Hemodynamic comparison of bioprostheses for complete supra-annular position in patients with small aortic annulus.
The present study evaluates complete supra-annular bioprostheses in patients with an aortic annulus of 18 to 23 mm in diameter. Aortic valve replacement in patients with small aortic annulus using stented bioprostheses is often associated with unsatisfactory hemodynamic results and high incidence of patient-prosthesis mismatch. Between February 2000 and January 2004, 156 patients with aortic valve disease and an aortic annulus of 18 to 23 mm in diameter received the stented bovine Soprano (Sorin Biomedica Cardio, Saluggia, Italy) (n = 18), Perimount (Edwards Lifesciences, Irvine, California) (n = 52), Perimount Magna (Edwards Lifesciences) (n = 42), or the stented porcine Mosaic (Medtronic Inc., Minneapolis, Minnesota) (n = 44) bioprostheses. Intraoperatively, the surgeon measured the aortic annulus diameter by inserting a hegar dilator. Thus, postoperative hemodynamic results could be referred to the patient's aortic annulus diameter instead of referring the results to the labeled valve size. This allows for objective comparisons between different valve types. There was no significant difference in hemodynamic results between the different valve types in patients with an aortic annulus 18 to 20 mm. In patients with an annulus 21 to 23 mm, the Magna was significantly superior to the other investigated devices in mean pressure gradient, effective orifice area, and incidence of patient-prosthesis mismatch. There was no significant difference between the complete supra-annular bioprostheses Mosaic and Soprano and the intra-supra-annular Perimount valve. In patients with an aortic annulus of 18 to 20 mm in diameter, hemodynamic performance is independent of the implanted stented valve type and the annular position. Root enlargement or stentless valves may be beneficial alternatives. Patients with annulus diameter 21 to 23 mm benefit from the Magna in complete supra-annular position leading to superior hemodynamic results.


Functional in vitro assessment of modified antibodies: Impact of label on protein properties.
Labelling of therapeutic antibodies with radionuclides or fluorophores is routinely used to study their pharmacokinetic properties. A critical assumption in utilizing labelled therapeutic antibodies is that the label has no unfavourable effects on antibody charge, hydrophobicity, or receptor affinity. Ideally, the labelled protein should not have any significant deviations from the physiological properties of the original molecule. This article describes an established quality in vitro assessment workflow for labelled antibodies that ensures better prediction of changes in antibody pharmacokinetic (PK) properties after modifications. This analysis package considers degradation and aggregation analysis by size-exclusion chromatography, changes in neonatal-Fc-receptor (FcRn) affinity, and heparin interaction. FcRn binding is important for antibody recycling and half-life extension, whereas heparin affinity provides estimates on the rate of endocytosis through unspecific cell surface binding. Additionally, mass spectrometric analysis to determine the degree of labelling (DoL) completes the package and the combined analysis data allow to predict the label contribution to the PK properties of the modified antibody. This analytical strategy for labelling 11 IgGs has been investigated using 2 different IgG1 constructs and applying 7 different types of labels. Each labelling resulted in a change in the physicochemical properties of the protein. Not only can the DoL of modified IgGs lead to a change in protein properties, but the type of label also can. Furthermore, it was demonstrated that the labelling process can also influence the behaviour of labelled mAbs. An identical label on different constructs of IgG1 can cause different affinities for FcRn and heparin. Considering the assessment data, only 6 of the 11 modified antibodies from this study can be recommended for subsequent experiments. In conclusion, a suitability assessment of labelled antibodies prior to any pharmacokinetic studies is essential to reduce cost, allocate resources and reduce the number of animal experiments during pre-clinical drug development.


