[Evidence for the production of a fusion factor during in vitro infection of sheep choroid plexus cells by visna virus].
One of the most important early events during the infection of sheep choroïd plexus cells in culture by Visna virus is the synthesis by these cells of a fusion factor distinct from the virus. The cell fusion activity of this factor does not seem transmissible. It promotes cell shape changes and a migration of the nucleus towards the cell wall.


Inverse relationship between Fusobacterium nucleatum amount and tumor CD274 (PD-L1) expression in colorectal carcinoma.
The CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) immune checkpoint axis is known to regulate the antitumor immune response. Evidence also supports an immunosuppressive effect of Fusobacterium nucleatum. We hypothesised that tumor CD274 overexpression might be inversely associated with abundance of F. nucleatum in colorectal carcinoma. We assessed tumor CD274 expression by immunohistochemistry and F. nucleatum DNA within tumor tissue by quantitative PCR in 812 cases among 4465 incident rectal and colon cancer cases that had occurred in two prospective cohort studies. Multivariable logistic regression analyses with inverse probability weighting were used to adjust for selection bias because of tissue data availability and potential confounders including microsatellite instability status, CpG island methylator phenotype, LINE-1 methylation level and KRAS, BRAF and PIK3CA mutations. Fusobacterium nucleatum DNA was detected in tumor tissue in 109 (13%) cases. Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue (P = 0.0077). For one category-unit increase in three ordinal F. nucleatum categories (negative vs. low vs. high), multivariable-adjusted odds ratios (with 95% confidence interval) of the low, intermediate and high CD274 categories (vs. negative) were 0.78 (0.41-1.51), 0.64 (0.32-1.28) and 0.50 (0.25-0.99), respectively (P trend = 0.032). Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting that different immunosuppressive mechanisms (i.e. PDCD1 immune checkpoint activation and tumor F. nucleatum enrichment) tend to be used by different tumor subgroups.


[Mechanism of the anti-arrhythmia action of potassium and magnesium nicotinates].
It has been shown in rat experimental aconitinic arrhythmia and in dog postinfarction arrhythmia that combined potassium and magnesium nicotinates show a pronounced anti-arrhythmic effect. The studies on the drug distribution in the tissues indicate that the content of potassium, magnesium and total coenzymatic forms of nicotinic acid rises in the myocardium by the 12th hour from the commencement of the drug administration. Intracellular and exocellular content of potassium and sodium has been shown to return to normal.


Wear of ceramic and antagonist--a systematic evaluation of influencing factors in vitro.
(1) To systematically review the existing literature on in vitro assessments of antagonist wear of ceramic materials; (2) To systematically evaluate possible influencing factors on material and antagonist wear of ceramic specimens. The database MEDLINE was searched with the terms "enamel," "wear" and "antagonist." The selected studies were analyzed with regard to wear parameters, type of antagonist and outcome. In the laboratory study, three ceramic materials were selected with different compositions and physical properties: IPS d.SIGN low-fusing metal ceramic, IPS Empress leucite ceramic, e.max Press lithium disilicate ceramic. These materials were subjected to the Ivoclar wear method (Willytec chewing simulator, 120,000cycles, 5kg weight) by systematically modifying the following variables which resulted in 36 tests with 8 specimens in each group: (1) configuration (flat, crown specimen), (2) surface treatment (polish, glaze), (3) type of antagonist (ceramic, two types of enamel stylus). Furthermore, the enamel styluses were cut to measure the enamel thickness and cusp width. Wear of both the material and the antagonist was quantified by scanning plaster replicas of the specimens with a laser scanner (etkon es1) and matching baseline and follow-up data with the Match 3D software (Willytec). The data were log-transformed to stabilize the variance and achieve near normality. To test the influence of specific test parameters, a four-way ANOVA with post hoc tests and Bonferroni correction was applied. The systematic review revealed 20 in vitro studies in which a material and the antagonist wear of the same material was examined. However, the results were inconsistent mainly due to the fact that the test parameters differed widely. Most studies used prepared enamel from extracted molars as the antagonist and flat polished ceramic specimens. The test chamber was filled with water and some sort of sliding movement was integrated in the wear generating process. However, there was a huge variation in relation to the applied force, the used force actuator, the number of cycles, and the frequency of cycles per time as well as the number of specimens. The results of the systematic laboratory tests revealed that the following factors strongly influence the wear: configuration (more material wear of flat versus crown specimens), surface treatment (more antagonist wear of glazed versus polished specimens), the antagonist system (more material wear and less antagonist wear for ceramic stylus versus enamel stylus), and enamel thickness (less wear for thicker enamel). Material wear was not very much different between the materials. However, e.max Press generally caused more antagonist wear than the other two materials, which were quite similar. However, the main influencing factors did not yield consistent results for all the subgroups and there was a huge variability of results within the subgroups especially in those groups that used enamel as antagonist. As far as consistency and correlation with clinical studies is concerned, the set-up that consists of unprepared enamel of molar cusps against glazed crowns seems to be the most appropriate method to evaluate a ceramic material with regard to antagonist wear. However, due to the high variability of results large sample sizes are necessary to differentiate between materials, which calls the whole in vitro approach into question.


Epsilonproteobacteria represent the major portion of chemoautotrophic bacteria in sulfidic waters of pelagic redoxclines of the Baltic and Black Seas.
Recent studies have indicated that chemoautotrophic Epsilonproteobacteria might play an important role, especially as anaerobic or microaerophilic dark CO(2)-fixing organisms, in marine pelagic redoxclines. However, knowledge of their distribution and abundance as actively CO(2)-fixing microorganisms in pelagic redoxclines is still deficient. We determined the contribution of Epsilonproteobacteria to dark CO(2) fixation in the sulfidic areas of central Baltic Sea and Black Sea redoxclines by combining catalyzed reporter deposition-fluorescence in situ hybridization with microautoradiography using [(14)C]bicarbonate and compared it to the total prokaryotic chemoautotrophic activity. In absolute numbers, up to 3 x 10(5) (14)CO(2)-fixing prokaryotic cells ml(-1) were enumerated in the redoxcline of the central Baltic Sea and up to 9 x 10(4) (14)CO(2)-fixing cells ml(-1) were enumerated in the Black Sea redoxcline, corresponding to 29% and 12%, respectively, of total cell abundance. (14)CO(2)-incorporating cells belonged exclusively to the domain Bacteria. Among these, members of the Epsilonproteobacteria were approximately 70% of the cells in the central Baltic Sea and up to 100% in the Black Sea. For the Baltic Sea, the Sulfurimonas subgroup GD17, previously assumed to be involved in autotrophic denitrification, was the most dominant CO(2)-fixing group. In conclusion, Epsilonproteobacteria were found to be mainly responsible for chemoautotrophic activity in the dark CO(2) fixation maxima of the Black Sea and central Baltic Sea redoxclines. These Epsilonproteobacteria might be relevant in similar habitats of the world's oceans, where high dark CO(2) fixation rates have been measured.


Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy.
Men with localized prostate cancer and a preoperative prostate-specific antigen (PSA) velocity greater than 2.0 ng/mL per year experience a 10-fold increase in prostate cancer-specific mortality despite surgery. To assess whether a greater than 2.0-ng/mL increase in PSA level during the year prior to diagnosis was significantly associated with prostate cancer-specific mortality following radiation therapy (RT). Between January 1, 1989, and December 1, 2002, 358 men treated with RT for localized prostate cancer formed the study cohort (median age at treatment, 71.2 [range, 43.2-83.5] years). A Cox regression multivariable analysis was used to evaluate whether a PSA velocity greater than 2.0 ng/mL per year was significantly associated with prostate cancer-specific mortality and all-cause mortality after controlling for prognostic factors available at diagnosis. Time to prostate cancer-specific mortality for the 125 men with low-risk prostate cancer (clinical tumor category T1c or T2a and PSA level <10.0 ng/mL and Gleason score < or =6) and the 233 men with higher-risk disease, stratified by the PSA velocity. A PSA velocity greater than 2.0 ng/mL per year was significantly associated with a shorter time to prostate cancer-specific mortality (adjusted hazard ratio [HR], 12.0; 95% confidence interval [CI], 3.0-54.0; P = .001) and all-cause mortality (adjusted HR, 2.1; 95% CI, 1.3-3.6; P = .005) when compared with men whose PSA velocity was 2.0 ng/mL per year or less. Men presenting with low-risk disease and a PSA velocity greater than 2.0 ng/mL per year had a 7-year estimate of prostate cancer-specific mortality of 19% (95% CI, 2%-39%) compared with 0% for men whose PSA velocity was 2.0 ng/mL per year or less. The corresponding values for men with higher-risk disease were 24% (95% CI, 12%-37%) and 4% (95% CI, 0%-11%), respectively. A greater than 2.0-ng/mL increase in PSA level during the year prior to diagnosis is associated with a significantly higher risk of death due to prostate cancer following RT despite having low-risk disease. Such men who are planning to undergo RT and are in good health could be considered for RT combined with androgen suppression therapy because this approach improves survival in men with higher-risk disease.


A novel non-word speech preparation task to increase stuttering frequency in experimental settings for longitudinal research.
The variable and intermittent nature of stuttering makes it difficult to consistently elicit a sufficient number of stuttered trials for longitudinal experimental research. This study tests the efficacy of using non-word pairs that phonetically mimic English words with no associated meaning, to reliably elicit balanced numbers of stuttering and fluent trials over multiple sessions. The study also evaluated the effect of non-word length on stuttering frequency, the consistency of stuttering frequency across sessions, and potential carry-over effects of increased stuttering frequency in the experimental task to conversational and reading speech after the task. Twelve adults who stutter completed multiple sessions (mean of 4.8 sessions) where they were video-recorded during pre-task reading and conversation, followed by an experimental task where they read 400 non-word pairs randomized for each session, and then a post-task reading and conversation sample. On average, across sessions and participants, non-word pairs consistently yielded a balanced distribution of fluent (60.7%) and stuttered (39.3%) trials over five sessions. Non-word length had a positive effect on stuttering frequency. No carryover effects from experimental to post-task conversation and reading were found. Non-word pairs effectively and consistently elicited balanced proportions of stuttered and fluent trials. This approach can be used to gather longitudinal data to better understand the neurophysiological and behavioral correlates of stuttering.


