unambiguous method for testing new therapies, with survival as an end point. Survival rates following various challenges were compared for three different groups of mice: (a) sickle cell mice expressing human hemoglobin-S exclusively ((h)beta(s)); (b) littermates that expressed both human hemoglobin S and murine beta major globin ((h)beta(s)(m)beta); and (c) wild-type C57BL/6 mice (wt). Two types of challenge were tested. The first set of studies was based upon recent observations indicating that granulocyte-colony stimulating factor (G-CSF) can precipitate severe complications in patients with sickle cell disease. While (h)beta(s) mice had higher neutrophil counts than (h)beta(s)(m)beta mice at baseline, (h)beta(s) mice tolerated several different doses and schedules of either human or murine G-CSF without adverse effects. A second type of challenge tested whether sickle cell mice exhibit an enhanced susceptibility to hemoglobin deoxygenation. Acute hemoglobin deoxygenation was accomplished either by a single intraperitoneal injection of sodium bisulfite or by a 1-h exposure to hypoxia. Neither intervention resulted in a significantly different survival rate for (h)beta(s) mice compared to either (h)beta(s)(m)beta or wt mice. Chronic twice-weekly exposures to hypoxia (1 h per exposure) also failed to produce significant differences in survival rates between (h)beta(s) mice, (h)beta(s)(m)beta, and wt mice over a period of 12 weeks. Our results demonstrate that neither G-CSF administration nor hypoxia accentuates survival differences between this model of sickle cell mouse and normal controls.