Risk and protective factors for relapse among individuals with schizophrenia: a qualitative study in Dar es Salaam, Tanzania.
Relapse in people with schizophrenia is a major challenge for mental health service providers in Tanzania and other countries. Approximately 10% of people with schizophrenia are re-admitted due to relapse at Muhimbili National Hospital (MNH) Psychiatric Unit each month. Relapse brings about negative effects and it results in a huge burden to patients, their families, the mental health sector and the country's economy. So far no study has been done to address relapse in Tanzania. The purpose of the study was to explore perspectives on risk and protective factors influencing relapse of people with schizophrenia and their caregivers attending Muhimbili National Hospital Psychiatric Out-patient Department, Dar es Salaam, Tanzania. A qualitative study was conducted, involving in-depth interviews of seven people with schizophrenia who are out-patients and their seven family caregivers at MNH. Purposive sampling procedure was used to select participants for the study. Audio recorded in-depth interviews in Swahili language were conducted with all study participants. The recorded information was transcribed and analyzed using NVivo 9 computer assisted qualitative data analysis software. Personal risk and protective factors for relapse, environmental risk and protective factors for relapse and suggestions to reduce relapse were the main themes that emerged from this study. People with schizophrenia and their caregivers (all of whom were relatives) perceived non adherence to antipsychotic medication as a leading risk factor of relapse; other risks included poor family support, stressful life events and substance use. Family support, adherence to antipsychotic medication, employment and religion were viewed as protective factors. Participants suggested strengthening mental health psycho-education sessions and community home visits conducted by mental health nurses to help reduce relapse. Other suggestions included strengthening the nurse-patient therapeutic relationship in provision of mental health care. This study calls for improvement in mental health care service delivery to individuals with schizophrenia. Establishing a curricular in mental health nursing that aims to produce competent mental health nurse force would improve nursing practice in mental health care service delivery.


Transport of resistance through a long microfluidic channel.
We introduce a continuous analytical model of propagation of resistance in pressure-driven flow of two-phase fluid in a single channel. This model can be used to predict and interpret experimental results in droplet microfluidics where the hydrodynamic resistance of a capillary comprises a constant part, specific to the channel and the viscosity of the continuous fluid, and a variable part, related to the presence and distribution of droplets. The continuous model is a convenient generalization of the discrete models as demonstrated via comparisons with discrete simulations and with experiments.


Cellular localization of oriC during the cell cycle of Escherichia coli as analyzed by fluorescent in situ hybridization.
The origin of replication of Escherichia coli, oriC, has been labeled by fluorescent in situ hybridization (FISH). The E. coli K12 strain was grown under steady state conditions with a doubling time of 79 min at 28 degrees C. Under these growth conditions DNA replication starts in the previous cell cycle at -33 min. At birth cells possess two origins which are visible as two separated foci in fully labeled cells. The number of foci increased with cell length. The distance of foci from the nearest cell pole has been measured in various length classes. The data suggest: i) that the two most outwardly located foci keep a constant distance to the cell pole and they therefore move apart gradually in line with cell elongation; and ii) that at the initiation of DNA replication the labeled origins occur near the center of prospective daughter cells.


[Idiopathic intracranial hypertension].
Idiopathic intracranial hypertension is a rare syndrome of increased intracranial pressure without a massive lesion or abnormal cerebrospinal fluid. Common symptoms include headache and visual disturbances such as transient visual obscurations or visual loss. Treatment may alleviate symptoms and prevent serious complications. In this study, we present 10 cases illustrating aspects of the disease including causes and treatment options. We also evaluated the effect of treatment and compared the incidence with other studies. We registered all patients and reviewed the medical notes on patients with intracranial hypertension treated at Tromsø University Hospital over a five-year period (1999-2003). We identified 10 patients with intracranial hypertension; 6 of them fulfilled the criteria of the International Headache Society for idiopathic intracranial hypertension while 4 had secondary intracranial hypertension caused by medication such as oral contraceptives or tetracycline, or by surgical therapy. Idiopathic or secondary intracranial hypertension should be considered in patients with unexplained chronic headache.


Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase.
Hypercholesterolemia is a central pathogenic factor of endothelial dysfunction caused in part by an impairment of endothelial nitric oxide (NO) production through mechanisms that remain poorly characterized. The activity of the endothelial isoform of NO synthase (eNOS) was recently shown to be modulated by its reciprocal interactions with the stimulatory Ca2+-calmodulin complex and the inhibitory protein caveolin. We examined whether hypercholesterolemia may reduce NO production through alteration of this regulatory equilibrium. Bovine aortic endothelial cells were cultured in the presence of serum obtained from normocholesterolemic (NC) or hypercholesterolemic (HC) human volunteers. Exposure of endothelial cells to the HC serum upregulated caveolin abundance without any measurable effect on eNOS protein levels. This effect of HC serum was associated with an impairment of basal NO release paralleled by an increase in inhibitory caveolin-eNOS complex formation. Similar treatment with HC serum significantly attenuated the NO production stimulated by the calcium ionophore A23187. Accordingly, higher calmodulin levels were required to disrupt the enhanced caveolin-eNOS heterocomplex from HC serum-treated cells. Finally, cell exposure to the low-density lipoprotein (LDL) fraction alone dose-dependently reproduced the inhibition of basal and stimulated NO release, as well as the upregulation of caveolin expression and its heterocomplex formation with eNOS, which were unaffected by cotreatment with antioxidants. Together, our data establish a new mechanism for the cholesterol-induced impairment of NO production through the modulation of caveolin abundance in endothelial cells, a mechanism that may participate in the pathogenesis of endothelial dysfunction and the proatherogenic effects of hypercholesterolemia.


