Driver kinematic and muscle responses in braking events with standard and reversible pre-tensioned restraints: validation data for human models.
The objectives of this study are to generate validation data for human models intended for simulation of occupant kinematics in a pre-crash phase, and to evaluate the effect of an integrated safety system on driver kinematics and muscle responses. Eleven male and nine female volunteers, driving a passenger car on ordinary roads, performed maximum voluntary braking; they were also subjected to autonomous braking events with both standard and reversible pre-tensioned restraints. Kinematic data was acquired through film analysis, and surface electromyography (EMG) was recorded bilaterally for muscles in the neck, the upper extremities, and lumbar region. Maximum voluntary contractions (MVCs) were carried out in a driving posture for normalization of the EMG. Seat belt positions, interaction forces, and seat indentions were measured. During normal driving, all muscle activity was below 5% of MVC for females and 9% for males. The range of activity during steady state braking for males and females was 13-44% in the cervical and lumbar extensors, while antagonistic muscles showed a co-contraction of 2.3-19%. Seat belt pre-tension affects both the kinematic and muscle responses of drivers. In autonomous braking with standard restraints, muscle activation occurred in response to the inertial load. With pre-tensioned seat belts, EMG onset occurred earlier; between 71 ms and 176 ms after belt pre-tension. The EMG onset times decreased with repeated trials and were shorter for females than for males. With the results from this study, further improvement and validation of human models that incorporate active musculature will be made possible.


Acute intravenous and sustained oral treatment with the beta1 agonist prenalterol in patients with chronic severe cardiac failure.
Prenalterol, a beta1 agonist, was given in a single blind acute intravenous study to seven patients with cardiac failure (New York Heart Association class II and III). It was then given in a double blind crossover study of sustained oral prenalterol to six of them. As a result of dose titration studies the oral dose of prenalterol given was 100 mg twice a day in all patients. Erect bicycle sprint tests were performed to exercise tolerance before and after treatment had been started. Cardiac function was assessed at rest and during graded supine bicycle exercise by determining haemodynamic indices using a Swan-Ganz catheter and radionuclide left ventricular ejection fractions. In the intravenous study cardiac function was assessed at rest and during exercise after a control infusion of dextrose and after an infusion of 5 mg prenalterol. In the oral crossover study a placebo or prenalterol were given for two periods of two weeks; at the end of each period exercise tolerance was measured and cardiac function assessed at rest and during exercise. Throughout the study period there was no change in symptoms, medication, or exercise tolerance. Intravenous prenalterol significantly improved cardiac function; left ventricular ejection fraction and cardiac index increased and left ventricular filling pressure fell both at rest and during exercise. Sustained oral treatment with prenalterol, however, did not improve resting left ventricular filling pressure or left ventricular ejection fraction at rest or during exercise but did increase heart rate at rest, and mean blood pressure and peripheral vascular resistance at rest and during exercise; in fact, during exercise left ventricular filling pressure was significantly increased while cardiac index and stroke volume index were decreased by prenalterol. Sustained oral treatment with prenalterol did not have the beneficial effects on cardiac function produced by intravenous treatment and in fact had deleterious effect on the measured indices of cardiac function during exercise.


Two amino acids, Phe 16 and Ala 776, on the polyprotein are most likely to be responsible for the diabetogenicity of encephalomyocarditis virus.
The diabetogenic D variant of encephalomyocarditis virus (EMC-D) was previously shown to differ from the non-diabetogenic B variant (EMC-B) by 14 nucleotides out of 7829 bases. Similar approaches with a new nondiabetogenic variant, EMC-DV1, obtained by plaque purification of the EMC-D variant stock pool, enabled us to narrow down further the possible genomic area responsible for the diabetogenicity of EMC virus. EMC-DV1 does not induce interferon in vitro, differing from the highly interferon-inducing EMC-B. The complete nucleotide sequence of EMC-DV1 was determined by RNA-dependent DNA sequencing and cDNA sequencing. The genomic size and organization of EMC-DV1 are similar to those of EMC-D and EMC-B, with a long open reading frame encoding a polyprotein of 2292 amino acids. Comparative analyses of sequence information as well as biological activities of EMC-DV1 with EMC-D and EMC-B suggest that (i) the diabetogenicity is apparently distinct from the ability to induce interferon, which is probably due to the single U base insertion at position 765 in EMC-B, and (ii) the diabetogenicity of EMC virus is most probably controlled by one or both of two amino acids, Phe 16 (on the leader peptide) and Ala 776 (152nd amino acid on the VP1) on the polyprotein.


Effect of a Digital Intervention on Depressive Symptoms in Patients With Comorbid Hypertension or Diabetes in Brazil and Peru: Two Randomized Clinical Trials.
Depression is a leading contributor to disease burden globally. Digital mental health interventions can address the treatment gap in low- and middle-income countries, but the effectiveness in these countries is unknown. To investigate the effectiveness of a digital intervention in reducing depressive symptoms among people with diabetes and/or hypertension. Participants with clinically significant depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score ≥10) who were being treated for hypertension and/or diabetes were enrolled in a cluster randomized clinical trial (RCT) at 20 sites in São Paulo, Brazil (N=880; from September 2016 to September 2017; final follow-up, April 2018), and in an individual-level RCT at 7 sites in Lima, Peru (N=432; from January 2017 to September 2017; final follow-up, March 2018). An 18-session, low-intensity, digital intervention was delivered over 6 weeks via a provided smartphone, based on behavioral activation principles, and supported by nurse assistants (n = 440 participants in 10 clusters in São Paulo; n = 217 participants in Lima) vs enhanced usual care (n = 440 participants in 10 clusters in São Paulo; n = 215 participants in Lima). The primary outcome was a reduction of at least 50% from baseline in PHQ-9 scores (range, 0-27; higher score indicates more severe depression) at 3 months. Secondary outcomes included a reduction of at least 50% from baseline PHQ-9 scores at 6 months. Among 880 patients cluster randomized in Brazil (mean age, 56.0 years; 761 [86.5%] women) and 432 patients individually randomized in Peru (mean age, 59.7 years; 352 [81.5%] women), 807 (91.7%) in Brazil and 426 (98.6%) in Peru completed at least 1 follow-up assessment. The proportion of participants in São Paulo with a reduction in PHQ-9 score of at least 50% at 3-month follow-up was 40.7% (159/391 participants) in the digital intervention group vs 28.6% (114/399 participants) in the enhanced usual care group (difference, 12.1 percentage points [95% CI, 5.5 to 18.7]; adjusted odds ratio [OR], 1.6 [95% CI, 1.2 to 2.2]; P = .001). In Lima, the proportion of participants with a reduction in PHQ-9 score of at least 50% at 3-month follow-up was 52.7% (108/205 participants) in the digital intervention group vs 34.1% (70/205 participants) in the enhanced usual care group (difference, 18.6 percentage points [95% CI, 9.1 to 28.0]; adjusted OR, 2.1 [95% CI, 1.4 to 3.2]; P < .001). At 6-month follow-up, differences across groups were no longer statistically significant. In 2 RCTs of patients with hypertension or diabetes and depressive symptoms in Brazil and Peru, a digital intervention delivered over a 6-week period significantly improved depressive symptoms at 3 months when compared with enhanced usual care. However, the magnitude of the effect was small in the trial from Brazil and the effects were not sustained at 6 months. ClinicalTrials.gov: NCT02846662 (São Paulo) and NCT03026426 (Lima).


Effects of let-7 microRNA on Cell Growth and Differentiation of Papillary Thyroid Cancer.
Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy and RET/PTC rearrangements represent key genetic events frequently associated to this cancer, enhancing proliferation and dedifferentiation by activation of the RET/PTC-RAS-BRAF-mitogen-activated protein kinase (MAPK) pathway. Recently, let-7 microRNA was found to reduce RAS levels in lung cancer, acting as a tumor suppressor gene. Here, we report that RET/PTC3 oncogenic activation in PCCL3 rat thyroid cells markedly reduces let-7f expression. Moreover, stable transfection of let-7 microRNA in TPC-1 cells, which harbor RET/PTC1 rearrangement, inhibits MAPK activation. As a result, let-7f was capable of reducing TPC-1 cell growth, and this might be explained, at least in part, by decreased messenger RNA (mRNA) expression of cell cycle stimulators such as MYC and CCND1 (cyclin D1) and increased P21 cell cycle inhibitor mRNA. In addition, let-7 enhanced transcriptional expression of molecular markers of thyroid differentiation such as TITF1 and TG. Thus, reduced expression of let-7f might be an essential molecular event in RET/PTC malignant transformation. Moreover, let-7f effects on thyroid growth and differentiation might attenuate neoplastic process of RET/PTC papillary thyroid oncogenesis through impairment of MAPK signaling pathway activation. This is the first functional demonstration of an association of let-7 with thyroid cancer cell growth and differentiation.


[Occupational regulations of the use of terpene compounds in the air of the workplace].
Based on results of 15-years complex study, the authors present toxicological and hygienic characteristics of terpene compounds (with mono- and bicyclic structure) and their compositions. The article deals with toxicodynamics and toxicokinetics of terpenoids, dependence of toxic properties on the chemical structure. The article also touches upon studies of biologic and specific (sensibilizing activity, embryotoxic and gonadotropic, membranotropic) effects of terpenoids. Some aspects concerning hygienic regulation of terpene compounds are also covered.


Shigellaflexneri Regulator SlyA Controls Bacterial Acid Resistance by Directly Activating the Glutamate Decarboxylation System.
Shigella flexneri is an important foodborne bacterial pathogen with infectious dose as low as 10-100 cells. SlyA, a transcriptional regulator of the MarR family, has been shown to regulate virulence in a closely related bacterial pathogen, Salmonella Typhimurium. However, the regulatory role of SlyA in S. flexneri is less understood. Here we applied unbiased proteomic profiling to define the SlyA regulon in S. flexneri. We found that the genetic ablation of slyA led to the alteration of 18 bacterial proteins among over 1400 identifications. Intriguingly, most down-regulated proteins (whose expression is SlyA-dependent) were associated with bacterial acid resistance such as the glutamate decarboxylation system. We further demonstrated that SlyA directly regulates the expression of GadA, a glutamate decarboxylase, by binding to the promotor region of its coding gene. Importantly, overexpression of GadA was able to rescue the survival defect of the ΔslyA mutant under acid stress. Therefore, our study highlights a major role of SlyA in controlling S. flexneri acid resistance and provides a molecular mechanism underlying such regulation as well.