Trivalent and quadrivalent MF59(®)-adjuvanted influenza vaccine in young children: a dose- and schedule-finding study.
Young children are at increased risk for influenza infections and related complications. The protection offered to children by conventional trivalent inactivated influenza vaccines (TIV) is suboptimal, due to poor immunogenicity and a higher exposure to infection and complications in this age group, particularly from influenza B strains. In this dose-ranging, factorial design trial, we report the safety and immunogenicity of different combinations of adjuvanted (ATIV) and non-adjuvanted trivalent (TIV) and quadrivalent (QIV) influenza vaccines in 480 healthy children 6 to <36 months of age. The results show that the second B strain added to TIV was immunogenic and did not affect immunogenicity of the other strains. The addition of the MF59(®) adjuvant promoted robust immune responses with notable elevations in antibodies observed even after one dose. A dose-response relationship was observed between the antibody response and MF59 adjuvant. No patterns in safety and tolerability emerged with different adjuvant and antigen doses nor with the addition of a second B strain. MF59-adjuvanted QIV offers potential advantages to young children.


Interaction of cytochrome c with the phosphorprotein phosvitin.
Candida krusei cytochrome c forms a molecular complex with phosphorprotein phosvitin in weakly alkaline solution of low ionic strength. At most, about 22 molecules of cytochrome c bind to a phosvitin molecule. The complex at the binding ratio below about 11 (half of the maximum ratio) as a much higher binding strength. Several lines of evidence indicate that the marked difference in the binding strength is due to the difference in negative charges on phosvitin molecule concerned in the binding of a cytochrome c molecule. The phosvitin-bound cytochrome c seems to have a preferred orientation with the front surface of the molecule containing the exposed heme edge in contact with the phosvitin molecule.


Exendin-4 does not modify growth or apoptosis of human colon cancer cells.
Glucagon-like peptide-1 (GLP-1) receptor agonists are a kind of very popular antidiabetes drugs. They promote cell proliferation and survival through activation of signaling pathways in human islet cells involving phosphate idylinositol 3 kinase (PI3K) and extracellular regulated kinases 1 and 2 (ERK1/2), which are frequently activated in human colon cancer cells. Then, it is possible that taking GLP-1 receptor (GLP-1R) agonists persistently would induce proliferation of β cells as well as colon cancer cells. So, clarifying the effects and mechanisms of GLP-1R agonists on colon cancer cells has important clinical implications. We investigated GLP-1R expression in human colon cancer tissue samples with immunohistochemisty analysis and explored the effects of exendin-4, a GLP-1 receptor agonist, on colon cancer cells in vitro and in vivo. The results showed lack of GLP-1R expression in both human colon cancer tissues and colon cancer cell lines. Exendin-4 did not enhance the proliferation and migration of colon cancer cell lines in vitro, and nor did it inhibit apoptosis induced by cytotoxic agents such as 5-fluorouracil (5-FU) or irinotecan. In addition, exendin-4 did not promote the propagation of colon cancer cells in vivo. Our study suggests that GLP-1R agonists do not modify the growth or survival of human colon cancer cells and may be safe for diabetic patients with colon cancer.


The distances travelled by drifting invertebrates in a Lake District stream.
The distances travelled by drifting invertebrates of 18 taxa were investigated at sites 3 and 4 in the Wilfin Beck, a small stony stream in the English Lake District. Fifty invertebrates of the same taxon were released into the stream at increasing distances upstream from a large net which caught all invertebrates drifting downstream.The relationship between the catch in the net (Y x ) and the distance from the release point to the net (X m) was well described by the regression equation:[Formula: see text] whereR is the constant relative rate of return of invertebrates to the bottom of the stream, andA=Y 0=number of invertebrates released at each point=50. Values ofR, the mean drift distance ([Formula: see text] m), and the distance (X p m) travelled byP% (1%, 10%, 50%) of the drifting invertebrates were calculated for each taxon at different modal water velocities. Values ofR,[Formula: see text] andX p were fairly constant for each taxon at a particular modal water velocity, and were not significantly affected by the source of the experimental animals (benthos or drift), by changes in illumination (daylight or darkness), or by seasonal changes, including water temperature.The experimental taxa at site 4 were divided into the following three groups according to their ability to return to the bottom: 1. Polycelis felina, Ancylus fluviatilis, Chironomidae, Eliminthidae, andAmphinemura sulcicollis. Values ofR,[Formula: see text],X p not significantly different from those obtained for dead invertebrates, which were removed from the drift by chance effects. 2. Protonemura meyeri, Leuctra spp.,Chloroperla spp.,Rhithrogena semicolorata, Simulium spp. Values ofR,[Formula: see text],X p not significantly different from those obtained for dead invertebrates at modal water velocities ≧19 cm/sec. At low velocities (10-12 cm/sec),R was significantly greater and[Formula: see text],X p significantly smaller than values obtained for dead invertebrates. 3. Erpobdella octoculata, Gammarus pulex, Hydropsyche spp.,Ecdyonurus venosus, Ephemerella ignita, Baëtis rhodani. Values ofR,[Formula: see text],X p significantly different (R greater,[Formula: see text] andX p smaller) from those obtained for dead invertebrates. The exponential law was not a good model for experiments with cased caddis larvae (Agapetus fuscipes and a mixed group ofSericostoma personatum, Drusus annulatus, Potamophylax cingulatus). Larvae sank rapidly after release and drifted over very short distances.Values ofR for each taxon were significantly higher at site 3 than at site 4, and the more rapid return at site 3 was presumably due to dense stands of aquatic macrophytes. The increase inR was greatest forSimulium spp. andE. ignita.The relationship between[Formula: see text] and modal water velocity (V cm/sec) was well described by the regression equation:[Formula: see text] wherea andb are constants. The relationship betweenR andV, orX p andV, was described by similar equations. Values ofa andb were calculated for each taxon at sites 3 and 4.The drift distance was also investigated by blocking the total drift and taking drift samples at several stations downstream from the blockage. Drift rate was markedly reduced immediately below the blockage and then gradually increased downstream until it was similar to that recorded before blocking. The mathematical model developed from the detailed experiments was a good fit to the results of the blocking experiments.The behaviour of the drifting invertebrates and their ability to return to the bottom are discussed. From the results of the present study and those of other workers, it is concluded that the mathematical model is a good model for invertebrate drift. The implications of the model are discussed, especially the relationship between drift rate and water velocity, and the proportion of the benthos in the drift.


Metformin improves skeletal muscle microvascular insulin resistance in metabolic syndrome.
Microvascular insulin resistance is present in metabolic syndrome and may contribute to increased cardiovascular disease risk and the impaired metabolic response to insulin observed. Metformin improves metabolic insulin resistance in humans. Its effects on macro and microvascular insulin resistance have not been defined. Eleven subjects with nondiabetic metabolic syndrome were studied four times (before and after 12 wk of treatment with placebo or metformin) using a crossover design, with an 8-wk washout interval between treatments. On each occasion, we measured three indices of large artery function [pulse wave velocity (PWV), radial pulse wave separation analysis (PWSA), brachial artery endothelial function (flow-mediated dilation-FMD)] as well as muscle microvascular perfusion [contrast-enhanced ultrasound (CEU)] before and at 120 min into a 150 min, 1 mU/min/kg euglycemic insulin clamp. Metformin decreased body mass index (BMI), fat weight, and % body fat (P < 0.05, each), however, placebo had no effect. Metformin (not placebo) improved metabolic insulin sensitivity, (clamp glucose infusion rate, P < 0.01), PWV, and FMD after insulin were unaffected by metformin treatment. PWSA improved with insulin only after metformin P < 0.01). Insulin decreased muscle microvascular blood volume measured by contrast ultrasound both before and after placebo and before metformin (P < 0.02 for each) but not after metformin. Short-term metformin treatment improves both metabolic and muscle microvascular response to insulin. Metformin's effect on microvascular insulin responsiveness may contribute to its beneficial metabolic effects. Metformin did not improve aortic stiffness or brachial artery endothelial function, but enhanced radial pulse wave properties consistent with relaxation of smaller arterioles.NEW & NOTEWORTHY Metformin, a first-line treatment for type 2 diabetes, is often used in patients with insulin resistance and metabolic syndrome. Here, we provide the first evidence for metformin improving muscle microvascular insulin sensitivity in insulin-resistant humans. Simultaneously, metformin improved muscle glucose disposal, supporting a close relationship between insulin's microvascular and its metabolic actions in muscle. Whether enhanced microvascular insulin sensitivity contributes to metformin's ability to decrease microvascular complications in diabetes remains to be resolved.


A survey of 37 cases with basal ganglia calcification (BGC): CT-scan findings of BGC and its relationship to underlying diseases and epilepsy.
Thirty-seven cases that showed bilateral basal ganglia calcification (BGC) were found in 5987 patients. These cases (0.6%) were studied in relation to their CT findings, underlying diseases and epilepsy. CT findings of BGC were divided into "localized" type (33 cases) and "diffuse" type (4 cases). The number of patients with the "localized" type clearly seemed to increase with age. The M:F ratio of the "localized" type was 1:2. The "localized" type was seen in both idiopathic BGC and familial BGC. The "diffuse" type was seen in hypoparathyroidism only. The specific relationship of these two types of BGC to underlying diseases, however, does not fully agree with results so far reported. We experienced a case with familial BGC during this study that appears to be only the 15th so far reported. Partial epilepsy occurred in 75% of epilepsy with BGC, but there seemed to be no direct relationship between BGC and epileptogenicity.


Liver graft bile duct necrosis--indication for retransplantation.
The authors describe the first in Poland case of liver retransplantation in an adult recipient, in whom the indication for the procedure was bile duct necrosis following liver transplantation due to liver cirrhosis of an uncertain origin.


Chlorination-induced enhancement of biological activities in imidazole antimycotics. A possible explanation to the molecular mechanism for their antimycotic activities.
The effect of imidazole antimycotics (clotrimazole, econazole, and miconazole) on mitochondrial functions were compared by the experiment with isolated rat liver mitochondria and it was found that their potencies in the uncoupling effect on oxidative phosphorylation, in the stimulation of latent ATPase activity, and in the induction of swelling in mitochondria were enhanced by the increased chlorination of the molecule, i.e. miconazole greater than econazole greater than clotrimazole.


Glu43 is an essential residue for coordinating the [Fe2S2] cluster of IscR from Acidithiobacillus ferrooxidans.
The iron-sulfur cluster regulator (IscR) was reported to be a repressor of the iscRSUA operon. In vitro transcription reactions revealed that the IscR had a repression effect on the iscR promoter. The IscR contains a [Fe2S2] cluster per each monomer, and three highly conserved cysteines were identified to ligate the [Fe2S2] cluster. It was proposed that a non-cysteine residue might be the fourth ligand for the [Fe2S2] cluster. In this study, using site-directed mutagenesis, Glu43 was found to be the fourth residue that coordinates the [Fe2S2] cluster of IscR.


