Introgression of tsv1 improves tungro disease resistance of a rice variety BRRI dhan71.
Rice Tungro disease poses a threat to rice production in Asia. Marker assisted backcross breeding is the most feasible approach to address the tungro disease. We targeted to introgress tungro resistance locus tsv1 from Matatag 1 into a popular but tungro susceptible rice variety of Bangladesh, BRRI dhan71. The tsv1 locus was traced using two tightly linked markers RM336 and RM21801, and background genotyping was carried out using 7 K SNPs. A series of three back crosses followed by selfing resulted in identification of plants similar to BRRI dhan71. The background recovery varied at 91-95% with most of the lines having 95%. The disease screening of the lines showed moderate to high level of tungro resistance with a disease index score of ≤ 5. Introgression Lines (ILs) had medium slender grain type, and head rice recovery (59.2%), amylose content (20.1%), gel consistency (40.1 mm) and gelatinization temperature were within the acceptable range. AMMI and Kang's stability analysis based on multi-location data revealed that multiple selected ILs outperformed BRRI dhan71 across the locations. IR144480-2-2-5, IR144483-1-2-4, IR144484-1-2-2 and IR144484-1-2-5 are the most promising lines. These lines will be further evaluated and nominated for varietal testing in Bangladesh.


Decreased concentrations and affinities of oestrogen and progesterone receptors of intrauterine tissue in human pregnancy.
Cytoplasmic and nuclear receptors for oestrogen and progesterone were measured in non-pregnant myometrium and endometrium and compared to concentrations found in decidua of ectopic pregnancy (6-8 weeks gestation) and therapeutic abortions (8-16 weeks). Amnion, chorion, placenta, decidua and myometrium at full term pregnancy were also assayed for the same receptors. High affinity binding was confirmed in the non-pregnant tissue; in early pregnancy, decreases in concentrations of cytoplasmic receptors were demonstrated, these decreases becoming more marked as pregnancy progressed in the 1st trimester. Nuclear receptor concentrations were not significantly different. Significant decreases in the occurrence of positive receptors with the progression of pregnancy were also demonstrated for cytoplasmic and nuclear oestrogen and nuclear progesterone receptors. Tissue at full term pregnancy had no detectable receptors, irrespective of whether the patients were in labour or not. Increasing the range of the labelled steroids failed to demonstrate any low affinity binding sites and pre-assay removal of endogenous hormones also had no effect on receptor status. When endogenous hormones were removed, displaceable binding was demonstrated in the presence of excess unlabelled ligand. However, this binding did not conform with receptor dynamics on Scatchard analysis. Heating the cytosol prior to assay or failure to remove endogenous steroid hormones eliminated this binding. Cytosolic oestrogen and progesterone levels increased significantly in the decidua of therapeutic abortions, whilst term pregnant tissue had the highest concentration of endogenous hormones.


Bacterial communities associated with Brassica napus L. grown on trace element-contaminated and non-contaminated fields: a genotypic and phenotypic comparison.
Cultivable bacterial strains associated with field-grown Brassica napus L. (soil, rhizosphere and roots) from a trace elements (Cd, Zn and Pb) contaminated field and a non-contaminated control field were characterized genotypically and phenotypically. Correspondence analysis of the genotypic data revealed a correlation between soil and rhizosphere communities isolated from the same field, indicating that local conditions play a more important role in influencing the composition of (rhizosphere) soil bacterial communities than root exudates. In contrast, endophytic communities of roots showed a correlation between fields, suggesting that plants on the two fields contain similar obligate endophytes derived from a common seed endophytic community and/or can select bacteria from the rhizosphere. The latter seemed not very likely since, despite the presence of several potential endophytic taxa in the rhizosphere, no significant correlation was found between root and rhizosphere communities. The majority of Cd/Zn tolerant strains capable of phosphorus solubilization, nitrogen fixation, indole-3-acetic acid production and showing 1-aminocyclopropane-1-carboxylate deaminase capacity were found in the rhizosphere and roots of plants growing on the contaminated field.


Metabolic and hemodynamic activation of postischemic rat brain by cortical spreading depression.
Following transient ischemia of the brain, the coupling between somatosensory activation and the hemodynamic-metabolic response is abolished for a certain period despite the partial recovery of somatosensory evoked responses. To determine whether this disturbance is due to alterations of the stimulus-induced neuronal excitation or to a breakdown of the coupling mechanisms, cortical spreading depression was used as a metabolic stimulus in rats before and after ischemia. Adult rats were subjected to 30 min of global forebrain ischemia and 3-6 h of recirculation. EEG, cortical direct current (DC) potential, and laser-Doppler flow were continuously recorded. Local CBF (LCBF), local CMRglc (LCMRglc), regional tissue contents of ATP, glucose, and lactate, and regional pH were determined by quantitative autoradiography, substrate-induced bioluminescence, and fluorometry. Amplitude and frequency of the DC shifts did not differ between groups. In control animals, spreading depression induced a 77% rise in cortical glucose consumption, a 66% rise in lactate content, and a drop in tissue pH of 0.3 unit. ATP and glucose contents were not depleted. During the passage of DC shifts, transient increases (less than 2 min) in laser-Doppler flow were observed, followed by a post-spreading depression hypoperfusion. A comparable although less expressed pattern of hemodynamic and metabolic changes was observed in the postischemic rats. Although baseline LCMRglc was depressed after ischemia, it was activated 47% during spreading depression. Lactate increased by 26%, pH decreased by 0.3 unit, and ATP and glucose remained unchanged. The extent of the transient increase in laser-Doppler flow did not differ from that of the control group, and a post-spreading depression hypoperfusion was also found.(ABSTRACT TRUNCATED AT 250 WORDS)


Apigenin inhibits hepatoma cell growth through alteration of gene expression patterns.
Apigenin, a common plant flavonoid, has been shown to possess anti-tumor properties; however, the underlying molecular mechanisms are still not completely understood. In the present study, we investigated the effects of apigenin on human hepatoma Huh7 cell proliferation, cell cycle distribution, apoptosis, and colony formation in vitro, as well as on the tumorigenicity of Huh7 cells in vivo. To get more insight into the mechanism of apigenin action, we performed genome-wide expression profiling of apigenin-treated Huh7 cells using cDNA microarrays (Agilent Whole Human Genome Oligo Microarray) that contain 41,000 genes. Ten of the most differentially expressed genes (≧5-fold changes) were selected for further evaluation by quantitative RT-PCR (qPCR) and Western blot analyses. Notably, apigenin (5-20 μg/ml) remarkably inhibited Huh7 cell proliferation and colony formation as compared to the vehicle control, which was in a dose-dependent manner. Accompanying with the decreased growth, apigenin-treated cells showed a cell cycle arrest at G2/M phase and an increased rate of apoptosis. Moreover, the xenografts derived from Huh7 cells were significantly (p<0.05) retarded by the delivery of apigenin (50 μg/mouse/day) relative to the control counterparts. Gene expression profile analysis revealed that 1336 genes were up-regulated and 428 genes were down-regulated by apigenin. The down-regulation of interleukin-4 receptor and ubiquitin specific protease 18 and the up-regulation of SLC27A3 and chemokine (C-C motif) receptor 2 were further confirmed by the qPCR and Western blot results. In conclusion, apigenin exhibits inhibitory effects on hepatoma cell growth, which is likely mediated through alteration of gene expression profiles.


[Objective and subjective evaluation of the rehabilitation of patients following heart valve prosthesis].
Some aspects of the character of life of 71 patients after prosthetics of the heart valves were studied in a complex according to a medico-psychological program. The functional condition improved as the result of the operation in most of them, but many neuro-psychic complaints, poor self-appraisal, and dissatisfaction due to many limitations remained. An unfavourable tendency in return to work was revealed, which corresponded to subjective appraisal of rehabilitation and not to functional restoration.


Differentiation of the musculature of the teleost Brachydanio rerio. II. Effects of immobilization on the shape and structure of somites.
The development of the shape and structure of somites in the teleost Brachydanio rerio was studied in embryos under normal conditions and in immobilized embryos. Three different immobilization methods were applied: enclosure in agar, a glass rod in the neural tube and anaesthesia in MS-222. When the performance of the lateral body movements is prevented, the shape development of the somites in embryos and young larvae becomes reversed. When the agar-immobilization is terminated, the larvae resume their normal movements. In about 10 days, the shape of the somites is again as in control larvae. We conclude, that the lateral body movements have both a shape-determining and a shape-stabilizing role during the early stages of somite morphogenesis. It is suggested that in normal embryos differences in shortening between lateral and medial muscle fibres, cause differences in longitudinal growth of the muscle fibres and that the oblique muscle fibre arrangement is a consequence of these differences in growth. In immobilized embryos and larvae, the longitudinal growth of the muscle fibres is decreased. Also the difference in the longitudinal growth rate between lateral and medial muscle fibres diminishes in all somites. We conclude that for the normal morphogenesis of the somites the performance of the specific function, that is to bring about lateral body movements, is required. We suggest, that the impact of the lateral body movements on the development of the structure of the somites is mediated through adaptive growth of the muscle fibres. The suggestion may also apply to the development of the pinnate structure of muscles of higher vertebrates.


Evaluation of the Role of the Immune System Response After Minibeam Radiation Therapy.
Minibeam radiation therapy (MBRT) is an innovative technique that uses a spatial dose modulation. The dose distribution consists of high doses (peaks) in the path of the minibeam and low doses (valleys). The underlying biological mechanism associated with MBRT efficacy remains currently unclear and thus we investigated the potential role of the immune system after treatment with MBRT. Rats bearing an orthotopic glioblastoma cell line were treated with 1 fraction of high dose conventional radiation therapy (30 Gy) or 1 fraction of the same mean dose in MBRT. Both immunocompetent (F344) and immunodeficient (Nude) rats were analyzed in survival studies. Systemic and intratumoral immune cell population changes were studied with flow cytometry and immunohistochemistry (IHC) 2 and 7 days after the irradiation. The absence of response of Nude rats after MBRT suggested that T cells were key in the mode of action of MBRT. An inflammatory phenotype was observed in the blood 1 week after irradiation compared with conventional irradiation. Tumor immune cell analysis by flow cytometry showed a substantial infiltration of lymphocytes, specifically of CD8 T cells and B cells in both conventional and MBRT-treated animals. IHC revealed that MBRT induced a faster recruitment of CD8 and CD4 T cells. Animals that were cured by radiation therapy did not suffer tumor growth after reimplantation of tumoral cells, proving the long-term immunity response generated after a high dose of radiation. Our findings show that MBRT can elicit a robust antitumor immune response in glioblastoma while avoiding the high toxicity of a high dose of conventional radiation therapy.


