Extension of the Kendrick Mass Defect Analysis of Homopolymers to Low Resolution and High Mass Range Mass Spectra Using Fractional Base Units.
Beyond the high resolution/low mass range data traditionally used, a Kendrick mass defect analysis (KMD) using the new concept of fractional base units has been successfully conducted on low resolution/low mass range and high resolution/high mass range data for the first time. Relying on a mathematical framework to rationalize the effect of the fractional base units, the electrospray ionization single stage and multistage mass spectra of a poly(vinylpyrrolidone) recorded from a low resolution ion trap analyzer were turned into information-rich KMD plots using vinylpyrrolidone/112 and pyrrolidone/86 as base units. The distributions detected in the matrix assisted laser desorption ionization spiralTOF mass spectra of high molecular weight poly(ethylene oxide) and poly(caprolactone) were conveniently discriminated in KMD plots using (ethylene oxide)/45 and caprolactone/113 as base units with an unprecedented resolution at such a mass range. The high resolution KMD analysis using fractional base units opens new perspectives for the acquisition, visualization, and presentation of mass spectra of polymers with less restrictions in terms of required resolution and molecular weights.


A dose-related curve of wound tensile strength following ultraviolet irradiation in the hairless guinea pig.
A dose-related curve of wound tensile strength was derived following exposure to three doses of predominantly UVA (Ultraviolet A) radiation (98.3% between 315 nm and 400 nm, 1.7% less than 315 nm). Forty female hairless guinea pigs were divided into four equal groups: Group 1 (controls); Group 2 (40 J[Joules]/cm2/day); Group 3 (80 J/cm2); and Group 4 (160 J/cm2). Preoperatively, the experimental groups were irradiated on alternate days for 16 weeks. Serial dorsal punch biopsies (4 mm) were taken prior to the initial exposure and subsequently at 2, 4, 8, 12, and 16 weeks and examined histologically and microscopically. Then, standard 6 cm midline dorsal surgical wounds were made and allowed to heal for 21 days. Wounds were excised and wound tensile strength was assessed. Significant decreases (p less than .05) were noted in wound tensile strength of Groups 2, 3, and 4 compared to the controls, with the decrease being directly related to the dose received. Dermal changes were noted in all irradiated groups as early as four weeks after initial UVA/B exposure. Electron microscopy revealed elastosis and disruption of collagen fibers. Prolonged exposure to radiation, predominantly in the UVA range, appears to impede wound healing in a dose-related fashion and elicits elastosis and collagen disruption.


Crystal structure of diferric hen ovotransferrin at 2.4 A resolution.
The three-dimensional structure of diferric hen ovotransferrin has been determined by X-ray crystallography at 2.4 A resolution. The structure was solved by molecular replacement, using the coordinates of diferric human lactoferrin as a search model. Several rounds of simulated annealing and restrained least-squares refinement have resulted in a model structure with an R-factor of 0.171 for the data between 11.0 and 2.4 A resolution. The model comprises 5284 protein atoms (residues 5 to 686), 2 Fe3+, 2 CO3(2)- and 132 water molecules. The overall structure of ovotransferrin is similar to those of human lactoferrin and rabbit serum transferrin, being folded into two homologous lobes, each containing two dissimilar domains with one Fe3+ and one CO3(2)- bound at a specific site in each interdomain cleft. However, the relative orientation of the two lobes, which may be related to the class specificity of transferrins to receptors, is different from either human lactoferrin or rabbit serum transferrin. The angle of the relative orientation in ovotransferrin is increased by 6.8 degrees and 15.7 degrees as compared with to those in rabbit serum transferrin and human lactoferrin, respectively. Interdomain Lys209-Lys301 and Gln541-Lys638 interactions are found near the metal binding site of each lobe. The interlobe interactions and their role in the stabilization of iron binding are discussed.


Development of needs-based quality of life instruments.
The methods employed in the development of needs-based quality of life (QoL) instruments have evolved with time as advances have been made in the field of psychometrics and as experience has grown. This paper illustrates the current instrument development methodology with reference to three needs-based QoL measures recently developed for use in dermatology: the Quality of Life Index for Atopic Dermatitis (QoLIAD); the Psoriasis Index of Quality of Life (PSORIQoL); and the Parents' Index of Quality of Life-Atopic Dermatitis (PIQoL-AD).


A Bednar tumor in a healthy woman.
A Bednar tumor (BT) is a soft tissue sarcoma that mimics neurofibroma and rarely occurs in the deeper layers of the skin. Local recurrence of BT is possible with incomplete resection, but the occurrence of distant metastasis is rare.


Psychotropic medication use in children and adolescents in an inpatient setting.
Medication can be an effective part of treatment for several psychiatric disorders of childhood and adolescence but its use should be based on a comprehensive psychiatric evaluation and treatment plan. The aim of this study was to evaluate psychotropic medication use for children and adolescents treated as inpatients and to compare it with principles of rational pharmacotherapy, thus identifying possible downsides of current practices and pointing a way towards safer and more efficient practices. This is a descriptive study of prescribing trends at the Clinical Department for Children and Adolescents of the Institute of Mental Health in Belgrade, during the period from September 2009 to September 2010. Analyzed demographic data (age, gender) and the number of hospitalizations were obtained from medical histories, while diagnoses were obtained from discharge notes. Prescribed therapy was copied from medication charts. Drug dosages were analyzed as average daily doses prescribed during the hospitalization. Psychiatric diagnoses were classified according to The International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). During the examined time period, 264 patients were hospitalized (61.4% males), with an average age of 11.4±5.1 years. We have found that 66.3% of admitted patients were treated with pharmacotherapy in addition to other treatment modalities. There was a highly significant correlation between the age of patients and the prescribed dosage (Spearman's rho=0.360, p<0.001) as well as the number of prescribed drugs (Spearman's rho=0.405, p<0.001). The most commonly diagnosed psychiatric disorders were: autism spectrum disorders (20.8%), conduct disorders(19.7%), mixed developmental disorder (14.8%), adjustment disorder (7.2%), mental retardation (7.2%),acute psychosis (4.5%), and ADHD (2.3%). The most commonly prescribed medications were antipsychotics(45.9%), followed by antidepressants (17.2%), mood stabilizers (16.1%), benzodiazepines (14.4%), and other psychotropic drugs (6.4%). The most commonly prescribed antipsychotic was risperidone, used for more than 50% of the patients treated with antipsychotics. Taken together risperidone and chlorpromazine were more than 75% of all prescribed antipsychotics. 98.4% of prescribed antidepressants belonged to the SSRIs,with sertraline and fluoxetine accounting for almost 90% of them. All prescribed dosages were in accordance with the official guidelines. This is the first survey in Serbia to document the practice of prescribing psychotropic medication in the field of child and adolescent psychiatry. Current drug-prescribing practices at the Clinical Department for Children and Adolescents of the Institute of Mental Health in Belgrade are in accordance with current practices in the United States and Europe. Not every child with symptoms of mental health problems needs pharmacological treatment; when they do, the general rule of thumb should be "start low, go slow, and taper slowly". Follow-up studies are necessary to assess the change of trends, as well as studies in different patient populations and health centers, in order to globally evaluate psychotropic medication use in children and adolescents in Serbia.


Molecular determinants of the cytotoxicity of platinum compounds: the contribution of in silico research.
Gene expression profiling of tumors allows the establishment of relationships between gene expression profiles and sensitivity to anticancer drugs. In an attempt to study the molecular determinants of the activity of platinum compounds, we explored the publicly available databases of the National Cancer Institute (NCI; http://dtp.nci.nih.gov), which allow access to the gene expression profiles of the 60 cell lines for which drug cytotoxicity patterns already existed. Using this database, we have conducted an in silico research to identify the genes the expression of which was positively or negatively correlated to the sensitivity to four platinum compounds (cisplatin, carboplatin, oxaliplatin and tetraplatin). Important similarities were noticed between cisplatin and carboplatin on one hand, and tetraplatin and oxaliplatin on the other hand. In the restricted panel of 1416 genes and molecular markers, we identified 204 markers, among which 120 corresponded to identified genes, that significantly correlated (P < 0.001) with the cytotoxicity of at least one platinum compound. For example, the functionality of the p53-activated pathway appeared positively correlated with the cytotoxicity of all platinum compounds. More specific are the positive correlations between RAS gene mutations and MYC expression and the cellular sensitivity to oxaliplatin. Among the parameters already known as related to the sensitivity to platinum compounds, we identified, in the complete set of 9400 genes, numerous significant relationships, such as the negative correlations between ERB-B2 and BCL-X(L) expressions and the cytotoxicity of the platinum compounds. Public databases mining, therefore, appears to be a valuable tool for the identification of determinants of anticancer drug activity in tumors.


Human transforming growth factor-beta activates a receptor serine/threonine kinase from the intravascular parasite Schistosoma mansoni.
The biology of the helminth parasite Schistosoma mansoni is closely integrated with that of its mammalian host. SmRK1, a divergent type I transforming growth factor-beta (TGF-beta) receptor of unknown ligand specificity, was previously identified as a candidate for a receptor that allows schistosomes to respond to host-derived growth factors. The TGF-beta family includes activin, bone morphogenetic proteins (BMPs), and TGF-beta, all of which can play crucial roles in metazoan development. The downstream signaling protein of receptors that respond to TGF-beta and activin is Smad2, whereas the receptors that respond to BMPs signal via Smad1. When a constitutively active mutant of SmRK1 was overexpressed with either schistosome Smad1 (SmSmad1) or SmSmad2, a receptor-dependent modulation of SmSmad phosphorylation and luciferase reporter activity occurred only with SmSmad2. To evaluate potential ligand activators of SmRK1, a chimeric receptor containing the extracellular domain of SmRK1 joined to the intracellular domain of the human type I TGF-beta receptor was used. The chimeric receptor bound radiolabeled TGF-beta and could activate a luciferase reporter gene in response to both TGF-beta 1 and TGF-beta 3 but not BMP7. Confirmatory results were obtained using full-length SmRK1. These experiments implicate TGF-beta as a ligand for SmRK1 and as a potential host-derived regulator of parasite growth and development.