Ultrafast electron localization dynamics following photo-induced charge transfer
Molecular dynamics occurring in the earliest stages following photo-induced charge transfer were investigated. Femtosecond time-resolved absorption anisotropy measurements on [Ru(bpy)(3)](2+), where bpy is 2,2'-bipyridine, reveal a time dependence in nitrile solutions attributed to initial delocalization of the excited state over all three ligands followed by charge localization onto a single ligand. The localization process is proposed to be coupled to nondiffusive solvation dynamics. In contrast, measurements sampling population dynamics show spectral evolution associated with wave packet motion on the excited state surface that is independent of solvent. The results therefore reveal two important contributions to the evolution of charge transfer states in condensed phase, one that is strongly coupled to the surrounding environment and another that follows a potential internal to the molecule.


The role of lenticular senescence in age-related color vision changes.
It has been reported that greater age-related losses in sensitivity occur for short-wavelength visual stimuli than for medium- and long-wavelength visual stimuli. The purpose of the current experiment was to determine to what extent optical, receptoral, and postreceptoral factors contribute to these age-related changes in color vision. One hundred two observers (ages 18-87) completed a minimum motion task to determine isoluminance between red and green and between red and blue. A motion-nulling task was also performed to assess the L-M postreceptoral chromatic mechanism. No significant age-related changes occurred in red-green isoluminance values. Red-blue isoluminance values showed a significant and systematic decrease with age in observers with phakic eyes. Pseudophakic eyes in older subjects performed this task as well as phakic eyes in young subjects. The motion-nulling results demonstrated small age-related losses in the postreceptoral color mechanisms. The findings of this experiment, particularly those of the red-blue isoluminance task, indicate that the optical factor of lenticular senescence is the main contributor to the age-related changes observed in color vision. A model based on age-related changes in lenticular absorbance shows good fit with the experimental data of observers with phakic eyes, suggesting that optical factors are the main cause of the age-related changes in these color vision tasks.


RNA splicing during terminal erythropoiesis.
Erythroid progenitors must accurately and efficiently splice thousands of pre-mRNAs as the cells undergo extensive changes in gene expression and cellular remodeling during terminal erythropoiesis. Alternative splicing choices are governed by interactions between RNA binding proteins and cis-regulatory binding motifs in the RNA. This review will focus on recent studies that define the genome-wide scope of splicing in erythroblasts and discuss what is known about its regulation. RNA-seq analysis of highly purified erythroblast populations has revealed an extensive program of alternative splicing of both exons and introns. During normal erythropoiesis, stage-specific splicing transitions alter the structure and abundance of protein isoforms required for optimized red cell production. Mutation or deficiency of splicing regulators underlies hematopoietic disease in myelopdysplasia syndrome patients via disrupting the splicing program. Erythroid progenitors execute an elaborate alternative splicing program that modulates gene expression posttranscriptionally, ultimately regulating the structure and function of the proteome in a differentiation stage-specific manner during terminal erythropoiesis. This program helps drive differentiation and ensure synthesis of the proper protein isoforms required to produce mechanically stable red cells. Mutation or deficiency of key splicing regulatory proteins disrupts the splicing program to cause disease.


Hyperosmolarity and cardiac function in chronic diabetic rat heart.
Serum hyperosmolarity is commonly associated with the poorly controlled diabetic state. The current investigation revealed that increased perfusate osmolarity using either glucose or mannitol caused a gradual decline in the aortic output of hearts from both normal and diabetic rats. However, aortic output decreased less rapidly in hearts from diabetic rats. Decreasing the extracellular calcium concentration to a level resulting in one-third of the maximal aortic output elicited a greater and more prolonged increase in aortic output from the diabetic compared with the normal heart when perfusate osmolarity was progressively increased. The coronary conductance of diabetic rat hearts improved when hyperosmolar solutions of either mannitol or glucose were utilized, irrespective of the external calcium ion concentration. In normal hearts, the coronary conductance tended to decline at higher perfusate osmolarities. The increased coronary conductance may play a role in the enhanced performance of diabetic hearts at higher levels of osmolarity. Hyperosmolar solutions influence the performance of hearts from chronic diabetic rats in a positive inotropic manner at low extracellular calcium concentrations (1 mM). These lower calcium levels are close to the normal physiological range of the freely ionized serum calcium. This effect is greater in hearts from diabetic animals than from normal animals and is similar to that obtained when perfusate calcium is increased. The results suggest that hyperosmolar solutions enhance calcium availability in the hearts of diabetic animals.


PECULIARITIES OF VITRECTOMY AND MORPHOLOGIC CHANGES IN THE EPIRETINAL MEMBRANE AFTER INTRAVITREAL AFLIBERCEPT IN PATIENTS WITH SEVERE PROLIFERATIVE DIABETIC RETINOPATHY.
To examine the peculiarities of vitrectomy and morphologic changes in the epiretinal membrane after intravitreal aflibercept in patients with proliferative diabetic retinopathy. Prospective study of 21 consecutive cases with proliferative diabetic retinopathy complicated by vascularized epiretinal membrane forming tractional retinal detachment that underwent pars plana vitrectomy 4 days after intravitreal injection of aflibercept. After removal, the epiretinal membranes were taken for histologic examination using light microscopy. Obliteration of neovascularization of epiretinal membranes, the lack of bleeding in the intraoperative and early postoperative periods, retinal attachment, and improvement of visual acuity were taken for the criteria of treatment effectiveness. On the fourth day after intravitreal injection, newly formed vessels of epiretinal membranes were completely obliterated. There was no bleeding during segmentation and delamination of epiretinal membranes during vitrectomy. In the early postoperative period, bleeding complications were not noted. A microscopic examination of epiretinal membranes showed single-thin-walled capillary vessels lined with endothelial cells, the lumen of which does not contain blood cells. Capillaries are submerged in the connective tissue of different degrees of maturity. Intravitreal aflibercept resulted in the obliteration of neovascularization of epiretinal membranes, thus avoiding intraoperative and postoperative bleeding during vitrectomy. The improvement in visual acuity was noted in all cases. Histologic examination of epiretinal membranes determined single-thin-walled capillary vessels lined with endothelial cells without blood cells.


Dissolution testing of sublingual tablets: a novel in vitro method.
In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40 mg SL tablet formulations under development and two commercial SL tablets, isosorbide dinitrate 5 mg and nitroglycerin 0.6 mg, were studied. The dissolution medium was 2 mL of distilled water at 25°C. Dissolution was measured at 60 and 120 s. The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and was compared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different (p < 0.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method.


Correlation between choroidal thickness and degree of myopia assessed with enhanced depth imaging optical coherence tomography.
To assess the choroidal thickness in different degrees of myopia using enhanced depth imaging optical coherence tomography (EDI-OCT) compared with healthy subjects. We included 240 patients with myopia and 60 emmetropes as controls. Participants underwent full ophthalmologic examination, axial length measurement, and EDI-OCT imaging of the choroid. Choroidal thickness (CT) was measured at 5 locations, including subfoveal (SFCT), 2 mm nasal, temporal, upper, and lower to fovea. Choroidal thickness was significantly lower in myopic eyes compared to controls. Regardless of the degree of myopia, nasal regions showed the lowest CT with decremental pattern with advance of myopia (low myopia 279.00 ± 24.50 µm, moderate myopia 269.58 ± 20.69 µm, high myopia 189.58 ± 25.95 µm, advanced myopia 96.75 ± 24.83 µm). Highest CT was variable according to the degree of myopia with decremental pattern with advance of myopia (low myopia in subfoveal region 354.40 ± 35.14 µm, moderate myopia in temporal region 337.87 ± 35.75 µm, high myopia in lower region 312.15 ± 38.90 µm, and advanced myopia in upper region 201.25 ± 18.27 µm). Axial length showed significant negative correlation with SFCT and CT in different studied regions. Different degrees of myopia showed thinner choroidal thickness than that of normal control eyes with decremental thinning with progress of myopia. This might be secondary to the longer axial length, which was the determining factor in some locations such as subfoveal, nasal, and upper CT.


[Socio-demographic factors associated with dental services among Brazilian older adults: a study based on the National Household Sample Survey].
The objective of this study was to determine the prevalence of (and social-demographic factors associated with) the use of dental services. It was based on a sample of 28,943 adults > 60 years of age from the Brazilian National Household Sample Survey. Socio-demographic characteristics of seniors who had visited a dentist in the last year were compared with those of seniors who had visited a dentist more than one year previously and those who had never been to the dentist. The study showed independent associations between intervals > 1 year in visits to the dentist and such variables as age, residence, years of schooling, and per capita household income. All these variables, in addition to male gender and residence in the rural area, showed independent associations with absence of dental visits during the individual's lifetime. The results indicate a low rate of use of dental services among elderly Brazilians and that regional and socioeconomic differences are important determinants of dental services' use by Brazilian seniors.