Correction to: Transsphenoidal surgery for pituitary adenomas: early results from a single center.
Unfortunately in the original publication, the affiliation of the author Paolo Marzullo was incorrect. The author inadvertently missed out to include his second affiliation.


Seismic air gun exposure during early-stage embryonic development does not negatively affect spiny lobster Jasus edwardsii larvae (Decapoda: Palinuridae).
Marine seismic surveys are used to explore for sub-seafloor oil and gas deposits. These surveys are conducted using air guns, which release compressed air to create intense sound impulses, which are repeated around every 8-12 seconds and can travel large distances in the water column. Considering the ubiquitous worldwide distribution of seismic surveys, the potential impact of exposure on marine invertebrates is poorly understood. In this study, egg-bearing female spiny lobsters (Jasus edwardsii) were exposed to signals from three air gun configurations, all of which exceeded sound exposure levels (SEL) of 185 dB re 1 μPa(2) · s. Lobsters were maintained until their eggs hatched and the larvae were then counted for fecundity, assessed for abnormal morphology using measurements of larval length and width, tested for larval competency using an established activity test and measured for energy content. Overall there were no differences in the quantity or quality of hatched larvae, indicating that the condition and development of spiny lobster embryos were not adversely affected by air gun exposure. These results suggest that embryonic spiny lobster are resilient to air gun signals and highlight the caution necessary in extrapolating results from the laboratory to real world scenarios or across life history stages.


Pressure pain sensitivity map of multifocal nummular headache: a case report.
Nummular headache (NH) is most commonly a localized unifocal headache; however, some patients infrequently exhibit multifocal symptomatic painful head areas retaining all features of NH. We present the pressure pain sensitivity map of an adolescent with multifocal NH. We describe a case of a 14 year-old-girl with a 3-year history of continuous pain in four rounded areas, all of them with the same size and shape. Pressure pain thresholds (PPT) were assessed on 21 points over the scalp and over the symptomatic areas. A pressure pain sensitivity map of the head was constructed. The neurological exam was unremarkable, with neither sensory symptoms nor trophic changes within the painful areas. As previously shown, symptomatic points exhibited lower PPTs compared to the surrounding areas. The map reflected 4 restricted areas of mechanical hyperalgesia confined just to the painful areas. Treatment with gabapentin achieved complete remission. This is the first pain sensitivity map of a patient with multifocal NH. Our results support peripheral mechanisms are maintained in multifocal NH.


The intrapancreatic anatomy as an index of adequacy of pancreatic arteriography.
Analysis of 100 pancreatic arteriograms in respect of intrapancreatic arteries shown has been performed. The results have been compared with Michels' classic series of 200 cadaveric dissections. Excellent correlation has been found. The degree of demonstration of small intrapancreatic arteries in our view is an index of the adequancy of pancreatic arteriography.


Gender and suicidality prediction in epilepsy.
The current study was carried out to compare the accuracy of suicidal risk prediction in patients with epilepsy for each gender separately and as a group (males+females). The discriminant function analysis was performed to create an algorithm for suicidal risk classification for males and females separately and as a group. The main characteristics of epilepsy, such as type and mean frequency of seizures and kind and mean daily dose of AEDs were used as independent variables. The accuracy of suicidality prediction is higher for each gender than for the joint group. There was a statistically significant difference between the joint group and male epileptic patients and a trend toward more precise suicidality prediction among men than women, although the discrepancies were not significant. It was concluded that gender is an important factor in suicidality prediction, and more precise prediction of suicidal risk is possible for male epileptic patients because of the better differentiation of suicide grades in males than in females.


Is reoperative coronary artery bypass grafting in patients with poor left ventricular ejection fractions < or = 25% worthwhile?
This study aimed to investigate whether patients with very low left ventricular ejection fractions (LVEF) should be accepted for reoperative coronary artery bypass grafting (CABG). Between January 1990 and December 1993, 1681 patients underwent primary CABG and 308 (15.5%) reoperative CABG. One hundred and eight patients (5.4%) had an LVEF < or = 25%, 91 patients for primary CAGB (group I) and 17 for CABG (group II). The mean age of the patients was 62 years. Sex distribution and preoperative risk factors did not differ. Urgent operations were more frequently necessary in group II (P < 0.01). Mitral regurgitation was present in 49% of the group I patients and 18% of the group II patients (P < 0.05). Pulmonary artery hypertension was observed in 24% of group I patients, but in only 6% in group II patients. The mean LVEF was 21% and left ventricular end-diastolic pressure 18 mmHg, without between-group differences. All patients had significant two- or three-vessel disease (stenosis > or = 70%). An average of 4.5 grafts per patient were performed. Mitral valve surgery was not performed in any of the patients. The postoperative mortality was significantly higher in reoperative CABG patients (group II; 23.5%) than in group I patients (12.1%; P < 0.05), whereas the incidence of non-fatal myocardial infarction did not differ. The incidence of postoperative complications did not differ between the groups, except for transient renal failure, more frequently encountered in group II (P < 0.05). After an average follow-up of 18 months, the New York Heart Association (NYHA) class and the LVEF were significantly improved in both groups (NYHA class from 3.5 to 1.8 and LVEF from 21% to 45%; P < 0.001). The mitral regurgitation had improved or completely disappeared at the end of follow-up in all patients in both groups. Our results suggest that patients with left ventricular ejection fraction < or = 25%, angina and significant two- or three-vessel coronary artery disease should not categorically be refused for reoperative CABG. Careful patient selection is necessary because of an increased operative risk.


Vinylene and benzo[c][1,2,5]thiadiazole: effect of the π-spacer unit on the properties of bis(2-oxoindolin-3-ylidene)-benzodifuran-dione containing polymers for n-channel organic field-effect transistors.
Two polymers based on (3E,7E)-3,7-bis(2-oxoindolin-3-ylidene)benzo[1,2-b:4,5-b']difuran-2,6(3H,7H)-dione (BIBDF) coupled with (E)-2-(2-(thiophen-2-yl)vinyl)thiophene (TVT) or dithienylbenzothiadiazole (TBT), namely PBIBDF-TVT and PBIBDF-TBT were synthesized via the Stille coupling reaction. The effect of benzothiadiazole or vinylene-π spacer of the copolymers on optical properties, energy levels, electronic device performance and microstructure were studied. It was found that PBIBDF-TBT based OFET devices, annealed at 180 °C, showed better performance with the highest electron mobility of 2.9 × 10-2 cm2 V s-1 whereas PBIBDF-TVT polymer exhibited 5.0 × 10-4 cm2 V s-1. The two orders of magnitude higher electron mobility of PBIBDF-TBT over PBIBDT-TVT is a clear indicator of the better charge transport ability of this polymer semiconductor arising from its higher crystallinity and better donor-acceptor interaction.


Escape from neutralization by the respiratory syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by changes in on-rate of binding to the fusion protein.
The role of binding kinetics in determining neutralizing potency for antiviral antibodies is poorly understood. While it is believed that increased steady-state affinity correlates positively with increased virus-neutralizing activity, the relationship between association or dissociation rate and neutralization potency is unclear. We investigated the effect of naturally-occurring antibody resistance mutations in the RSV F protein on the kinetics of binding to palivizumab. Escape from palivizumab-mediated neutralization of RSV occurred with reduced association rate (Kon) for binding to RSV F protein, while alteration of dissociation rate (Koff) did not significantly affect neutralizing activity. Interestingly, linkage of reduced Kon with reduced potency mirrored the effect of increased Kon found in a high-affinity enhanced potency palivizumab variant (motavizumab). These data suggest that association rate is the dominant factor driving neutralization potency for antibodies to RSV F protein antigenic site A and determines the potency of antibody somatic variants or efficiency of escape of viral glycoprotein variants.


Fibrocytes are involved in inflammation as well as fibrosis in the pathogenesis of Crohn's disease.
We previously showed that fibrocytes, a hematopoietic stem cell source of fibroblasts/myofibroblasts, infiltrated the colonic mucosa of a murine colitis model. We investigated whether fibrocytes were involved in the pathogenesis of Crohn's disease. Human surgical intestinal specimens were stained with anti-leukocyte-specific protein 1 and anti-collagen type-I (ColI) antibodies. Circulating fibrocytes in the human peripheral blood were quantified by fluorescence-activated cell sorting with anti-CD45 and anti-ColI antibodies. Cultured human fibrocytes were prepared by culturing peripheral CD14(+) monocytes. In the specimens of patients with Crohn's disease, the fibrocyte/total leukocyte percentage was significantly increased in inflammatory lesions (22.2 %, p < 0.01) compared with that in non-affected areas of the intestine (2.5 %). Interestingly, the percentage in fibrotic lesions was similar (2.2 %, p = 0.87) to that in non-affected areas. The percentages of circulating fibrocytes/total leukocytes were significantly higher in patients with Crohn's disease than in healthy controls. Both CXC-chemokine receptor 4(+) and intercellular adhesion molecule 1(+) fibrocyte numbers were significantly increased in Crohn's disease, suggesting that circulating fibrocytes have a higher ability to infiltrate injured sites and traffic leukocytes. In cultured fibrocytes, lipopolysaccharide treatment remarkably upregulated tumor necrosis factor (TNF)-α mRNA (17.0 ± 5.7-fold) and ColI mRNA expression (12.8 ± 5.7-fold), indicating that fibrocytes stimulated by bacterial components directly augmented inflammation as well as fibrosis. Fibrocytes are recruited early in the inflammatory phase and likely differentiate into fibroblasts/myofibroblasts until the fibrosis phase. They may enhance inflammation by producing TNF-α and can directly augment fibrosis by producing ColI.


Endovascular administration after intravenous infusion of thrombolytic agents for the treatment of patients with acute ischemic strokes.
To determine the feasibility of combined intravenous and intra-arterial thrombolytic therapy for acute ischemic strokes and to evaluate its associated risks, using magnetic resonance imaging as a triage tool. Intravenous treatment followed by intra-arterial infusion may increase the rate of recanalization and lead to better clinical results, with reduced frequency of intracranial hemorrhage. Our Brain Attack Team evaluated patients who presented within 3 hours after symptom onset. Patients who did not demonstrate improvement and exhibited no evidence of intracranial hemorrhage on head computed tomographic scans were treated with intravenously administered recombinant tissue plasminogen activator (0.6 mg/kg) and underwent emergency magnetic resonance imaging of the head. T2-weighted turbo-gradient and spin echo and echo-planar diffusion- and perfusion-weighted imaging scans were obtained. Patients with evidence of imaging abnormalities indicating acute cortical infarction underwent cerebral angiography. After determination of vessel occlusion, intra-arterially administered urokinase (up to 750,000 units) or intra-arterially administered recombinant tissue plasminogen activator (maximal dose, 0.3 mg/kg) was used to achieve recanalization. We treated 45 patients with this protocol. The mean age was 67 +/- 13 years, and 58% of the patients were women. There was a significant improvement in National Institutes of Health Stroke Scale scores after treatment. There was good correlation between abnormal perfusion-weighted imaging findings and cerebral angiographic findings (complete vessel occlusion). The incidence of symptomatic intracranial hemorrhage was 4.4% in this cohort. Seven patients died in the hospital, and the majority of survivors (77%) experienced good outcomes (Barthel index of >or=95) 3 months after treatment. Our data demonstrate that this protocol is feasible and that combined intravenous and intra-arterial thrombolysis to treat acute ischemic strokes is sufficiently safe to warrant further evaluation.