DNA histogram debris theory and compensation.
In this paper we describe a theory of DNA histogram debris generation and compensation that can be applied to paraffin-embedded frozen tissue preparations. The theory predicts the distribution of fragments generated from single and multiple random sectioning of three-dimensional ellipsoids representing nuclei. The fragment distribution is assumed to be a major component of the underlying debris in DNA histograms. A comparison of S-phase fractions (SPF) from matched tissue prepared by frozen and formalin-fixed paraffin-embedded DNA methods demonstrates the usefulness of the theory.


Sport Mega-Events and Displacement of Host Community Residents: A Systematic Review.
The aim of this study was to conduct a systematic literature review to understand how empirical data have informed the knowledge about the relationship between hosting sport mega-events and displacement of host community residents. Following the PRISMA protocol, we conducted a search of academic and gray literature in sport, social sciences, and humanities databases. We excluded conceptual papers, conference abstracts, and works that discuss urban transformation or displacement but are not related to sport events. We also excluded works that associate sport mega-events with urban transformations but are not related to resident displacement. From the initial 2,372 works reviewed, 22 met the inclusion criteria. In empirical studies, displacement of residents has been studied exclusively in the context of the Olympic Games, since Seoul 1988, but with a higher frequency in most recent Games (Beijing, London, and Rio). The gigantism and the sense of urgency created by the Olympic Games may explain why this event has been frequently associated with resident displacement. Findings showed that residents suffered either direct, forced evictions or indirect displacements. The selected studies show a contradiction between the discourse of sport mega-events guardians for supporting the United Nations Sustainable Goals (SDG) and the practice of human rights within host cities of such events.


[Concentrations of persistent toxic compounds in the Spanish population: a puzzle without pieces and the protection of public health].
The contamination by persistent toxic compounds (PTCs) of the general population is a fact of relevance from a public health perspective. It is also relevant to health care professionals, as well as for environmental, food, industrial and economic policies. Though in Spain information on food contamination by PTCs shows large time and geographic gaps, the scarcity of data is even more severe on the concentrations that PTCs have in people: a representative study of a general healthy population living in a wide geographic area has never been conducted in the country. However, the available studies indicate that around 80-100% of the population has detectable concentrations of DDE, PCBs, hexachlorbenzene or lindane. Studies on the effects that PTCs have upon humans are extremely infrequent in Spain. Yet, the international literature suggests that some PTCs may induce significant biological and clinical effects at doses below those traditionally deemed "safe". The mechanism of action of PTCs are not restricted to endocrine disruption. Assessing the clinical and social relevance of the more subtle and long-term effects of PTCs presents interesting challenges and opportunities. Spain and other European countries lack population indicators on the impact that environmental processes have on human health. Several government levels have a role to fulfill in the monitoring of biological levels of PTCs among persons in order to assess the risks of adverse health effects. Along with over a hundred other countries. Spain will soon try to implement the Stockholm treaty on persistent organic pollutants (POPs). This constitutes a new opportunity to develop more efficient policies to control PTC residues in food, humans and the environment. As part of the treaty implementation it is necessary to launch a Report on factors that influence body concentrations of PTCs in the Spain general population.


New top-down approach for fabricating high-aspect-ratio complex nanostructures with 10 nm scale features.
We describe a new patterning technique, named "secondary sputtering lithography" that enables fabrication of ultrahigh-resolution (ca. 10 nm) and high aspect ratio (ca. 15) patterns of three-dimensional various shapes. In this methodology, target materials are etched and deposited onto the side surface of a prepatterned polymer by using low Ar ion bombarding energies, based on the angular distribution of target particles by ion-beam bombardment. After removal of the prepatterned polymer, high aspect ratios and high-resolution patterns of target materials are created.


Effect of housing tenure on fertility.
"This article used the 1984 Canadian Fertility Survey data to examine the effects of housing tenure and a number of sociodemographic and economic factors (e.g., education, religion, income) on both completed fertility and selected parity progression. Results showed a statistically significant positive effect of housing tenure on completed fertility.... Age at marriage, education, religiosity, nativity, and region of residence were highly associated with completed fertility. Housing tenure effects on the parity progression were similar in pattern, although statistically significant effect occurred only in the progression from two to three children. Furthermore, religious attendance was found to increase the likelihood of higher order births among Canadian women."


Amelioration of small bowel injury by switching from nonselective nonsteroidal anti-inflammatory drugs to celecoxib in rheumatoid arthritis patients: a pilot study.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in patients with rheumatoid arthritis (RA) but have several side effects including mucosal damage in the small intestine. We aimed to evaluate whether the small bowel injury is ameliorated by switching from nonselective NSAIDs to celecoxib in patients with RA. Sixteen patients with RA who were treated with nonselective NSAIDs were enrolled in this study. Nonselective NSAIDs were converted to celecoxib for 12 weeks. Capsule endoscopy was performed before and after treatment with celecoxib. Videos were screened by gastroenterologists blinded to the patients' treatment. Before the administration of celecoxib, reddened folds, denuded areas, petechiae/red spots and mucosal breaks were observed in 63, 63, 88 and 69% of the patients, respectively. In the 14 patients who completed this study, conversion to celecoxib significantly reduced the number of petechiae/red spots, the number of mucosal breaks, and Lewis scores. RA activity and cytokine levels in the peripheral blood were not significantly different before and after treatment with celecoxib. The incidence of small bowel injury by nonselective NSAIDs is high in patients with RA. Conversion from nonselective NSAIDs to celecoxib can be useful for protecting patients with RA from small bowel injury.


Mass spectrometric analytical methods for the determination of endocrine disrupting chemicals (EDCs).
This paper describes a method for the determination of endocrine disrupting chemicals (EDCs) in waste water. The method involves a SPE-C18 extraction followed by a SPE-silica gel column clean up and elution of the analytes with a mixture of acetone/pentane (2+1). Thereafter derivatisation of the analytes with heptafluorobutyric acid anhydride (HFBA) and analysis by gas chromatography/mass spectrometry (GC/MS) with positive electron impact ionisation (EI) or negative chemical ionisation (NCI) using methane as reactant gas was performed. The two different ionisation techniques were compared and the negative chemical ionisation technique proved significant lower limits of detection (LODs) and quantitation (LOQs) than positive electron impact ionisation. Recoveries of the analytes in various spiked waste water samples ranged from 75.4 to 96.9%. The concentrations of the EDCs in feed waste water from three different waste water treatment plants (WWTPs) ranged from non-detectable up to a concentration of 10,305 ng/L for 4-NP and in the corresponding effluent samples from non-detectable to 723 ng/L for BPA.


A case of achondroplasia with severe pulmonary hypertension due to obstructive sleep apnea.
Achondroplasia is the most common skeletal dysplasia in children. Achondroplasic patients have a short cranial face and midface hypoplasia. They often have sleep-related respiratory disturbances that lead to hypoxemia caused by midfacial hypoplasia, a small upper airway, hypotonia of airway muscles, or brain stem compression. It has been well described that obstructive sleep apnea can cause pulmonary hypertension (PH) through the mechanism of chronic hypoxemia. However, severe PH due to obstructive-type sleep disorder is rare in patients with achondroplasia. In this report, we describe a 5-year-old girl with achondroplasia whose severe PH was caused by upper-airway obstruction and was resolved gradually after adenotonsillectomy.


Rapid LC-MS Determination of Acromelic Acids A and B, Toxic Constituents of the Mushroom Paralepistopsis acromelalga.
A rapid LC-MS method was developed for determination of acromelic acids A and B, which are toxic constituents of Paralepistopsis acromelalga (=Clitocybe acromelalga), in mushroom samples. Acromelic acids were extracted twice with 50% methanol and the extract was passed through a syringe filter, and then analyzed by LC-MS. The LC separation was performed on a multi-mode ODS column. The recoveries of acromelic acids A and B spiked into blank mushroom samples at 2.5 μg/g were 93 and 74%, respectively. This method was applied to the remaining mushroom sample from a food poisoning case. Acromelic acids A and B were detected at 2.0 and 1.4 μg/g, respectively, in the remaining sample. Another toxic constituent, which appeared to be clitidine, was also detected in the sample.


Dielectric response of electric-field distortions of the twist-bend nematic phase for LC dimers.
Wide band dielectric spectroscopy of bent-shaped achiral liquid-crystal dimers 1″-n″-bis(4-cyanobiphenyl-4'-yl) n-alkanes (CBnCB n = 7, 9, 11) has been investigated in a frequency range 0.1 Hz-100 MHz using planar-aligned cells of sample thicknesses ranging from 2 to 10 (μm) over a temperature range that covers both nematic and twist bend nematic phases. Two peaks in the dielectric spectrum in the higher frequency range are assigned to the molecular relaxation processes. The peak at the highest frequency, ∼40 to 80 MHz, is assigned to an internal precessional rotation of a single unit of the dimer around the director. The mode in the next lower frequency range of 2-10 MHz is assigned to the spinning rotation of the dimer around its long axis. This involves fluctuations of the dipole moment of the bent-shaped conformation that is directed along its arrow direction of the bow shape formed by the dimer. The peak in the frequency range 100 kHz-1 MHz can be assigned to the collective fluctuations of the local director with reference to the helical axis of the NTB structure. The dependence of its frequency on temperature is reminiscent of the soft mode observed at the SmA* to SmC* phase transition. This result clearly corresponds to the electro-clinic effect-the response of the director to the applied electric field in an electro-optic experiment. The lowest frequency mode, observed in the frequency range of 0.1 Hz-100 Hz, is identified with the Goldstone mode. This mode is concerned with the long range azimuthal angle fluctuations of the local director. This leads to an alternating compression and expansion of the periodic structure of the NTB phase.