Puncture site decision method for venipuncture robot based on near-infrared vision and multiobjective optimization.
Venipuncture robots have superior perception and stability to humans and are expected to replace manual venipuncture. However, their use is greatly restricted because they cannot make decisions regarding the puncture sites. Thus, this study presents a multi-information fusion method for determining puncture sites for venipuncture robots to improve their autonomy in the case of limited resources. Here, numerous images have been gathered and processed to establish an image dataset of human forearms for training the U-Net with the soft attention mechanism (SAU-Net) for vein segmentation. Then, the veins are segmented from the images, feature information is extracted based on near-infrared vision, and a multiobjective optimization model for puncture site decision is provided by considering the depth, diameter, curvature, and length of the vein to determine the optimal puncture site. Experiments demonstrate that the method achieves a segmentation accuracy of 91.2% and a vein extraction rate of 86.7% while achieving the Pareto solution set (average time: 1.458 s) and optimal results for each vessel. Finally, a near-infrared camera is applied to the venipuncture robot to segment veins and determine puncture sites in real time, with the results transmitted back to the robot for an attitude adjustment. Consequently, this method can enhance the autonomy of venipuncture robots if implemented dramatically.


Comparison of binding characteristics and in vitro activities of three inhibitors of vascular endothelial growth factor A.
The objectives of this study were to evaluate the relative binding and potencies of three inhibitors of vascular endothelial growth factor A (VEGF), used to treat neovascular age-related macular degeneration, and assess their relevance in the context of clinical outcome. Ranibizumab is a 48 kDa antigen binding fragment, which lacks a fragment crystallizable (Fc) region and is rapidly cleared from systemic circulation. Aflibercept, a 110 kDa fusion protein, and bevacizumab, a 150 kDa monoclonal antibody, each contain an Fc region. Binding affinities were determined using Biacore analysis. Competitive binding by sedimentation velocity analytical ultracentrifugation (SV-AUC) was used to support the binding affinities determined by Biacore of ranibizumab and aflibercept to VEGF. A bovine retinal microvascular endothelial cell (BREC) proliferation assay was used to measure potency. Biacore measurements were format dependent, especially for aflibercept, suggesting that biologically relevant, true affinities of recombinant VEGF (rhVEGF) and its inhibitors are yet to be determined. Despite this assay format dependency, ranibizumab appeared to be a very tight VEGF binder in all three formats. The results are also very comparable to those reported previously.1-3 At equivalent molar ratios, ranibizumab was able to displace aflibercept from preformed aflibercept/VEGF complexes in solution as assessed by SV-AUC, whereas aflibercept was not able to significantly displace ranibizumab from preformed ranibizumab/VEGF complexes. Ranibizumab, aflibercept, and bevacizumab showed dose-dependent inhibition of BREC proliferation induced by 6 ng/mL VEGF, with average IC50 values of 0.088 ± 0.032, 0.090 ± 0.009, and 0.500 ± 0.091 nM, respectively. Similar results were obtained with 3 ng/mL VEGF. In summary Biacore studies and SV-AUC solution studies show that aflibercept does not bind with higher affinity than ranibizumab to VEGF as recently reported,4 and both inhibitors appeared to be equipotent with respect to their ability to inhibit VEGF function.