Influence of body composition on bone mass in children and adolescents.
To evaluate the influence of body composition on bone mass in children and adolescents. A cross-sectional study with 267 healthy students of both sexes (141 males and 126 females) aged 8 to 18 years. Weight, height, body mass index, lean mass, fat mass, fat mass index, body fat percentage, waist and hip circumferences, and waist-to-hip ratio were evaluated. Bone mass was assessed using ultrasound of hand phalanges (DBM Sonic BP IGEA, Carpi, Italy). Females showed greater bone mass in relation to males with advances in age and pubertal stage. In both sexes, the bone mass showed significant and positive correlations with age, weight, height, body mass index, lean mass, waist and hip circumferences; and negative correlations with waist-to-hip ratio. In females, there was also a positive correlation with fat mass, fat mass index, and body fat percentage. Age and lean mass were predictors for bone mass in males, and age, pubertal stage and fat mass index were predictors in females. The correlation between bone mass and body composition occurred in both sexes, with lean mass and fat mass index being the predictor of bone mass in males and females, respectively.


Cerebral ischemia and brain histamine.
Cerebral ischemia induces excess release of glutamate and an increase in the intracellular Ca(2+) concentration in neurons, which provokes enzymatic process leading to irreversible neuronal injury. Histamine plays a role as a neurotransmitter in the mammalian brain, and histamine release from nerve endings is enhanced in ischemia by facilitation of histaminergic activity. Dissimilar to ischemia-induced release of glutamate, histamine release is gradual and long lasting. The enhancement may contribute to neuroprotection against ischemic damage, because suppression of histaminergic activity aggravates the histologic outcome caused by ischemia. Preischemic administration of histamine (i.c.v.) suppresses ischemic release of glutamate and ameliorates neuronal damage, whereas blockade of central histamine H(2) receptors aggravates ischemic injury. These suggest that histamine provides beneficial effects against ischemic damage through histamine H(2) receptors, when administered before induction of ischemia. Postischemic loading with histidine, a precursor of histamine, alleviates both brain infarction and delayed neuronal death. Since the alleviation is abolished by blockade of central histamine H(2) receptors, facilitation of central histamine H(2) action caused by histidine may prevent reperfusion injury after ischemic events. Because the ischemia-induced increase in the glutamate level rapidly resumes after reperfusion of cerebral blood flow, beneficial effects caused by postischemic loading with histidine may be due to other mechanisms besides suppression of excitatory neurotransmitter release. Anti-inflammatory action by histamine H(2) receptor stimulation is a likely mechanism responsible for the improvement.


Bone marrow-derived recipient cells in murine transplanted hearts: potential roles and the effect of immunosuppression.
Currently, there is intense debate regarding the origin of reparative cells in injured hearts and vasculature. To determine the contribution of recipient bone marrow (BM)-derived cells to the regeneration of cells in the vasculature of transplanted hearts and to examine the effect of immunosuppression on this phenomenon, we evaluated the fate of green fluorescent protein (GFP)-positive recipient BM cells in non-GFP-expressing cardiac allografts. C57BL/6 BM-GFP chimeric recipients underwent cardiac transplantation. Allografts were immunosuppressed with tacrolimus for 14 or 30 days post-transplantation or were saline treated. Hearts were excised and stained with markers for endothelial cells (EC) or smooth muscle cells (SMC). Colocalization with BM-derived recipient cells was evaluated using confocal microscopy with three-dimensional image analysis. Immunosuppression with tacrolimus did not affect the frequency of recipient BM-derived cell chimerism as EC or SMC phenotypes. A higher frequency of EC chimerism was found at 14 days as compared to 30 days post-transplantation in allograft hearts. BM-derived recipient cells are recruited to areas of donor vascular injury with intercalation of recipient EC and SMC in the setting of ongoing alloimmune recognition of the allograft. Our findings confirm that immunosuppression with tacrolimus does not affect the frequency of recipient BM-derived cell repopulation at an early time point 14 days post-transplantation. EC repopulation by BM-derived recipient cells was found to be an early event in transplanted allograft hearts, which decreased in frequency over time.


Comparison of tyrosine phosphorylation of proteins by membrane fractions from mouse liver, Ehrlich ascites tumor and MH134 hepatoma.
When membrane fractions from mouse liver, Ehrlich ascites tumor and MH134 hepatoma were incubated with [gamma-32P]ATP at 0 degree C in the presence of MnCl2, ZnCl2 and NaVO3, proteins were phosphorylated on tyrosines to a larger extent in liver membranes than in tumor membranes. Separation of labelled proteins by SDS-gel electrophoresis showed phosphorylated alkali-resistant bands of 170, 140, 130, 80, 56, 53 and 46 kDa proteins in Ehrlich ascites tumor membranes; liver membranes exhibited more strongly phosphorylated bands of 170, 56, 53 and 46 kDa proteins. Epidermal growth factor stimulated the tyrosine phosphorylation of only a 170 kDa protein, which was more significant in liver membranes. Liver membranes exhibited slightly higher levels of tyrosine protein kinase activity compared to tumor membranes.


β-Cyclodextrin Polymers with Different Cross-Linkers and Ion-Exchange Resins Exhibit Variable Adsorption of Anionic, Zwitterionic, and Nonionic PFASs.
Per- and polyfluoroalkyl substances (PFASs) occur in groundwater as mixtures of anionic, cationic, zwitterionic, and nonionic species, although few remediation technologies have been evaluated to assess the removal of different types of PFASs. In this study, we evaluated the performance of three β-cyclodextrin polymers (CDPs), an anion-exchange (AE) resin, and a cation-exchange (CE) resin for the removal of anionic, zwitterionic, and nonionic PFASs from water. We found that a CDP with a negative surface charge rapidly removes all zwitterionic PFASs with log KD values ranging between 2.4 and 3.1, and the CE resin rapidly removes two zwitterionic PFASs with log KD values of 1.8 and 1.9. The CDPs with a positive surface charge rapidly remove all anionic PFASs with log KD values between 2.7 and 4.1, and the AE resin removes all anionic PFASs relatively slowly with log KD values between 2.0 and 2.3. All adsorbents exhibited variable removal of the nonionic PFASs and some adsorption inhibition at higher pH values and in the presence of groundwater matrix constituents. Our findings provide insight into how adsorbents can be combined to remediate groundwater contaminated with complex mixtures of different types of PFASs.


[Enrolment and follow-up of a birth cohort in Rome].
Longitudinal studies on cohorts of babies enrolled at birth are ongoing in Europe. On the basis of these experiences, a birth cohort study should be implemented in Italy at a national level. A pilot study is ongoing in Rome, from which we report data on adherence at recruitment and follow-up. Prospective cohort study. the birth cohort was enrolled between June 2003 and October 2004, in two hospital ofRome in the district ofthe Local Health Unit RME. we enrolled children of women older than 18 years, Italian citizens and residents in the Local Health Unit RME. Baseline characteristics of enrolled women were compared with those of refusals, and characteristics of children with a complete follow-up with those lost at follow-up. Prevalence Rate ratio (PR) and the relative 95% confidence interval were calculated. The cohort consisted of 704 women (54% of the contacted) and 719 children. A low level of instruction (PR 2.84), and a caesarean delivery (OR 1.41) were significantly associated with the refusal. After the enrolment 25 children were lost, 117 were partially followed-up and 577 had a complete follow-up until the 15 month visit. Mothers of children lost at follow-up were less instructed (PR 1.69) and smoked during pregnancy (PR 1.57). During the enrolment and the follow-up of a birth cohort greater efforts must be done to avoid selection for the socioeconomic level of the family. Keeping a high response rate to follow-up is the only way to ensure a good level of internal validity.


Best options for preoperative biliary drainage in patients with Klatskin tumors.
Operative treatment combined with PBD has been established as a safe management strategy for Klatskin tumors. However, controversy exists regarding the preferred technique for PBD among percutaneous transhepatic biliary drainage (PTBD), endoscopic biliary stenting (EBS), and endoscopic nasobiliary drainage (ENBD). This study aimed to identify the best technique for preoperative biliary drainage (PBD) in Klatskin tumor patients. This study evaluated 98 Klatskin tumor patients who underwent PBD prior to operation with a curative aim between 2005 and 2012. The PTBD, EBS, and ENBD groups included 43, 42, and 13 patients, respectively. Baseline characteristics, technical success rate, complications of PBD, and surgical outcomes were compared. Initial technical success rates (97.3 %, PTBD; 90.2 %, endoscopic methods, including EBS and ENBD) and mean duration until biliary decompression (31.0, PTBD; 28.7, EBS; 35.8 days, ENBD) were not significantly different between the groups. Total frequency of complications did not significantly differ between the EBS group (42.9 %) and the PTBD (27.9 %, p = 0.149) and ENBD (15.4 %, p = 0.072) groups. The ENBD group showed a significantly higher rate of conversion to other methods (76.9 %) than the PTBD (4.7 %, p < 0.0001) and EBS (35.7 %, p = 0.009) groups. PTBD, EBS, and ENBD showed comparable results regarding initial technical success rates, complication rates, and surgical outcomes. As Klatskin tumor patients must undergo PBD prior to 3 weeks before surgery, PTBD and ENBD are uncomfortable and disadvantageous in terms of compliance. EBS was the most suitable method for initial PBD in terms of compliance among Klatskin tumor patients.