Enhancement of DNA vaccine potency through coadministration of CIITA DNA with DNA vaccines via gene gun.
Administration of DNA vaccines via gene gun has emerged as an important form of Ag-specific immunotherapy. The MHC CIITA is a master regulator of MHC class II expression and also induces expression of class I molecules. We reasoned that the gene gun administration of CIITA DNA with DNA vaccines employing different strategies to improve MHC I and II processing could enhance DNA vaccine potency. We observed that DC-1 cells transfected with CIITA DNA lead to higher expression of MHC I and II molecules, leading to enhanced Ag presentation through the MHC I/II pathways. Furthermore, our data suggested that coadministration of DNA-encoding calreticulin (CRT) linked to human papillomavirus (HPV) 16 E6 Ag (CRT/E6) with CIITA DNA leads to enhanced E6-specific CD8(+) T cell immune responses in vaccinated mice. In addition, coadministration of the combination of CRT/E6 DNA with CIITA DNA and DNA encoding the invariant chain (Ii) linked to the pan HLA-DR-reactive epitope (Ii-PADRE) further enhanced E6-specific CD8(+) T cell immune responses in vaccinated mice. Treatment with the combination vaccine was also shown to enhance the antitumor effects and to prolong survival in TC-1 tumor-bearing mice. Vaccination with the combination vaccine also led to enhanced E6-specific CD8(+) memory T cells and to long-term protection against TC-1 tumors and prolonged survival in vaccinated mice. Thus, our findings suggest that the combination of CIITA DNA with CRT/E6 and Ii-PADRE DNA vaccines represents a potentially effective means to combat tumors in the clinical setting.


A model for drying control cosolvent selection for spin-coating uniformity: the thin film limit.
Striation defects in spin-coated thin films are a result of unfavorable capillary forces that develop due to the physical processes commonly involved in the spin-coating technique. Solvent evaporation during spinning causes slight compositional changes in the coating during drying, and these changes lead to instability in the surface tension, which causes lateral motions of the drying fluid up to the point where it gels and freezes in the thickness variations. In an earlier publication, we looked at the case where evaporation happens fast enough that the compositional depletion is mostly a surface effect. In terms of the mass transport rate competition within the coating solution, that work covered the thick film limit of this instability problem. However, in many cases, the coatings are thin enough or diffusion of solvent within the coating is fast enough to require a different solvent mixing strategy, which is developed here. A simple perturbation analysis of surface roughness is developed, and evaporation is allowed in the thin film limit. The perturbation analysis allows for a simple rubric to be laid out for cosolvent additions that can reduce the Marangoni effect during the later stages of coating deposition and drying when the thin film limit applies.


[The effect of mineral water on serotonin and insulin production (an experimental study)].
Radioimmunoassay (DRG kits) and orthotoluidine test were conducted to measure blood serotonin, insulin and glucose in 70 intact Wistar rat males before and after a course of drinking mineral water Essentuki 17 (MW). After the MW drinking course, a single dose of mineral water increases basal levels of serotonin and insulin, sensitivity of endocrine cells to MW. Serotonin and insulin rose maximally on minute 5 after the drink while in contrast to minute 15 and 30 before initiation of the MW drinking course. A direct correlation was found between blood concentrations of serotonin and insulin.


Dynamic enhancer function in the chromatin context.
Enhancers serve as critical regulatory elements in higher eukaryotic cells. The characterization of enhancer function has evolved primarily from genome-wide methodologies, including chromatin immunoprecipitation (ChIP-seq), DNase-I hypersensitivity (DNase-seq), digital genomic footprinting (DGF), and the chromosome conformation capture techniques (3C, 4C, and Hi-C). These population-based assays average signals across millions of cells and lead to enhancer models characterized by static and sequential binding. More recently, fluorescent microscopy techniques, including fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, and single molecule tracking (SMT), reveal a highly dynamic binding behavior for these factors in live cells. Furthermore, a refined analysis of genomic footprinting suggests that many transcription factors leave minimal or no footprints in chromatin, even when present and active in a given cell type. In this study, we review the implications of these new approaches for an accurate understanding of enhancer function in real time. In vivo SMT, in particular, has recently evolved as a promising methodology to probe enhancer function in live cells. Integration of findings from the many approaches now employed in the study of enhancer function suggest a highly dynamic view for the action of enhancer activating factors, viewed on a time scale of milliseconds to seconds, rather than minutes to hours. WIREs Syst Biol Med 2018, 10:e1390. doi: 10.1002/wsbm.1390 This article is categorized under: Analytical and Computational Methods > Computational Methods Laboratory Methods and Technologies > Genetic/Genomic Methods Laboratory Methods and Technologies > Imaging.


99mTc-MIBI scintigraphy in musculoskeletal tumors.
The aim of this study was to assess the value of 99mTc-hexakis2-methoxyisobutylisonitrile (MIBI) scintigraphy in patients with clinical and radiologic features of primary or metastatic musculoskeletal tumors. The scintigraphic findings for 84 patients were compared with the surgical and histologic findings. Each patient underwent three-phase bone scanning with 99mTc-methylene diphosphonate (MDP) and dynamic and static MIBI scintigraphy. The MIBI scans were evaluated by visual and quantitative analysis. The count ratio of the lesion to the adjacent or contralateral normal area (L/N) was calculated from the region of interest drawn on the MIBI scan. The Mann-Whitney test was used to determine the differences between the uptake ratios of malignant and benign lesions. Although increased MDP uptake was not specific for bone malignancy, a significant difference was found between benign tumors (L/N = 1.22 +/- 0.43) and malignant tumors (L/N = 2.25 +/- 1.03) on MIBI scans. Sensitivity and specificity were 81% and 87%, respectively. Forty-six of 53 proven benign lesions did not show significant MIBI uptake. The negative predictive value was 88%. In all seven sites of pathologic fracture, significant uptake was seen. However, three malignant lesions were not detected by MIBI scintigraphy, whereas seven benign lesions showed false-positive results. The major diagnostic worth of MIBI scintigraphy is its high negative predictive value. Although not capable of replacing tissue biopsy as a definitive diagnostic modality for musculoskeletal neoplasms, MIBI scintigraphy does appear to have a role in better preoperative assessment and in distinguishing between pathologic and simple fractures.


13. Operational planning for a specific intervention.
Every intervention must follow an operational plan. Operational plans delineate actions required to meet an objective that is part of the strategic plan (overarching goal). Operational plans dictate the critical pathways for the interventions that will be followed during and following the implementation of the intervention. Operational plans include: (1) an introduction and brief situation report; (2) an overview of the task(s), objectives, and the overarching goal to be addressed; (3) the methods that will be employed; (4) planning factors; (5) the resources that will be required including personnel, equipment, and supplies; (6) timelines, benchmarks, and milestones including their respective indicators, startup time, end point, and estimates of the time required for completion; (7) the administrative structure to be employed; (8) an operating budget; (9) the strategy for acquiring the funding required; (10) roles and responsibilities of the personnel including position descriptions and the competencies required of the personnel (skill sets); (11) mechanisms for monitoring the progress including the indicators that will be employed, (12) safety, including health of the personnel, required immunisations, accommodations, and reporting structure; (13) self-sufficiency; and (14) reporting and accounting. There are many generic items in an operational plan that can be used in successive plans. Without a detailed operational plan, interventions are doomed to probable failure and can profoundly negatively impact other projects operational in the area.


Identification and characterization of a Mucilaginibacter sp. strain QM49 β-glucosidase and its use in the production of the pharmaceutically active minor ginsenosides (S)-Rh1 and (S)-Rg2.
Here, we isolated and characterized a new ginsenoside-transforming β-glucosidase (BglQM) from Mucilaginibacter sp. strain QM49 that shows biotransformation activity for various major ginsenosides. The gene responsible for this activity, bglQM, consists of 2,346 bp and is predicted to encode 781 amino acid residues. This enzyme has a molecular mass of 85.6 kDa. Sequence analysis of BglQM revealed that it could be classified into glycoside hydrolase family 3. The enzyme was overexpressed in Escherichia coli BL21(DE3) using a maltose binding protein (MBP)-fused pMAL-c2x vector system containing the tobacco etch virus (TEV) proteolytic cleavage site. Overexpressed recombinant BglQM could efficiently transform the protopanaxatriol-type ginsenosides Re and Rg1 into (S)-Rg2 and (S)-Rh1, respectively, by hydrolyzing one glucose moiety attached to the C-20 position at pH 8.0 and 30°C. The Km values for p-nitrophenyl-β-d-glucopyranoside, Re, and Rg1 were 37.0 ± 0.4 μM and 3.22 ± 0.15 and 1.48 ± 0.09 mM, respectively, and the Vmax values were 33.4 ± 0.6 μmol min(-1) mg(-1) of protein and 19.2 ± 0.2 and 28.8 ± 0.27 nmol min(-1) mg(-1) of protein, respectively. A crude protopanaxatriol-type ginsenoside mixture (PPTGM) was treated with BglQM, followed by silica column purification, to produce (S)-Rh1 and (S)-Rg2 at chromatographic purities of 98% ± 0.5% and 97% ± 1.2%, respectively. This is the first report of gram-scale production of (S)-Rh1 and (S)-Rg2 from PPTGM using a novel ginsenoside-transforming β-glucosidase of glycoside hydrolase family 3.


Perceived cognitive difficulties and cognitive test performance as predictors of employment outcomes in people with multiple sclerosis.
Perceived cognitive difficulties and cognitive impairment are important determinants of employment in people with multiple sclerosis (pwMS). However, it is not clear how they are related to adverse work outcomes and whether the relationship is influenced by depressive symptoms. Thus, this study examined perceived and actual general cognitive and prospective memory function, and cognitive appraisal accuracy, in relation to adverse work outcomes. The possible mediating and/or moderating role of depression was also examined. A cross-sectional community-based sample of 111 participants (33 males, 78 females) completed the Multiple Sclerosis Work Difficulties Questionnaire (MSWDQ), Beck Depression Inventory - Fast Screen (BDI-FS), and questions related to their current or past employment. They then underwent cognitive testing using the Screening Examination for Cognitive Impairment, Auditory Consonant Trigrams test, Zoo Map Test, and Cambridge Prospective Memory Test. Perceived general cognitive and prospective memory difficulties in the workplace and performance on the respective cognitive tests were found to predict unemployment and reduced work hours since MS diagnosis due to MS. Depression was also related to reduced work hours, but it did not explain the relationship between perceived cognitive difficulties and the work outcomes. Nor was it related to cognitive test performance. The results highlight a need to address the perceptions of cognitive difficulties together with cognitive impairment and levels of depression in vocational rehabilitation programs in pwMS.