Conformation of myosin interdomain interactions during contraction: deductions from muscle fibers using polarized fluorescence.
Myosin cross-bridge subfragment 1 (S1) is the ATP catalyzing motor protein in muscle. It consists of three domains that catalyze ATP and bind actin (catalytic), conduct energy transduction (converter), and transport the load (lever arm). Force development during contraction is thought to result from rotary lever arm movement with the cross-bridge attached to actin. To elucidate cross-bridge structure during force development, two crystal structures of S1 were extrapolated to working "in solution" or oriented "in tissue" forms, using structure-sensitive optical spectroscopic signals from two extrinsic probes. The probes were located at two interfaces containing the catalytic, converter, and lever arm domains of S1. Observed signals included circular dichroism (CD) and absorption originating from S1 in solution in the presence and absence of actin and fluorescence polarization from cross-bridges in muscle fibers. Theoretical signals were calculated from S1 crystal structure models perturbed with lever arm movement from swiveling at three conserved glycines, 699, 703, and 710 (chicken skeletal myosin numbering). Best agreement between the computed and observed signals gave structures showing that actin binding to S1 causes movement of the lever arm. A three-state model of S1 conformation during contraction consists of three actin-bound cross-bridge states observed from muscle fibers in isometric contraction, in the presence of MgADP, and in rigor. Structures best representing these states show that most of the lever arm rotation occurs between isometric contraction and the MgADP states, i.e., during phosphate release. Smaller but significant lever arm rotation occurs with ADP dissociation. Structural changes within the S1 interfaces studied are discussed in the accompanying paper [Burghardt et al. (2001) Biochemistry 40, 4834-4843].


Anti-tumor promoting activity of polyphenols from Cowania mexicana and Coleogyne ramosissima.
Chemical investigation on polyphenol-rich fractions of Cowania mexicana and Coleogyne ramosissima (Rosaceae) which showed significant inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), has led to the characterization of 10 compounds including C-glucosidic ellagitannin monomers and dimers from the former plant, and 17 polyphenols including flavonoid glycosides from the latter. The effects of individual components and their analogues with related structures on the TPA-induced EBV-EA activation were then evaluated. Among the compounds isolated from C. mexicana, two C-glucosidic ellagitannins, alienanin B and stenophyllanin A and a nitrile glucoside (lithospermoside), and among the constituents from C. ramosissima, two flavonoid glycosides, isorhamnetin 3-0-beta-D-glucoside and narcissin were revealed to possess strong inhibitory effects on EVB-EA activation, the potencies of which were either comparable to or stronger than that of a green tea polyphenol, (-)-epigallocatechin gallate. These polyphenols except for nitrile glucoside, which was not tested owing to an insufficient amount, were also found to exhibit anti-tumor promoting activity in two-stage mouse skin carcinogenesis using 7,12-dimethylbenz[a]anthracene (DMBA) and TPA.


Priorities for antiretroviral therapy research in sub-Saharan Africa: a 2002 consensus conference in Zambia.
A consensus conference was held to discuss priorities for antiretroviral therapy (ART) research in Zambia, one of the world's most heavily HIV-afflicted nations. Zambia, like other resource-limited settings, has increasing access to highly active antiretroviral therapy (HAART) because of declining drug costs, use of government-purchased generic medications, and increased global donations. For sustained delivery of care with HAART in a resource-constrained medical and public health context, operational research is required and clinical trials are desirable. The priority areas for research are most relevant today given the increasing availability of HAART. A conference was held in Lusaka, Zambia, in January 2002 to discuss priority areas for ART research in Zambia, with participants drawn from a broad cross section of Zambian society. State-of-the-art reviews and 6 intensive small group discussions helped to formulate a suggested research agenda. Conference participants believed that the most urgent research priorities were to assess how therapeutic resources could be applied for the greatest overall benefit and to minimize the impact of nonadherence and viral resistance. Identified research priorities were as follows:Conference participants recommended that HIV-related clinical care and research be integrated within home-based care services and operated within the existing health delivery structures to ensure sustainability, reduce costs, and strengthen the structures. Our consensus was that antiretroviral clinical trials and operational research are essential for Zambia to address the new challenges arising from increasing ART availability. There is global consensus that antiretroviral clinical trials in resource-constrained countries are possible, and the capacity for such trials should be developed further in Africa.