Salt concentration effects on equilibrium melting curves from DNA microarrays.
DNA microarrays find applications in an increasing number of domains where more quantitative results are required. DNA being a charged polymer, the repulsive interactions between the surface of the microarray and the targets in solution are increasing upon hybridization. Such electrostatic penalty is generally reduced by increasing the salt concentration. In this article, we present equilibrium-melting curves obtained from dedicated physicochemical experiments on DNA microarrays in order to get a better understanding of the electrostatic penalty incurred during the hybridization reaction at the surface. Various salt concentrations have been considered and deviations from the commonly used Langmuir adsorption model are experimentally quantified for the first time in agreement with theoretical predictions.


sST2 Levels Show No Association with Helicobacter pylori Infection in Asymptomatic Patients: Implications for Biomarker Research.
Helicobacter pylori (H. pylori) is a prevalent stomach bacterium that can cause a range of clinical outcomes, including gastric cancer. In recent years, soluble suppression of tumorigenicity-2 (sST2) has gained attention as a biomarker associated with various diseases, such as gastric cancer. The purpose of this study was to explore the possible connection between H. pylori infection and sST2 levels in patients who do not exhibit symptoms. A total of 694 patients from the Salzburg Colon Cancer Prevention Initiative (Sakkopi) were included in the study. The prevalence of H. pylori infection was determined by histology, and sST2 levels were measured in serum samples. Clinical and laboratory parameters, such as age, sex, BMI, smoking status, hypertension, and metabolic syndrome, were also collected. The median sST2 concentration was similar between patients with (9.62; 7.18-13.44 ng/mL; p = 0.66) and without (9.67; 7.08-13.06 ng/mL) H. pylori. Logistic regression analysis did not show any association (OR 1.00; 95%CI 0.97-1.04; p = 0.93) between sST2 levels and H. pylori infection, which remained so (aOR 0.99; 95%CI 0.95-1.03; p = 0.60) after adjustment for age, sex, educational status, and metabolic syndrome. In addition, sensitivity analyses stratified by age, sex, BMI, smoking status, educational status, and the concomitant diagnosis of metabolic syndrome could not show any association between sST2 levels and H. pylori infection. The results indicate that sST2 may not serve as a valuable biomarker in the diagnosis and treatment of H. pylori infection. Our findings are of relevance for further research investigating sST2, as we could not find an influence of asymptomatic H. pylori infection on sST2 concentration. WHAT IS ALREADY KNOWN?: Soluble suppression of tumorigenicity-2 (sST2) has gained attention as a biomarker associated with various diseases, such as gastric cancer. WHAT IS NEW IN THIS STUDY?: The median sST2 concentration was similar between patients with (9.62; 7.18-13.44 ng/mL; p = 0.66) and without (9.67; 7.08-13.06 ng/mL) H. pylori. WHAT ARE THE FUTURE CLINICAL AND RESEARCH IMPLICATIONS OF THE STUDY FINDINGS?: The results indicate that sST2 may not serve as a valuable biomarker in the diagnosis and treatment of H. pylori infection.


Antipyretic effect of central [Pyr1]apelin13 on LPS-induced fever in the rat.
Intracerebroventricular (i.c.v.) injections of apelins have been shown to modulate the central control of cardiovascular function, as well as the homeostasis of fluid and salt balance, and to some extent also body core temperature. Here, we investigated the effects of i.c.v. administration of [Pyr(1)]apelin13 (PyrAp13; 20nmol) dissolved in artificial cerebrospinal fluid (aCSF), as compared to aCSF alone, on fever and sickness behavior elicited in rats by intraperitoneal injection of bacterial lipopolysaccharide (LPS, 100 μg/kg). Injections of LPS induced a short phase of hypothermia followed by a biphasic fever, depression of motor activity, anorexia and adipsia. I.c.v. injections of PyrAp13 without systemic LPS application slightly augmented motor activity at statistically unaltered core temperature. In combination with LPS, central administration of PyrAp13 significantly reduced fever during the time period of 3-9h after injection, but did not significantly attenuate anorexia and adipsia, and had no effect on LPS-induced lethargy. Rats injected with PyrAp13 along with LPS showed a reduced level of LPS-induced circulating tumor necrosis factor-α (TNF-α). Primary neuroglial cultures established from the hypothalamic paraventricular nucleus (PVN) and the median preoptic nucleus (MnPO), brain sites being of major importance for central thermoregulation and also expressing the apelin receptor, were incubated with medium alone, medium containing LPS (100 μg/ml) or LPS plus PyrAp13 (10(-6) mol/L). Ninety minutes after start of the incubation, LPS alone but not LPS in combination with PyrAp13 (10(-6) mol/L) caused a significant elevation of TNF-α in the supernatants. The novel observation that PyrAp13 represents a centrally acting endogenous antipyretic peptide is discussed in relation to its capacity to modulate peripheral and central formation of TNF-α.


Oral supplementation of policosanol alleviates carbon tetrachloride-induced liver fibrosis in rats.
Liver fibrosis is a prevalent liver disease that requires rapid and effective treatment prior to its progression to cirrhosis and liver damage. Recently, several reports have investigated the efficacy of phytotherapy using natural herbal extracts rather than synthetic drugs to treat several liver diseases. Policosanol is a herbal extract used to treat patients with cardiovascular. However, its therapeutic effect on liver fibrosis is still unknown. Therefore, the present study aimed to assess the potential antifibrotic effect of policosanol compared to silymarin and the possible underlying molecular mechanisms. Rats were categorized into four groups; negative control group "NCG", the fibrotic group "FG", silymarin treated group "STG", and policosanol treated group "PTG". Serum liver enzymes, oxidative stress markers, angiogenic growth factors, and pro-inflammatory cytokines were measured biochemically. The relative mRNA expressions of liver caspase-3 and alpha-smooth muscle actin (α-SMA) were assessed. Immunohistochemical staining was carried out using anti- α-SMA, and anti-caspase-3 antibodies. Compared to NCG, the FG group demonstrated a significant decrease in the level of serum liver enzymes "GSH, TAC, and SDF. Nevertheless, it demonstrateda significant increase in the level of pro-inflammatory cytokines "Il-6, TNF"; oxidative stress markers "NO, MDA", and angiogenic growth factors "VEGF and PDGF" and the expression of α-SMA, and Caspase-3. Interestingly, the values of these measurements were restored to normal levels in the treated groups, particularly the PTG. In conclusion, our data revealed the beneficial effects of co-administration of policosanol or silymarin on the fibrotic liver rat model and thus could be a promising natural therapeutic drug.


NegAIT: A new parser for medical text simplification using morphological, sentential and double negation.
Many different text features influence text readability and content comprehension. Negation is commonly suggested as one such feature, but few general-purpose tools exist to discover negation and studies of the impact of negation on text readability are rare. In this paper, we introduce a new negation parser (NegAIT) for detecting morphological, sentential, and double negation. We evaluated the parser using a human annotated gold standard containing 500 Wikipedia sentences and achieved 95%, 89% and 67% precision with 100%, 80%, and 67% recall, respectively. We also investigate two applications of this new negation parser. First, we performed a corpus statistics study to demonstrate different negation usage in easy and difficult text. Negation usage was compared in six corpora: patient blogs (4K sentences), Cochrane reviews (91K sentences), PubMed abstracts (20K sentences), clinical trial texts (48K sentences), and English and Simple English Wikipedia articles for different medical topics (60K and 6K sentences). The most difficult text contained the least negation. However, when comparing negation types, difficult texts (i.e., Cochrane, PubMed, English Wikipedia and clinical trials) contained significantly (p<0.01) more morphological negations. Second, we conducted a predictive analytics study to show the importance of negation in distinguishing between easy and difficulty text. Five binary classifiers (Naïve Bayes, SVM, decision tree, logistic regression and linear regression) were trained using only negation information. All classifiers achieved better performance than the majority baseline. The Naïve Bayes' classifier achieved the highest accuracy at 77% (9% higher than the majority baseline).


An overview of the crosstalk between YAP and cGAS-STING signaling in non-small cell lung cancer: it takes two to tango.
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is recognized as a main mediator bridging innate and adaptive immunity, recent advances have expanded its roles to anti-tumor immunity and carcinogenesis. Loss of cGAS-STING signaling in non-small cell lung cancer (NSCLC) leads to enhanced tumorigenicity and decreased cytotoxic T lymphocyte infiltration. Apart from its anticancer response, persistent overreaction of cGAS-STING signaling promotes progression of certain inflammation-aggravated cancers. Activation of the pro-inflammatory nucleic acid sensing pathway can trigger Hippo pathway, which mediates the inactivation of Yes-associated protein 1 (YAP1) and its paralogue transcriptional co-regulators with PDZ-binding motif (TAZ, also known as WWTR1), and subsequent suppression of tumorigenesis. Active YAP acts as a transcriptional driver in bolstering immunosuppressive cytokines to evade immune surveillance and promote occurrence of preneoplasia. It is reasonable that aggressive tumors co-opt these regulators to generate few immunogenic antigens and drive tumorigenic behaviors via a highly cooperative manner. Given their multifaced roles, we profile the molecular biology characteristic and current status underpinning oncogenic YAP, review its crosstalk roles with cGAS/STING pathway in NSCLC, and summarize the major clinical investigations in NSCLC with TCGA database.


Functional changes in cerebral and paraspinal muscle physiology of healthy women during exposure to whole-body vibration.
The objective of this study was to investigate the effects of whole-body vibration on multiple tissues simultaneously in fourteen healthy women. On three separate days, participants were exposed to frequencies, 3, 4.5, or 6 Hz (at 0.9 g(r.m.s) acceleration in vertical direction) per day on a simulator for 16 min. While sitting 'with' and 'without' backrest support, participants also performed handgrip contractions for 1 min. Cerebral and lumbar muscle oxygenation and blood volume responses were measured using near-infrared spectroscopy. Cardiorespiratory responses were collected using a metabolic cart. In general, cerebral and cardiorespiratory responses increased with vibration compared to without vibration, whereas in the lumbar region oxygenation and blood volume responses decreased. Greatest cerebral responses were observed at 6 Hz (P<0.05). When compared to exposure to vibration without performing work, significant decrease in lumbar responses was observed during handgrip contractions in both conditions of sitting 'with' and 'without' a backrest (P<0.05). Such decreases in the lumbar responses suggest postural load due to prolonged sitting combined with physical activity during vibration, might reduce vascular supply to the paraspinal muscles. This study reiterates the importance of understanding the physiological basis for various health disorders in women due to exposure to whole-body vibration.