Anticancer activity of Voacangine against human oral cancer cells is due to G2/M cell cycle arrest, ROS-mediated cell death and inhibition of PI3K/AKT signalling pathway.
Oral cancer is the 6th most prevalent type of cancer and is responsible for high human morbidity and mortality. The present study was designed to investigate the anticancer effects of Voacangine against human oral cancer and to decipher the underlying molecular mechanisms responsible for its anticancer properties. CCC-1 oral cancer cell line and normal hTRET-OME cell line were used in this study. Cell viability was determined by MTT assay. Acridine orange (AO)/ ethidium bromide (EB) and annexin V/propidium iodide (PI) assay were used for assessment of apoptosis. Cell cycle analysis and reactive oxygen species (ROS) determination was done by flow cytometry. The protein expression was determined by western blot analysis. The results showed that Voacangine caused a remarkable decline in proliferation of SCC-1 human oral cancer cells with negligible toxic effects on the normal human hTRET-OME cells. The IC50 of Voacangine was 9 µM against SCC-1 cells relative to IC50 of 100 µM against normal hTRET-OME cells. The reduction of the proliferative rates was attributed to the induction of ROS triggered apoptosis which was associated with activation of Caspase-3, upregulation of Bax and suppression of Bcl-2. Voacangine induced G2/M cell cycle arrest in a dose-dependent manner. Additionally, the anticancer effects of Voacangine on oral cancer cells were exerted through the inhibition of PI3K/AKT signaling cascade. Taken all together, we conclude that Voacangine is a potent anticancer molecule and may be utilized for the development of systemic therapy for oral cancer.


Negative polysomnogram in patients with obstructive sleep apnea syndrome.
We evaluated the possibility that in some patients with obstructive sleep apnea, the initial polysomnogram may be negative. We reviewed polysomnograms performed at the Medical College of Georgia from 1984 to 1990 and found nine patients whose initial polysomnogram was negative but whose repeat polysomnogram confirmed obstructive sleep apnea. All nine patients (five women and four men; average age, 44.2 years) had an apnea index of less than 5 (fewer than five apneic episodes per hour) and had a total of fewer than 20 apneic episodes during the initial overnight polysomnogram. The change in average weight was not significant. Three patients had received short-term oxygen therapy, and two of these three received nasal continuous positive airway pressure prior to the initial study. The time that patients spent supine increased from 101 min in the initial study to 180 min in the second, but this was not significant (p = 0.12). Comparison of the initial and diagnostic polysomnograms showed significantly reduced total sleep time (from 3.75 +/- 1.84 h to 5.32 +/- 1.11 h; p = 0.04) and reduced rapid eye movement (REM) sleep time (from 0.27 +/- 0.27 h to 0.75 +/- 0.58 h; p = 0.037) in the initial study. We conclude that in a small subset of patients with obstructive sleep apnea, the initial polysomnogram may be falsely negative, which could be due to previous therapy, a reduction in total sleep time and REM sleep, or other unidentified factors.


The histopathological effects of the CO2 versus the KTP laser on the brain and spinal cord: a canine model.
Because no data are available concerning the histopathological effects of the potassium titanyl phosphate (KTP) laser on central nervous tissue, a study was performed using a canine model to compare the histopathological effects of a commonly used laser (CO2) and the KTP laser on brain and spinal cord tissue. Exposed brain and spinal cord tissue were irradiated with 0.1-s pulses (x10), with spot sizes of 1 mm (in focus) over a range of 1 to 10 W. Wedge-shaped lesions were produced with the CO2 laser, while more blunt, semilunar-shaped lesions were produced by the KTP laser. The depth and width of the lesions were proportional to the energy applied. The lesions ranged in surface diameter from 0.6 to 1.3 mm for CO2 and 0.8 to 1.6 mm for KTP lasers, respectively. The depth of the lesions varied from 0.4 to 2.0 mm for CO2 and 0.3 to 1.1 mm for KTP lesions. Histopathologically, a central zone of tissue destruction and vaporization was surrounded by a zone of coagulative necrosis, in turn surrounded peripherally by a zone of pallor. CO2-induced lesions were histologically more hemorrhagic than KTP-induced lesions. In view of the histopathological findings, the KTP laser appears as safe as the CO2 laser in terms of tissue lateral thermal change (penetration) and tissue absorption. The additional hemostatic advantage observed clinically for the KTP laser is demonstrated histologically as well. Although the wavelength of the KTP and argon laser light are similar, the histopathological effects seem to be less pigment dependent. The KTP laser seems well suited for neurosurgery and has the versatility provided by a fiberoptic delivery system.


Circular DNA intermediate in the duplication of Nile tilapia vasa genes.
vasa is a highly conserved RNA helicase involved in animal germ cell development. Among vertebrate species, it is typically present as a single copy per genome. Here we report the isolation and sequencing of BAC clones for Nile tilapia vasa genes. Contrary to a previous report that Nile tilapia have a single copy of the vasa gene, we find evidence for at least three vasa gene loci. The vasa gene locus was duplicated from the original site and integrated into two distant novel sites. For one of these insertions we find evidence that the duplication was mediated by a circular DNA intermediate. This mechanism of gene duplication may explain the origin of isolated gene duplicates during the evolution of fish genomes. These data provide a foundation for studying the role of multiple vasa genes in the development of tilapia gonads, and will contribute to investigations of the molecular mechanisms of sex determination and evolution in cichlid fishes.


Al2O3:Cr3+ nanotubes synthesized via homogenization precipitation followed by heat treatment.
Cr3+-doped NH4Al(OH)2CO3 nanotubes, templated by surfactant assemblies, were successfully synthesized via the homogenization precipitation method, and various crystallographic phase Al2O3:Cr3+ nanotubes were also obtained by postannealing at different temperatures. The characteristic R1, R2 doublet line transitions of ruby can be observed in the high crystalline alpha-Al2O3 nanotubes calcined at temperatures higher than 1200 degrees C. The results also indicate that the formation mechanism of the tubular nanostructures should result from the self-rolling action of layered compound NH4Al(OH)2CO3 under the assistance of the surfactant soft-template. The convenient synthetic procedure, excellent reproducibility, clean reactions, high yield, and fine quality of products in this work make the present route attractive and significant. Aluminum oxide nanotubes with high specific surface area could be used as fabricating nanosized optical devices doped with different elements and stable catalyst supports of metal clusters.


[Study on concentration quenching and energy transfer in Ln3+ (Ln = Tb, Tm, Eu) in Y2O3 nanocrystal powders].
Nano-powders Y2O3 with various particle sizes and different doping concentrations of Ln (Ln = Tb, Tm, Eu) were prepared by using a combustion technique. The bulky powders doped with concentrations corresponding to nano-powders were obtained by annealing the nano-powders at high temperature. The emission spectra, XRD spectra and TEM were used in the present study. The concentration quenching of luminescent centers and energy transfer between luminescent centers in Y2O3 : Ln nanocrystal powders were investigated. It was found that the behaviors of luminescence concentration quenching for 5D4 --> 7F5 : Tb3+ and 5D0 --> 7F2 : Eu3+ in nano-powders are similar to that in bulky powders. On the contrary, the quenching concentrations for 5D3 --> 7F5 : Tb3+ and 1D2 --> 3H4 : Tm3+ are distinctly higher than that in bulk powders. This owes to the size confinement effect: the interface of nanocrystal particles can stop a portion of the energy transfer, which happens in the bulk ones, between luminescent centers. The size confinement effect can bring different influences to the different types of energy transfer. For instance, it will restrain the energy transfer (governed by electric dipole-dipole interaction) between the ions in long distances, and will hardly affect the energy transfer (governed by exchange interaction) between the ions locating at near intervals.


Combination inhalers containing inhaled corticosteroids and long-acting beta2-agonists: improved clinical efficacy and dosing options in patients with asthma.
Combination therapy with inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is a recognized treatment for adults with moderate to severe asthma. The introduction of inhalers containing both an ICS and a LABA simplifies treatment and improves asthma control. This review discusses clinical evidence that budesonide/formoterol and salmeterol/fluticasone are effective and well tolerated in asthma treatment. Moreover, the rapid onset of effect and long duration of action of budesonide and formoterol make once-daily dosing, adjustable maintenance dosing, and the novel treatment strategy of using budesonide/formoterol for maintenance and as needed for symptom relief, valuable treatment options for patients with asthma.


Neuromuscular block: atracurium and vecuronium compared and combined.
The neuromuscular blocking action of atracurium and vecuronium acting separately and in combination have been compared using the evoked EMG of the adductor pollicis muscle. Dose response curves have been drawn for the drugs given separately and found to be nonparallel (P less than 0.05). Atracurium was calculated to be 5.25 and 4.1 times less potent than vecuronium, ED50 and ED95 respectively. The effect on neuromuscular transmission of a combined medication using equipotent doses of atracurium and vecuronium, determined from the dose response plots, was found to be greater than would be expected by addition of their separate actions. The combination of small doses resulted in significant neuromuscular blockade.


Wavy fronts in a hyperbolic FitzHugh-Nagumo system and the effects of cross diffusion.
We study a hyperbolic version of the FitzHugh-Nagumo (also known as the Bonhoeffer-van der Pol) reaction-diffusion system. To be able to obtain analytical results, we employ a piecewise linear approximation of the nonlinear kinetic term. The hyperbolic version is compared with the standard parabolic FitzHugh-Nagumo system. We completely describe the dynamics of wavefronts and discuss the properties of the speed equation. The nonequilibrium Ising-Bloch bifurcation of traveling fronts is found to occur in the hyperbolic case as well as in the parabolic system. Waves in the hyperbolic case typically propagate with lower speeds, in absolute value, than waves in the parabolic one. We find the interesting feature that the hyperbolic and parabolic front trajectories coincide in the phase plane for the FitzHugh-Nagumo model with a diagonal diffusion matrix, which is the case of self-diffusion, and differ for the system with cross diffusion.