Prevalence of hepatitis virus infections in Kosovar refugees.
To assess the prevalence of viral hepatitis infections in a sample of Kosovar refugees having arrived in southern Italy as a result of the 1999 war in the Balkans. The 526 subjects who enrolled on voluntary basis from all age groups were tested for the prevalence of serologic markers for hepatitis virus types A, B, C, D, and E (HAV, HBV, HCV, HDV, HEV). Among the 526 refugees, the prevalence of total anti-HAV antibodies was 81%. A relevant finding was the presence of total anti-HAV antibodies in 61% of the children up to 10 years of age. The prevalence of anti-HEV antibodies was 2.5% among the subjects. Fifteen subjects (2.9%) were positive for hepatitis B surface antigen (HBsAg), whereas 17.5% tested positive for anti-hepatitis B core antigen (anti-HBc). In children up to 10 years of age, the prevalence of HBsAg and anti-HBc was found to be 0.4% and 6%, respectively. In subjects aged 11 to 20 years, 4.2% tested positive for HBsAg and 20.2% for anti-HBc. In the age group 21 to 30 years, 7.1% of the subjects were found to be HBsAg carriers, whereas 25.9% were found to be positive for anti-HBc. Among the refugees over 30 years of age, the prevalence of HBsAg was 4.2%, whereas anti-HBc was 43.7%. None of the refugees tested positive for anti-HDV. The prevalence of anti-HCV antibodies was 0.7%. The results of this seroepidemiologic study indicate a high circulation of HAV in the Kosovar population, whereas the prevalence of HEV antibodies was low and comparable to that of other European countries. The HBV infection seems to be at an intermediate level of endemicity and an immunization policy against HBV infection, through vaccination of all newborns and children before adolescence, may be advisable. Results of this study indicate that the level of endemicity of HCV infection in the Kosovar population is low.


New-onset seizures associated with human immunodeficiency virus infection: causation and clinical features in 100 cases.
We attempt to define the significance and most common causes of new-onset seizures in patients with human immunodeficiency virus (HIV) infection. In addition, we review the seizure type, neurologic examination, and other clinical features to better address diagnostic and management issues in these patients. We reviewed 100 cases of new-onset seizures in HIV-infected patients who underwent complete evaluations at the University of California, San Francisco, hospitals. Seizures were the presenting symptom of HIV-related illness in 18 patients, six of whom developed no other HIV-related illness until at least four months after the first seizure. Common causes in the 100 patients included mass lesions, HIV encephalopathy, and meningitis. No cause for the seizures was found in 23 patients despite a complete evaluation. An underlying cause was found in all patients with focal neurologic deficits but in only two of 24 who had normal results on an interictal neurologic examination. Focal ictal features were not predictive of cause. A cause was found in all 12 patients with status epilepticus or medically refractory seizures. A total of 12 of the 87 (14%) patients who received phenytoin developed a hypersensitivity reaction. Despite the brevity of follow-up in some patients, many patients, including those with no definable cause, had multiple seizures prior to the administration of anticonvulsants. The direct effects of HIV on the brain may be the single most common cause of seizures in this population. We favor treatment of a single seizure in patients with HIV infection.


Kostmann's disease or severe hereditary neutropenia-the man behind the syndrome.
Seventy years ago, the Swedish pediatrician Rolf Kostmann (1909-1982) was the first to report on a previous unknown lethal hereditary neutropenia in infants, Kostmann's disease. This essay presents the man behind the syndrome rather than focusing on the disease itself.


Penicimenolides A-F, Resorcylic Acid Lactones from Penicillium sp., isolated from the Rhizosphere Soil of Panax notoginseng.
Five new 12-membered resorcylic acid lactone derivatives, penicimenolides A-E (1-5), one new ring-opened resorcylic acid lactone derivative penicimenolide F (6), and six known biogenetically related derivatives (7-12) were isolated from the culture broth of a strain of Penicillium sp. (NO. SYP-F-7919), a fungus obtained from the rhizosphere soil of Panax notoginseng collected from the Yunnan province of China. Their structures were elucidated by extensive NMR analyses, a modified Mosher's method, chemical derivatization and single crystal X-ray diffraction analysis. Compounds 2-4 exhibited potent cytotoxicity against the U937 and MCF-7 tumour cell lines and showed moderate cytotoxic activity against the SH-SY5Y and SW480 tumour cell lines. The substitution of an acetyloxy or 2-hydroxypropionyloxy group at C-7 significantly increased the cytotoxic activity of the resorcylic acid lactone derivatives. Subsequently, the possible mechanism of compound 2 against MCF-7 cells was preliminarily investigated by in silico analysis and experimental validation, indicating compound 2 may act as a potential MEK/ERK inhibitor. Moreover, proteomics analysis was performed to explore compound 2-regulated concrete mechanism underlying MEK/ERK pathway, which is still need further study in the future. In addition, compounds 2-4 and 7 exhibited a significant inhibitory effect on NO production induced by LPS.


Consultant-led UK paediatric palliative care services: professional configuration, services, funding.
To systematically gather information on the professional team members, services provided, funding sources and population served for all consultant-led specialised paediatric palliative care (SPPC) teams in the UK. Two-part online survey. Survey 1: All 17 medical leads from hospital-based or hospice-based SPPC teams responded to the survey (100% response rate).Only six services met the NICE guidance for minimum SPPC team.All services reported providing symptom management, specialist nursing care, end-of-life planning and care, and supporting discharges and transfers to home or hospice for the child's final days-hours. Most services also provided care coordination (n=14), bereavement support (n=13), clinical psychology (n=10) and social work-welfare support (n=9). Thirteen had one or more posts partially or fully funded by a charity.Survey 2: Nine finance leads provided detailed resource/funding information, finding a range of statutory and charity funding sources. Only one of the National Health Service (NHS)-based services fully funded by the NHS. One-third of services met the minimum criteria of professional team as defined by NICE. Most services relied on charity funding to fund part or all of one professional post and only one NHS-based service received all its funding directly from the NHS.


Morphological spectrum of immune check-point inhibitor therapy-associated gastritis.
Immune check-point inhibitors are frequently used in the treatment of a variety of solid tumours. The mechanism of action of these drugs involves up-regulation of cytotoxic T cells, which can lead to a lack of self-tolerance and immune-related adverse events, including those involving the gastrointestinal tract. This study was performed to characterise the histological features of immune check-point inhibitor therapy-associated gastritis. Gastric biopsies from patients on immune check-point inhibitor therapy with clinical suspicion of drug-associated gastrointestinal injury were identified. The predominant histological pattern of injury, distribution of injury, degree of tissue eosinophilia and prominence of apoptosis were recorded. Presenting symptoms, treatment and follow-up data were obtained by medical chart review. The 12 patients included in the study group were treated with ipilimumab, nivolumab or pembrolizumab for a variety of tumours. Symptoms at presentation included nausea, vomiting and diarrhoea. Chronic active gastritis with intra-epithelial lymphocytosis and prominent apoptosis was seen in eight of 12 patients, and was the most useful combination for the diagnosis of drug-induced gastritis in these patients. Four patients showed focal enhancing gastritis with a lymphohistiocytic cuff around inflamed glands reminiscent of Crohn's disease. One of those four patients was homozygous for the ATG16L1 Crohn's disease-associated gene variant, but had no history of inflammatory bowel disease. Ten patients responded to medication withdrawal and steroid therapy, while two required treatment with infliximab. Awareness of the morphological spectrum of immune check-point inhibitor therapy-associated gastritis is important for the accurate diagnosis and prompt management of these patients.


Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a.
It was recently demonstrated that none of the hepatitis B e antigen (HBeAg)-negative patients without any serum hepatitis B surface antigen (HBsAg) decline and with <2log hepatitis B virus (HBV) DNA decline at week 12 of a 48-week peginterferon alfa-2a (PEG-IFN) treatment course achieved a sustained response (SR). We aimed at validating this stopping rule in two independent trials. HBeAg-negative patients receiving 48 or 96 weeks of PEG-IFN in the phase III registration trial (N=85) and PegBeLiver study (N=75) were stratified according to the presence of any HBsAg decline and/or 2log HBV DNA decline at week 12. SR was defined as HBV DNA <2000IU/ml and normal alanine aminotransferase 24 weeks after treatment. The original PARC trial included 102 patients (genotype A/D/other: 14/81/7), 25 (25%) had an SR. The validation dataset consisted of 160 patients (genotype A/B/C/D/other: 10/18/34/91/7), 57 (36%) achieved an SR. The stopping rule performed well across the two studies (p=0.001) and its negative predictive value [NPV] was 95% in the validation dataset harbouring genotypes A-D. Its performance was best for genotype D. Moreover, among the 34 patients treated for 96 weeks, none of the 7 (21%) without HBsAg decline and with <2log HBV DNA decline at week 12 achieved an SR (NPV 100%). We confirmed in two independent studies that the combination of HBsAg and HBV DNA levels at week 12 identifies HBeAg-negative patients with a very low chance of SR to either 48 or 96 weeks of PEG-IFN therapy.


Interaction between sphingomyelin and a cytolysin from the sea anemone Stoichactis helianthus.
The cytolytic toxin from the sea anemone Stoichactis helianthus was inhibited up to 90--95% by suspensions of sphingomyelin but not by phosphatidylcholine or other membrane lipids. When the toxin was incubated with sphingomyelin and the mixture fractionated either by isoelectric focusing or Sephadex gel filtration, the residual hemolytic units migrated together with the lipid and not as free toxin. Incubation with phosphatidylcholine, however, did not shift the toxin peak in either type of column. A toxin-ferritin conjugate retaining hemolytic activity was observed by negative staining to bind to liposomes prepared with sphingomyelin but not with liposomes containing phosphatidylcholine. The results provide evidence that the membrane binding site of the toxin is sphingomyelin.