Robotic-guided sacro-pelvic fixation using S2 alar-iliac screws: feasibility and accuracy.
To review our experience with robotic guided S2-alar iliac (S2AI) screw placement. We retrospectively reviewed patients who underwent S2AI fixation with robotic guidance. Screw placement and deviation from the preoperative plan were assessed by fusing preoperative CT (with the planned S2AI screws) to postoperative CT. The software's measurement tool was used to compare the planned vs. actual screw placements in axial and lateral views, at entry point to the S2 pedicle and at a 30 mm depth at the screws' mid-shaft, in a resolution of 0.1 mm. Medical charts were reviewed for technical issues and intra-operative complications. 35 S2AI screws were reviewed in 18 patients. The patients' mean age was 60 years. No intra-operative complications that related to the placement of S2AI screws were reported and robotic guidance was successful in all 35 screws. Post-operative CT scans showed that all trajectories were accurate. No violations of the iliac cortex or breaches of the anterior sacrum were noted. At the entry point, the screw deviated from the pre-operative plan by 3.0 ± 2.2 mm in the axial plane and 1.8 ± 1.6 mm in the lateral plane. At 30 mm depth, the screw deviated from the pre-operative plan by 2.1 ± 1.3 mm in the axial plane and 1.2 ± 1.1 mm in the lateral plane. Robotic guided S2AI screw placement is feasible and accurate. No screw malpositions or complications that related to the placement of S2AI screws occurred in this series. Larger studies are needed to assess the long-term clinical outcomes of robotic guided sacral-pelvic fixation.


Factors affecting the toxicity of dioxin-like toxicants: a molecular approach to risk assessment of dioxins.
The numerous toxic responses of dioxin-like compounds are mediated by the intracellular Ah (aryl hydrocarbon) receptor. It has been suggested that the regulation of dioxins and similar substances could be placed on a molecular foundation by considering the proportion of Ah-receptor sites occupied by toxicant molecules. The present work has shown that the following formation not yet available would be needed in order to develop this approach: correlation between dioxin exposure and human tissue levels; accurate determination of the association constants for human Ah-receptor with toxicant, and for human receptor-ligand complex with DNA; and knowledge of the intracellular concentrations of both receptor binding sites and DNA binding sites. Furthermore, since not all dioxin-like substances behave identically, this information would need to be gathered for a wide variety of substances.


Biosynthesis of silver nanoparticles from Schizophyllum radiatum HE 863742.1: their characterization and antimicrobial activity.
Development of reliable and eco-friendly process for synthesis of silver nanoparticles is an important step in the field of application in nanotechnology. One of the options to achieve this objective is to use natural biological processes. They have an advantage over conventional methods involving chemical agents associated with environmental toxicity. This study demonstrates the extra-cellular synthesis of stable silver nanoparticles using the white rot fungus, Schizophyllum radiatum with GenBank Accession no HE 863742.1. The supernatant of the seed media obtained after separating the cells has been used for the synthesis of silver nanoparticles. The morphology and structure of synthesized silver nanoparticles were characterized using FT-IR, XRD, UV-visible spectrum of the aqueous medium containing silver ion showed a peak in the range of 420-430 nm corresponding to the Plasmon absorbance of silver nanoparticles. Scanning electron microscopy micrograph showed formation of well-dispersed silver nanoparticles in the range of 10-40 nm. The effect of different carbon sources and the time taken for formation particles and the anti-microbial activity of synthesized nanoparticles were carried and compared with silver nitrate solution and with standard streptomycin. The process of reduction being extra-cellular and fast may lead to the development of an easy bioprocess for synthesis of silver nanoparticles.


Analysis of pharmaceutical preparations containing antihistamine drugs by micellar liquid chromatography.
Rapid chromatographic procedures for analytical quality control of pharmaceutical preparations containing antihistamine drugs, alone or together with other kind of compounds are proposed. The method uses C18 stationary phases and micellar mobile phases of cetyltrimethylammonium bromide (CTAB) with either 1-propanol or 1-butanol as organic modifier. The proposed procedures allow the determination of the antihistamines: brompheniramine, chlorcyclizine, chlorpheniramine, diphenhydramine, doxylamine, flunarizine, hydroxyzine, promethazine, terfenadine, tripelennamine and triprolidine, in addition to caffeine, dextromethorphan, guaifenesin, paracetamol and pyridoxine in different pharmaceutical presentations (tablets, capsules, suppositories, syrups and ointments). The methods require minimum handling sample and are rapid (between 3 and 12 min at 1 mLmin(-1) flow rate) and reproducible (R.S.D. values<5%). Limits of detection are lower than 1 microgmL(-1) and the recoveries of the analytes in the pharmaceutical preparations are in the range 100+/-10%.


Antiglucocorticoid treatment disrupts endocrine cycle and nocturnal sleep pattern.
Mifepriston (RU 486) is a steroid antagonist which binds with high affinity to glucocorticoid receptors (GR), and also to progesterone receptors. The antiglucocorticoid action of Mifepriston in man has been demonstrated by blockade of the negative feedback action of endogenous cortisol and by antagonism of the effects of exogenously administered dexamethasone. In the present study Mifepriston was administered to a normal male volunteer at 14.00 h and its effects on pituitary-adrenal activity and nocturnal sleep pattern were recorded. Mifepriston caused a large rise in plasma ACTH levels during the morning hours in comparison to untreated male control subjects. Plasma ACTH levels in the Mifepriston treated subject at 7.00 h were threefold greater than in the control subjects (104.4 pg/ml vs. 37.6 +/- 13.9 pg/ml; mean +/- SD). Subsequently the cortisol secretion was enhanced and the rise was advanced by about 60 minutes compared to controls. The main effects of Mifepriston on EEG sleep pattern were a dramatic disruption of sleep quality with a prolonged sleep onset latency, increased nocturnal awakenings and a considerable reduction of both slow wave sleep (SWS) and REM sleep. After Mifepriston, SWS was reduced by about 80% in comparison to placebo, and REM sleep was reduced by more than 50%. While the present data were collected from only a single subject the effects observed were so pronounced that tentative conclusions seem to be justified: The well-established pharmacological properties of Mifepriston as a glucocorticoid antagonist are reflected by its action on sleep physiology since it influences sleep in a direction opposite to that produced by cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)


Initial management of the trauma patient.
Critical care specialists should be familiar with the initial management of injured patients. Dividing the evaluation and treatment of the patient into the primary, secondary, and tertiary surveys ensures that the multiply injured patient will be managed expeditiously. The primary survey identifies the acute life-threatening problems that must be managed immediately. The secondary survey identifies the remaining major injuries and sets priorities for definitive management. The tertiary survey identifies occult injuries before they become missed injuries.


Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1.
Bacterial expression of β-lactamases, which hydrolyze β-lactam antibiotics, contributes to the growing threat of antibacterial drug resistance. Metallo-β-lactamases, such as NDM-1, use catalytic zinc ions in their active sites and hydrolyze nearly all clinically available β-lactam antibiotics. Inhibitors of metallo-β-lactamases are urgently needed to overcome this resistance mechanism. Zinc-binding compounds are promising leads for inhibitor development, as many NDM-1 inhibitors contain zinc-binding pharmacophores. Here, we evaluated 13 chelating agents containing benzimidazole and benzoxazole scaffolds as NDM-1 inhibitors. Six of the compounds showed potent inhibitory activity with IC50 values as low as 0.38 μM, and several compounds restored the meropenem susceptibility of NDM-1-expressing E. coli. Spectroscopic and docking studies suggest ternary complex formation as the mechanism of inhibition, making these compounds promising for development as NDM-1 inhibitors.


Bilateral papillitis as the initial presentation of neurosyphilis in a patient previously treated for primary and secondary syphilis.
To report a patient previously treated for primary and secondary syphilis who presented with papillitis. The patient was found to have neurosyphilis likely due to inadequate treatment of primary and secondary syphilis. A 60-year-old male with human immunodeficiency virus (HIV) and hepatitis C was referred for evaluation of blurry vision for the past several months. Anterior segment examination was notable for 1+ diffuse non-granulomatous keratic precipitates and 2+ flare with trace cell in both eyes. Dilated fundus exam revealed grade 2 optic disc edema in both eyes with no evidence of infectious retinitis. He was recently treated for syphilis with a single dose of intramuscular (IM) penicillin. These findings were consistent with syphilitic papillitis likely secondary to neurosyphilis. The patient underwent a lumbar puncture which confirmed the diagnosis of neurosyphilis. He was admitted to the hospital for intravenous (IV) penicillin. He later revealed a prior history of syphilis that was treated 3 years ago and 1 year ago. Ocular syphilis can have a wide variety of presentations. Any patient with syphilis and uveitis should have prompt work up for neurosyphilis. Patients with any stage of syphilis need close follow up with repeat titers after treatment to ensure adequate treatment and prevent progression and permanent ocular or neurologic sequelae.


Axonal localization of neuritin/CPG15 mRNA in neuronal populations through distinct 5' and 3' UTR elements.
Many neuronal mRNAs are actively transported into distal axons. The 3' untranslated regions (UTRs) of axonal mRNAs often contain cues for their localization. The 3' UTR of neuritin mRNA was shown to be sufficient for localization into axons of hippocampal neurons. Here, we show that neuritin mRNA localizes into axons of rat sensory neurons, but this is predominantly driven by the 5' rather than 3' UTR. Neuritin mRNA shifts from cell body to axon predominantly after nerve crush injury, suggesting that it encodes a growth-associated protein. Consistent with this, overexpression of neuritin increases axon growth but only when its mRNA localizes into the axons.


Urease activity in different soils of Egypt.
Samples from two depths (0--15 and 15--30 cm) of five Egyptian soils: sandy, calcareous, fertile alluvial, saline alluvial, and alkali alluvial were tested for urease activity. Samples were treated with farmyard manure at rates of 0 and 0.5% C, and moisture at levels of 50, 65, and 80% of the water holding capacity. The studied Egyptian soils showed different activities of urease. Decreases in the values were shown by depth of sampling and varied in their intensities according to soil type, except for saline soil which revealed an opposite trend by the higher activity of its sub-surface layer. Order of activity was the following: fertile, saline, alkali, calcareous, and sandy soil. Farmyard manure slightly increased the activity of the enzyme. Incubation of moistened samples revealed that the optimum moisture content was 50% of W.H.C. for the tested soils, except for saline which showed best results at 65% of W.H.C.


Inhibition of plasma prolactin in the rat by amantadine.
A single iv injection of 15 or 30 but not 7.5 mg/kg BW of an antiviral drug, amantadine, significantly (P less than 0.05) decreased plasma prolactin (PRL) concentrations in male rats. This effect was dose-dependent, with the highest dose producing a longer-lasting decrease in plasma PRL. The amantadine-induced decrease was unaffected by a simultaneous injection of 5-hydroxytryptophan (30 mg/kg BW) but was completely blocked by a simultaneous injection of haloperidol (0.05 mg/kg BW). It is concluded that this novel effect of amantadine on PRL is produced by an interaction with the dopaminergic system.