Effects of spaceflight on rhesus quadrupedal locomotion after return to 1G.
Effects of spaceflight on Rhesus quadrupedal locomotion after return to 1G. Locomotor performance, activation patterns of the soleus (Sol), medial gastrocnemius (MG), vastus lateralis (VL), and tibialis anterior (TA) and MG tendon force during quadrupedal stepping were studied in adult Rhesus before and after 14 days of either spaceflight (n = 2) or flight simulation at 1G (n = 3). Flight simulation involved duplication of the spaceflight conditions and experimental protocol in a 1G environment. Postflight, but not postsimulation, electromyographic (EMG) recordings revealed clonus-like activity in all muscles. Compared with preflight, the cycle period and burst durations of the primary extensors (Sol, MG, and VL) tended to decrease postflight. These decreases were associated with shorter steps. The flexor (TA) EMG burst duration postflight was similar to preflight, whereas the burst amplitude was elevated. Consequently, the Sol:TA and MG:TA EMG amplitude ratios were lower following flight, reflecting a "flexor bias." Together, these alterations in mean EMG amplitudes reflect differential adaptations in motor-unit recruitment patterns of flexors and extensors as well as fast and slow motor pools. Shorter cycle period and burst durations persisted throughout the 20-day postflight testing period, whereas mean EMG returned to preflight levels by 17 days postflight. Compared with presimulation, the simulation group showed slight increases in the cycle period and burst durations of all muscles. Mean EMG amplitude decreased in the Sol, increased in the MG and VL, and was unchanged in the TA. Thus adaptations observed postsimulation were different from those observed postflight, indicating that there was a response unique to the microgravity environment, i.e., the modulations in the nervous system controlling locomotion cannot merely be attributed to restriction of movement but appear to be the result of changes in the interpretation of load-related proprioceptive feedback to the nervous system. Peak MG tendon force amplitudes were approximately two times greater post- compared with preflight or presimulation. Adaptations in tendon force and EMG amplitude ratios indicate that the nervous system undergoes a reorganization of the recruitment patterns biased toward an increased recruitment of fast versus slow motor units and flexor versus extensor muscles. Combined, these data indicate that some details of the control of motor pools during locomotion are dependent on the persistence of Earth's gravitational environment.


Activated Drosophila Ras1 is selectively suppressed by isoprenyl transferase inhibitors.
Ras CAAX (C = cysteine, A = aliphatic amino acid, and X = any amino acid) peptidomimetic inhibitors of farnesyl protein transferase suppress Ras-dependent cell transformation by preventing farnesylation of the Ras oncoprotein. These compounds are potential anticancer agents for tumors associated with Ras mutations. The peptidomimetic FTI-254 was tested for Ras1-inhibiting activity in whole animals by injection of activated Ras1val12 Drosophila larvae. FTI-254 decreased the ability of Ras1val12 to form supernumerary R7 photoreceptor cells in the compound eye of transformed flies. In contrast, it had no effect on the related supernumerary R7 phenotypes of flies transformed with either the activated sevenless receptor tyrosine kinase, Raf kinase, or a chimeric Ras1val12 protein that is membrane associated through myristylation instead of isoprenylation. Therefore, FTI-254 acts as an isoprenylation inhibitor to selectively inhibit Ras1val12 signaling activity in a whole-animal model system.


Olfactory function in patients with chronic rhinosinusitis before and after functional endoscopic sinus surgery.
The olfactory loss in patients with chronic rhinosinusitis has been measured by different methods. However, the results have been variable and it is not clear whether functional endoscopic sinus surgery (FESS) significantly improves olfactory function. This study was performed to evaluate the influences of FESS on olfactory function in patients with chronic rhinosinusitis using three different types of olfactory tests. Seventy patients with chronic rhinosinusitis were administered the University of Pennsylvania Smell Identification Test (UPSIT), a single staircase phenyl ethyl alcohol odor detection threshold test (STT), and a short-term odor memory/discrimination test a day before and 6 months after FESS. A questionnaire inquiring about the patients' self-perception of olfactory function was administered also. Independent ratings of the severity of chronic rhinosinusitis before FESS were established from CT scans. Fifty-two (74.3%) of the patients reported that their olfactory function was impaired before surgery, and 68.6% of the patients reported impaired olfactory function after surgery, a difference that was not significant. No meaningful changes in any of the olfactory test scores were noted 6 or more months after FESS. Preoperatively, small correlations between CT scores and the symptom scores (r = 0.278; p = 0.024), threshold scores (r = -0.27; p = 0.031), and UPSIT scores (r = -0.36; p = 0.003) were observed. In patients with severe rhinosinusitis, FESS had little impact on the ability to smell, regardless of the method for assessing smell function. Subtle associations between olfactory function and the severity of chronic rhinosinusitis determined by CT were observed, however, preoperatively. The olfactory test measures were correlated with one another both pre- and postoperatively.


Dissemination of multiple carbapenem-resistant clones of Acinetobacter baumannii in the Eastern District of Saudi Arabia.
It has previously been shown that carbapenem-resistant Acinetobacter baumannii are frequently detected in Saudi Arabia. The present study aimed to identify the epidemiology and distribution of antibiotic resistance determinants in these bacteria. A total of 83 A. baumannii isolates were typed by pulsed-field gel electrophoresis (PFGE), and screened by PCR for carbapenemase genes and insertion sequences. Antibiotic sensitivity to imipenem, meropenem, tigecycline, and colistin were determined. Eight different PFGE groups were identified, and were spread across multiple hospitals. Many of the PFGE groups contained isolates belonging to World-wide clone 2. Carbapenem resistance or intermediate resistance was detected in 69% of isolates. The bla VIM gene was detected in 94% of isolates, while bla OXA-23-like genes were detected in 58%. The data demonstrate the co-existence and wide distribution of a number of clones of carbapenem-resistant A. baumannii carrying multiple carbapenem-resistance determinants within hospitals in the Eastern Region of Saudi Arabia.


Does the administration route of leucovorin have any influence on the impairment of colonic healing caused by intraperitoneal 5-fluorouracil treatment?
Intraperitoneal chemotherapy with 5-fluorouracil (5-FU) is a new, promising alternative in adjuvant treatment of advanced colorectal cancer. Leucovorin (LV), a biomodulator of 5-FU, potentiates the antineoplastic effect of 5-FU. The aim of this study was to determine whether the administration routes of LV had any influence on the impairment of colonic healing caused by intraperitoneal 5-FU treatment. 48 male Wistar rats were subjected to left colonic resection and anastomosis, and randomized to 1 of 4 groups: control group (receiving intraperitoneal NaCl, intravenous NaCl); ipFU group (receiving intraperitoneal 5-FU, intravenous NaCl); ipFU+ivLV group (receiving intraperitoneal 5-FU, intravenous LV), and ipFU+LV group (receiving intraperitoneal 5-FU+LV, intravenous NaCl). Treatment was started after surgery and continued for 5 days with daily injections. The animals were sacrificed on the 7th day postoperatively. Anastomotic complications were more common in the ipFU, ipFU+ivLV, and ipFU+LV groups (p < 0.05) compared to the control group. The anastomotic breaking strength was significantly reduced in the ipFU, ipFU+ivLV, ipFU+LV groups (p < 0.05) than in the control group, but it did not differ between the ipFU, ipFU+ivLV, and ipFU+LV groups. The hydroxyproline content of the anastomotic segment was also significantly reduced in the ipFU, ipFU+ivLV and ipFU+LV groups (p < 0.05) compared to the control group. However, there was no difference between the anastomotic hydroxyproline content of the ipFU, ipFU+ivLV, and ipFU+LV groups. In this experiment, colonic healing was impaired after intraperitoneal 5-FU administration as judged by the higher rates of anastomotic complications, reductions in anastomotic breaking strength and hydroxyproline content; but LV administration either intravenously or intraperitoneally did not cause further deterioration in colonic healing.


Inhibition of endochondral ossification during fracture repair in experimental hypothyroid rats.
Using a rat fracture model, we investigated the effects of a decrease in serum levels of thyroid hormone on the fracture-repair process. Rats were divided into the following groups: (a) controls, (b) those treated with methimazole for the duration of the experiment, and (c) those treated with methimazole and L-thyroxine, receiving both for the same duration. Three weeks after the initiation of pharmacologic treatment, closed femoral fractures were produced. The formation of cartilage tissue in the fracture callus in all rats was not obviously different on day 7 after fracture. In the rats treated with methimazole, differentiation from proliferating to hypertrophic chondrocytes in the fracture callus was less advanced and vascular invasion was clearly inhibited on day 12. Gene expression of alkaline phosphatase and osteocalcin in the callus was significantly lower in these rats than in the controls on days 10, 12, and 14. The mechanical properties of the fracture callus were also significantly weaker in these animals than in the controls on day 21, resulting in impaired fracture repair. These results demonstrate that hypothyroidism inhibits endochondral ossification, resulting in an impaired fracture-repair process. L-thyroxine replacement in the rats treated with methimazole caused the impaired repair process to revert to normal. These results indicate that thyroid hormone is one of the critical systemic factors for fracture repair.


An analysis of the complete strain field within Flexercell membranes.
The purpose of the current investigation was to use finite element analysis to quantify the complete strain field for the membranes of the Flexercell apparatus, a device extensively used to study the effects of mechanical loading on cultured cells. Four vacuum pressure simulations were run for the membrane for both the uniaxial and biaxial loading post, yielding the distribution of longitudinal (Exx) and transverse (Eyy) strain for the uniaxial post, and the radial (Err) and the circumferential (Ethetatheta) strain for the biaxial post. The discrete values of each strain were evaluated at the center of the loading post as well as the region off of the post. Experimental measurements were made for both types of loading posts in order to validate our simulations. The biaxial post simulation was found to provide a central circular region of equal and constant Err and Ethetatheta in the membrane on the post. Likewise, the uniaxial post simulation provided a definitive region of constant Exx for a central rectangular region on the post. For the uniaxial simulation, the region on the post resulted in small compressive Eyy, while the region off the post resulted in tensile Eyy. The biaxial simulation resulted in large tensile Err and Ethetatheta on the post, while the region off the post resulted in large Err and smaller Ethetatheta. Our simulations were reasonably consistent with the experimental measurements made for both types of loading posts. We believe that the results of this study will allow scientists to more accurately describe the response of cells to known strains on all portions of the membrane, thus increasing the range of known strain regions for investigation in the Flexercell apparatus.


Hepatic Fibrosis in a Long-term Murine Model of Sepsis.
Chronic sequelae of sepsis represent a major, yet underappreciated clinical problem, contributing to long-term mortality and quality-of-life impairment. In chronic liver disease, inflammation perpetuates fibrogenesis, but development of fibrosis in the post-acute phase of systemic inflammation has not been studied. Therefore, a mouse model of post-acute sequelae of sepsis was established based on polymicrobial peritonitis under antibiotic protection. Survival decreased to approximately 40% within 7 days and remained constant until day 28 (post-acute phase). In survivors, clinical recovery was observed within 1 week, whereas white blood cell and platelet count, as well as markers of liver injury, remained elevated until day 28. Macroscopically, inflammation and abscess formation were detected in the peritoneal space and on/in the liver. Microscopically, acute-chronic inflammation with ductular proliferation, focal granuloma formation in the parenchyma, and substantial hepatic fibrosis were observed. Increased numbers of potentially pathogenetic macrophages and α-smooth muscle actin-positive cells, presumably activated hepatic stellate cells, were detected in the vicinity of fibrotic areas. Fibrosis was associated with the presence of elastin and an augmented production/deposition of collagen types I and III. Microarray analyses revealed early activation of canonical and noncanonical pathways of hepatic stellate cell transdifferentiation. Thus, chronic sequelae of experimental sepsis were characterized by abscess formation, persistent inflammation, and substantial liver injury and fibrosis, the latter associated with increased numbers of macrophages/α-smooth muscle actin-positive cells and deposition of collagen types I and III. This suggests persistent activation of stellate cells, with consecutive fibrosis-a hallmark of chronic liver disease-as a result of acute life-threatening infection.