Understanding the Role of Emerging Vitamin D Biomarkers on Short-term Persistence of High-Risk Human Papillomavirus Infection Among Mid-Adult Women.
Associations between vitamin D biomarkers and persistent high-risk human papillomavirus (hrHPV) detection have not been evaluated. 2011-2012 stored sera from 72 women aged 30-50 years with prevalent hrHPV (n = 116 type-specific infections) were tested for 5 vitamin D biomarkers: 25(OH)D and 4 emerging biomarkers, 1,25(OH)2D; 24,25(OH)2D; free vitamin D; and vitamin D binding protein (DBP). The hrHPV detection patterns (persistent vs transient/sporadic) were determined using cervicovaginal swabs collected monthly for 6 months. Associations between vitamin D and short-term type-specific hrHPV persistence were estimated using logistic regression. Our primary exposure was continuous 25(OH)D, with additional biomarkers evaluated as secondary exposures. Primary models were adjusted for age, race, body mass index, education, contraceptives, smoking, season, and calcium/phosphate levels. Sensitivity analyses were restricted from 19 hrHPV types to 14 used in cervical cancer screening. In primary analyses, nonsignificant positive associations with hrHPV persistence were observed for measures of 25(OH)D and 24,25(OH)2D. Associations were stronger and significant when restricting to 14 hrHPV types (25(OH)D per 10 ng/mL increase: adjusted odds ratio [aOR], 1.82 [95% confidence interval {CI}, 1.15-2.88] and aOR, 4.19 [95% CI, 1.18-14.88] DBP-adjusted; 25(OH)D ≥30 vs <30 ng/mL: aOR, 8.85 [95% CI, 2.69-29.06]; 24,25(OH)2D: aOR, 1.85 [95% CI, 1.18-2.88]). 1,25(OH)2D was unassociated with persistence. Serum vitamin D measured by multiple biomarkers showed positive associations with short-term hrHPV persistence that were significant only when restricting to 14 clinically relevant hrHPV types.


Thioproline prevents carcinogenesis in the remnant stomach induced by duodenal reflux.
An excessive duodenal reflux induced by surgery has been widely accepted to cause gastric carcinogenesis in the remnant stomach. As one of causative factors for malignancy, N-nitroso compounds produced by enteric bacteria have been postulated. However, there is no concrete information to prove this hypothesis. This study was undertaken to elucidate the factors underlying the remnant stomach carcinogenesis, by giving thiazolidine-4-carboxylic acid (thioproline; TPRO) to the rats with duodenal reflux as a nitrite scavenger. Operated 39 animals were used, divided into 2 groups; one with a diet containing 0.5% TPRO (n=18), and the other with a diet without TPRO (n=21). Adenocarcinoma developed in 16 rats out of 21 (76.2%) of untreated rats, whereas adenocarcinoma was detected in 1 rat of the TPRO-treated rats (5.6%). TPRO thus prevented the development of gastric cancer in the remnant stomach, thereby suggesting a concern of nitroso compounds to the carcinogenesis.


The cyclic 3',5'-adenosine monophosphate receptor protein and regulation of cyclic 3',5'-adenosine monophosphate synthesis in Escherichia coli.
Rates of synthesis of cyclic 3',5'-adenosine monophosphate (cAMP) were measured in cultures of Escherichia coli aerating without a carbon source. This technique provides a representative measure of adenylate cyclase activity in the absence of inhibition caused by transport of the carbon source. Adenylate cyclase activity was found to vary more than 20-fold depending on the carbon source that had been available during growth. Synthesis of cAMP in cells aerating in the absence of the carbon source was highest when cells had been grown with glucose or fructose which inhibit adenylate cyclase activity severely. Synthesis of cAMP was much lower when cells had been grown with glycerol or succinate which cause only minimal inhibition of the activity. The variation in cAMP synthesis due to different carbon sources requires a functional cAMP receptor protein (CRP). Crp- mutants synthesize cAMP at comparable rates regardless of the carbon source that afforded growth. A novel mutant of E. coli having a CRP no longer dependent on cAMP has been isolated and characterized. Adenylate cyclase activity in this mutant no longer responds normally to variations in the carbon source.


Can we transfer pharmacokinetics/pharmacodynamics of antimicrobials into clinical practice?
In critically ill patients there is extensive evidence of subtherapeutic antibiotic exposure from standard doses across different antibiotic classes. This can be a direct consequence of pharmacokinetic alterations emanating from the complex pathophysiological processes associated with severe infection. Therapeutic drug monitoring (TDM) is being increasingly used for antibiotic dose optimisation in an attempt to improve the attainment of pharmacokinetic/pharmacodynamic (PK/PD) targets and the outcomes of severe infection in critically ill patients. In clinical practice, it is necessary to reduce the number of blood samples collected from the patient to a minimum because of the cost (personnel, devises and analysis). TDM to calculate PK/PD indices is easily feasible only when a single blood sample is adequate to perform the analysis.


Effects of sulfhydryl agents on the activation of tryptophan-5-monooxygenase from bovine pineal glands.
Partially purified tryptophan-5-monooxygenase (L-tryptophan, tetrahydropteridine: oxygen oxidoreductase (5-hydroxylating) EC 126.96.36.199)from bovine pineal gland was activated by preincubation with sulfhydryl agents such as dithiothreitol, L-cysteine, cysteamine, L-cysteine ethylester, N-acetyl-L-cysteine, 2-mercaptoethanol and reduced glutathione, at alkaline pH (optimum pH equals 8.5). Dithiothreitol was the most effective of these, leading to approximately 50-fold activation of the enzyme after preincubation. Fe-2+ or other reducing agents such as borohydride, dithionite and ascorbate facilitated the velocity of the activation in the presence of sulfhydryl agents. In the absence of sulfhydryl agents, no activation was observed even in the presence of Fe-2+ or other reducing agents, suggesting an obligatory role or sulhydryl agents during the activation. The relative velocity and full extent of the activation were dependent on the concentrations of both the sulfhydryl agent and the enzyme in the activation mixture. The kinetic analysis of the activation indicated that the sulfhydryl agent reacts with more than 2 sites in the enzyme; one type of site is reduced by sulfhydryl agents, Fe-2+ or other reducing agents and the other specifically modified by a sulfhydryl agent. The activated enzyme did not require any exogenous Fe-2+ for its catalytic activity, but some roles of iron maybe exist in its catalytic reaction. The optimum pH for catalytic reaction of the activated enzyme was approximately 6.5. The apparent Km for L-tryptophan and pteridine cofactor, tetrahydro-pteridine (2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropterin), of the activated enzyme were 30 and 35 muM respectively.


Injectable fillers for facial rejuvenation: a review.
Health care practices are moving toward a more preventative focus. In addition to leading healthier lives and seeking help to eradicate disease, patients are enlisting the help of plastic surgeons to reduce the visible signs of aging. Traditionally, facial rejuvenation focused on skin tightening through resection and resurfacing. In recent years, increasing emphasis has been placed on minimally invasive cosmetic improvement. Today, plastic surgeons combat the effects of aging with a variety of non-incisional methods such as soft-tissue augmentation with facial fillers. A multitude of soft-tissue fillers exist, each with their own chemical constituents, indications, and effectiveness. It is imperative that plastic surgeons understand these agents when treating patients with cosmetic complaints.


Does the position of interference screw in tibial tunnel effect anatomic orientation in single bundle anterior cruciate ligament reconstruction?
The purpose of the study was to evaluate the change in orientation of the reconstructed ACL with the change in position of the interference screw in the tibial tunnel. It was a retrospective review of Magnetic Resonance Imaging (MRI) in which 51 normal and 61 MRI of patients who had undergone ACL reconstruction at our institute were evaluated. Postoperative ACL reconstruction group MRI studies were obtained and evaluated by two sports medicine fellows independently to assess the position of interference screw, distance of the graft from the anterior cortex of tibia and inclination of the graft. The data was collected and compared with MRI data of normal ACL patients. There were total 61 patients with ACL reconstruction. 32 patients had anterior screw placement and 29 patients had posterior screw placement in the tibial tunnel. The distance of the graft from the anterior cortex was 39.18% in ACL intact group, 50.35% in anterior screw group and 41.64% in posterior screw group. The inclination angle was 44.49⁰ in intact group, 49.69° and 42.20° in anterior and posterior screw group respectively. The difference between intact group and anterior screw group was statistically significant. Posterior position of interference screw in tibial tunnel increases graft obliquity than anterior position and decreases its distance from the anterior tibial cortex. This increased graft obliquity and distance from the anterior tibial cortex is similar to the native ACL.


Nonepileptic paroxysmal sleep disorders.
Events occurring during nighttime sleep in children can be easily mislabeled, as witnesses are usually not immediately available. Even when observers are present, description of the events can be sketchy, as these individuals are frequently aroused from their own sleep. Errors of perception are thus common and can lead to diagnosis of epilepsy where other sleep-related conditions are present, sometimes initiating unnecessary therapeutic interventions, especially with antiepileptic drugs. Often not acknowledged, paroxysmal nonepileptic behavioral and motor episodes in sleep are encountered much more frequently than their epileptic counterpart. The International Classification of Sleep Disorders (ICSD) 2nd edition displays an extensive list of such conditions that can be readily mistaken for epilepsy. The most prevalent ones are reviewed, such as nonrapid eye movement (NREM) sleep parasomnias, comprised of sleepwalking, confusional arousals and sleep terrors, periodic leg movements of sleep, repetitive movement disorders, benign neonatal myoclonus, and sleep starts. Apnea of prematurity is also briefly reviewed. Specific issues regarding management of these selected disorders, both for diagnostic consideration and for therapeutic intervention, are addressed.


The relationship between intimate partner violence and PTSD: an application of Cox regression with time-varying covariates.
This study uses Cox regression with time-varying covariates to examine the relationship between intimate partner violence and posttraumatic stress disorder (PTSD) in a random sample of Japanese American women and immigrant women from Japan (N = 211). Because applications of survival analysis in trauma research are scarce, this paper presents the utility of this analytical approach by contrasting it with other common methods of analysis (chi-square tests and Cox regression with covariates that do not change over time).


Advances in the treatment of carcinoma of the penis.
The aim of this article is to define the therapeutic advances in the treatment of penile cancer over the past 2 decades. A literature search was conducted for articles in which a major change in therapy was documented as beneficial. Case records were then reviewed in patients who underwent such procedures. Major advances have involved less disfiguring treatment of the primary lesion in selected cases and the recognition of improved survival by altering the timing of groin dissection for those at risk for metastatic disease.


Lack of chemokine (C-C motif) ligand 3 leads to decreased survival and reduced immune response after bacterial meningitis.
Pneumococcal meningitis, caused by Streptococcus pneumoniae, is the most common type of bacterial meningitis. The clinical management of this disease has been challenged by the emergence of multidrug-resistant Streptococcus pneumoniae, requiring the urgent development of new therapeutic alternatives. Over the course of bacterial meningitis, pathogen invasion is accompanied by a massive recruitment of peripheral immune cells, especially neutrophil granulocytes, which are recruited under the coordination of several cytokines and chemokines. Here, we used chemokine (C-C motif) ligand 3 (Ccl3)-deficient mice to investigate the functional role of CCL3 in a mouse model of pneumococcal meningitis. Following intrathecal infection with Streptococcus pneumoniae Ccl3-deficient mice presented a significantly shorter survival and higher bacterial load than wildtype mice, paralleled by an ameliorated infiltration of neutrophil granulocytes into the CNS. Blood sample analysis revealed that infected Ccl3-deficient mice showed a significant decrease in erythrocytes, hemoglobin and hematocrit as well as in the number of banded neutrophils. Moreover, infected Ccl3-deficient mice showed an altered cytokine expression profile. Glial cell activation remained unchanged in both genotypes. In summary, this study demonstrates that CCL3 is beneficial in Streptococcus pneumoniae-induced meningitis. Pharmacological modulation of the CCL3 pathways might, therefore, represent a future therapeutic option to manage Streptococcus pneumoniae meningitis.