Introduction of afterloading low dose-rate brachytherapy for cervical cancer in Kenya.
The Amersham afterloading low dose-rate brachytherapy system for cervical cancer was introduced in Kenya in 1986. The long intrauterine and medium size vaginal applicators were the most frequently used. Complications were generally few except for vesicovaginal fistulae (4%), some of which may not have been entirely due to irradiation. The system was acceptable to both patients and staff. The prolonged treatment times of approximately 50 hours was however, a drawback, and grossly limited the number of patients treatable per week. Low dose-rate brachytherapy is safe and acceptable but is not recommended for units with heavy patient loads. Constraints to establishment of radiotherapy facilities in developing countries are discussed and recommendations for further improvement of services in Kenya highlighted.


Anthracyclines as tumor cell differentiating agents: effects on the regulation of erythroid gene expression.
Tumor cells, and particularly leukemic cells, can be considered as maturation-arrested cells which have escaped some normal control and continue to proliferate. This maturation arrest can be reversed by differentiation agents such as antitumor drugs currently used in conventional cytotoxic chemotherapy. In this respect, anthracyclines have been shown to trigger the differentiation of leukemic and solid tumor cells, but the molecular mechanisms by which such drugs lead to the differentiating phenotype are still poorly understood. Using human leukemic multipotent K562 cells, we have demonstrated that subtoxic concentrations of aclacinomycin (ACLA) and doxorubicin (DOX) preferentially stimulate the hemoglobinic pathway (globins and heme synthesis) and the expression of mRNAs of globins and of porphobilinogen deaminase (PBGD). However, our results indicate that both drugs exert this differentiating effect along distinct regulatory pathways. Indeed, only ACLA and not DOX induces the expression of erythropoietin receptor (EpoR) mRNAs and of membrane EpoR, as well as an overexpression of the erythroid transcription factors GATA-1 and NF-E2 known to play a central role in erythroid gene regulation. Similarly, using transfection assays, ACLA but not DOX activates the regulatory regions (promoters and enhancers) of GATA-1, EpoR, PBGD, epsilon- and gamma-globin genes. Finally, results of run-on assays indicate that ACLA induces an enhancement of the transcription rate of these erythroid genes whereas DOX preferentially increases stability of GATA-1, NF-E2 and PBGD mRNAs. In conclusion, ACLA mainly acts at the transcriptional level via specific activation of erythroid regulatory regions whereas DOX rather acts at the posttranscriptional level by increasing the half-lives of erythroid mRNAs.


Morphologic changes in arterial grafts in rabbit ears.
The morphology of auto- and allografted segments of rabbit central ear arteries was studied at various times after grafting. Autografts showed thrombosis only in the immediate postoperative period. Autografts developed intimal thickenings whose cellular elements at all stages were almost exclusively myointimal in type. Their medial smooth muscle cells were viable at all stages. Allografts frequently thrombosed within 8 weeks of grafting. Intimal thickenings that developed in the first 6 weeks in allografts mainly contained infiltrating hematogenous cells with few myointimal cells. Immune cells infiltrated all of the layers of allograft walls, and the smooth muscle cells of their medias showed increasingly severe degeneration and by 8 weeks had completely disappeared. In long established allografts, the intima was extremely thick and contained myointimal cells and fibrous tissue. Their medias were fibrosed. In long standing allografts, immune cell infiltration was no longer present. The thrombosis of allografted arteries that occurred within 8 weeks of grafting was related to immunologic events observed within the vessel grafts. Differences between myointimal cells and smooth muscle cells with regard to their morphology and orientation were identified. A possible origin of myointimal cells from endothelial cells is suggested.


The modulation of endothelial cell morphology, function, and survival using anisotropic nanofibrillar collagen scaffolds.
Endothelial cells (ECs) are aligned longitudinally under laminar flow, whereas they are polygonal and poorly aligned in regions of disturbed flow. The unaligned ECs in disturbed flow fields manifest altered function and reduced survival that promote lesion formation. We demonstrate that the alignment of the ECs may directly influence their biology, independent of fluid flow. We developed aligned nanofibrillar collagen scaffolds that mimic the structure of collagen bundles in blood vessels, and examined the effects of these materials on EC alignment, function, and in vivo survival. ECs cultured on 30-nm diameter aligned fibrils re-organized their F-actin along the nanofibril direction, and were 50% less adhesive for monocytes than the ECs grown on randomly oriented fibrils. After EC transplantation into both subcutaneous tissue and the ischemic hindlimb, EC viability was enhanced when ECs were cultured and implanted on aligned nanofibrillar scaffolds, in contrast to non-patterned scaffolds. ECs derived from human induced pluripotent stem cells and cultured on aligned scaffolds also persisted for over 28 days, as assessed by bioluminescence imaging, when implanted in ischemic tissue. By contrast, ECs implanted on scaffolds without nanopatterning generated no detectable bioluminescent signal by day 4 in either normal or ischemic tissues. We demonstrate that 30-nm aligned nanofibrillar collagen scaffolds guide cellular organization, modulate endothelial inflammatory response, and enhance cell survival after implantation in normal and ischemic tissues.


Synthesis and structure of spirocyclic tetraethers derived from [1,1'-binaphthalene]-2,2'-diol and pentaerythritol.
Molecular scaffolds that have well-defined geometries, are easy to synthesize and functionalize, and can hold attached sites of molecular recognition in suitable orientations are useful tools in various areas of science and technology. The utility of the tetraphenyl ether of pentaerythritol (4) as a scaffold in crystal engineering led us to study rigidified analogue SBINOX (5), the spirocyclic tetraether derived from pentaerythritol and [1,1'-binaphthalene]-2,2'-diol (BINOL). We have found that SBINOX (5) and derivatives can be prepared conveniently in acceptable yields and in stereoisomerically pure (S,S), (R,S), and (R,R) forms. X-ray crystallographic studies have revealed that the benzannulated 9-membered dioxonane rings in these structures adopt characteristic conformations of C1 symmetry. Intraannular C-H...O interactions help maintain the conformations of the individual rings, and the geometry of the spirocyclic SBINOX core is also controlled in part by distinctive short interannular C-H...O and C-H...pi interactions. Despite the inherent flexibility of the dioxonane rings, derivatives of SBINOX (5) can be expected to orient peripheral substituents in preferred ways, making SBINOX a potentially useful scaffold for applications in drug discovery, crystal engineering, and other fields.


Kaposi's sarcoma in childhood. A report of 3 cases.
Three cases of Kaposi's sarcoma in Black children aged under 4 years are described. In all cases the diagnosis was made on lymph node biopsy. The difference in presentation of Kaposi's sarcoma in childhood and adulthood is discussed and attention is drawn to the frequency of lymph node involvement in children. Response to combination chemotherapy is encouraging and the potential for long-term survival appears to be good.


Declining frequency of blood donation among elites in Maiduguri, Nigeria.
This study evaluated the causes of declining frequency of voluntary blood donations among educated elites as seen at the blood bank of University of Maiduguri Teaching Hospital, Maiduguri, Nigeria, over the last decade. The number of blood units received from educated elite donors during a 10-year period (1995-2004) at the blood bank were determined and expressed as percentages of total donations collected annually. The reasons for elite donor default were obtained through the use of questionnaires filled by defaulting donors. The proportion of educated elite donations steadily fell from 28% in 1995 to 7% in 2004. Reasons for defaulting from voluntary blood donations included fear for HIV screening in 86.7% of respondents, economic hardship/poor nourishment in 50.6% of respondents, changed address/logistic difficulties in 4.8% of respondents and ill health in 2.4% of respondents. Therefore, the steady fall in the proportion of elite donors over the years was mainly due to fear of HIV screening coupled with economic difficulties. Hence, there is the need to review our donor campaign strategy with respect to predonation counseling for HIV, initiate regular haematinics supplementation for donors and introduce sustainable mobile donor clinic services for distant donors. Further more, there is the need for a functional national blood transfusion service in Nigeria.


[Role of cholinergic mechanisms in central regulation of respiratory activity in Periplaneta americana cockroaches].
Studies have been made on cholinergic mechanisms in the thoracic ganglion of the cockroach P. americana. It was shown that cholinergic systems are involved not only in the transmission of excitation, but in realization of the inhibitory effects as well. Both types of cholinereceptors were found on motoneurones. Nicotinic, muscarinic or both of the cholinoreceptors may be present on a single interneurone. Nicotinic cholinoreceptors play key role in transmission of excitation. Both types of the cholinoreceptors are involved in realization of the inhibitory influences.


Segmental order parameters in a nonionic surfactant lamellar phase studied with 1H-13C solid-state NMR.
A lyotropic nonionic lamellar system composed of pentaethyleneglycol mono n-dodecyl ether and D(2)O was studied using natural abundance (13)C NMR under magic-angle spinning. Applying a two-dimensional recoupling method proposed by Dvinskikh (R-PDLF), (1)H-(13)C dipolar couplings were estimated over a range of temperatures (300-335 K), thus enabling analysis of structural changes in the liquid crystalline system. The results obtained are used to correlate the conformation and mobility of local sites in the surfactant molecule with overall changes in the lamellar structure.


Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases.
The authors determined the safety and efficacy of recombinant high-dose interleukin-2 administration in patients with brain metastases. This retrospective review included 1,069 patients with metastatic melanoma or renal cell carcinoma who received high-dose interleukin-2 alone or in combination with other immunotherapy or chemotherapy from July 1985-July 2000. All patients were evaluated for both toxicity and response. Only the first exposure to interleukin-2 was considered. Parameters evaluated among the groups included toxicity profiles, reasons for stopping treatment, number of interleukin-2 doses per cycle, and response to therapy. Three patient groups were compared. Group I (n = 27) comprised patients with previously treated brain metastases (surgery or radiation), group 2 (n = 37) comprised patients with untreated brain metastases, and group 3 (n = 1,005) comprised patients without brain metastases. For most comparisons between patients with brain metastases and those without, no significant differences were noted in toxicity profiles or reasons for stopping interleukin-2 therapy. Patients with previously treated brain metastases received fewer interleukin-2 doses per cycle (median, 6.5) than patients with previously untreated brain metastases (median, 7.5) or patients without brain metastases (median, 7.5). Patients with previously treated brain metastases demonstrated an 18.5% overall clinical response to interleukin-2 treatment. However, patients with evaluable (previously untreated) brain metastases had an overall 5.6% response rate, which was less than the 19.8% response rate of patients without brain metastases. Two of thirty-six patients with evaluable brain metastases demonstrated objective regression of intracranial and extracranial disease after receiving interleukin-2. Carefully selected patients with brain metastases can safely receive high-dose interleukin-2, and some can experience a response to treatment at intracranial and extracranial disease sites.