[Apnea in premature infants. Epidemiology, pathophysiology and possibilities for prevention].
The pathogenesis of apnoea in preterm infants is poorly understood. Thus, it is yet unknown (1) whether the descriptive distinction between "central", "obstructive" and "mixed" apnoeas is also reflected by differences in their respective pathogenesis, (2) how and where the airway closure occurs during the so-called "obstructive" apnoeas, (3) whether "central" apnoeas do indeed result from a disturbance in the central nervous control of breathing, as implied by their name, or whether they constitute a reflex response to a disturbance in the periphery of the lung, and (4) whether non-apnoeic mechanisms contribute to the hypoxaemia so frequently observed during these episodes. This paper summarises the present knowledge regarding the above issues. It also reviews the current definitions for apnoea, bradycardia and hypoxaemia in preterm infants, describes indications for intervention, and discusses some strategies aimed at preventing these episodes.


HIV screening in pregnant women.
Abstract. The following recommendations are made for prenatal screening for HIV infection 1) Routine voluntary screening for HIV infection in all pregnant women is feasible and worthwhile. 2) Every seropositive result should be repeated for confirmation before coming to a definititve conclusion to avoid a misdiagnosis. 3) Fetal blood sampling in the mid-trimester for PCR and p24 antigen assay seems inappropriate as a diagnostic tool for in utero HIV infection of the HIV seropositive pregnant women as the infection mostly occurs after this time. 4) Routine screening of seronegative pregnant women should be repeated during the third trimester to detect seroconversion since this offers a chance for antiretroviral administration to the seroconverted pregnant women for reduction of perinatal transmission. 5) There should be available the appropriate back up services for seropositive pregnant women. There is sufficient evidence indicating a higher vertical HIV-1 transmission rate in the last trimester and during labour compared with the first and second trimesters. Antiretroviral therapy either single or in combination given to the mother during the last trimester and delivery can reduce the viral load in the maternal circulation. Vertical HIV-1 transmission during delivery can be minimized by appropriate timing and route of delivery. Elective Cesarean section before the onset of labour with an intact bag of forewaters provides the least mother-to-fetus microtransfusion compared to other modes of delivery. Since an effective combination of HIV-1 immunoglobulin and HIV-1 vaccine given to the HIV-1 exposed newborns to prevent HIV-1 transmission similar to the viral hepatitis B model is not firmly established at present, postexposure antiretroviral prophylaxis and nonbreast-feeding are advocated for infants born from the HIV-1 infected mothers. In cases of advanced stage of maternal HIV-1 infection, and in developing areas where malnutrition prevails, an adequate supply of essential micronutrients is proposed as an adjunctive measure to reduce HIV-1 perinatal transmission.


Parent-adolescent interactions and psychosocial risk in adolescents: an analysis of communication, support and gender.
The main purpose of this study was to verify the correlation between family functioning and the presence of psychosocial risk in adolescents. The sample of 279 intact families with a late adolescent and their parents complete self-report instruments in order to evaluate support and communication in parent-adolescent relationships. An index of risk was constructed with the MAUT technique. Data analysis was conducted on individual and relational dyadic levels. It was found that: (a) a supportive relationship and adequate communication between parents and adolescents are correlated to the absence or presence of psychosocial risk; and (b) the father in this phase of life is a reliable source of information regarding his relationship with his children and their psychosocial adjustment.


DINTD: Detection and Inference of Tandem Duplications From Short Sequencing Reads.
Tandem duplication (TD) is an important type of structural variation (SV) in the human genome and has biological significance for human cancer evolution and tumor genesis. Accurate and reliable detection of TDs plays an important role in advancing early detection, diagnosis, and treatment of disease. The advent of next-generation sequencing technologies has made it possible for the study of TDs. However, detection is still challenging due to the uneven distribution of reads and the uncertain amplitude of TD regions. In this paper, we present a new method, DINTD (Detection and INference of Tandem Duplications), to detect and infer TDs using short sequencing reads. The major principle of the proposed method is that it first extracts read depth and mapping quality signals, then uses the DBSCAN (Density-Based Spatial Clustering of Applications with Noise) algorithm to find the possible TD regions. The total variation penalized least squares model is fitted with read depth and mapping quality signals to denoise signals. A 2D binary search tree is used to search the neighbor points effectively. To further identify the exact breakpoints of the TD regions, split-read signals are integrated into DINTD. The experimental results of DINTD on simulated data sets showed that DINTD can outperform other methods for sensitivity, precision, F1-score, and boundary bias. DINTD is further validated on real samples, and the experiment results indicate that it is consistent with other methods. This study indicates that DINTD can be used as an effective tool for detecting TDs.


[Study on the cost-effectiveness of therapeutic scheme of acute bacillary dysentery].
A prospective study on the casts of acute bacillary dysentery treatment with antibiotics of aminoglycoside and the 3rd generation of cephalosporin, along with drug sensitive test in vitro was carried out. The results showed that the clinical therapeutic effects and the sensitive rates to drug in vitro between the two kinds of antibiotics were not statistically different (P > 0.05), but the costs of treatment with these two methods were significantly different. The therapeutic costs were calculated in Ren Ming Bi per day per kilogram body weight. The average therapeutic cost with the 3rd generation of cephalosporin was 44.85 times as that with aminoglycoside. The highest cost by Fortum was 364 times Higher than by Gentamycin. Through cost analysis, conclusion was drawn that the 3rd generation of cephalosporin should not be taken as first choice to treat a acute bacillary dysentery.


[Retrospective study of 34 urogenital fistulas of obstetricalal origin].
The aim of the study was to determine the etiologic and epidemiological aspects of the obstetrical uro-genital fistulas in Congo in order to propose a strategy of prevention. It is a retrospective study concerning 34 files of obstetrical uro-genital fistulas selected within 7 years in the department of Urology of the University Hospital Center of Brazzaville. The etiopathogenic, anatomoclinical and therapeutic aspects have been analysed for each file. The uro-genital fistula represents 23% of the female admissions in urology and 85% of them are related to obstetrical causes. Fifty-five percent of the patients were less than 30 years old, most of them being primiparas. Sixty-one percent of the patients came from rural areas. The prolonged time of the delivering labour and the foetal extraction manoeuvres were the main mechanisms causing the fistulas. With the surgical therapy, 77% of the abnormalities have been treated. In spite of progress made in the realm of surgical techniques, the best treatment for uro-genital fistulas remains their prevention as targeted on the education for health and the management of pregnant women. Besides, the development of the infrastructure of health and roads, the training and reeducation of the health personnel contribute to improve this management.


[Electroacupuncture at "huatuo jiaji point" inhibits the expression of Fos protein in rat spinal cord induced by traumatic pain].
SD rats were used to study the change of Fos-like immunoreactivity (FLI) in the lumbar spinal cord by traumatic pain following hind limb amputation and the effect of electro-acupuncture (EA) at "Huatuo Jiaji point" on it. The results showed (1) FLI cells induced by amputation were found in all of the I-X laminae of the ipsilateral spinal cord, but most of the labeled cells were located in the laminae I-II and V-VI; (2) EA at "Huatuo Jiaji point" suppressed the Fos expression following amputation, which was indicated by decrease of the number of FLI cells in the spinal cord. It suggests that, the traumatic pain impulse following amputation could activate pain sensitive neurons (PSN) in spinal cord. The impulse of electro-stimulation could suppress activities of these PSN, producing the effect of analgesia.


Leukocyte interferon in the treatment of chronic myelogenous leukemia in second chronic phase.
Four patients with Philadelphia chromosome positive CML were treated with 18-42 x 10(6) IU of purified natural leukocyte IFN-alpha per week, after high-dose chemotherapy for blast phase and attainment of 2nd chronic phase. The second blast phase occurred within 3 months in 3 patients, but one patient is still in second chronic phase after 22 months of treatment. Treatment consisted of interferon only during the first year, and interferon in combination with hydroxyurea during the second year. During the second year suppression of the Philadelphia chromosome was seen in one patient, with 20% Philadelphia negative bone marrow metaphases. The toxicity of purified natural leukocyte IFN-alpha was similar to the toxicity of recombinant IFN-alpha. Antibodies to IFN-alpha were not detected in any patient.


Selective Degradation of GSPT1 by Cereblon Modulators Identified via a Focused Combinatorial Library.
Cereblon (CRBN) is an E3 ligase adapter protein that can be reprogrammed by imide-class compounds such as thalidomide, lenalidomide, and pomalidomide to induce the degradation of neo-substrate proteins. In order to identify additional small molecule CRBN modulators, we implemented a focused combinatorial library approach where we fused an imide-based CRBN-binding pharmacophore to a heterocyclic scaffold, which could be further elaborated. We screened the library for CRBN-dependent antiproliferative activity in the multiple myeloma cell line MM1.S and identified five hit compounds. Quantitative chemical proteomics of hit compounds revealed that they induced selective degradation of GSPT1, a translation termination factor that is currently being explored as a therapeutic target for the treatment of acute myeloid leukemia. Molecular docking studies with CRBN and GSPT1 followed by analogue synthesis identified a possible hydrogen bond interaction with the central pyrimidine ring as a molecular determinant of hit compounds' selectivity. This study demonstrates that a focused combinatorial library design, phenotypic screening, and chemical proteomics can provide a suitable workflow to efficiently identify novel CRBN modulators.