The independent roles of attentional engagement with, and disengagement from, negative information in intrusive re-experiencing of negative events.
Intrusive re-experiencing of negative events represents a key vulnerability factor for Post-Traumatic Stress Disorder. Thus, delineating attentional mechanisms that might contribute to key facets of intrusive re-experiencing would be highly advantageous. The present study sought to evaluate the novel hypothesis that biased attentional engagement and disengagement differentially contribute to two central facets of intrusive re-experiencing, frequency and controllability, respectively. One hundred undergraduates were exposed to an acutely negative event, followed by completion of an attentional task that permitted the discrete assessment of biased attentional engagement with, and biased attentional disengagement from, negative vs. non-negative information. Intrusions concerning this negative event were assessed daily, for the subsequent seven days, by means of an electronic diary. Results revealed that enhanced attentional engagement with negative vs. non-negative information predicted unique variance in intrusion frequency, whereas impaired attentional disengagement from negative vs. non-negative information predicted unique variance in intrusion controllability. These intrusion-linked patterns of attentional selectivity were evident at shorter (500 ms) stimulus exposure durations only, and not at longer (1000 ms) stimulus exposure durations. The current study did not assess attentional selectivity prior to the negative event. Additionally, a time-based approach, rather than an event-based approach, was employed in the assessment of intrusions. The current findings suggest that engagement bias and disengagement bias may underpin differing facets of intrusive re-experiencing, raising the possibility that therapeutically targeting each type of attentional bias may attenuate a distinctive aspect of intrusive re-experiencing.


Prediction of antioxidant proteins using hybrid feature representation method and random forest.
Natural antioxidant proteins are mainly found in plants and animals, which interact to eliminate excessive free radicals and protect cells and DNA from damage, prevent and treat some diseases. Therefore, accurate identification of antioxidant proteins is important for the development of new drugs and research of related diseases. This article proposes novel method based on the combination of random forest and hybrid features that can accurately predict antioxidant proteins. Four single feature extraction methods (188D, profile-based Auto-cross covariance (ACC-PSSM), N-gram, and g-gap) and hybrid feature representation methods were used to feature extraction. Three feature selection methods (MRMD, t-SNE, and the optimal feature set selection) were adopted to determine the optimal features. The new hybrid feature vectors derived by combining 188D with the other three features all have indicators ranging from 0.9550 to 0.9990. The novel method showed better performance compared with the other methods.


Measurement of (12)CO(2):(13)CO(2) ratios for medical diagnostics with 1.6-µm distributed-feedback semiconductor diode lasers.
We have observed some of the absorption lines from the molecules (12)CO(2) and (13)CO(2)in the 1.6-µm spectral region with the use of specially fabricated single-mode InGaAsP distributed-feedback semiconductor diode lasers. Using a 23.6-m-long multipass absorption cell in combination with radio-frequency modulation and detection techniques, we measured the (12)CO(2):(13)CO(2) isotopic ratio of two specific lines at 6253.73 and 6253.90 cm(-1) with sufficient precision for diagnostic medical tests that analyze CO(2) on human breath.


Safety, Tolerability, Bioavailability, and Biological Activity of Inhaled Interferon-α2b in Healthy Adults: The IN2COVID Phase I Randomized Trial.
Interferons have been identified as a potential treatment alternative for coronavirus disease 2019. This study assessed the safety, tolerability, bioavailability, and biological activity of inhaled interferon-α2b (IFN)-α2b in healthy adults. A double-blind, randomized, phase I clinical trial was conducted with two cohorts of healthy subjects aged 18-50 years. The first cohort received 2.5 MIU of inhaled IFN-α2b twice daily for 10 days (n = 6) or placebo (n = 3); the second cohort received 5.0 MIU of inhaled IFN-α2b in a similar scheme (n = 6) or placebo (n = 3). The first two doses were administered in an emergency department, then participants completed their treatment at home. Safety was measured through vital signs, new symptoms, and laboratory tests. Tolerability was measured as participants' treatment acceptability. Bioavailability and biological activity were measured from serum IFNα concentrations and real-time quantitative polymerase chain reaction of interferon-induced genes in blood before and after treatments. Exposure to inhaled IFN-α2b at 2.5-MIU or 5-MIU doses did not produce statistically significant changes in participant vital signs, or elicit new symptoms, and standard hematological and biochemical blood measurements were comparable to those recorded in individuals who received placebo. A total of 58 adverse events were observed. All were mild or moderate and did not require medical care. All participants reported very high tolerability towards a twice-daily nebulized treatment for 10 days (98.0, 97.0, and 97.0 in the placebo, 2.5-MIU, and 5-MIU groups, respectively, on a 0- to 100-mm visual analog scale). A dose-dependent mild increase in serum IFN-α concentrations and an increase in serum RNA expression of IFN-induced genes were observed 11 days after treatment (p < 0.05 for all between-group comparisons). Inhaled IFN-α2b was preliminarily safe and well tolerated, and induced systemic biological activity in healthy subjects. The trial was registered in ClinicalTrials.gov (NCT04988217), 3 August, 2021.


Intranasal delivery of interferon-β-loaded nanoparticles induces control of neuroinflammation in a preclinical model of multiple sclerosis: A promising simple, effective, non-invasive, and low-cost therapy.
Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). Interferon (IFN)-β constitutes one of the first-line therapies to treat MS, but has limited efficacy due to the injectable systemic administration, short half-life, and limited CNS access. To address these limitations, we developed IFN-β-loaded chitosan/sulfobutylether-β-cyclodextrin nanoparticles (IFN-β-NPs) for delivery of IFN-β into the CNS via the intranasal (i.n.) route. The nanoparticles (NPs) (≈200 nm, polydispersity ≈0.1, and zeta potential ≈20 mV) were prepared by mixing two aqueous solutions and associated human or murine IFN-β with high efficiency (90%). Functional in vitro assays showed that IFN-β-NPs were safe and that IFN-β was steadily released while retaining biological activity. Biodistribution analysis showed an early and high fluorescence in the brain after nasal administration of fluorescent probe-loaded NPs. Remarkably, mice developing experimental autoimmune encephalomyelitis (EAE), an experimental model of MS, exhibited a significant improvement of clinical symptoms in response to intranasal IFN-β-NPs (inIFN-β-NPs), whereas a similar dose of intranasal or systemic free IFN-β had no effect. Importantly, inIFN-β-NPs treatment was equally effective despite a reduction of 78% in the total amount of weekly administered IFN-β. Spinal cords obtained from inIFN-β-NPs-treated EAE mice showed fewer inflammatory foci and demyelination, lower expression of antigen-presenting and costimulatory proteins on CD11b+ cells, and lower astrocyte and microglia activation than control mice. Therefore, IFN-β treatment at tested doses was effective in promoting clinical recovery and control of neuroinflammation in EAE only when associated with NPs. Overall, inIFN-β-NPs represent a potential, effective, non-invasive, and low-cost therapy for MS.


Probabilistic approach for health hazard assessment of trihalomethanes through successive showering events.
Trihalomethanes (THMs) are common disinfection by-products in chlorinated tap waters. They can cause various cancers and non-cancer health hazards. Ingestion, dermal contact, and inhalation are the three exposure routes considered in the THM hazard or risk assessments. Among these, inhalation hazard is generally calculated by assuming the initial concentration as zero. This assumption fails to address the case of continuous or successive showers that can happen in shared showering facilities such as student hostels or gymnasiums. In the present study, the leftover THM concentration from the previous bath was considered to assess the chronic daily intakes (CDI) and hazard index (HI) for successive showers. For this, tap water of a university campus was analyzed to understand the extent of THM exposure at consumer points and the result obtained was used for the hazard assessment. Total THM concentrations varied from 0.51 to 68.9 µg L-1. To address the variability of the model input parameters, 50,000 iterations of Monte Carlo simulation were carried out. Maximum HI values of 7.94E - 02 ± 3.63E - 02, and 6.69E - 02 ± 3.08E-02 were observed for the 1st shower for females and males, respectively. This value increased exponentially up to the 5th shower and thereafter, the value was constant. The methodology followed in the present study successfully determines the risk and hazard of THMs through successive showers.


PLFace: Progressive learning for face recognition with mask bias.
The outbreak of the COVID-19 coronavirus epidemic has promoted the development of masked face recognition (MFR). Nevertheless, the performance of regular face recognition is severely compromised when the MFR accuracy is blindly pursued. More facts indicate that MFR should be regarded as a mask bias of face recognition rather than an independent task. To mitigate mask bias, we propose a novel Progressive Learning Loss (PLFace) that achieves a progressive training strategy for deep face recognition to learn balanced performance for masked/mask-free faces recognition based on margin losses. Particularly, our PLFace adaptively adjusts the relative importance of masked and mask-free samples during different training stages. In the early stage of training, PLFace mainly learns the feature representations of mask-free samples. At this time, the regular sample embeddings shrink to the prototype. In the later stage of training, PLFace converges on mask-free samples and further focuses on masked samples until the masked sample embeddings are also gathered in the center of the class. The entire training process emphasizes the paradigm that normal samples shrink first and masked samples gather afterward. Extensive experimental results on popular regular and masked face benchmarks demonstrate the superiority of our PLFace over state-of-the-art competitors.


A three-dimensional model of the Rev-binding element of HIV-1 derived from analyses of aptamers.
Coordinated variations in the sequence of the Rev-binding element of HIV-1, identified by in vitro genetic selections, have been used as distance and conformational constraints for molecular modelling. Three-dimensional models of the wild-type Rev-binding element and several, evolved RNA ligands (aptamers) have been constructed. These models demonstrate that non-Watson-Crick pairings open the major groove allowing access of an alpha-helical peptide from Rev, and explain why some selected RNA sequences can bind Rev more tightly than others.


A palladium-free gallium-based alloy: analysis of composition and microstructure.
To study the microstructure of a palladium-free gallium-based alloy (Galloy) before and after mixing to identify the metallic phases produced by the setting reaction and assess the quantitative elemental analysis of the phases present. The Galloy powder was analyzed using X-ray diffraction (XRD) and scanning electron microscopy (SEM) and the particle size distribution was determined using a high resolution particle size analyzer. Cylindrical test specimens were mechanically condensed in accordance with ISO 1559: 1986 for XRD, energy dispersive spectroscopy (EDS) and SEM analyses of the set alloy. Disc shaped specimens were prepared by manual condensation to compare the width of the reaction zone with specimens condensed mechanically. The Galloy powder consisted of spherical particles varying between 0.1 and 40 microm in diameter which contained a network of grooves and clefts extending deep within the substance of the particles. The reaction zone appeared 'grainy' and 'fragmented' compared with the well defined reaction zone previously observed for Pd-containing gallium-based alloys. The student t-test indicated the width of reaction zone varied significantly (P<0.001) with method of specimen fabrication.Significance. The significantly larger reaction zone in the manually condensed specimens was possibly due to failure of the condensation technique to force out excessive liquid alloy present in the triturated mass. The surface topography of the Pd-free Galloy powder particles could be responsible for the characteristically fragmented and ill-defined reaction zone observed in the set material compared with the well defined reaction zone previously observed for Pd-containing gallium-based alloys.