Cell-substrate contacts in cultured chick embryonic cells: an interference reflection study.
Cell-substrate contacts in explants of different regions of early chick tissues were investigated using the technique of interference reflection microscopy. All the explants spread as epithelial sheets. During initial spreading a peripheral zone of 2-3 cells formed broad contacts with the substrate. In spread explants some cells in the centre made broad substrate contacts. A mat of extracellular material containing fibronectin was found under the explants. Focal contacts and focal adhesions increased in number during culture, and stress fibres were associated with them. These changes in cell contacts appeared more quickly in some tissues than in others. After 24 h, explants of hypoblast and definitive endoblast could easily be distinguished but by 7 days they were very similar. In the absence of serum, specialized cell contacts developed more quickly; in higher concentrations of serum, more slowly. Confrontations between explants were also examined. The most conspicuous feature was that cells in invading explants normally underlapped invaded cells. Invasion from above by an unspread explant could occur even if the invaded explant had formed many focal adhesions.


Genu valgum deformity - correction by a wedgeless implantless femoral "V" osteotomy.
Coronal malalignment of the knee joint is very common in developing countries especially because of nutritional rickets. Significant valgus deformity needs to be treated surgically to improve appearance, gait and function of the patient. The purpose of this prospective study was to evaluate the results of supracondylar "V" osteotomy as a surgical technique for correction of the valgus knee deformity. This study was conducted in a tertiary level teaching hospital and 30 cases were included in the study. For all the patients deformity was assessed using ana- tomical tibiofemoral angle, mechanical axis deviation and intermalleolar distance preoperatively and post- operatively. The average age of our patients was 13.7 years and the average follow up was3.29 years (1.39-14.22 yrs). Clinically the average value of intermalleolar distance preoperatively was 16cm and 3.2 cm postperatively. Average pre-operative tibiofemoral angle was 23° and the average postoperative angle was 6 0 which was found to be statistically significant using the Paired t test (p<0.005). The average value of preoperative mechanical axis deviation was 3.1 cm which decreased to an average value of 1.1 cm postoperatively. The results with this technique have been encouraging. The advantages of this technique are low morbidity, good stability allowing early ambulation, ability to adjust alignment postoperatively by casting and no need for internal fixation. Few studies have been conducted on osteotomies that do not require internal fixation and are inherently stable. This technique has the advantage of practically no occurrence of any infection or a second surgery to remove hardware in children and adolescents. Since no specialized instrumentation, image intensifier and implants are required, it is cost effective and can be used in any primary care or district level surgical setup in a developing country like ours.


Purification and chemical characterization of the heat-stable enterotoxin produced by porcine strains of enterotoxigenic Escherichia coli.
Heat-stable enterotoxin (ST) produced by porcine strains of enterotoxigenic (ENT+) Escherichia coli has been purified to apparent homogeneity by sequential ultrafiltration, acetone fractionation, preparative gel electrophoresis, diethylaminoethyl Bio-Gel A ion-exchange chromatography, and Bio-Gel P-10 gel filtration. The enterotoxin, purified more than 1,500-fold, exhibited a molecular weight of 4,400, as determined by both sodium dodecyl sulfate-gel electrophoresis and gel filtration. A molecular weight of 5,100, representing 47 residues, was calculated from amino acid analysis data. The amino acid content was distinctive, with an unusually high proportion of cystines and few hydrophobic amino acids. A single amino-terminal residue, glycine, was observed. Purified ST was stable to heating (100 degrees C, 30 min) and did not lose biological activity after treatment with Pronase, trypsin, proteinase K, deoxyribonuclease, ribonuclease, and phospholipase C. Periodic acid oxidation and several organic solvents (acetone, phenol, chloroform, and methanol) had no effect on the biological activity of ST. Further, purified ST was stable to acid treatment at pH 1.0 but lost biological activity at pH values greater than 9.0. Neither lipopolysaccharide nor lipid contamination was evident in purified preparations. A characteristic absorption spectrum was observed during the course of the purification, which shifted from a maximum at 260 nm in crude preparations to 270 nm for the purified toxin. Antiserum obtained from rabbits immunized with ST or ST coupled to bovine serum albumin neutralized the action of the enterotoxin in suckling mice; however, passive hemagglutination and hemolysis titer assays suggested that ST is a poor antigen.