Ultrastructure of the human egg.
This report on the fine structure of human oocyte is based on 20 years research where over 2000 eggs were examined by TEM in conjunction with our research on various methods of assisted reproduction. The eggs were routinely fixed in glutaraldehyde/osmium tetroxide, flat embedded in araldite, serially sectioned and examined by TEM. The oocytes were usually recovered after gonadotrophin stimulation. The general organisation of the mature human oocyte conforms to that of other mammals but has some unique features. The oocyte has the basic cell organelles such as mitochondria, lysosomes, two types of smooth endoplasmic reticulum (SER)-vesicular and tubular aggregates, multivesicular residual bodies, lipofuschin, microfilaments and microtubules. Golgi, RER and ribosomes are very rare and the egg has no yolk. It's surface has few microvilli, pinocytolic caveolae and 1-3 layers of cortical granules. The zona pellucida is composed of fine fibrils and granules embedded in an amorphous matrix and encloses a perivitelline space containing polar bodies. Remnants of corona cell junctions may be found at the oolemma. The metaphase II spindle is often oriented perpendicular to the surface and is barrel-shaped, anastral and lacks centrioles. Osmiophilic centrosomes are not demonstrable in human eggs since the maternal centrosome is inactive. The sperm centrosome organizes mitotic spindles of the embryo after fertilization, whereas in mice the maternal centrosome is active and dominant during cleavage. The stages of peri-ovulatory maturation and differences in oocyte structure during maturation are also presented. Oocytes ageing in culture show progressive swelling of vesicular SER culminating in vacuolation, denser mitochondria (clouding together or associated with vacuoles) peripheral conglomerations or centripetal migration of cortical granules and increased lysosomal activity. Prolonged culture also causes displacement and disorganisation of metaphase II spindles, loss of microtubules and consequent displacement of chromosomes. Evidently the cytoskeleton becomes disorganized. Some observations on oocyte maturation in vitro and spontaneous activation of oocytes are included.


A Prognostic Gene-Expression Signature and Risk Score for Meningioma Recurrence After Resection.
Prognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy. To identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis. Targeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence. We identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P < .001 vs .09, log-rank test), shorter time to failure (TTF, F-test, P < .0001), and overall survival (OS, P < .0001 vs .07) and was independently associated with worse LFFR (relative risk [RR] 1.56, 95% CI 1.30-1.90) and OS (RR 1.32, 95% CI 1.07-1.64), after adjusting for clinical covariates. When tested on an independent validation cohort, the gene-signature risk score remained associated with shorter TTF (F-test, P = .002), compared favorably to WHO grade in stratifying cases by OS (P = .003 vs P = .10), and was significantly associated with worse OS (RR 1.86, 95% CI 1.19-2.88) on multivariate analysis. The prognostic meningioma gene-expression signature and risk score presented may be useful for identifying patients at risk for recurrence.


Perceived versus objective sleep quality in long-stay hospitalised older adults-a mixed methods study.
Hospital inpatients experience substantial sleep problems that have been linked with worse health outcomes, poor quality of life and the post-hospital syndrome. However, little is known about assessing sleep issues in older hospitalised patients. To conduct an in-depth investigation on hospitalised older adults' sleep challenges and methods of sleep assessment. Cross-sectional observational study. Public hospital inpatient unit. Long-stay hospitalised older adults. Data were collected using validated sleep questionnaires, actigraphy devices and qualitative interviews. Quantitative data were analysed with descriptive statistics, multiple logistic regression and Cohen's Kappa. Qualitative data were analysed with qualitative content analysis; findings compared to the quantitative assessments. We collected data on 33 older long-stay hospital inpatients, who were mean (SD) 80.2(7.4) years old, 57.6% female and were hospitalised following stroke, medical illness and orthopaedic fracture. Mean (SD) total sleep time and actigraphic sleep efficiency were 480.6(73.6) minutes and 81.5(11.2)%, respectively. About, 57.6% were poor sleepers (Pittsburgh Sleep Quality Index [PSQI]) and 30.8% had indicators of clinical depression/low quality of life (WHO-5 well-being index). Three main themes were identified: "sleep assessment"; "factors that affect sleep"; "expectations of sleep". Bad sleepers were more likely to feel a lack of control over their sleep, while good sleepers spoke about the ability to adjust and accept their circumstances. We found high levels of sleep problems and identified substantial discrepancies between the validated sleep questionnaire and qualitative response data. Our findings indicate that standard assessment tools, such as PSQI, may not be suitable to assess sleep in hospitalised older adults and call for further investigations to build more appropriate methods. Further exploring psychological factors and expectations could potentially lead to novel interventions to improve sleep in this setting.


Modeling bone marrow toxicity using kinase structural motifs and the inhibition profiles of small molecular kinase inhibitors.
The cellular function of kinases combined with the difficulty of designing selective small molecule kinase inhibitors (SMKIs) poses a challenge for drug development. The late-stage attrition of SMKIs could be lessened by integrating safety information of kinases into the lead optimization stage of drug development. Herein, a mathematical model to predict bone marrow toxicity (BMT) is presented which enables the rational design of SMKIs away from this safety liability. A specific example highlights how this model identifies critical structural modifications to avoid BMT. The model was built using a novel algorithm, which selects 19 representative kinases from a panel of 277 based upon their ATP-binding pocket sequences and ability to predict BMT in vivo for 48 SMKIs. A support vector machine classifier was trained on the selected kinases and accurately predicts BMT with 74% accuracy. The model provides an efficient method for understanding SMKI-induced in vivo BMT earlier in drug discovery.


Synthesis of Allahabadolactone A.
A synthesis of allahabadolactone A is described employing diastereoselective Diels-Alder and selenocyclization reactions, starting from (R)-citronellal and propylene oxide. The Diels-Alder substrate is built up in an efficient manner by rhodium-catalyzed alkyne hydroboration and palladium-catalyzed coupling reactions of E-1,2-dichloroethene. It is observed that the Diels-Alder reaction only displays high diastereoselectivity when the diene bears an additional alkene substituent but not an alkyne substituent.


Overview of bile acid signaling in the cardiovascular system.
Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.


Evaluation of radiation-induced cardiac toxicity in breast cancer patients treated with Trastuzumab-based chemotherapy.
Patients with Her2-positive breast cancer treated with trastuzumab have higher rates of cardiotoxicity (CT). Left-breast radiation might increase the risk for CT from cardiac exposure to radiation. The goal of our study is to evaluate the contribution of radiotherapy (RT) in the development of CT in breast cancer patients receiving trastuzumab. Two hundred and two patients were treated with RT and trastuzumab from 2000 to 2014. The RT plans for left-side disease were recalled from archives. The heart, each chamber, and left anterior descending artery (LAD) were independently contoured. New dose-volume histograms (DVH) were generated. Their serial left-ventricular ejection fractions (LVEF) were studied. CT for left and right side were compared using Fisher's exact test. The DVH data were correlated with the predefined cardiac events using actuarial Cox regression analysis. Compared to the right sided, the left-side cases showed statistically significant development of arrhythmia (14.2%) versus (< 1%) (p < 0.001). Cardiac ischemia was found in 10 patients in left and one patient in right side (p = 0.011). The equivalent uniform dose (EUD) to the left ventricle (LV), right ventricle (RV), and LAD was significantly associated with decrease in LVEF by > 10% (p = 0.037, p = 0.023 and p = 0.049, respectively). Among patients treated for left-sided lesions, there were no significant differences in EF decline. However, there was a higher rate of ischemia and arrhythmia compared to those with right-sided disease. The EUD index of LV, RV, and LAD could be considered as a parameter to describe the risk of radiation-induced CT.


Chemotherapy of pancreatic carcinoma.
Cancer of the pancreas is the fourth leading cause of cancer death in the United States. Until recently, this tumor has not been the subject of a systematic evaluation of nonsurgical therapies. In particular, there have been remarkably few anticancer agents specifically studied for activity in pancreatic cancer, but at the present time 5-fluorouracil, mitomycin-C, streptozotocin, and Adriamycin have demonstrated single-agent effectiveness. Despite the limited number of agents available for the development of combination chemotherapy, several programs have demonstrated an apparent improvement in response relative to single-agent treatment. These include 5-FU and mitomycin-C, SMF, and FAM; response rates of 30-43% have been reported for patients with advanced measurable pancreatic cancer. For the locally advanced stage of this disease, the combined modality approach of 5-fluorouracil plus external irradiation has produced superior survivals when compared with radiation therapy used alone. Although chemotherapy of pancreatic cancer is a developing field, clinically meaningful responses correlated with improved patient survival can be obtained with existing regimens. Phase II trials of new anticancer agents remain a high priority research effort with the intent of identifying useful drugs for future regimens of combination chemotherapy.


The Alfieri stitch: the advantages for mitral valve repair in difficult circumstances.
In certain complex cases, where there is severe calcification of the mitral annulus but significant mitral regurgitation or systolic anterior motion (SAM), or in high-risk cases where prolonged bypass is to be avoided, the Alfieri-stitch repair of the mitral valve may be the most appropriate option available, particularly as it can be performed quickly through the aortic valve. We describe three cases undergoing aortic valve replacement, in which this technique was successfully applied in patients in whom more conventional repair techniques or valve replacement would have been hazardous, due to annular calcification and patient frailty.


Fungal-fungal co-culture: a primer for generating chemical diversity.
Covering: 2002 to 2020In their natural environment, fungi must compete for resources. It has been hypothesized that this competition likely induces the biosynthesis of secondary metabolites for defence. In a quest to discover new chemical diversity from fungal cultures, a growing trend has been to recapitulate this competitive environment in the laboratory, essentially growing fungi in co-culture. This review covers fungal-fungal co-culture studies beginning with the first literature report in 2002. Since then, there has been a growing number of new secondary metabolites reported as a result of fungal co-culture studies. Specifically, this review discusses and provides insights into (1) rationale for pairing fungal strains, (2) ways to grow fungi for co-culture, (3) different approaches to screening fungal co-cultures for chemical diversity, (4) determining the secondary metabolite-producing strain, and (5) final thoughts regarding the fungal-fungal co-culture approach. Our goal is to provide a set of practical strategies for fungal co-culture studies to generate unique chemical diversity that the natural products research community can utilize.