The cost of reproduction in the glaucous-winged gull.
Experimental enlargement of brood size in the glaucous-winged gull (Larus glaucescens) resulted in increased adult foraging time, decreased adult body weight at the end of the breeding season, and decreased over-winter adult survival. The decreased survival of breeding adults was associated with reduced body condition at the end of breeding (resulting from physiological costs of reproduction). Decreased survival was not due to an increased risk of injury or predation during the breeding season. Brood size did not directly affect the fecundity of surviving birds in the subsequent year. However, brood size may have an indirect effect on subsequent fecundity because the probability of mate loss increased among birds with large broods and the reproductive performance of birds with new mates was reduced. Based on estimates of life-time fitness calculated from fecundity and survivorship, birds with two- or three-chick broods (the normal brood size) have higher fitness than birds with one- or four-chick broods. However, the decreased fitness of birds with four-chick broods was slight, and probably not a sufficient explanation for the absence of natural four-chick broods in the glaucouswinged gull.


High-density polystyrene-grafted silver nanoparticles and their use in the preparation of nanocomposites with antibacterial properties.
The achievement of uniform nanoparticles distribution in polymer matrix is still a major challenge in the design and fabrication of polymer nanocomposites with desired properties. In this paper we propose a novel approach for the preparation of homogeneous polystyrene/silver nanocomposites utilizing Nitroxide Mediated Radical Polymerization (NMRP). In the first step of the developed procedure, the polystyrene grafted silver nanoparticles (Ag@PS) with well-defined core-shell structure and exceptionally high grafting density (from 2 chains/nm2 to 5.9 chains/nm2) have been synthesized through late injection of nitroxide-coated silver nanoparticles (N-AgNPs) into a TEMPOL mediated styrene polymerization system. Afterwards, the synthesized Ag@PS have been used for the preparation of nanocomposites (PS/Ag@PS) by mixing them with narrow-dispersity polystyrenes and thermoforming at 140°C. Due to the high flexibility of polymer chains attached to silver surface through nitroxide linker, free volume effect enables interpenetration of polystyrene molecules that provides excellent mutual miscibility of Ag@PS with polymer matrix. The synthesized nanohybrids (Ag@PS) and their nanocomposites (PS/Ag@PS) exhibit effective antibacterial activity with respect to pathogenic bacteria: Pseudomonas aeruginosa (Gram-negative representative) and Staphylococcus aureus (Gram-positive representative).


Specific binding of lectins with the nucleus of the sea urchin embryo and changes in the lectin affinity of the embryonic chromatin during the course of development.
(1) Embryonic cells of sea urchins were made permeable by treating them with glycerol solution for the purpose of allowing penetration of macromolecules into the cell. With the use of such permeabilized cells, several kinds of fluorescent dye-labeled lectins were introduced into the cell, and it was found that some lectins showed notable affinity with the nucleus as compared with cytoplasmic structures. (2) Isolated chromatin was incubated with several kinds of fluorescent dye-labeled lectins in vitro, and the amount of lectins bound with the chromatin was measured by fluorometry. By means of this method, the lectin-binding capacity of chromatin was estimated and compared at various stages of development. It was found that lectins could be classified into three groups according to the mode of binding with the chromatin: (a) Extent of binding increased notably at the gastrula stage (Con A and RCA-120); (b) extent of binding showed a temporary decrease at the gastrula stage (TTA); and (c) very low level of binding was maintained throughout all stages, and no particular change was observed at any stage of development (WGA, SBA, and UEA-I). (3) These facts seem to suggest that lectin-binding components are contained in sea urchin chromatin, and that drastic changes occur in these components of chromatin at the stage of gastrulation. It was proposed that the lectin-binding components such as proteoglycans and glycoproteins may play regulatory roles in embryonic chromatin at early stages of development.


Squid proteoglycans: isolation and characterization of three populations from cranial cartilage.
Squid cranial cartilage is poor in proteoglycans. They were extracted by 2% SDS and purified by isopycnic centrifugation in the presence of detergent. According to their buoyant density and hydrodynamic size they were fractionated into three structurally different populations of Mr 1.3.10(6), 0.6.10(6) and 1.0.10(6). The proteoglycans of each population differ in the number of oversulphated chondroitin sulphate chains, ranging from two to five, in the number and size of uronic acid and sulphate containing oligosaccharides and in the size of their core protein. The majority, if not all, of the oligosaccharides are linked to the protein via an O-glycosidic bond involving galactosamine and most likely xylose. The chondroitin sulphate chains are segregated on a small peptide segment of the molecule which also contains a large proportion of the oligosaccharides. The proteoglycans have no tendency to interact with hyaluronate.


Morphology of basal cell carcinoma in high definition optical coherence tomography: en-face and slice imaging mode, and comparison with histology.
Optical coherence tomography (OCT) allows real-time, in vivo examination of basal cell carcinoma (BCC). A new high definition OCT with high lateral and axial resolution in a horizontal (en-face) and vertical (slice) imaging mode offers additional information in the diagnosis of BCC and may potentially replace invasive diagnostic biopsies. To define the characteristic morphologic features of BCC by using high definition optical coherence tomography (HD-OCT) compared to conventional histology. A total of 22 BCCs were examined preoperatively by HD-OCT in the en-face and slice imaging mode and characteristic features were evaluated in comparison to the histopathological findings. The following features were found in the en-face mode of HD-OCT: lobulated nodules (20/22), peripheral rimming (17/22), epidermal disarray (21/22), dilated vessels (11/22) and variably refractile stroma (19/22). In the slice imaging mode the following characteristics were found: grey/dark oval structures (18/22), peripheral rimming (13/22), destruction of layering (22/22), dilated vessels (7/22) and peritumoural bright stroma (11/22). In the en-face mode the lobulated structure of the BCC was more distinct than in the slice mode compared to histology. HD-OCT with a horizontal and vertical imaging mode offers additional information in the diagnosis of BCC compared to conventional OCT imaging and enhances the feasibility of non-invasive diagnostics of BCC.


Mouse saliva prevents the beta-nerve growth factor-dependent neurite formation in PC-12 cells.
A highly sensitive and specific competitive beta-nerve growth factor radioimmunoassay (beta NGF-RIA) was utilized to determine the beta NGF levels in epinephrine-provoked saliva of adult male and female Swiss-Webster mice. Saliva beta NGF levels in males were higher than in females. In order to assess the immunoreactive material measured in the RIA as biologically active beta NGF, saliva of male and female mice was examined for the neurite outgrowth responsiveness both in the rat pheochromocytoma tumor cell line (PC-12) and 8-day-old chick embryo dorsal root sensory ganglion (DRG) bioassay systems. At concentrations (based on the RIA values) sufficient to saturate both high and low affinity beta NGF-receptors (100 ng and above), saliva of both male and female mice did not elicit neurite outgrowth in the PC-12 bioassay system. In contrast, similar concentrations of saliva stimulated extensive neurites in the DRG bioassay system. When serum of aggression-provoked male mice (which also contained high serum beta NGF levels as indicated by the RIA) was tested, both the PC-12 and DRG bioassay systems readily responded with neurite extension. In the PC-12 bioassay system, saliva of both sexes stimulated cell proliferation and cell aggregation, but not cell substratum-adhesion. Addition of saliva also prevented the cell substratum adhesion and the formation of neurites induced by purified submandibular gland (SMG)-beta NGF. Epidermal growth factor (EGF), a potent mitogen present in mouse saliva, did not prevent the neurite outgrowth induced by the purified SMG-beta NGF. In summary, the results suggest that saliva of adult male and female mice may contain biologically interfering substances for beta NGF-dependent neurite formation in the PC-12 bioassay system.


An Integrated Polymeric mRNA Vaccine without Inflammation Side Effects for Cellular Immunity Mediated Cancer Therapy.
Among the few available mRNA delivery vehicles, lipid nanoparticles (LNPs) are the most clinically advanced but they require cumbersome four components and suffer from inflammation-related side effects that should be minimized for safety. Yet, a certain level of proinflammatory responses and innate immune activation are required to evoke T-cell immunity for mRNA cancer vaccination. To address these issues and develop potent yet low-inflammatory mRNA cancer vaccine vectors, a series of alternating copolymers "PHTA" featured with ortho-hydroxy tertiary amine (HTA) repeating units for mRNA delivery is synthesized, which can play triple roles of condensing mRNA, enhancing the polymeric nanoparticle (PNP) stability, and prolonging circulation time. Unlike LNPs exhibiting high levels of inflammation, the PHTA-based PNPs show negligible inflammatory side effects in vivo. Importantly, the top candidate PHTA-C18 enables successful mRNA cancer vaccine delivery in vivo and leads to a robust CD8+ T cell mediated antitumor cellular immunity. Such PHTA-based integrated PNP provides a potential approach for establishing mRNA cancer vaccines with good inflammatory safety profiles.


Theoretical stereoelectroencephalography density on the brain convexity.
Invasive electroencephalography (EEG) remains the "gold standard" for diagnosing the epileptogenic zone in patients with drug-resistant epilepsy and discrepancies between seizure semiology, video-EEG and magnetic resonance imaging (MRI) findings. However, the possibilities of stereoelectroencephalography (SEEG) to explore the brain surface remain a matter of debate and subdural EEG (SDEEG) is still preferred in some centers for cases when the supposed epileptogenic zone is on the brain convexity. The aim of our study was to evaluate the theoretical safe SEEG coverage on the brain convexity and to compare the theoretical SEEG cortical density with the usual SDEEG density. Our material included 10 hemispheres in 5 patients, who had been already investigated with SEEG for drug-resistant epilepsy. We translated our previously described technique in a theoretical model in an attempt to calculate the maximal number of avascular windows for each cerebral hemisphere. The distance between every entry point and the other entry points for each hemisphere was calculated using a mathematical formula. Subsequently, the theoretical SEEG coverage on the brain convexity was described using the maximal, minimal and average distances between each entry point and the closest 4 neighboring points. This type of measurement allows a direct comparison between SEEG and SDEEG in their ability to explore the brain convexity. Ten hemispheres had 1328 safe entry points with a safety margin of 2.5 mm and a minimal distance of 2.5 mm between 2 entry points (average number of entry points: 132.8 (SD ± 5). The number of entry points in the explored 10 hemispheres varied from 104 to 156. The average distance between each entry point and its 4 neighbors was 11.47 mm. The maximal distance between two entry points in these 10 hemispheres was ranging from 20.28 to 27.23 mm (average: 24.67 mm). The closest entry points for the explored hemispheres were at an average distance of 4.67 mm (range: 2.82 - 5.96 mm). The average convexity surface was 223.68 cm2 (range: 204.63-238.77 cm2). The safe electrode density without electrode collision on the cortical surface was ranging from 0.46 to 0.69 electrodes per cm2 (average: 0.59 electrodes per cm2) (SD ± 0.023). The theoretical SEEG cortical density is comparable with the usual SDEEG density. These findings, combined with the better safety profile of SEEG and the possibilities to explore deep cortical structures, explain the progressive shift from SDEEG to SEEG during the last years.