Innervated human corneal equivalents as in vitro models for nerve-target cell interactions.
A sensory nerve supply is crucial for optimal tissue function. However, the mechanisms for successful innervation and the signaling pathways between nerves and their target tissue are not fully understood. Engineered tissue substitutes can provide controllable environments in which to study tissue innervation. We have therefore engineered human corneal substitutes that promote nerve in-growth in a pattern similar to in vivo re-innervation. We demonstrate that these nerves (a) are morphologically equivalent to natural corneal nerves; (b) make appropriate contact with target cells; (c) can generate action potentials; (d) respond to chemical and physical stimuli; and (e) play an important role in the overall functioning of the bioengineered tissue. This model can be used for studying the more general topics of nerve ingrowth or regeneration and the interaction between nerves and their target cells and, more specifically, the role of nerves in corneal function. This model could also be used as an in vitro alternative to animals for safety and efficacy testing of chemicals and drugs.


Effect of silver nanoparticles synthesized by gamma radiation on the cytotoxicity of doxorubicin in human cancer cell lines and experimental animals.
Silver nanoparticles (AgNPs)embedded poly ( N-vinylpyrrolidone/dextran) hydrogels were prepared by gamma radiation. Highly stable and uniformly distributed AgNPs have been obtained within hydrogel networks as nanoreactors via in situ reduction of silver nitrate using sodium borohydride as reducing agent. The formation of AgNPs has been confirmed by Fourier transform infrared spectroscopy. The ultraviolet-visible spectroscopy measurements show a distinct characteristic absorption peaks around 420 nm, indicating the formation of AgNPs. X-ray diffraction analysis and dynamic light scattering demonstrated that the hydrogels have regulated the AgNPs size to a nanoscale. The combination of the AgNPs with doxorubicin (DOX) as a model of antitumor drug forms a new biocompatible nanodrug. Our results show that the AgNPs effectively increased survival rate and decreased tumor volume of Ehrlich ascites carcinoma-bearing mice more than the DOX-treated group and enhanced the cytotoxicity of DOX in different human cancer cell lines (HepG2, T47D, and PC3). DOX-AgNPs decreased malondialdehyde and total nitrate/nitrite levels and increased superoxide dismutase activity and glutathione content in the rat cardiac tissues compared with the DOX-treated group. In conclusion, DOX-AgNPs improved therapeutic index and reduced DOX-induced cardiotoxicity via preservation of cardiac markers, which represents a promising candidate for cancer treatment.


A stable miniature protein with oxaloacetate decarboxylase activity.
An 18-residue miniature enzyme, Apoxaldie-1, has been designed, based on the known structure of the neurotoxic peptide apamin. Three lysine residues were introduced on the solvent-exposed face of the apamin alpha-helix to serve as an active site for decarboxylation of oxaloacetate. The oxidised form of Apoxaldie-1, in which two disulfide bonds stabilise the alpha-helix, formed spontaneously. CD spectroscopy measurements revealed that, in its oxidised form, Apoxaldie-1 adopted a stably folded structure, which was lost upon reduction of the disulfide bonds. Despite its small size and the absence of a designed binding pocket, Apoxaldie-1 displayed saturation kinetics in its oxidised form and catalysed the decarboxylation of oxaloacetate at a rate that was almost four orders of magnitude faster than that observed with n-butylamine. This rivals the performance of the best synthetic oxaloacetate decarboxylases reported to date. Unlike those, however, Apoxaldie-1 displayed significant stability. It maintained its secondary structure at temperatures in excess of 75 degrees C, in the presence of high concentrations of guanidinium chloride and at pH values as low as 2.2. Apamin-based catalysts have potential for the generation of miniature peptides that display activity under nonphysiological conditions.


Involuntary attentional capture is determined by task set: evidence from event-related brain potentials.
To find out whether attentional capture by irrelevant but salient visual objects is an exogenous bottom-up phenomenon, or can be modulated by current task set, two experiments were conducted where the N2pc component was measured as an electrophysiological marker of attentional selection in response to spatially uninformative color singleton cues that preceded target arrays. When observers had to report the orientation of a uniquely colored target bar among distractor bars (color task), behavioral spatial cueing effects were accompanied by an early cue-induced N2pc, indicative of rapid attentional capture by color singleton cues. In contrast, when they reported the orientation of target bars presented without distractors (onset task), no behavioral cueing effects were found and no early N2pc was triggered to physically identical cue arrays. Experiment 2 ruled out an alternative interpretation of these N2pc differences in terms of distractor inhibition. These results do not support previous claims that attentional capture is initially unaffected by top-down intention, and demonstrate the central role of task set in involuntary attentional orienting.