Design, Characterization, and Optimization of Controlled Drug Delivery System Containing Antibiotic Drug/s.
The objective of this work was design, characterization, and optimization of controlled drug delivery system containing antibiotic drug/s. Osmotic drug delivery system was chosen as controlled drug delivery system. The porous osmotic pump tablets were designed using Plackett-Burman and Box-Behnken factorial design to find out the best formulation. For screening of three categories of polymers, six independent variables were chosen for Plackett-Burman design. Osmotic agent sodium chloride and microcrystalline cellulose, pore forming agent sodium lauryl sulphate and sucrose, and coating agent ethyl cellulose and cellulose acetate were chosen as independent variables. Optimization of osmotic tablets was done by Box-Behnken design by selecting three independent variables. Osmotic agent sodium chloride, pore forming agent sodium lauryl sulphate, and coating agent cellulose acetate were chosen as independent variables. The result of Plackett-Burman and Box-Behnken design and ANOVA studies revealed that osmotic agent and pore former had significant effect on the drug release up to 12 hr. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of the optimization procedure in successful development of porous osmotic pump tablets containing antibiotic drug/s by using sodium chloride, sodium lauryl sulphate, and cellulose acetate as key excipients.


Kinetics and metabolism of inhaled methyl chloroform (1,1,1-trichloroethane) in male volunteers.
The kinetics of inhaled methyl chloroform (MC) and its principal metabolites, trichloroethanol (TCE) and trichloroacetic acid (TCA), were defined in six healthy male volunteers following single 6-hr exposures of 350 and 35 ppm. Blood and expired air MC concentrations were proportional to the exposure concentration and indicated that about 25% of the MC inhaled during the 6-hr exposure was absorbed. Elimination of MC was triexponential with half-lives estimated as 44 min, 5.7 hr, and 53 hr for the initial, intermediate, and terminal phases. Over 91% of the absorbed MC was excreted unchanged via the lungs, 5-6% was metabolized and excreted as TCE and TCA, and less than 1% remained in the body after 9 days. Urinary TCE and TCA excretion was extremely variable and indicated that urinary TCE and TCA measurements provide at best only a rough estimate of the exposure. These data suggest that the kinetics of MC in man are essentially first order at or below the current TLV of 350 ppm. Based on a comparison of the blood MC levels and amounts of MC metabolized, the rat is a better model than the mouse to predict the toxicity of MC in man.


Gut bacteria-derived peptidoglycan induces a metabolic syndrome-like phenotype via NF-κB-dependent insulin/PI3K signaling reduction in Drosophila renal system.
Although microbiome-host interactions are usual at steady state, gut microbiota dysbiosis can unbalance the physiological and behavioral parameters of the host, mostly via yet not understood mechanisms. Using the Drosophila model, we investigated the consequences of a gut chronic dysbiosis on the host physiology. Our results show that adult flies chronically infected with the non-pathogenic Erwinia carotorova caotovora bacteria displayed organ degeneration resembling wasting-like phenotypes reminiscent of Metabolic Syndrome associated pathologies. Genetic manipulations demonstrate that a local reduction of insulin signaling consecutive to a peptidoglycan-dependent NF-κB activation in the excretory system of the flies is responsible for several of the observed phenotypes. This work establishes a functional crosstalk between bacteria-derived peptidoglycan and the immune NF-κB cascade that contributes to the onset of metabolic disorders by reducing insulin signal transduction. Giving the high degree of evolutionary conservation of the mechanisms and pathways involved, this study is likely to provide a helpful model to elucidate the contribution of altered intestinal microbiota in triggering human chronic kidney diseases.


Cold saline enema in priapism--a useful tool for underprivileged.
Priapism, prolonged painful erection of the penis, is a urological emergency. Untreated, the patient can end up with impotence. Various methods have been described for its treatment but the initial management remains conservative. This study presents our experience with the use of sedation followed by an ice-cold saline enema in the management of priapism.


Overexpression of apelin receptor (APJ/AGTRL1) on hepatic stellate cells and sinusoidal angiogenesis in human cirrhotic liver.
The apelin receptor (APJ) is related to angiotensin-like-receptor 1 (AGTRL1). This study was designed to elucidate the in vivo localization and changes of APJ in cirrhotic liver, and the in vitro changes of APJ expression in cultured hepatic stellate cells (HSCs) and capillarized sinusoidal endothelial cells (SECs) activated by growth factors. In vivo studies used control liver samples, cirrhotic liver samples from patients with Child's A cirrhosis undergoing surgical resection (Child-A-LC), and cirrhotic liver samples from autopsied cases of decompensated Child's C cirrhosis (Child-C-LC). Immunohistochemical (IHC), Western blot, laser-capture microdissection (LCM) coupled with reverse transcription -polymerase chain reaction (RT-PCR), and immunoelectron microscopic (IEM) studies for APJ expression were conducted. In vitro examinations used commercial human HSCs and SECs. APJ expression was examined in cultured HSCs activated by growth factors and in capillarized SECs activated by angiogenic factors. The IHC study of liver samples revealed only slight APJ expression in hepatic sinusoids in control liver tissue. In cirrhotic liver (Child-A-LC and Child-C-LC), APJ expression was evident mainly along the sinusoids and on portal fibroblasts in fibrotic septa. Western blot analysis of whole-liver homogenate and LCM-PCR of sinusoids revealed overexpression of APJ in Child-C-LC samples. The results of IEM studies showed that APJ expression was increased significantly on HSCs, but it was sparse on SECs in Child-C-LC tissue. In vitro examination revealed that APJ was overexpressed in cultured HSCs activated by platelet-derived growth factor-β. Enhanced expression of APJ on HSCs in cirrhosis indicates markedly increased vascular remodeling.


Update on phototherapeutic keratectomy.
To review all recent publications on the use of phototherapeutic keratectomy (PTK). Recent studies confirm the beneficial outcomes of PTK in a variety of anterior corneal disorder: anterior stromal scars, dystrophies of the corneal epithelium and the anterior stroma, and elevated corneal lesions. They also try to evaluate the biomechanical properties of eyes with granular corneal dystrophy undergoing PTK, in an effort to prevent iatrogenic ectasia. The different genotypes in patients with transforming growth factor, beta-induced linked corneal dystrophies have recently been correlated to the surgical outcome after PTK. An extensive review of recurrent corneal erosion syndrome identified PTK as the most effective treatment. In the developing world, the most common indication for PTK is still bullous keratopathy, as PTK can be successfully used while waiting for penetrating keratoplasty. PTK can successfully treat a variety of conditions of the anterior cornea. New studies may further expand its use.


The impact of the method of genetic identity disclosure on the donor conceived adult.
Aim: 106 donor conceived people (DCP) responded to an anonymous survey study that examined the impact of the method of genetic identity disclosure and age at the time of the disclosure on their emotional wellbeing, familial relations, and perceptions of donor conception practices.Methods: Participants were asked to select the way in which they were informed they are DCP and the age group at which this occurred, and then were asked to select strongly agree, agree, neither agree or disagree, disagree, or strongly disagree in response to 26 statements that examined their perceptions of the topics listed above. Responses were grouped based on the age of genetic identity disclosure and the method of genetic identity disclosure, then numerically compared by assigning each type of response a number. Statistical analysis using repeatedmeasures ANOVA was performed to identify differences among these factors.Results: This analysis revealed that most participants 18 ≥ years and most participants who discovered their genetic identity through means other than through their parent(s) had worse emotional wellbeing and familial relations. However, most participants among all categories had a negative perception of donor conception practices.Conclusion: Continued work is needed to understand and support the growing DCP population.


Osteoarticular Infections Following Open or Penetrating Trauma in Children in the Post-Community-Acquired Methicillin-resistant Staphylococcus aureus Era: The Impact of Enterobacter cloacae.
Most cases of pediatric osteoarticular infections (OAIs) are hematogenous in nature and caused by Staphylococcus aureus. OAI in children can also occur through direct inoculation of microorganisms secondary to penetrating or open trauma. No studies in the United States have evaluated the microbiology or outcomes of trauma-related OAI (TROAI) in children in the era of community-acquired methicillin-resistant S. aureus (CA-MRSA). Cases were identified from the inpatient infectious diseases consultation database at Texas Children's Hospital from January 2011 to December 2016. TROAI cases were those in which OAI developed following a clear history of penetrating trauma, open fracture, crush injury or traumatic amputation. Only cases with radiographic evidence of bone abscess, gross appearance of infection at the time of surgery and/or positive cultures from bone or joint were included. Complications included recurrence of infection, pathologic fracture or chronic osteomyelitis. During the study period, 692 consultations for OAI were performed, with 34 meeting inclusion criteria. In 68%, at least 1 organism was isolated, and the most commonly isolated organisms were S. aureus (32% overall, 21% MRSA) and Enterobacter cloacae (24%). Polymicrobial infections occurred in 38% of patients. Eighty-five percentage of patients had at least 1 surgical procedure, and 38% underwent ≥ 2 procedures. Eighty-two percentage of patients were discharged on oral therapy. Complications developed in 15% of patients and were more commonly associated with E. cloacae (80% vs. 14%, P = 0.007) and fungi (P = 0.03). TROAI are relatively uncommon in children but cause significant morbidity. While MRSA contributes substantially to TROAI, the highly diverse microbiology emphasizes the importance of obtaining cultures for microbiologic diagnosis and management. Clinicians should be aware of the frequency of E. cloacae in TROAI and its high risk for sequelae.


A rare complication of laparoscopic surgery.
Gallstone disease is one of the most common problems affecting the digestive tract. Symptomatic patients are advised to undergo laparoscopic cholecystectomy (LC), which is considered the gold standard of care in these patients. LC has clear advantages over traditional surgery such as a shorter hospital stay, an earlier return to work and better patient satisfaction. Despite LC being a common surgical procedure, it is not totally free from complications. These include cardiorespiratory problems, biliary leakage, peritonitis, hemorrhage and superior mesenteric artery (SMA) occlusion. We report an unusual and fatal complication of LC, being SMA thrombosis complicated by multiple intra-abdominal collections, abdominal compartment syndrome, multiorgan failure and septic shock.