Isolation and DNA sequence of ADH3, a nuclear gene encoding the mitochondrial isozyme of alcohol dehydrogenase in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae nuclear gene, ADH3, that encodes the mitochondrial alcohol dehydrogenase isozyme ADH III was cloned by virtue of its nucleotide homology to ADH1 and ADH2. Both chromosomal and plasmid-encoded ADH III isozymes were repressed by glucose and migrated heterogeneously on nondenaturing gels. Nucleotide sequence analysis indicated 73 and 74% identity for ADH3 with ADH1 and ADH2, respectively. The amino acid identity between the predicted ADH III polypeptide and ADH I and ADH II was 79 and 80%, respectively. The open reading frame encoding ADH III has a highly basic 27-amino-acid amino-terminal extension relative to ADH I and ADH II. The nucleotide sequence of the presumed leader peptide has a high degree of identity with the untranslated leader regions of ADH1 and ADH2 mRNAs. A strain containing a null allele of ADH3 did not have a detectably altered phenotype. The cloned gene integrated at the ADH3 locus, indicating that this is the structural gene for ADH III.


Sub-surface imaging of carbon nanotube-polymer composites using dynamic AFM methods.
High-resolution sub-surface imaging of carbon nanotube (CNT) networks within polymer nanocomposites is demonstrated through electrical characterization techniques based on dynamic atomic force microscopy (AFM). We compare three techniques implemented in the single-pass configuration: DC-biased amplitude modulated AFM (AM-AFM), electrostatic force microscopy (EFM) and Kelvin probe force microscopy (KPFM) in terms of the physics of sub-surface image formation and experimental robustness. The methods were applied to study the dispersion of sub-surface networks of single-walled nanotubes (SWNTs) in a polyimide (PI) matrix. We conclude that among these methods, the KPFM channel, which measures the capacitance gradient (∂C/∂d) at the second harmonic of electrical excitation, is the best channel to obtain high-contrast images of the CNT network embedded in the polymer matrix, without the influence of surface conditions. Additionally, we propose an analysis of the ∂C/∂d images as a tool to characterize the dispersion and connectivity of the CNTs. Through the analysis we demonstrate that these AFM-based sub-surface methods probe sufficiently deep within the SWNT composites, to resolve clustered networks that likely play a role in conductivity percolation. This opens up the possibility of dynamic AFM-based characterization of sub-surface dispersion and connectivity in nanostructured composites, two critical parameters for nanocomposite applications in sensors and energy storage devices.


Traditional practices used by the infertile women to become pregnant and their effects on the quality of life.
The present research was planned to determine the traditional practices used by infertile women to become pregnant and their effects on the quality of life. A hospital-based, descriptive and cross-sectional study. Participant Information Forms and SF-36 quality of life scales were applied to 269 women diagnosed as infertile. Some of the infertile women (32.7%) were determined to use a traditional method. The traditional methods used by women included herbal remedies (those edible and drinkable) (87.5%), sitting on the herbal mixtures (8%) and using both practices (4.5%). The SF-36 Mental Health component was determined to be better in infertile women not using traditional practices than those using traditional practices (P < 0.05). Considering the results of the study, health professionals can question women about the traditional practices and guide them about their damages.


Anisocoria and middle cerebral artery saccular (berry) aneurysm in a rhesus macaque (Macaca mulatta).
A 27-year-old female rhesus macaque (Macaca mulatta) developed anisocoria. The left pupil was dilated and unresponsive to light. The macaque was euthanized because of unrelated reasons and the body was submitted for necropsy. On gross examination, a berry aneurysm of the right middle cerebral artery causing marked compression of the right optic tract was found. Arteriosclerotic changes were observed microscopically in the right middle cerebral and in the internal carotid arteries. The left iris was markedly degenerated, with atrophy of the constrictor muscle. Compression of the right optic tract may cause homonimus hemianopsia. A dilated and unresponsive left pupil indicated a lesion in the ipsilateral parasympathetic efferent pathway. In the absence of appreciable lesions of the left oculomotor nerve, the most likely cause of mydriasis was the iridic lesion. Intracranial aneurysms are common in humans (2 to 5%), but not in other species. Only about 10% of unruptured aneurysms are associated with neurologic deficits related to mechanical compression, such as visual deficits or anisocoria. Meticulous investigation of the ocular vascular and neural pathways led us to conclude that the anisocoria was unrelated to the aneurysm. To our knowledge, this report represents the first documented case of a naturally occurring intracranial aneurysm in nonhuman primates.


Gel-to-Solution Transition of Sulfhydryl Self-Assembled Peptide Hydrogels Undergoing Oxidative Modulation.
The design of self-assembling biomaterials needs to take into consideration the timing and location of the self-assembly process. In recent decades, the principal strategy has been to control the peptide self-assembly under specific conditions to enable its functional performance. However, few studies have explored the responsive elimination of functional self-assembled peptide hydrogels after their function has been performed. We designed peptide ECAFF (ECF-5), which under reductive conditions can self-assemble into a hydrogel. Upon exposure to oxidizing conditions, disulfide bonds form between the peptides, altering their molecular structure and impacting their self-assembly capability. As a result, the peptide hydrogels transition to a soluble state. This study investigates the utilization of oxidation to induce a gel-to-solution transition in peptide hydrogels and provides an explanation for their degradation following free radical treatment. Self-assembled peptide hydrogel materials can be designed from a fresh perspective by considering the degradation that takes place after functional execution.


Novel and simple prognostic index for nasal natural killer/T-cell lymphoma.
Few studies have investigated the prognostic factors for nasal natural killer (NK)/T-cell lymphoma. This was a retrospective multicenter clinical study. The clinical records of 36 patients with nasal NK/T-cell lymphoma who had been first treated between 1996 and 2011 were collected from 12 hospitals. High serum levels of C-reactive protein (≥1.0 mg/dL), lactate dehydrogenase (≥350 IU/L), and soluble interleukin-2 receptor (sIL-2R; ≥600 U/mL) were associated with worse prognosis. A prognostic score was devised by totaling the number of these 3 predictors: 0 or 1 = score 0; and 2 or 3 = score 1. As for tumor invasion, local invasion beyond the nasal cavity was associated with poor prognosis, and a prognostic score was devised as: tumor restricted to nasal cavity, yes = score 0; no = score 1. A novel prognostic index (NPI) was established based on these scores from 0 to 2. Disease-specific survival rates at 5 years were: 90.0% for NPI = 0; 29.3% for NPI = 1; and 0.0% for NPI = 2. Our NPI is valid for anticipating prognosis of nasal NK/T-cell lymphoma.


Prevalence and clinical correlates of microalbuminuria in children with sickle cell disease.
Sickle cell disease (SCD) is associated with a large spectrum of renal abnormalities, one of which, microalbuminuria/proteinuria (MA/P), is a known predictor of end-stage renal disease. We studied 90 children with SCD (57% male; mean age 11.4 +/- 5.2 years) to determine the prevalence and examine clinical correlates of MA/P. The average of two spot urine microalbumin-to-creatinine samples obtained 6 months apart was recorded. Medical records were reviewed for demographic and biochemical data. Medication use, resting office blood pressures (BP), vaso-occlusive pain crises (VOC), and monthly transfusions were recorded. Fourteen children (15.5%) had MA/P. Hemoglobin (Hb) levels were significantly lower in the children with MA than in those without MA/P (8.8 +/- 1.1 vs. 9.8 +/- 1.4 g/dL, respectively) and were significantly correlated with MA (rho = 0.24, p = 0.03). Children with MA were more likely to have abnormal BP (p = 0.058), with 5/14 being hypertensive or pre-hypertensive. In a multivariate logistic regression model of MA, both Hb and BP classification remained in the final model. MA is a simple screening biomarker of early kidney injury in children with SCD. Larger studies to evaluate predictive factors of MA and the relationship to BP are needed.


Cell-cell adhesion molecules and the development of an epithelial phenotype in cultured human retinal pigment epithelial cells.
For most epithelial cells, the adherens junction protein E-cadherin is an epithelial morphogen, inducing the development of an epithelial phenotype in vitro after cell contact at confluency. Here retinal pigment epithelial cells (RPE), which lack E-cadherin but express a cadherin that is also found in many non-epithelial cells (N-cadherin), were examined for the ability to produce an epithelial phenotype in vitro. Subpopulations of grossly epithelioid or fusiform cells were selected for analysis from RPE cultures derived from adult human donors. After confluency, epithelioid RPE cells were observed to undergo time-dependent changes that were similar to those previously found in epithelial cells expressing E-cadherin: the cadherin gradually developed a zonular distribution of detergent-resistant protein that co-localized with forming circumferential actin bundles; Na/K ATPase accumulated at cell contact sites, then polarized to its tissue-specific domain (the apical membrane for RPE); the cells formed elevated domes on the impermeant culture substrate. In contrast to cells expressing E-cadherin, these events in RPE required weeks rater than days at confluency. Additional proteins were examined in epithelioid RPE cells revealing that cytokeratins reorganized after confluency producing a zonular array, and several other adhesion proteins (alpha5beta1 integrin, ICAM-1, PECAM-1, NCAM) became enriched at cell-cell contact sites, each developing a distinct pattern at a distinct postconfluency interval. In contrast to epithelioid RPE, in fusiform RPE the adhesion molecules did not develop discrete distribution patterns after confluency, although the same complement of adhesion proteins was expressed. In cells expressing E-cadherin, the absence of epithelial properties is often due to underexpression of the cadherin or of the catenins, adherens junction proteins that link the cadherin to actin. Fusiform RPE, however, were not deficient in these proteins, expressing amounts of N-cadherin, alpha-catenin, beta-catenin, plakoglobin, p120, alpha-actinin and vinculin that were equivalent to epithelioid cells. It appears, therefore, that a subset of epithelial cells that express N-cadherin can produce a highly-developed epithelial phenotype in vitro through a slow morphogenetic process. However, the expression alone of adhesion molecules, including those with a morphoregulatory function in other cells, is insufficient to produce an epithelial phenotype in all cells derived from the pigment epithelium.