Reactive DNA. 2. Thioguanine used as a peg site for direct and specific introduction of biologically useful functional groups.
An efficient method is described for one-step and specific introduction onto thioguanine in DNA of a variety of biologically useful functional groups, including carboxymethyl, hydroxyethyl, aminoethyl groups and fluorescent tag. Reaction mechanisms were examined. The method could provide new tools for biochemical studies, such as DNA repair and sister chromatid exchange, and the method may be also applicable to RNA.


Microglial Inhibitory Mechanism of Coenzyme Q10 Against Aβ (1-42) Induced Cognitive Dysfunctions: Possible Behavioral, Biochemical, Cellular, and Histopathological Alterations.
Alzheimer's disease (AD) is a debilitating disease with complex pathophysiology. Amyloid beta (Aβ) (1-42) is a reliable model of AD that recapitulates many aspects of human AD. The intent of the present study was to investigate the neuroprotective potential of Coenzyme Q10 (CoQ10) and its modulation by minocycline (microglial inhibitor) against Aβ (1-42) induced cognitive dysfunction in rats. Intrahippocampal (i.h.) Aβ (1-42) (1 μg/μl; 4μl/site) were administered followed by drug treatment with galantamine (2 mg/kg), CoQ10 (20 and 40 mg/kg), minocycline (50 and 100 mg/kg) and their combinations for a period of 21 days. Various neurobehavioral parameters followed by biochemical, acetylcholinesterase (AChE) level, proinflammatory markers (TNF-α), mitochondrial respiratory enzyme complexes (I-IV) and histopathological examinations were assessed. Aβ (1-42) administration significantly impaired cognitive performance in Morris water maze (MWM) performance test, causes oxidative stress, raised AChE level, caused neuroinflammation, mitochondrial dysfunction and histopathological alterations as compared to sham treatment. Treatment with CoQ10 (20 and 40 mg/kg) and minocycline (50 and 100 mg/kg) alone for 21 days significantly improved cognitive performance as evidenced by reduced transfer latency and increased time spent in target quadrant (TSTQ), reduced AChE activity, oxidative damage (reduced LPO, nitrite level and restored SOD, catalase and GHS levels), TNF-α level, restored mitochondrial respiratory enzyme complex (I, II, III, IV) activities and histopathological alterations as compared to Aβ (1-42) treated animals. Further, combinations of minocycline (50 and 100 mg/kg) with CoQ10 (20 and 40 mg/kg) significantly modulates the protective effect of CoQ10 dose dependently as compared to their effect alone. The present study suggests that the neuroprotective effect of CoQ10 could be due to its microglia inhibitory mechanism along with its mitochondrial restoring and anti-oxidant properties.


A Short ERAP2 That Binds IRAP Is Expressed in Macrophages Independently of Gene Variation.
The M1 zinc metalloproteases ERAP1, ERAP2, and IRAP play a role in HLA-I antigen presentation by refining the peptidome either in the ER (ERAP1 and ERAP2) or in the endosomes (IRAP). They have also been entrusted with other, although less defined, functions such as the regulation of the angiotensin system and blood pressure. In humans, ERAP1 and IRAP are commonly expressed. ERAP2 instead has evolved under balancing selection that maintains two haplotypes, one of which undergoing RNA splicing leading to nonsense-mediated decay and loss of protein. Hence, likewise in rodents, wherein the ERAP2 gene is missing, about a quarter of the human population does not express ERAP2. We report here that macrophages, but not monocytes or other mononuclear blood cells, express and secrete an ERAP2 shorter form independent of the haplotype. The generation of this "short" ERAP2 is due to an autocatalytic cleavage within a distinctive structural motif and requires an acidic micro-environment. Remarkably, ERAP2 "short" binds IRAP and the two molecules are co-expressed in the endosomes as well as in the cell membrane. Of note, the same phenomenon could be observed in some cancer cells. These data prompt us to reconsider the role of ERAP2, which might have been maintained in humans due to fulfilling a relevant function in its "short" form.


Specific disruption of glutathione-defense system with activatable single molecule-assembled nanoprodrug for boosted photodynamic/chemotherapy eradication of drug-resistant tumors.
Developing single molecule-assembled nanoprodrugs that can reverse the glutathione (GSH)-mediated drug resistance of tumors provides promising potentials for precision and effective cancer theranostics. Herein, we developed a novel single molecule-assembled nanoprodrug for effective photodynamic/chemotherapeutic eradication of drug-resistant tumors via the multistage GSH-depletion. The nanoprodrug MSSP-NP could be fancily fabricated by self-assembly of an amphiphilic activatable molecular MSSP, which is synthesized by covalently conjugating the photosensitizer methylene blue (MB) with a GSH-sensitive cisplatin prodrug via a tumor targeting thiolated polypeptide. Upon the nanoprodrug MSSP-NP systematic administrated, its photoactivities and pharmacological effects can be thoroughly switched on by intracellular GSH to produce the photosensitizer MB and chemotherapeutic drug cisplatin, along with the multi-step consumption of GSH, which could remarkably boost oxidative stress and reverse the drug resistance. As a result, the nanoprodrug could effectively disrupt the tumor GSH-defense system to afford high-efficiency photodynamic/chemotherapeutic inhibition of drug resistance tumors (96.4%) with minimum side effects.


Reciprocal associations between housing instability and youth criminal legal involvement: a scoping review.
Youth experiencing homelessness have disproportionate contact with the criminal legal system. This system contact represents a critical inflection point for enhancing risk or opportunities for stabilization; however, the policy and scholarly traditions examining the criminal legal system have not traditionally incorporated housing or other social determinants as a central focus of intervention. We conducted a scoping review using PRISMA-ScR guidelines to examine how the research literature is currently addressing housing within the context of youth involvement in the legal system. Databases searched included PubMed, Web of Science, and Academic Search Complete. Google Scholar was used to identify papers not indexed in the academic databases of interest. Database searches were conducted between September and December 2019 and articles were restricted to those published in English between the year 2000 and 2019. Key study components extracted included demographic information regarding each sample, type of article, study methodology, direction of effects of interest, outcome measures and primary findings, as well as theoretical frameworks engaged by the authors. The search results returned 2154 titles for review. After screening all 2154 titles, 75 met eligibility for inclusion. Abstract reviews were conducted for all 75 papers. 36 abstracts met eligibility criteria and underwent full-text review. Ultimately, 29 articles satisfied eligibility criteria and were included in this scoping review. Publications are primarily focused on the social epidemiology of risk factors and behaviors determining youth justice contact, but relatively less so on studies of interventions targeting youth delinquency, crime reduction, or recidivism that included housing support. The lack of continuity in theorizing from epidemiology to applied science in this area represents a gap in the literature that is likely reducing the effectiveness of interventions to interrupt patterns of legal system contact for youth. Integrating a public health framework that emphasizes the upstream social determinants leading to contact with the youth justice system would represent a paradigm shift for the field that would have beneficial effects on long term health outcomes for youth.


Adeno-associated virus-mediated bone morphogenetic protein-4 gene therapy for in vivo bone formation.
Adeno-associated virus (AAV) is so far the most valuable vehicle for gene therapy because it has no association with immune response and human disease. The present study was conducted to investigate the feasibility of AAV-mediated BMP4 gene transfer for bone formation. In vitro study suggested that AAV-BMP4 vectors could transduce myoblast C2C12 cells and produce osteogenic BMP4. In vivo study demonstrated that new bone formation could be induced by direct injection of AAV-BMP4 into the skeletal muscle of immunocompetent rats. Histological analysis revealed that the newly formed bone was induced through endochondral mechanism. Immunohistochemical staining further demonstrated that AAV-BMP4 gene delivery could mediate long-term transduction, and the involvement of BMP4 expression was responsible for the endochondral ossification. This study is, to our knowledge, the first report in the field of AAV-based BMP gene transfer and should be promising for clinical orthopaedic applications.


Qualitative Evaluation of Historical and Relational Factors Influencing Pregnancy and Sexually Transmitted Infection Risks in Foster Youth.
To explore how attitudes, norms, behaviors, responses to early life experiences, and protective factors influence pregnancy and sexually transmitted infection risks from the perspectives of current and former foster youth to inform the development of prevention strategies. We conducted semi-structured individual qualitative interviews with a diverse sample of 22 current/former foster youth aged 15-21 years (63% female; average age = 18.6 years). We then used Theoretical Thematic Analysis to systematically analyze the data for key themes related to sexual health in four categories: 1) norms and attitudes, 2) responses to early life experiences, 3) protective factors, and 4) youth-driven intervention ideas. Participants reported a range of sexual experience levels, varied sexual orientations, and also reported varied life experiences prior to and during foster care. We detected several norms and attitudes that likely contribute to risks of early pregnancies and sexually transmitted infections. These included that one can tell by looking whether a partner is trustworthy or has a sexually transmitted infection, that condoms aren't necessary with long-term or infrequent partners or if birth control is used, and that teen pregnancy is an inevitable event. With respect to responses to early life experiences, youth frequently described difficulties dealing with strong emotions in the context of romantic and/or sexual relationships; many attributed these difficulties to early experiences with biological family members or in foster care. Participants linked emotion regulation difficulties with struggles in trust appraisal, effective communication, and impulsive behaviors. Youth also described a variety of protective factors that they felt helped them prevent sexual risk behaviors or improved their lives in other respects. Finally, participants endorsed factors likely to improve intervention acceptability and efficacy, including an open, non-judgmental group-based environment, involvement of peer mentors, and inclusion of caregiver and caseworker training components. Trauma-informed, tailored intervention strategies which address key norms and attitudes and provide broad-based assertiveness and emotion regulation skills are likely to be the most effective strategies to reduce risks of teen pregnancies and sexually transmitted infections among teens in foster care. Group-based interventions that involve peer mentors and caregiver and caseworker components may be especially acceptable and effective for teens in foster and/or kinship care.