Efficient introduction of a gene into hematopoietic cells in S-phase by electroporation.
Cells of the hematopoietic cell line K562 were synchronized by three different methods: single aphidicolin treatment, thymidine treatment followed by hydroxyurea exposure, and double hydroxyurea treatment. The synchronized cells were transfected via electroporation with plasmid pMoZtk, which contains the beta-galactosidase gene, using a square wave pulse immediately after synchronization or at various time points during culture. Simultaneously, synchronized cells were fluorescence-activated cell sorter (FACS) analyzed to determine their stage in the cell cycle using double staining with bromodeoxyuridine (BrdU) and propidium iodide. Highly efficient introduction of pMoZtk was observed for the cell fraction, which predominantly consisted of the cells in S-phase. These results suggest that by increasing the proportion of cells in S-phase, the efficiency of gene transfer into hematopoietic cells such as hematopoietic stem cells can be improved.


Emerging digital technologies in cancer treatment, prevention, and control.
The very first issue of the journal of Translational Behavioral Medicine (TBM) was dedicated, in part, to the theme of Health Information Technology as a platform for evidence implementation. The topic was timely: legislation in the USA was passed with the intent of stimulating the adoption of electronic health records; mobile smartphones, tablets, and other devices were gaining traction in the consumer market, while members within the Society of Behavioral Medicine were gaining scientific understanding on how to use these tools to effect healthy behavior change. For the anniversary issue of TBM, we evaluated the progress and problems associated with deploying digital health technologies to support cancer treatment, prevention, and control over the last decade. We conducted a narrative review of published literature to identify the role that emerging digital technologies may take in achieving national and international objectives in the decade to come. We tracked our evaluation of the literature across three phases in the cancer control continuum: (a) prevention, (b) early detection/screening, and (c) treatment/survivorship. From our targeted review and analyses, we noted that significant progress had been made in the adoption of digital health technologies in the cancer space over the past decade but that significant work remains to be done to integrate these technologies effectively into the cancer control systems needed to improve outcomes equitably across populations. The challenge for the next 10 years is inherently translational.


CXCL13 plasma levels function as a biomarker for disease activity in patients with chronic lymphocytic leukemia.
The chemoattractant CXCL13 organizes the cellular architecture of B-cell follicles and germinal centers. During adaptive immune responses, CXCL13 plasma concentrations transiently increase and function as a biomarker for normal germinal center activity. Chronic lymphocytic leukemia (CLL) cells express high levels of CXCR5, the receptor for CXCL13, and proliferate in pseudofollicles within secondary lymphoid organs (SLO). Given the morphologic and functional similarities between normal and CLL B-cell expansion in SLO, we hypothesized that CXCL13 plasma concentrations would correlate with CLL disease activity and progression. We analyzed CXCL13 plasma concentrations in 400 CLL patients and correlated the findings with other prognostic markers, time to treatment (TTT), CCL3 and CCL4 plasma concentrations, and in vivo CLL cell proliferation. We found that CXCL13 plasma concentrations were higher in CLL patients with active and advanced stage disease, resulting in a significantly shorter TTT. Accordingly, high CXCL13 levels correlated with other markers of disease activity and CCL3 levels. Higher CLL cell birth rates in vivo also associated with higher CXCL13 plasma concentrations. Interestingly, elevated CXCL13 plasma levels normalized during ibrutinib therapy, and increased in ibrutinib resistance patients. Collectively, these studies emphasize the importance of CXCL13 in crosstalk between CLL cells and the SLO microenvironment.


Type 1 diabetes mellitus and oral health: assessment of periodontal disease.
The periodontal disease status of 320 dentate adults, diagnosed 23.7 years previously with Type 1 insulin dependent diabetes mellitus, was evaluated. These patients had been monitored at 2-year intervals as part of a large University of Pittsburgh longitudinal study assessing the medical complications associated with insulin dependent diabetes. During one of their regularly scheduled medical examinations, a group of 320 adult dentate subjects (mean age of 32.1 years) received a periodontal examination as part of a comprehensive oral health assessment. The oral health assessment collected data regarding demographics, oral health behaviors, tooth loss, coronal and root caries, salivary functions, and soft tissue pathologies. For the periodontal assessments, 3 facial sites (mesial, midcervical, distal) of the teeth in the right maxillary/left mandibular or left maxillary/right mandibular quadrants were evaluated for calculus, bleeding on probing (BOP) and loss of gingival attachment (LOA). Attachment loss was significantly greater for older patients whereas BOP and calculus levels were relatively constant across age categories. Univariate analyses of factors possibly related to extensive periodontal disease (LOA > or =4 mm for at least 10% of sites examined) indicated an association with older age; lower income and education; past and current cigarette smoking; infrequent visits to the dentist; tooth brushing less than once per day; older age of onset; longer duration of diabetes; and the diabetic complication of neuropathy. A multivariate regression model of all possibly significant factors found current cigarette use (odds ratio [OR] = 9.73), insulin dependent diabetes onset after 8.4 years of age (OR = 3.36), and age greater than 32 years (OR = 3.00) explained the majority of the extensive periodontal disease in this group of diabetic patients. Management and prevention of extensive periodontal disease for Type 1 diabetic patients should include strong recommendations to discontinue cigarette smoking.


Henry's Constants of Persistent Organic Pollutants by a Group-Contribution Method Based on Scaled-Particle Theory.
A group-contribution method based on scaled-particle theory was developed to predict Henry's constants for six families of persistent organic pollutants: polychlorinated benzenes, polychlorinated biphenyls, polychlorinated dibenzodioxins, polychlorinated dibenzofurans, polychlorinated naphthalenes, and polybrominated diphenyl ethers. The group-contribution model uses limited experimental data to obtain group-interaction parameters for an easy-to-use method to predict Henry's constants for systems where reliable experimental data are scarce. By using group-interaction parameters obtained from data reduction, scaled-particle theory gives the partial molar Gibbs energy of dissolution, Δg̅2, allowing calculation of Henry's constant, H2, for more than 700 organic pollutants. The average deviation between predicted values of log H2 and experiment is 4%. Application of an approximate van't Hoff equation gives the temperature dependence of Henry's constants for polychlorinated biphenyls, polychlorinated naphthalenes, and polybrominated diphenyl ethers in the environmentally relevant range 0-40 °C.


GAGA factor-dependent transcription and establishment of DNase hypersensitivity are independent and unrelated events in vivo.
Using a Drosophila transgenic system we investigated the ability of GAGA factor, a putative anti-repressor, to modulate transcription-related events in the absence or presence of a bona fide activator, the Adf-1 transcription factor. In contrast to previous in vitro and in vivo data linking the binding of GAGA factor to the acquisition of DNase hypersensitivity at heat shock promoters, we observed that inserting multiple GAGA binding motifs adjacent to a minimal alcohol dehydrogenase (Adh) promoter led to strongly elevated embryonic transcription without creation of a promoter-associated DNase-hypersensitive (DH) site. Establishment of DNase hypersensitivity required the presence of both GAGA and Adf-1 binding sites and was accompanied by a further, synergistic increase in transcription. Because Adf-1 is capable neither of establishing a DH site nor of promoting efficient transcription by itself in embryos, it is likely that DH site formation depends on a GAGA factor-mediated binding of Adf-1 to chromatin, perhaps facilitated by a locally remodeled downstream promoter region. More generally we suggest that GAGA factor-binding sequences may operate in a promoter-specific context, with transcriptional activation, polymerase pausing, and/or DH site formation critically dependent on the nature of the sequences (and their binding partners) linked in cis.


Isolation of Plastids from Sunflower Cotyledons during Germination.
Plastids from cotyledons of sunflower (Helianthus annus L.) seedlings, germinated in the dark or in the light, were isolated by isopycnic sucrose density gradient centrifugation. At all stages of development the whole plastids contained triose phosphate isomerase, NADPH-glyoxylate reductase, and l-dihydroxyphenylalanine oxidase, which were used as marker enzymes. At the beginning of germination the isopycnic density of whole plastids (proplastids) was about 1.22 g cm(-3). During development of proplastids into etioplasts in the dark, their isopycnic density increased to 1.26 g cm(-3). During exposure of germinating seedlings to white light for 2 days, the isopycnic density of whole plastids decreased from 1.26 to 1.22 g cm(-3). These changes in isopycnic density of plastids on sucrose density gradients are consistent with changes in the plastid ultrastructure caused by the protein-rich prolamellar body or by the lipid-rich thylakoids. Broken plastids (thylakoids), determined by the main peak of chlorophyll, increased in isopycnic density from less than 1.14 to about 1.17 g cm(-3) during illumination. During germination no major changes occurred in the isopycnic density of mitochondria. Microbodies had an isopycnic density of 1.24 g cm(-3) in very early stages of germination, and their density increased to 1.265 g cm(-3), when glyoxysomal enzymes reached maximum development.


[Epidemiology of pulmonary embolism].
There are few conditions in medicine as difficult to diagnose as pulmonary embolism. This is certainly not due to the rarity of the disease which is probably as common as myocardial infarction in France. The circumstances surrounding pulmonary embolism and the risk factors of deep venous thrombosis have been well identified. The risk of thromboembolic venous disease has been assessed for each type of surgery. The methods of treatment and prevention have progressed over a number of years. However, in practice, these advances have not "transformed" the frequency of the disease or reduced its mortality. Further progress could come from improved identification of patients at risk, especially by biological tests and new abnormalities of blood coagulation.


Control of protein adsorption: molecular level structural and spatial variables.
The adsorption of fibrinogen (Fb) and bovine serum albumin onto polycrystalline Au coated with HS(CH2)3O(CH2CH2O)5CH3 was determined by surface plasmon resonance from bare Au (0% coverage) to the complete ( approximately 100% coverage) self-assembled monolayer (SAM). Both proteins exhibit similar adsorption curves with common onset ( approximately 60% coverage) and range ( approximately 60% to 80% coverage) of minimal protein adsorption. Reflection-absorption infrared spectroscopic data show that widespread order is not present in the films over this range of coverage, indicating loosely packed, bound oligomers that are uniformly distributed and fully screen the underlying substrate. On the basis of our data, we propose a mechanism of protein rejection by oligo(ethylene oxide) (OEO)-modified surfaces in terms of changes in free energy (DeltaGsystem; system = protein + surface) due to oligomer conformational constriction over an area greater than the contact area. Minimal protein adsorption corresponds to the maximum DeltaGsystem for a given compression. This controlled study of protein adsorption provides insights into the molecular level understanding of protein adsorption unavailable from previous polymer and comparative SAM studies.