High genetic compatibility and increased pathogenicity of reassortants derived from avian H9N2 and pandemic H1N1/2009 influenza viruses.
H9N2 influenza viruses have been circulating worldwide in multiple avian species and repeatedly infecting mammals, including pigs and humans, posing a significant threat to public health. The coexistence of H9N2 and pandemic influenza H1N1/2009 viruses in pigs and humans provides an opportunity for these viruses to reassort. To evaluate the potential public risk of the reassortant viruses derived from these viruses, we used reverse genetics to generate 127 H9 reassortants derived from an avian H9N2 and a pandemic H1N1 virus, and evaluated their compatibility, replication ability, and virulence in mice. These hybrid viruses showed high genetic compatibility and more than half replicated to a high titer in vitro. In vivo studies of 73 of 127 reassortants revealed that all viruses were able to infect mice without prior adaptation and 8 reassortants exhibited higher pathogenicity than both parental viruses. All reassortants with higher virulence than parental viruses contained the PA gene from the 2009 pandemic virus, revealing the important role of the PA gene from the H1N1/2009 virus in generating a reassortant virus with high public health risk. Analyses of the polymerase activity of the 16 ribonucleoprotein combinations in vitro suggested that the PA of H1N1/2009 origin also enhanced polymerase activity. Our results indicate that some avian H9-pandemic reassortants could emerge with a potentially higher threat for humans and also highlight the importance of monitoring the H9-pandemic reassortant viruses that may arise, especially those that possess the PA gene of H1N1/2009 origin.


Interleukin-11 inhibits macrophage interleukin-12 production.
IL-12 is a heterodimeric cytokine produced by phagocytic and other cells with important physiologic and pathologic properties. Regulated IL-12 production is crucial for the generation of protective Th1 responses to infectious agents. In contrast, IL-12 excess contributes to the pathogenesis of a variety of autoimmune and inflammatory disorders. To further understand the processes regulating IL-12 production, we determined whether IL-11 regulated monocyte/macrophage production of this cytokine moiety. IL-11 did not alter the IL-12 (p70) production of unstimulated THP-1 monocytic cells or human blood monocytes. It did, however, inhibit, in a dose-dependent fashion, the IL-12 production of IFN-gamma plus Staphylococcus aureus Cowan strain 1-stimulated THP-1 cells and stimulated blood monocytes. This inhibition of IL-12 protein production was associated with a proportionate decrease in IL-12 p35 and p40 mRNA accumulation. Nuclear run-on assays revealed comparable decreases in IL-12 p35 and p40 gene transcription. IL-11 did not similarly regulate monocyte/macrophage production of IL-8 or macrophage inflammatory protein-1alpha (MIP-1alpha) and IL-6 did not similarly inhibit IL-12 elaboration. These studies demonstrate that IL-11 is a potent inhibitor of monocyte/macrophage IL-12 production and that this inhibitory effect is, at least in part, transcriptionally mediated. They also demonstrate that this inhibition is not the result of a generalized suppression of macrophage effector function and that the ability to inhibit monocyte/macrophage IL-12 production is not a generalized property of all IL-6-type cytokines.


[Current status of the treatment of laryngeal cancer].
The state of the art in laryngeal cancer treatment in the RSFSR is outlined on the basis of an analysis of morbidity and other statistical data. Measures which can be taken to considerably improve the effectiveness of treatment are discussed. The importance of a complex of diagnostic procedures to be employed in therapy planning is shown. Preoperative HBO-mediated gamma therapy and mean fractionation of radiation were used to improve combined treatment. The following function-saving procedures were suggested for radical removal of stage III laryngeal malignancies: an endoprosthetic procedure, improved modifications of horizontal resection, and lower larynx resection. A randomized study suggested that prophylactic surgery be performed on the lymphatics of the neck for cancer (T4) of the vestibular area involving the laryngopharynx. The report discusses the good functional and oncological results of 252 function-saving operations carried out after preoperative gamma therapy conducted as a component of combined treatment. The study also established a high effectiveness of tracheoesophageal shunting as a postlaryngectomy voice rehabilitation device.


Estimation of the association between antibody titers and protection against confirmed influenza virus infection in children.
Antibody titers measured by hemagglutination inhibition (HAI) correlate with protection against influenza virus infection and are used to specify criteria for vaccine licensure. In a randomized, controlled trial of seasonal influenza vaccination in 773 children aged 6-17 years, we estimated that HAI titers of 1:40 against A(H1N1)pdm09 and B(Victoria lineage) were associated with 48% (95% confidence interval [CI], 30%-62%) and 55% (95% CI, 32%-70%) protection against PCR-confirmed infection with each strain. Our analysis accounted for waning in antibody titers over time, and could be particularly useful in settings where influenza activity is delayed or prolonged relative to measurement of antibody titers.


[Theophylline--contemporary views on cellular mechanism of action].
Theophylline has been used in the treatment of obstructive pulmonary diseases since 30s. However, its mechanism of action is still poorly defined. Up to now, its several different actions on the cellular levels are known or hypothesised including most important--inhibition of phosphodiesterase isoenzymes and antagonism of adenosine, as well as enhancement of catecholamine secretion and modulation of calcium ions fluxes. Author reviews all of the proposed theories, outlining existing arguments for and against.


Associations and impact factors between living arrangements and functional disability among older Chinese adults.
To examine the association of living arrangements with functional disability among older persons and explore the mediation of impact factors on the relationship. Cross-sectional analysis using data from Healthy Aging study in Zhejiang Province. Analyzed sample was drawn from a representative rural population of older persons in Wuyi County, Zhejiang Province, including 1542 participants aged 60 and over in the second wave of the study. Living arrangements, background, functional disability, self-rated health, number of diseases, along with contemporaneous circumstances including income, social support (physical assistance and emotional support). Instrument was Activities of Daily Living (ADL) scale, including Basic Activities Daily Living (BADL) and Instrumental Activities of Daily Living (IADL). Living arrangements were significantly associated with BADL, IADL and ADL disability. Married persons living with or without children were more advantaged on all three dimensions of functional disability. Unmarried older adults living with children only had the worst functional status, even after controlling for background, social support, income and health status variables (compared with the unmarried living alone, ß for BADL: -1.262, ß for IADL: -2.112, ß for ADL: -3.388; compared with the married living with children only, ß for BADL: -1.166, ß for IADL: -2.723, ß for ADL: -3.902). In addition, older adults without difficulty in receiving emotional support, in excellent health and with advanced age had significantly better BADL, IADL and ADL function. However, a statistically significant association between physical assistance and functional disability was not found. Functional disabilities vary by living arrangements with different patterns and other factors. Our results highlight the association of unmarried elders living with children only and functioning decline comparing with other types. Our study implies policy makers should pay closer attention to unmarried elders living with children in community. Community service especially emotional support such as psychological counseling is important social support and should be improved.


Temperature and charge transfer in a receptor membrane.
The rate of rise and the amplitude of a mechanically elicited generator potential in a receptor membrane (Pacinian corpuscle) increases markedly with temperature. By contrast, the amplitude of the action potential of the Ranvier node adjacent to the receptor membrane remains practically unchanged over a wide range of temperature. The activation energy of the rate-limiting process in excitation of the receptor membrane is high; it indicates the existence of a high potential energy barrier for charge transfer.


Pertussis (whooping cough). The GP view.
Pertussis is still a common cause of debility in the infant. David Muecke describes the classical case and the variations in presentation which may cause diagnostic problems. Immunisation remains the mainstay of control of this highly infectious disease and is the responsibility of the general practitioner.


Chronic vulvovaginal candidiasis.
Frequently ignored by the medical community, chronic vulvovaginal symptoms are relatively common and can frustrating for patients and physicians. Establishing a proper diagnosis will lay the foundation for an effective therapeutic therapeutic plan. Fungal cultures are an important component of the work-up. The most common causes of chronic vaginal symptoms are recurrent vulvovaginal candidiasis (RVVC), vulvar vestibulitis syndrome and irritant dermatitis. In patients with RVVC caused by Candida albicans, host factors may play an important role. Long-term oral antifungal therapy will break the pattern of recurrence in many patients. Infections caused by other species of yeast may be more resistant to standard treatment approaches.


NPH4/ARF7 and ARF19 promote leaf expansion and auxin-induced lateral root formation.
Auxin response factors (ARFs) bind auxin response promoter elements and mediate transcriptional responses to auxin. Five of the 22 ARF genes in Arabidopsis thaliana encode ARFs with glutamine-rich middle domains. Four of these can activate transcription and have been ascribed developmental functions. We show that ARF19, the fifth Q-rich ARF, also activates transcription. Mutations in ARF19 have little effect on their own, but in combination with mutations in NPH4/ARF7, encoding the most closely related ARF, they cause several phenotypes including a drastic decrease in lateral and adventitious root formation and a decrease in leaf cell expansion. These results indicate that auxin induces lateral roots and leaf expansion by activating NPH4/ARF7 and ARF19. Auxin induces the ARF19 gene, and NPH4/ARF7 and ARF19 together are required for expression of one of the arf19 mutant alleles, suggesting that a positive feedback loop regulates leaf expansion and/or lateral root induction.