Successful surgical repair of double outlet right ventricle with situs inversus, l-loop, l-malposition and subaortic VSD in a 16-month-old patient.
The case of a 16-mth-old patient who had double outlet right ventricle, l-loop and l-malposition in the presence of dextrocardia and situs inversus is presented. A successful repair was performed using an internal conduit to divert the blood from the left ventricle to the aorta. The outflow tract of the right ventricle was then enlarged with a dacron patch. The anatomic variations of double outlet right ventricle surgically corrected are reviewed.


Organization of the reach and grasp in head-fixed vs freely-moving mice provides support for multiple motor channel theory of neocortical organization.
Multiple motor channel (MMC) theory of neocortical organization proposes that complex movements, such as reaching for a food item to eat, are produced by the coordinated action of separate neural channels. For example, the human reach-to-grasp act is mediated by two visuo-parieto-motor cortex channels, one for the reach and one for the grasp. The present analysis asked whether there is a similar organization of reach-and-grasp movements in the mouse. The reach-to-eat movements of the same mice were examined from high-shutter speed, frame-by-frame video analysis in three tasks in which the mice obtained equivalent success scores: when freely-moving reaching for food pellets, when head-fixed reaching for food pellets, and when head-fixed reaching for pieces of pasta. To reach, the mice used egocentric cues to vary upper arm movements in a task-appropriate manner to place an open hand on the food or to locate the food using a "touch-release-grasp" strategy. Although mice could not hand-shape offline when reaching, they could hand-shape using online touch-related cues from the mouth to manipulate the food at the mouth. That the reach can be performed offline in relation to egocentric cues whereas hand shaping for the grasp requires online cues supports the idea that for the mouse, as for primates, the reach and grasp are separate acts. The results are further discussed in relation to the use of the head-fixed behavioral procedure to identify the independent neural substrates of the reach and the grasp using mesoscale stimulation/imaging methods.


Emotion generation and regulation following an intrusion induction: Implications for taboo or autogenous obsessions.
Research demonstrates that autogenous (AO) and reactive obsessions (RO) differ in obsessional content; however, no experimental research has examined differences in emotion generation and regulation. Characterizing this taxonomy with respect to emotion generation and regulation could refine conceptualizations of obsessionality and optimize clinical interventions. Seventy undergraduates were randomly assigned to imagine a personally-relevant AO or RO. Subsequently, emotional reactivity was assessed. Participants then rated their emotion regulation efforts and the degree to which the intrusion violated their values. Broadly aligning with expectations, bootstrapped linear regression models indicated that AOs led to a significant increase in self-conscious emotions (guilt, shame, and embarrassment), and these effects were stronger for those whose values were more severely threatened by the intrusion. A conditional process analysis revealed that the relationship between the AO condition and emotion regulation difficulties was explained by an increase in negative emotional reactivity, and the strength of this effect depended upon the degree of conflict with participants' values. The use of an analogue sample, and minimal emotional reactivity in the RO condition, threaten the ecological and external validity of the study. The current study employed a novel experimental design demonstrating a meaningful relationship between AOs and both emotional activation and regulation. Results highlight the relevance of self-conscious emotions to the conceptualization of AOs and the utility of addressing them in the context of exposure therapy.


Patterns of amino acid utilization by aquatic hyphomycetes.
The utilization of amino acids in leaf protein and leaf leachate by aquatic hyphomycetes was studied during decomposition in a combined field and laboratory experiment. Leaves were sampled from a stream which exhibited a seasonal variation in free amino acid concentration in surface water, reaching peaks in autumn and winter. In the leaf drift environment the concentration of amino acids was approximately two orders of magnitude higher than in surface water. Protein amino acid content, which was higher in alder leaves than in beech leaves, decreased exponentially and faster in alder leaves, so that protein amino acid content was similar in the two leaf types after 9-10 weeks decomposition. From 55% to 75% of leaf amino acids were used instantaneously by attached fungi, which grew well, especially on alder leaves, regardless of the presence of a grazing amphipod. If nitrogen was a limiting nutrient source for fungi, it appeared to be more advantageous to colonize alder leaves. Four times more fungal species were found on alder leaves than on beech leaves. The changes in concentration of amino acids in leaves and water was described by a set of differential equations. Rate constants for the transfer of amino acids from leaves and water were estimated from experimental data and the preference in fungi for protein-bound and free amino acids evaluated.The amounts of free amino acids in water absorbed by fungi varied between leaf types and leaves at different stages of decay. Experimental data showed a switching behaviour in fungal absorption of dissolved amino acids so that absorption became superproportional at a certain proportion of free amino acids available in the water.


Phenotypic heterogeneity in Woodhouse-Sakati syndrome: two new families with a mutation in the C2orf37 gene.
Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome [also known as Woodhouse-Sakati syndrome (WSS)] is a rare autosomal recessive neuroendocrine and ectodermal disorder. The syndrome was first described by Woodhouse and Sakati in 1983, and 47 patients from 23 families have been reported so far. We report on an additional seven patients (four males and three females) from two highly consanguineous Arab families from Qatar, presenting with a milder phenotype of WSS. These patients show the spectrum of clinical features previously found in WSS, but lack evidence of diabetes mellitus and extrapyramidal symptoms. These two new families further illustrate the natural course and the interfamilial phenotypic variability of WSS that may lead to challenges in making the diagnosis. In addition, our study suggests that WSS may not be as infrequent in the Arab world as previously thought.


Modeling hospital length of stay by Coxian phase-type regression with heterogeneity.
Hospital length of stay (LOS) is an important measure of healthcare utilization and is generally positively skewed and heterogeneous. We fit a Coxian phase-type distribution to LOS and identify the hidden states of the underlying latent homogeneous Markov model. We demonstrate that selecting an appropriate number of phases and a regression model for hazard rates can account for some heterogeneity in LOS. Reversible jump MCMC method enables us to dynamically uncover the hidden stochastic Markov structure. A classification method is used to assign patients to different LOS groups. The methodology is illustrated with application to hospital admissions for acute myocardial infarction in the 2003 Nationwide Inpatient Sample from the Healthcare Utilization Project.


Synchronous presentation of breast carcinoma and lymphoma in the axillary nodes.
We report the first series of cases in the literature of three female patients with a synchronous presentation of breast carcinoma with coincidental axillary lymphoma. Aspects of each case are described and learning points for clinician discussed.


Stage-specific cell-surface antigens of oligodendrocytes in the peripheral nervous system. Expression during development and regeneration and in myelin-deficient mutants.
Monoclonal antibodies to stage-specific cell surface antigens of oligodendrocytes have been used to investigate the expression of antigens 05 through 011 in the peripheral nervous system of the mouse by immunohistology. In the adult sciatic nerve antigens 05 through 09 and 011 were diffusely positive. 010 antigen was not detectable in the peripheral nervous system at any age tested. During development antigens 05, 06 and 07 were first detectable at birth in tracts at the proximal part of the sciatic nerve. At day 2 the whole diameter of the nerve was positive for 05 antigen, while antigens 06 and 07 were detectable only in part of the nerve and antigens 08 and 09 were just about to appear. At day 4 antigen 011 was the last to appear. At day 7 all antigens were strongly detectable throughout the nerve. After transection of adult sciatic nerve expression of antigens 05 through 09 and 011 was studied at the proximal and distal ends of the cut. Three days after transection all antigens were fully detectable in the degenerating myelin and its debris. After 15 days residual debris was still distinctly positive, while Schwann cells in the bands of Bünger were antigen-negative. At approximately two weeks a connecting bridge between proximal and distal ends of the cut nerve had developed, but the 0 antigens were not detectable in this bridge until day 21. At day 42 all antigens were again fully detectable in the regenerating nerve. In hypomyelinating mouse mutants no difference to the normal control littermates was seen in staining pattern and intensity for jimpy and shiverer, while quaking showed an increase in staining intensity for 05 through 08 antigens. In trembler antigens 05, 06 and 07, but not 08, 09 and 011 appeared associated with non-myelin-forming Schwann cells, while the few recognizable myelin-forming Schwann cells expressed all antigens. These observations show that we have characterized 4 new monoclonal antibodies as further reagents to look at developmentally distinct steps in myelination of the peripheral nervous system.


Inhibition of liver microsome-mediated mutagenesis, metabolism and DNA-binding of benzo[a]pyrene and benzo[a]pyrene 7,8-dihydrodiol in the rat following glucose administration.
Aroclor 1254-induced rat liver microsomes prepared from control and glucose-treated rats (30% glucose in drinking water 48 h prior to sacrifice) were used in studies of benzo[a]pyrene (BaP) and BaP 7,8-dihydrodiol (BaP 7,8-DHD)-induced mutagenesis in Salmonella typhimurium TA100. Microsome-dependent metabolism and metabolite binding of BaP and BaP 7,8-DHD to calf thymus DNA was also investigated. BaP-induced mutagenesis in TA100 was inhibited 27% and BaP 7,8-DHD-induced mutagenesis was inhibited 55% by microsomes from glucose-treated rats. [3H]BaP and [3H]BaP 7,8-DHD metabolite binding to DNA was inhibited 17% and 20%, respectively. High performance liquid chromatographic (hplc) analysis of enzyme-hydrolyzed DNA yielded 7R and 7S-diol epoxide-1 deoxyguanosine (BPDE-1:dG) adducts and BPDE-2:dG adducts of [3H]BaP and [3H]BaP 7,8-DHD. These adducts were inhibited 38% and 50%, respectively, by microsomes from glucose-treated rats. Hplc analysis of organosoluble metabolites of [3H]BaP and [3H]BaP 7,8-DHD showed an inhibition of metabolism of 28% and 50%, respectively, by microsomes from glucose-treated rats. The inhibition of metabolism correlated with the effect of glucose treatment on inhibition of BaP and BaP 7,8-DHD-induced mutagenesis and adduct formation. These results suggest that the mechanism by which glucose produces its effects on mutagenesis, DNA-binding and adduct formation is by an inhibition of microsome-mediated metabolism of BaP and BaP 7,8-DHD.


Ultrafast interleaved gradient-echo-planar imaging on a standard scanner.
Ultra-fast imaging traditionally implies either echo-planar imaging on specially developed gradient systems, or very short repetition time gradient-echo imaging on standard magnetic resonance imaging scanners. An alternative strategy for very fast imaging with conventional whole-body scanners is discussed here. The technique is a hybrid, whereby the advantages of gradient-echo imaging and echo-planar imaging are combined. It is here denoted interleaved gradient-echo-planar imaging. It is not a single specific measurement sequence, but rather a continuum of sequences whereby multiple excitations with multiple gradient-echos are employed. The power of this fast imaging approach is that one has much more flexibility toward the optimization of the measurement sequence with respect to imaging time, T2 relaxation, gradient power, resolution, image distortion, and signal-to-noise ratio. In vivo human heart images, acquired in 110 ms, and with a resolution of 2.5 mm, have been obtained with a standard whole-body scanner.