Enhanced cytotoxicity of an anti-transferrin receptor IgG3-avidin fusion protein in combination with gambogic acid against human malignant hematopoietic cells: functional relevance of iron, the receptor, and reactive oxygen species.
The human transferrin receptor (hTfR) is a target for cancer immunotherapy due to its overexpression on the surface of cancer cells. We previously developed an antibody-avidin fusion protein that targets hTfR (anti-hTfR IgG3-Av) and exhibits intrinsic cytotoxicity against certain malignant cells. Gambogic acid (GA), a drug that also binds hTfR, induces cytotoxicity in several malignant cell lines. We now report that anti-hTfR IgG3-Av and GA induce cytotoxicity in a new broader panel of hematopoietic malignant cell lines. Our results show that the effect of anti-hTfR IgG3-Av is iron-dependent whereas that of GA is iron-independent in all cells tested. In addition, we observed that GA exerts a TfR-independent cytotoxicity. We also found that GA increases the generation of reactive oxygen species that may play a role in the cytotoxicity induced by this drug. Additive cytotoxicity was observed by simultaneous combination treatment with these drugs and synergy by using anti-hTfR IgG3-Av as a chemosensitizing agent. In addition, we found a concentration of GA that is toxic to malignant hematopoietic cells but not to human hematopoietic progenitor cells. Our results suggest that these two compounds may be effective, alone or in combination, for the treatment of human hematopoietic malignancies.


Paroxysmal events in infants: persistent eye closure makes seizures unlikely.
Paroxysmal events are frequent in infancy. A precise diagnosis is often difficult to assign despite adequate history and physical examination. Certain clinical signs may help to suggest the diagnosis, thereby avoiding unnecessary and costly investigations. The aim of this study was to determine the frequency of eye opening during infantile seizures and evaluate the potential usefulness of this simple observation in the differential diagnosis of acute events in infants. We performed a retrospective video electroencephalogram review of the seizures recorded in infants at our Epilepsy Center, paying specific attention to eye opening. Ninety-one seizures in 69 infants were included. Eyes were open in 85 (93.4%) cases. Infants whose eyes are closed throughout the paroxysmal event are most likely not having seizures.


A social distancing measure governing the whole proteome.
Protein folding in vivo has been largely understood in the context of molecular chaperones preventing aggregation of nascent polypeptides in the crowded cellular environment. Nascent chains utilize the crowded environment in favor of productive folding by direct physical connection with cellular macromolecules. The intermolecular repulsive forces by large excluded volume and surface charges of interacting cellular macromolecules, exerting 'social distancing' measure among folding intermediates, could play an important role in stabilizing their physically connected polypeptides against aggregation regardless of the physical connection types. The generic intrinsic chaperone activity of cellular macromolecules likely provides a robust cellular environment for the productive protein folding and solubility maintenance at the whole proteome level.


Immunotherapy of human tumour xenografts overexpressing the EGF receptor with rat antibodies that block growth factor-receptor interaction.
Athymic mice bearing xenografts of human tumours that overexpress the receptor (EGFR) for EGF and TGF alpha have been used to evaluate the therapeutic potential of three new rat monoclonal antibodies (mAbs) directed against two distinct epitopes on the extracellular domain of the human EGFR. The antibodies, ICR16 (IgG2a), ICR62 (IgG2b) and ICR64 (IgG1), have been shown (Modjtahedi et al., 1993) to be potent inhibitors of the growth in vitro of a number of human squamous cell carcinomas because they block receptor-ligand interaction. When given i.p. at 200 micrograms dose, the three antibodies were found to induce complete regression of xenografts of the HN5 tumour if treatment with antibody commenced at the time of tumour implantation (total doses: ICR16, 3.0 mg; ICR62, 1.2 mg; ICR64, 2.2 mg). More importantly when treatment was delayed until the tumours were established (mean diam. 0.5 cm) both ICR16 and ICR62 induced complete or almost complete regression of the tumours. Furthermore, treatment with a total dose of only 0.44 mg of ICR62 was found to induce complete remission of xenografts of the breast carcinoma MDA-MB 468, but ICR16 was less effective at this dose of antibody and only 4/8 tumours regressed completely. ICR16 and ICR62 were poor inhibitors of the growth in vitro of the vulval carcinoma A431, but both induced a substantial delay in the growth of xenografts of this tumour and 4/8 tumours regressed completely in the mice treated with ICR62 (total dose 2.2 mg). Although ICR16 and ICR64 were more effective than ICR62 as growth inhibitors in vitro, ICR62 was found to be substantially better at inducing regression of the tumour xenografts due perhaps to additional activation of host immune effector functions by the IgG2b antibody. We conclude that these antibodies may be useful therapeutic agents that can be used alone without conjugation to other cytotoxic moieties.


Avoiding inappropriate therapy of single-lead implantable cardioverter-defibrillator by using atrial-sensing electrodes.
The single-chamber implantable cardioverter-defibrillator (ICD) can be associated with more frequent inappropriate therapies compared with dual-chamber ICDs, when they are accompanied by a simpler implantation procedure. The aim of this study was to investigate whether the use of a single-lead ICD system with atrial-sensing electrodes results in a reduction of inappropriate ICD therapy. The study population consisted of 212 consecutive patients, who underwent primary prophylactic single-lead ICD implantation at our institute. A ventricular lead with atrial-sensing electrodes was implanted in 77 patients (36%; Group-VDD) and a ventricular lead without atrial-sensing electrodes was implanted in 135 patients (64%; Group-VVI). Procedural and follow-up data were collected in a prospective registry. A higher prevalence of atrial fibrillation was present in Group-VDD. There were no other significant differences in patient baseline characteristics (age, sex, and other comorbidities) or follow-up period between the two groups. The operative parameters including fluoroscopic burden showed no significant differences between Group-VDD and Group-VVI. During a mean follow-up period of 697 ± 392 days, 26 patients (12%) experienced appropriate ICD therapies and 13 patients (6%) suffered inappropriate ICD therapies. The incidence of inappropriate ICD therapies in Group-VDD was significantly lower as compared to that of Group-VVI (1/77 [1%] vs 12/135 [9%]; log-rank, P = 0.028). The incidence of appropriate ICD therapies and the occurrence of device-related complications showed no significant difference between the two groups. Single-lead ICD with atrial-sensing electrodes shows a lower incidence of inappropriate ICD therapy compared with the absence of atrial-sensing electrodes, without additional operative burden or increased complications.


Characterization of cerebral macro- and microvascular hemodynamics during transient hypotension.
The aim of the current study was to establish the interplay between blood flow patterns within a large cerebral artery and a downstream microvascular segment under conditions of transiently reduced mean arterial pressure (MAP). We report data from nine young, healthy participants (5 women; 26 ± 4 yr) acquired during a 15-s bout of sudden-onset lower body negative pressure (LBNP; -80 mmHg). Simultaneous changes in microvascular cerebral blood flow (CBF) and middle cerebral artery blood velocity (MCAvmean) were captured using diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound (TCD), respectively. Brachial blood pressure (finger photoplethysmography) and TCD waveforms were extracted at baseline and during the nadir blood pressure (BP) response to LBNP and analyzed using a modified Windkessel model to calculate indices of cerebrovascular resistance (Ri) and compliance (Ci). Compared with baseline, rapid-onset LBNP decreased MAP by 22 ± 16% and Ri by 14 ± 10% (both P ≤ 0.03). Ci increased (322 ± 298%; P < 0.01) but MCAvmean (-8 ± 16%; P = 0.09) and CBF (-2 ± 3%; P = 0.29) were preserved. The results provide evidence that changes in both vascular resistance and compliance preserve CBF, as indexed by no significant changes in MCAvmean or DCS microvascular flow, during transient hypotension.NEW & NOTEWORTHY To characterize the relationship between cerebrovascular patterns within the large middle cerebral artery (MCA) and a downstream microvascular segment, we used a novel combination of transcranial Doppler ultrasound of the MCA and optical monitoring of a downstream microvascular segment, respectively, under conditions of transiently reduced mean arterial pressure (i.e., lower body negative pressure, -80 mmHg). A rapid increase in vessel compliance accompanied the maintenance of MCA blood velocity and downstream microvascular flow.


Outcomes of a Comprehensive Youth Program for HIV-infected Adolescents in Thailand.
We developed an intervention program for HIV-infected Thai adolescents with two group sessions and two individual sessions, focusing on four strategies: health knowledge, coping skills, sexual risk reduction, and life goals. An audio computer-assisted self-interview (ACASI) was administered to assess knowledge, attitudes, and practices (KAP) regarding antiretroviral therapy management, reproductive health, and HIV-associated risk behavior. The program was implemented in two HIV clinics; 165 (84%) adolescents (intervention group) participated in the program; 32 (16%) completed the ACASI without participating in the group or individual sessions (nonintervention group). The median age was 14 years, and 56% were female. Baseline KAP scores of the intervention and nonintervention groups were similar. Two months after the intervention, knowledge and attitude scores increased (p < .01) in the intervention group, and the increase was sustained at 6 months. KAP scores did not change from baseline in the nonintervention group at 6 or 12 months after enrollment.


Genetic mapping of nuclear mucidin resistance mutations in Saccharomyces cerevisiae. A new pdr locus on chromosome II.
In the yeast Saccharomyces cerevisiae, two nuclear pleiotropic drug resistance mutations pdr3-1 (former designation mucPR) and pdr3-2 (former designation DRI9/T7) have been selected as resistant to mucidin and as resistant to chloramphenicol plus cycloheximide, respectively. The pdr3 mutations were found not to affect the plasma membrane ATPase activity measured in a crude membrane fraction. Meiotic mapping using strains with standard genetic markers revealed that mutation pdr3-1 is centromere linked on the left arm of chromosome II at a distance of 5.9 +/- 3.3 cM from its centromere and 11.6 +/- 3.1 cM from the marker pet9. The centromere linked pdr3-2 mutation exhibited also genetic linkage to pet9 with a map distance of 9.8 +/- 3.2 cM. These results indicate that pdr3-1 and pdr3-2 are alleles of the same pleiotropic drug resistance locus PDR3 which is involved in the control of the plasma membrane permeability in yeast.