[Forensic-medical significance of the characteristics of gunshot perforating fractures of the skull bones].
The study was made of gunshot perforating fractures of calvarial bones in cases of lethal perforating head wounds in long distance shots from a 9-mm Makarov gun. Morphological characteristics of inlet and outlet perforating fractures and bone fragments were found to differ. Gunshot fractures in calvarial bones inflicted by bullets from a 9-mm Makarov gun were studied in experiments with different kinetic energy. In low kinetic energy, bullets make oval holes on the outer table of the skull and round holes on the inner table with radial prominences on the walls of bullet channels, large bone fragments; in moderate kinetic energy--make round holes in the outer table and oval on the inner table with skew prominences on the walls of the outlet part of the channels, large and middle-sized flat bone fragments; in high kinetic energy injuries on both tables were round, prominences were cross, bone fragments were flat, small and middle-sized.


Fingerprinting of mixed bacterial strains and BIOLOG gram-negative (GN) substrate communities by enterobacterial repetitive intergenic consensus sequence-PCR (ERIC-PCR).
PCR-based genomic fingerprinting by use of enterobacterial repetitive intergenic consensus primers (ERIC-PCR) was evaluated for its use in fingerprinting DNA of mixed Gram-negative bacterial strains and BIOLOG Gram-negative (GN) microplate substrate communities. ERIC-PCR fingerprints of six different pure bacterial strains and a combined mixture of the strains were compared with fingerprints obtained by two more established methods: amplified ribosomal DNA restriction analysis (ARDRA) and random amplified polymorphic DNA analysis (RAPD-PCR). The ERIC-PCR fingerprint of the mixed strains was highly reproducible and was more species-specific and representative of the individual strain fingerprints than the ARDRA and RAPD-PCR fingerprints, respectively. ERIC-PCR fingerprinting of model and rhizosphere BIOLOG GN substrate communities also provided clearly distinguishable fingerprints. Results of this study suggest that ERIC-PCR represents a rapid and highly discriminating method for fingerprinting DNA of mixed Gram-negative bacterial strains and BIOLOG GN substrate communities.


Dietary aspartyl-phenylalanine-1-methyl ester delays osteoarthritis and prevents associated bone loss in STR/ORT mice.
STR/ORT mice provide a well-known model for murine idiopathic OA, with histological joint lesions resembling those of human OA. This model was used to investigate protective effects of the dipeptide aspartyl-phenylalanine-1-methyl ester (Asp-Phe-OMe or aspartame) via the oral route vs a regular diet. STR/ORT mice were housed individually and fed diets with or without Asp-Phe-OMe (4 mg/kg), after weaning at the age of 3 weeks, until 15 months of age (average of 20 animals per group). The study groups were kept blinded to the investigators, who measured food consumption and body weight and performed gait mobility tests. Radiographic scans were also performed at regular time intervals to evaluate differential radiographic anomalies associated with progress of OA in response to oral Asp-Phe-OMe therapy. The Asp-Phe-OMe-fed animals presented a pattern of significantly delayed disease onset. In addition, their muscle and bone mass were highly preserved, even at later time points after OA was established. Moreover, control animals presented a higher variability in gait motility in comparison with the Asp-Phe-OMe-fed animals, suggesting a protective effect from movement limitations associated with advanced OA. Asp-Phe-OMe, given orally, delays OA in the spontaneous STR/ORT model, improves bone cortical density and muscle mass, and may contribute to a better quality of life for these diseased animals.


Neurotoxic Zanthoxylum chalybeum root constituents invoke mosquito larval growth retardation through ecdysteroidogenic CYP450s transcriptional perturbations.
Intracellular effects exerted by phytochemicals eliciting insect growth-retarding responses during vector control intervention remain largely underexplored. We studied the effects of Zanthoxylum chalybeum Engl. (Rutaceae) (ZCE) root derivatives against malaria (Anopheles gambiae) and arbovirus vector (Aedes aegypti) larvae to decipher possible molecular targets. We report dose-dependent biphasic effects on larval response, with transient exposure to ZCE and its bioactive fraction (ZCFr.5) inhibiting acetylcholinesterase (AChE) activity, inducing larval lethality and growth retardation at sublethal doses. Half-maximal lethal concentrations (LC50) for ZCE against An. gambiae and Ae. aegypti larvae after 24-h exposure were 9.00 ppm and 12.26 ppm, respectively. The active fraction ZCFr.5 exerted LC50 of 1.58 ppm and 3.21 ppm for An. gambiae and Ae. aegypti larvae, respectively. Inhibition of AChE was potentially linked to larval toxicity afforded by 2-tridecanone, palmitic acid (hexadecanoic acid), linoleic acid ((Z,Z)-9,12-octadecadienoic acid), sesamin, β-caryophyllene among other compounds identified in the bioactive fraction. In addition, the phenotypic larval retardation induced by ZCE root constituents was exerted through transcriptional modulation of ecdysteroidogenic CYP450 genes. Collectively, these findings provide an explorative avenue for developing potential mosquito control agents from Z. chalybeum root constituents.


Antiviral treatment of chronic hepatitis C in clinical routine.
Pegylated interferon plus ribavirin is the standard treatment for chronic hepatitis C. Sustained virological response (SVR) rates of up to 60% are reported in randomized controlled trials, but it is unclear whether the results from such trials are reproducible in the clinical routine setting. We investigated consecutive treatment-naïve chronic hepatitis C patients at our center to examine the efficacy of treatment with pegylated interferon plus ribavirin in clinical routine. Between 2000 and 2006 we treated a total of 219 patients with pegylated interferon alpha (2a or 2b) and ribavirin (800-1200 mg/d). Among them, 34.8% of patients infected with HCV genotypes 1/4/6 and 18.4% of those with genotypes 2/3 had advanced fibrosis or cirrhosis (F3-F4). For analysis of outcome we subdivided our series into two groups of patients: those who fulfilled standard inclusion criteria in randomized controlled trials and those who did not. The overall SVR rate was 44.3%. In patients with F0-F2 an SVR was achieved in 52.5%; in those with F3-F4 the SVR rate was 20.8%. In patients infected with genotypes 1/4/6 the SVR rate was 35.4% (SVR: F0-F2 47.7%; F3-F4 19.6%); in those with genotypes 2/3 the rate was 67.8%. The SVR rate in patients with unfavorable baseline factors was significantly lower (32.4% vs. 50%; P = 0.017) and they were more likely to be non-responders (30.9% vs. 13.8%). In everyday clinical practice, up to one-third of patients show unfavorable baseline factors for antiviral therapy, resulting in worse therapeutic outcome. Differences in therapeutic outcome are influenced by patient selection and by the proportion and severity of the underlying liver disease.


The prognostic value of E-cadherin and Ki-67 compared to standard histopathologic examination in non-muscle invasive bladder cancer.
The objectives of this study were to determine the prognostic value of expression levels of selected biomarkers and their statistical analysis in relation to survival and standard histopathologic examination and other clinicopathologic variables in non-muscle invasive bladder cancer (NMIBC). Worldwide, bladder cancer is a frequent malignant disease with rising incidence. Characteristic invasiveness and high recurrence rates call for more diagnostic methods to obtain more accurate information. Prognosis is affected by a significant interpersonal variability of the disease. For this reason, constant search for alternative and better diagnostic methods is essential. We analysed cancer tissue from patients with Ta and T1 bladder cancer. E-cadherin and Ki-67 expression levels were analysed using immunohistochemical staining. The expression levels quantified to a percentual amount were statistically analysed in relation to survival and their frequency distribution in the study group. E-cadherin and Ki-67 expression levels show high association with tumor stage and grade (p<0.001), in contrast, the association with recurrence has proven insignificant. Patients with non-aberrant biomarker expression levels have much higher survival rates than the cases with aberrant expression. Low expression levels of Ki-67 and high expression levels of E-cadherin positively affect survival of patients, whereas aberrant expressions pose poorer prognosis (Tab. 2, Fig. 2, Ref. 33).


Hsa-miR-10a-5p downregulation in mutant UQCRB-expressing cells promotes the cholesterol biosynthesis pathway.
Ubiquinol cytochrome c reductase binding protein (UQCRB) is known to play crucial roles in the development of various types of diseases. However, the link between UQCRB and microRNAs remains unknown. In the present study, we performed microRNA sequencing of mutant UQCRB-expressing stable cell lines that exhibited pro-oncogenic activities caused by expression of the mutant UQCRB gene. Results showed that hsa-miR-10a-5p was significantly downregulated in the mutant UQCRB-expressing cell lines. Furthermore, mRNA sequencing and gene ontology analysis of differentially expressed genes (DEGs) revealed that the cholesterol biosynthesis pathway might be activation by mutant UQCRB expression. Moreover, inhibition of cholesterol synthesis in mutant UQCRB-expressing cells via treatment with the specific inhibitors suppressed the cell proliferation. Transfection with a hsa-miR-10a-5p mimic validated that lanosterol synthase (LSS) is a target of hsa-miR-10a-5p. In addition, hsa-miR-10a-5p was found to be downregulated in liver cancer cell lines overexpressing UQCRB. Taken together, our findings highlighted the potential use of hsa-miR-10a-5p as a biomarker for UQCRB related diseases.


Employing Multiple Mini Interviews in Selection Processes for Psychology Professional Training Programs: Ten Tips for Effective Implementation.
This article was migrated. The article was marked as recommended. In Australia and internationally, entry into many professional psychology training programs is highly competitive, and as a duty of care to the public, training institutions must seek to offer places to those best-suited to training to become a psychologist. Typically, part of this selection process involves an interview. While panel interviews have been widely utilised, recently, in a range of health disciplines, these have been substituted for multiple mini interviews (MMIs) with evidence for their acceptability, validity and reliability. There is limited research on the use of MMIs in psychology professional training selection processes. We have used this approach for three years to select approximately 100 trainees for Clinical, Health and Organisational and Human Factors postgraduate psychology training programs. Based on our experience and feedback from applicants, we provide information that suggests this selection method is well-received by applicants. We also provide ten tips on how to effectively implement this approach to determine those most suitable for further training.