Heritable metabolic and dysplastic bone diseases.
Endocrinologists may be challenged not only by the great diversity of rare heritable metabolic bone diseases, but also by an unusual array of genetically transmitted skeletal dysplasias. The striking impact that many such skeletal dysplasias have on bone leads physicians naturally to question whether there is a metabolic component that might respond to mineral or hormonal therapy. Indeed, overt derangements in mineral or hormonal therapy. Indeed, overt derangements in mineral homeostasis occur, and a few do respond to medical treatment. Accordingly, some skeletal dysplasias do "bridge the gap" with the disorders that are traditionally regarded as metabolic in origin. The skills of the endocrinologist may be called on for either group of patients.


Comprehensive metabolite profiling of Solanum tuberosum L. (potato) leaves by HPLC-ESI-QTOF-MS.
The objective of this work was to study the non-targeted metabolite profiling of potato leaves using high performance liquid chromatography coupled to quadrupole-time of flight mass spectrometry (HPLC-ESI-QTOF-MS). The mass accuracy, true isotopic pattern in both MS and MS/MS spectra provided by QTOF-MS made possible the tentative identification of 109 compounds present in potato leaves, including organic acids, amino acids and derivatives, phenolic acids, flavonoids, iridoids, oxylipins and other polar and semi-polar compounds. Among them, 32 compounds have been found for the first time in potato leaf and in the Solanaceae family. Quinic acid and its derivatives represented more than 45% of the bioactive compounds quantified in the extract. Derivatives of hydroxybenzoic acid and gentisic acid were also founded at considerable concentrations. This study shed light on the composition of potato leaf extract and will serve as a base for further research into activities of the various compounds found in this matrix which has demonstrated a potential use as functional ingredients.


Effect of percutaneous tracheostomy on intracerebral pressure and perfusion pressure in patients with acute cerebral dysfunction (TIP Trial): an observational study.
Bedside percutaneous tracheostomy (PT) is very commonly used for patients who require prolonged mechanical ventilation. The effect of tracheostomy on intracranial pressure (ICP) is currently a subject of controversy. The aim of our study is to clarify the relation between PT and its effect on ICP and cerebral perfusion pressure. 38 patients on our intensive care unit were included prospectively in an observational study. We examined mean values of HF, SpO(2), ICP, CPP, and MAP for changes over five different phases of the procedure using paired Mann-Whitney U tests. A p value of <0.05 was considered significant. p values were Bonferroni corrected for multiple testing. PT was performed on 38 patients (f = 19, m = 19; mean = 56 years). Median ICP before intervention was 9 mmHg. During positioning of the patient, ICP had risen to 14, during bronchoscopy to 16, and during tracheostomy to 18 mmHg, all being significantly higher than baseline level. Monitoring of MAP showed a significant increase to 101 mmHg only during tracheostomy. SpO(2) and HF did not show any significant changes. Mean duration of positioning, bronchoscopy and tracheostomy was 19, 10, and 17 min. 8 patients received osmotherapy due to a rise of ICP of more than 30 mmHg. PT only leads to a significant rise of ICP during the procedure. Nevertheless, therapy of ICP is necessary in some patients. From our point of view, therefore, tracheostomy should only be performed under continuous monitoring of ICP and CPP in patients with severe cerebral dysfunctions and critically elevated ICP.


Interaction of increasing atmospheric carbon dioxide and soil nitrogen on the carbon balance of tundra microcosms.
Natural cores of vegetation and soils of arctic tundra were collected in frozen condition in winter near Barrow, Alaska (71°20'N). These cores were used as microcosms in a phytotron experiment to measure the interactions, if any, between increasing atmospheric CO2 concentration and fertilization by ammonium nitrate on net ecosystem CO2 exchange and net yield of tundra vegetation. Increased soil N significantly enhanced net ecosystem CO2 uptake. The effect of increased CO2 concentration had little or no effect on mean net ecosystem carbon balance of the tundra microcosms. Added N significantly increased leaf area and phytomass of vascular plants in the microcosms while increased atmospheric CO2 had no effect on these parameters. We conclude that atmospheric CO2 is not now limiting net ecosystem production in the tundra and that its direct effects will be slight even at double the present concentration. the most probable effects of carbon dioxide in the coastal tundra will be through its indirect effects on temperature, water table, peat decomposition, and the availability of soil nutrients.


Real-time assessment of corneal endothelial cell damage following graft preparation and donor insertion for DMEK.
To establish a method for assessing graft viability, in-vivo, following corneal transplantation. Optimization of calcein AM fluorescence and toxicity assessment was performed in cultured human corneal endothelial cells and ex-vivo corneal tissue. Descemet membrane endothelial keratoplasty grafts were incubated with calcein AM and imaged pre and post preparation, and in-situ after insertion and unfolding in a pig eye model. Global, macroscopic images of the entire graft and individual cell resolution could be attained by altering the magnification of a clinical confocal scanning laser microscope. Patterns of cell loss observed in situ were compared to those seen using standard ex-vivo techniques. Calcein AM showed a positive dose-fluorescence relationship. A dose of 2.67μmol was sufficient to allow clear discrimination between viable and non-viable areas (sensitivity of 96.6% with a specificity of 96.1%) and was not toxic to cultured endothelial cells or ex-vivo corneal tissue. Patterns of cell loss seen in-situ closely matched those seen on ex-vivo assessment with fluorescence viability imaging, trypan blue/alizarin red staining or scanning electron microscopy. Iatrogenic graft damage from preparation and insertion varied between 7-35% and incarceration of the graft tissue within surgical wounds was identified as a significant cause of endothelial damage. In-situ graft viability assessment using clinical imaging devices provides comparable information to ex-vivo methods. This method shows high sensitivity and specificity, is non-toxic and can be used to evaluate immediate cell viability in new grafting techniques in-vivo.


Promoter activation of pepper class II basic chitinase gene, CAChi2, and enhanced bacterial disease resistance and osmotic stress tolerance in the CAChi2-overexpressing Arabidopsis.
The activation of the CAChi2 promoter as the result of bacterial infection and osmotic stresses was examined using the Agrobacterium-mediated transient expression assay. Several stress-related cis-acting elements were revealed within the upstream genomic sequence of the CAChi2 gene. In tobacco leaf tissues transiently transformed with the CAChi2 promoter-beta-glucuronidase (GUS) gene, the CAChi2 promoter was up-regulated by Pseudomonas syringae pv. tabaci infection. The CAChi2-GUS activation was closely related to osmotic stresses, including treatment with mannitol and NaCl. The -378 CAChi2 promoter was sufficient for the CAChi2 gene induction by salicylic acid treatment. CAChi2 overexpression in the transgenic Arabidopsis plants enhanced bacterial disease resistance against Pseudomonas syringae pv. tomato infection. CAChi2-overexpressing Arabidopsis plants also exhibited increased tolerance to NaCl-induced osmotic stresses during seed germination and seedling growth. CAChi2 overexpression induced the expression of the NaCl stress-responsive gene RD29A in the absence of NaCl stress. The CAChi2-overexpressing transgenic plants exhibited increased sensitivity to abscisic acid during seed germination.


Cryo-electron tomography: The power of seeing the whole picture.
Cryo-electron tomography allows to visualize the molecular architecture of pristinely preserved cellular landscapes in three dimensions. In favorable scenarios, macromolecular and supramolecular structures can be determined in situ with near-atomic resolution. The aim of visual proteomics is the parallel identification and annotation of all densities in the tomograms allowing for a comprehensive description of the molecular sociology of cells.


Late xerostomia after intensity-modulated radiation therapy versus conventional radiotherapy.
To evaluate xerostomia following intensity-modulated radiation therapy (IMRT). An institutional review board-approved study of xerostomia was conducted in 210 head and neck cancer patients who were beyond the acute recovery phase (> 1 year) after radiation therapy. Xerostomia was evaluated with the 8-question XQ developed and validated at the University of Michigan. Median XQ scores (normalized so that no xerostomia = 0 and maximum xerostomia = 100) were larynx-only group, 4 points, ipsilateral radiotherapy, 34 points; bilateral radiotherapy, 64 points; IMRT with mean contralateral parotid dose more than 26 Gy, 44 points; and IMRT with mean contralateral parotid dose 26 Gy or less, 32 points (P < 0.05 for all major comparisons). The XQ is an excellent tool for identifying important differences in xerostomia after radiation therapy for head and neck cancer. The authors' IMRT program decreases the severity of xerostomia symptoms compared with what is typically seen after conventional radiation therapy.


Analysis of the 100 most cited articles on ameloblastoma.
An increasing number of articles are published each year. The aim of this is to provide a list of the 100 most cited articles on the subject of ameloblastoma. A bibliographic search was performed on Google Scholar (GS), Microsoft Academic (MA), and Dimensions for ameloblastoma. A ranking was created in order of citation density. Graphical representations of keywords and authorship were created with VOSviewer. Statistical analysis was performed and only results with a 95% confidence interval were considered significant. A helpful list of top 100 articles was developed to help professionals in a variety of ways. Some curiosities are discussed about this scientometric analysis in ameloblastoma articles. A useful list of the top 100 most cited articles on ameloblastoma has been provided. Bibliometric and altmetric analysis using Google Scholar, Microsoft Academic, and Dimensions is a free and excellent tool, not only as a citation manager but also as a study reference.


GediNET for discovering gene associations across diseases using knowledge based machine learning approach.
The most common approaches to discovering genes associated with specific diseases are based on machine learning and use a variety of feature selection techniques to identify significant genes that can serve as biomarkers for a given disease. More recently, the integration in this process of prior knowledge-based approaches has shown significant promise in the discovery of new biomarkers with potential translational applications. In this study, we developed a novel approach, GediNET, that integrates prior biological knowledge to gene Groups that are shown to be associated with a specific disease such as a cancer. The novelty of GediNET is that it then also allows the discovery of significant associations between that specific disease and other diseases. The initial step in this process involves the identification of gene Groups. The Groups are then subjected to a Scoring component to identify the top performing classification Groups. The top-ranked gene Groups are then used to train a Machine Learning Model. The process of Grouping, Scoring and Modelling (G-S-M) is used by GediNET to identify other diseases that are similarly associated with this signature. GediNET identifies these relationships through Disease-Disease Association (DDA) based machine learning. DDA explores novel associations between diseases and identifies relationships which could be used to further improve approaches to diagnosis, prognosis, and treatment. The GediNET KNIME workflow can be downloaded from: https://github.com/malikyousef/GediNET.git or https://kni.me/w/3kH1SQV_mMUsMTS .