Field epidemiology training programs contribute to COVID-19 preparedness and response globally.
Field epidemiology training programs (FETPs) have trained field epidemiologists who strengthen global capacities for surveillance and response to public health threats. We describe how FETP residents and graduates have contributed to COVID-19 preparedness and response globally. We conducted a cross-sectional survey of FETPs between March 13 and April 15, 2020 to understand how FETP residents or graduates were contributing to COVID-19 response activities. The survey tool was structured around the eight Pillars of the World Health Organization's (WHO) Strategic Preparedness and Response Plan for COVID-19. We used descriptive statistics to summarize quantitative results and content analysis for qualitative data. Among 88 invited programs, 65 (74%) responded and indicated that FETP residents and graduates have engaged in the COVID-19 response across all six WHO regions. Response efforts focused on country-level coordination (98%), surveillance, rapid response teams, case investigations (97%), activities at points of entry (92%), and risk communication and community engagement (82%). Descriptions of FETP contributions to COVID-19 preparedness and response are categorized into seven main themes: conducting epidemiological activities, managing logistics and coordination, leading risk communication efforts, providing guidance, supporting surveillance activities, training and developing the workforce, and holding leadership positions. Our findings demonstrate the value of FETPs in responding to public health threats like COVID-19. This program provides critical assistance to countries' COVID-19 response efforts but also enhances epidemiologic workforce capacity, public health emergency infrastructure and helps ensure global health security as prescribed in the WHO's International Health Regulations.


[Effect of fetal behavioral reactions and respiratory movements on the blood flow in the ductus arteriosus].
Relationship between blood flow velocity waveform and fetal behavioral states was studied in 16 normal pregnancies at 37 to 38 weeks' gestation. The peak flow velocity has demonstrated a statistically significant reduction during active sleep, as against that in quite sleep. These data reflect reduced ductal flow and suggest a redistribution in the left-ventricular and right-ventricular output in favor of the left side of the heart during active sleep. In a prospective cross-sectional study of 49 pregnancies (50 fetuses) between 25th and 38th weeks an exponential increase in breathing-related ductal blood flow velocity modulation was observed with advancing gestational age, reflecting the developing pulmonary vascular bed. Fetal ductal flow velocity waveforms were also recorded in 13 cases of prolonged severe oligohydramnios after membrane rupture before 28 weeks' gestation. Normal ductal blood flow velocity modulation values were associated with normal neonatal lung performance, whereas reduced blood flow velocity modulation values were associated with pulmonary hypoplasia. Fetal breathing-related ductal flow velocity modulation appears to be a promising predictor of neonatal lung performance.


Motivational Interviewing to promote self-awareness and engagement in rehabilitation following acquired brain injury: A conceptual review.
The benefits of rehabilitation following acquired brain injury (ABI) are all too often disrupted by a lack of engagement in the process, variously attributed to cognitive, emotional and neurobehavioural sequelae, and prominently to impaired self-awareness of deficits. Motivational Interviewing (MI) has been widely applied to address treatment adherence in health settings, including a small but emerging evidence base in brain injury contexts. A conceptual review of the literature is offered, examining the interplay of neurological and psychosocial determinants of engagement difficulties after ABI, and discussing the possibilities and limitations of MI as a therapeutic strategy to enhance motivation. The theoretical bases of MI are outlined, focusing particularly on the transtheoretical stages of change model and self-determination theory. The converging evidence suggests that the guiding philosophy and principles of MI - characterised by non-confrontation, collaboration and self-efficacy - might help to foster readiness for participation in rehabilitation. A dynamic motivational model of engagement is presented, identifying MI's potential contribution in three key areas: firstly, to set the stage for therapeutic alliance and case formulation; secondly, to facilitate acceptance of deficits and realistic goal-setting; and thirdly, to promote constructive engagement in the range of clinical interventions that comprise a holistic neurorehabilitation programme.


Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.
The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.


Perioperative safety of simultaneous off-pump coronary artery bypass grafting with non-cardiac surgery of moderate-to-severe severity.
To evaluate the perioperative safety of simultaneous off-pump coronary artery bypass grafting (OPCABG) with non-cardiac surgery. From September 2013 to January 2019, patients who underwent OPCABG surgery in the Department of Cardiology, Peking University First Hospital were included in this retrospective study. A total of 54 patients who underwent simultaneous surgery were defined as simultaneous surgery group. A total of 108 patients who had recently undergone isolated OPCABG surgery, and had similar vascular reconstruction methods were selected for matching, and these patients were defined as the OPCABG group. The general data and laboratory indicators were detected and were used as baseline data, and the EuroSCORE II scoring system was used to evaluate the surgical risk of patients based on these data. During surgery, intraoperative indicators were assessed and evaluated during surgery. In addition, evaluation of postoperative indicators was performed, including mechanical ventilation time, residence time in ICU, and proportion of perioperative myocardial infarction, perioperative stroke, postoperative renal failure, and surgical wound infection. All the combined non-cardiac surgeries were assessed to be of moderate-to-severe grade by operative severity scoring system. The analysis of intraoperative indicators showed that there were no significant differences in proportion of emergency or urgent surgery, cases of arterial and venous anastomosis, and proportion of intraoperative blood transfusion between two groups (P > 0.05). Meanwhile, the values of operation time and intraoperative blood loss of patients in simultaneous surgery group were significantly higher than that in OPCABG group (P < 0.05). No perioperative death events occurred in this study. In terms of postoperative indicators, the values of operation duration and intraoperative blood loss of patients in simultaneous surgery group were significantly higher than that in OPCABG group (P < 0.05). Simultaneous OPCABG surgery with non-cardiac surgeries of moderate-to-severe severity may not be associated with increased postoperative risks when compared with isolated OPCABG.


[Neuropsychological study of the schizophrenic defect].
As many as 30 patients (18 men and 12 women) aged 17 to 47 years were examined. Use was made of A. R. Luria's method. Deficiency of both activation components of the activity and higher form of regulation was recorded in all the cases. 3 variants of the neuropsychological syndrome were distinguished. The first variant was characterized by insufficiency of the function of the nonspecific brain systems, primarily of the medial formations of the frontal lobes. The second variant was marked by dyscoordination of the ++fronto-subcortical relations associated with the weakening of the functions of the primarily prefrontal convex formations of the frontal lobes. The third variant was determined by remarkable insufficiency of the convex formations of the frontal lobes and parietotemporal and occipital parts of the brain. A high correlation was discovered (r = +0.75) between the intensity of neuropsychological disorders and the magnitude of anergy. Comparison of the results with the computer-aided tomography (CT) data did not reveal any differences between the groups. However, in the third group patients, grosser changes on the CT were found. The same group manifested significant accumulation of pre-, peri-, and postnatal harm.


Total synthesis of (+/-)-gleenol and (+/-)-axenol via a functionalized spiro[4.5]decane.
Total synthesis of the biologically important axane sesquiterpenes, gleenol (1) and axenol (2), was accomplished through a readily available spiro[4.5]decane. The key features of the synthesis of 1 and 2 include Claisen rearrangement to afford the multi-functionalized spiro[4.5]decane 4 as a single diastereomer in excellent yield, installation of the C7 isopropyl group via ketene dithioacetal instead of direct alkylation and a diastereoselective reduction of ketone under the Birch conditions.


Ganirelix for luteolysis in poor responder patients undergoing IVF treatment: a Scandinavian multicenter 'extended pilot study'.
To enhance oocyte yield and pregnancy outcome in poor responder women undergoing IVF treatment, daily low dose GnRH antagonist administration was given during the late luteal phase to induce luteolysis and possibly secure a more synchronous cohort of recruitable follicles. An open extended pilot study in four Scandinavian fertility centers was done including 60 patients. Poor response was defined as when < or = 5 follicles developed in a preceding cycle following a long agonist protocol with the use of > 2000 IU FSH. GnRH antagonist (ganirelix) was given, 0.25 mg s.c. daily, from days 3 to 5 before expected start of menstruation and continued for 4-7 days. On cycle day 2-3 a starting dose of rFSH (300-400 IU/day) was given. At a leading follicle diameter of 14 mm, ganirelix administration was resumed until final oocyte maturation was induced with 10,000 IU hCG. GnRH antagonist only marginally affected the intercycle FSH rise; basal levels of FSH remained similar to those seen after 4 days of antagonist administration. The protocol effectively induced low LH levels and luteolysis, but daily administration of 350 IU rFSH (median) for 11 days only led to the collection of 3 oocytes in 49 oocyte retrievals resulting in 5 pregnancies (4 delivered). Despite GnRH antagonist administration in the late luteal phase and menstrual bleeding, FSH was not sufficiently reduced to secure a more synchronic cohort of recruitable follicles. Novel GnRH antagonists more specifically targeting FSH release may improve the stimulation results in poor responders.


Febrile response after knee and hip arthroplasty.
Documentation of the normal fever response after total knee and hip replacement is important to avoid an unnecessary workup for sepsis, and to provide justification for early discharge (dictated by the current medical reimbursement climate) despite persistent postoperative fever. One hundred patients who underwent total knee arthroplasty and 100 patients who underwent total hip arthroplasty were reviewed, several of whom had extensive sepsis workups for evaluation of postoperative fever. No patient in this series had a documented joint infection. All patients were treated with warfarin for deep vein thombrosis prophylaxis. All patients used incentive spirometry and were started on ambulation training on postoperative Day 1. All were given antibiotic prophylaxis for 48 hours. The maximum daily postoperative temperature occurred in most patients on postoperative Day 1 and gradually leveled off toward normal by postoperative Day 5. Only one patient had a maximum temperature on postoperative Day 4 that was greater than that on postoperative Day 3. Patients undergoing revision procedures tended to have a more pronounced febrile response, but the differences were not statistically significant. No significant differences were seen between patients who had epidural anesthesia and patients who had general anesthesia. Seventeen patients had postoperative chest radiographs for evaluation of fever. None had significant atelectasis. The presence of a positive urine culture had no effect on the fever response, with most positive results being identified after the fever had returned toward normal. Postoperative fever after total joint arthroplasty is a normal inflammatory response. A workup for sepsis is not indicated in the perioperative period unless corroborating signs or symptoms are present. Early discharge is appropriate if the febrile response is decreasing progressively.