The tail domain of PRRSV NSP2 plays a key role in aggrephagy by interacting with 14-3-3ε.
Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) is one of the most severe swine diseases that affects almost all swine-breeding countries. Nonstructural protein 2 (NSP2) is one of the most important viral proteins in the PRRSV life cycle. Our previous study showed that PRRSV NSP2 could induce the formation of aggresomes. In this study we explored the effects of aggresome formation on cells and found that NSP2 could induce autophagy, which depended on aggresome formation to activate aggrephagy. The transmembrane and tail domains of NSP2 contributed to aggrephagy and the cellular protein 14-3-3ε played an important role in NSP2-induced autophagy by binding the tail domain of NSP2. These findings provide information on the function of the C-terminal domain of NSP2, which will help uncover the function of NSP2 during PRRSV infection.


Non-vascularized Fibular Cortex Grafts with Osteocutaneous Free Fibula Transfer: A Novel Technique in Midface Reconstruction.
To present a method to reconstruct the midface using the fibula as both a microvascular free flap and as a free cortex graft. 22-year-old male presented with bilateral maxillary odonotogenic myxoma. Bilateral total maxillectomy defects were reconstructed using an osteocutaneous fibula free flap. The nasomaxillary buttresses were augmented using free cortex grafts to provide additional soft tissue projection and lateral nasal support. The patient received dental implants at 10 months postoperatively and resumed a normal diet. His midface height, nasal and maxillary projection were adequate. At 36 months post-treatment he has no evidence of disease recurrence or resorption of the free bone grafts. The fibula free flap can be used to provide additional support to a patient's reconstruction by means of free cortex grafts. The patient has had successful restoration of pyriform aperture, nasal projection, mastication, and dental restoration using a single donor site.


Urban U.S. hospitals and the mission to provide HIV-related services: changes and correlates.
In 1988, the vast majority of urban U.S. hospitals (84 percent) exhibited some formal response to the demand for HIV-related services. Despite the fact that HIV-related care is now normative in many respects and the demand for inpatient care has decreased, nearly half of hospitals surveyed in 1997 (42 percent) report no formalized service provision, suggesting a heightened distinction between hospitals in terms of their varying commitments to providing HIV-related services. Certain organizational variables (such as ownership, size, system affiliation, and stigmatized services and post-acute care services indices) were connected to HIV-related services provision. When the sample was controlled for other variables, the study found that changes in teaching status, changes in bed size, and changes in post-acute services from 1988 to 1997 did influence the provision of HIV-related services. Despite significant changes over the study period in the treatment of persons living with HIV/AIDS, and structural changes in the delivery of U.S. healthcare, the organizational-level predictors of HIV-related service provision have remained remarkably stable among U.S. hospitals in urban settings. These data also suggest that organizational missions consistent with serving indigent and socially marginalized populations continue to influence the ways that the pluralistic U.S. hospital system organizes HIV-related care.


Effects of acute ethanol exposure on class I HDACs family enzymes in wild-type and BDNF(+/-) mice.
Alterations of brain-derived neurotrophic factor (BDNF) have been associated with the development of addiction to different drugs of abuse, including ethanol (EtOH). EtOH exposure activates the BDNF-signaling cascade in dorsal striatum, which in turn affects further EtOH intake. Different alcohol exposures have been widely demonstrated to modulate chromatin remodeling, affecting histone acetylation/deacetylation balance. Recently, class I histone deacetylases (HDACs) inhibition has been reported to modulate BDNF mRNA expression and to attenuate morphological and behavioral phenomena related to EtOH exposure. However, the role played by different HDAC isoforms in EtOH-induced plasticity is still unclear. We investigated the effects induced by acute EtOH exposure on the protein levels of class I HDAC 1-3 isoforms of wild-type (WT) and BDNF heterozygous mice (BDNF(+/-)), in nuclear and cytoplasmic extracts of specific brain regions associated with EtOH addiction. Nuclear HDAC 1-3 levels were markedly reduced after acute EtOH treatment in the caudate putamen (CPu) of WT mice only. Furthermore, CPu basal levels of nuclear HDAC isoforms were significantly lower in BDNF(+/-) mice compared to WT. With the exception of nuclear HDAC 3, no significant changes were observed after acute EtOH treatment in the prefrontal cortex (PFCx) of BDNF(+/-) and WT mice. In this area, the nuclear HDAC basal levels were significantly different between the two experimental groups. These results provide details about EtOH effects on class I HDAC isoforms and strongly support a correlation between BDNF and class I HDACs, suggesting a possible influence of BNDF on these enzymes.


Significance of IgM antibody to hepatitis C virus in patients with chronic hepatitis C.
We assessed the correlation between the positivity for serum IgM antibody to hepatitis C virus and the activity of liver disease in patients with chronic hepatitis C virus infection. Serum samples were taken from 10 antibody to hepatitis C virus-positive asymptomatic patients with normal serum ALT levels, from 14 untreated patients with clinically and histologically proven chronic hepatitis C and from 26 patients with clinically and histologically proven chronic hepatitis C assigned to receive recombinant interferon alpha-2a (6 million IU three times a week for 6 mo). Each serum specimen was tested for IgM antibody to hepatitis C virus-associated C100-3 antigen by enzyme-linked immunosorbent assay. Patients were observed for at least 12 mo. All 10 patients with normal ALT values tested negative for IgM antibody to hepatitis C virus. In contrast, 33 of 40 (82%) patients with chronic hepatitis C had IgM antibody to hepatitis C virus, and a positive correlation was seen between the ALT level and the level of IgM antibody to hepatitis C virus (r = 0.803, p less than 0.001). During interferon treatment, ALT levels declined into the normal range in 18 of 26 treated patients (69%) and remained normal after stopping treatment in 8 patients (31%). In untreated patients, in treated patients who did not respond to interferon treatment and in responder patients who relapsed, no significant changes in IgM antibody to hepatitis C virus levels were seen during the study period. In contrast, IgM antibody to hepatitis C virus became undetectable by the end of interferon treatment in seven of eight patients with a sustained response.(ABSTRACT TRUNCATED AT 250 WORDS)


Doubly ortho-linked quinoxaline/triarylamine hybrid as a bifunctional, dipolar electroluminescent template for optoelectronic applications.
The titled hybrid (Q-H) works as a clippable optoelectronic unit. Q-spacer-Q systems function as efficient orange emitters reaching EL intensities (L) of up to 6840 cd m-2 with etaext of 0.77% and operation efficiencies of 1.60 cd A-1 and 0.8 lm W-1. Notably, Q-An acts as a (bluish) green emitter, reaching L of 12347 cd m-2 with similar operational efficiency.


Glutathione and neodiosmin feedback sustain plant immunity.
Plants have evolved a two-layer immune system comprising pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) that is activated in response to pathogen invasion. Microbial patterns and pathogen effectors can be recognized by surface-localized pattern-recognition receptors (PRRs) and intracellularly localized nucleotide-binding leucine-rich repeat receptors (NLRs) to trigger PTI and ETI responses, respectively. At present, the metabolites activated by PTI and ETI and their roles and signalling pathways in plant immunity are not well understood. In this study, metabolomic analysis showed that ETI and PTI induced various flavonoids and amino acids and their derivatives in plants. Interestingly, both glutathione and neodiosmin content were specifically up-regulated by ETI and PTI, respectively, which significantly enhanced plant immunity. Further studies showed that glutathione and neodiosmin failed to induce a plant immune response in which PRRs/co-receptors were mutated. In addition, glutathione-reduced mutant gsh1 analysis showed that GSH1 is also required for PTI and ETI. Finally, we propose a model in which glutathione and neodiosmin are considered signature metabolites induced in the process of ETI and PTI activation in plants and further continuous enhancement of plant immunity in which PRRs/co-receptors are needed. This model is beneficial for an in-depth understanding of the closed-loop mode of the positive feedback regulation of PTI and ETI signals at the metabolic level.


Antinociceptive effects of morphine injected into the nucleus parafascicularis thalami of the rat.
The antinociceptive action of morphine microinjected into the nucleus parafascicularis thalami (nPf) on pain behaviors organized at different levels of the neuraxis was examined in the rat. Behaviors organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations during shock, VDSs), and forebrain (vocalization afterdischarges, VADs) levels were elicited by noxious tailshock. Morphine administered into nPf generated dose-dependent increases in thresholds of VDS and VAD, but failed to elevate SMR thresholds. Increases in vocalization thresholds were reversed in a dose-dependent manner by the microinjection of the mu-opiate receptor antagonist, methylnaloxonium, into nPf. Results are discussed in terms of the relative influence of nPf-administered morphine on nociceptive processing at spinal versus supraspinal levels of the neuraxis.


ELICIT: An alternative imprecise weight elicitation technique for use in multi-criteria decision analysis for healthcare.
In this paper, the readers are introduced to ELICIT, an imprecise weight elicitation technique for multicriteria decision analysis for healthcare. The application of ELICIT consists of two steps: the rank ordering of evaluation criteria based on decision-makers' (DMs) preferences using the principal component analysis; and the estimation of criteria weights and their descriptive statistics using the variable interdependent analysis and the Monte Carlo method. The application of ELICIT is illustrated with a hypothetical case study involving the elicitation of weights for five criteria used to select the best device for eye surgery. The criteria were ranked from 1-5, based on a strict preference relationship established by the DMs. For each criterion, the deterministic weight was estimated as well as the standard deviation and 95% credibility interval. ELICIT is appropriate in situations where only ordinal DMs' preferences are available to elicit decision criteria weights.


Dynamic microwave-assisted extraction coupled with on-line spectrophotometric determination of safflower yellow in Flos Carthami.
A rapid dynamic microwave-assisted extraction and on-line detection by spectrophotometry is proposed for the determination of safflower yellow in Flos Carthami. A high pressure and a peristaltic pump were used to deliver the solvent. A TM010 microwave resonance cavity was applied to concentrate the microwave energy and the forward power about 60 W was enough for the extraction. Other extraction conditions also were examined and optimized. In this work, the extraction process can be monitored by measuring the absorption of safflower yellow in the extract, which would be convenient for rapid optimization of the extraction process. The detection and quantification limits are 8 and 27 microg mL(-1), respectively. The within-day and between-day precision (R.S.D.) are 1.6-3.2% and 2.8-4.2%, respectively. Compared with off-line detection, the proposed method may provide more rapid measurement and is more convenient for obtaining continuous measurements.