Medawar redux - an overview on the use of farm animal models to elucidate principles of reproductive immunology.
Farm animals have been important models for the development of reproductive immunology. Two of the major concepts underpinning reproductive immunology, the idea of the fetal allograft and progesterone's role in regulation of uterine immunity, were developed using the bovine as a model. This volume of the American Journal of Reproductive Immunology is composed of review articles that highlight the continued relevance of farm animals as models for research in mammalian biology. It is important that a diverse array of genotypes are used to elucidate biological principles relevant to mammalian biology and human health because the nature of mammalian evolution has resulted in a situation where the genome of the most commonly used animal model, the laboratory mouse, is less similar to the human than other species like the cow. Moreover, the evolution of placental function has been accompanied by formation of new genes during recent evolution so that orthologs do not exist in any but closely related species. Given the infrastructure needs to study farm animal species, optimal utilization of these animals as models for biomedical research will require significant increases in funding to reverse a historical erosion of resources devoted to animal agricultural research.


Non-symbolic numerosity encoding escapes spatial frequency equalization.
The exact visual mechanisms underpinning the approximate number system are still debated. Recent evidence suggests that numerosity is extracted on segmented visual objects, at least for a moderate numerical range (e.g., < 100 items), whereas alternative models rather propose that numerosity is derived from low-level features (e.g., power spectrum) of an unsegmented image, independently from the range. Here, to disentangle these accounts, we generated stimuli that were equalized for spatial frequency amplitude spectrum and luminance across sets of moderate range numerosities (e.g., 9-15 dots), while independently manipulating the perceived item segmentation by connecting dots with illusory contours (ICs). In Experiment 1, participants performed a numerical discrimination task, in which they had to select the numerically larger between two stimuli: a reference stimulus (always 12 dots) and a test stimulus (from 9 to 15 dots) containing 0, 2 or 4 pairs of dots grouped by ICs lines. In Experiment 2, participants were presented only the test stimulus and performed an estimation task. Results clearly showed that in both experiments participants' performance followed well-known numerical signatures (e.g., distance effect and scalar variability), with numerosity that was underestimated as the illusory connections increased. Crucially, this was found despite spatial frequencies and luminance were kept constant across all the experimental stimuli and these variables were thus uninformative about numerosity. Taken together, these findings indicate that power spectrum in its own cannot explain numerical processing. Rather, visual segmentation mechanisms may be crucial in such processing at least for a moderate numerosity range.


Femtosecond linear dichroism of DNA-intercalating chromophores: solvation and charge separation dynamics of [Ru(phen)2dppz]2+ systems.
The DNA-intercalating chromophore [Ru(phen)(2)dppz](2+) has unique photophysical properties, the most striking of which is the "light-switch" characteristic when binding to DNA. As a dimer, it acts as a molecular staple for DNA, exhibiting a remarkable double-intercalating topology. Herein, we report femtosecond dynamics of the monomeric and the covalently linked dimeric chromophores, both free in aqueous solution and complexed with DNA. Transient absorption and linear dichroism show the electronic relaxation to the lowest metal-to-ligand charge-transfer (CT) state, and subpicosecond kinetics have been observed for this chromophore for what is, to our knowledge, the first time. We observe two distinct relaxation processes in aqueous solution with time constants of 700 fs and 4 ps. Interestingly, these two time constants are very similar to those observed for the reorientational modes of bulk water. The 700-fs process involves a major dichroism change. We relate these observations to the change in charge distribution and to the time scales involved in solvation of the CT state. Slower processes, with lifetimes of approximately 7 and 37 ps, were observed for both monomer and dimer when bound to DNA. Such a difference can be ascribed to the change of the structural and electronic relaxation experienced in the DNA intercalation pocket. Finally, the recombination lifetime of the final metal-to-ligand CT state to the ground state, which is a key in the light-switch process, is found in aqueous solution to be sensitive to structural modification, ranging from 260 ps for [Ru(phen)(2)dppz](2+) and 360 ps for the monomer chromophore derivative to 2.0 ns for the dimer. This large change reflects the direct role of solvation in the light-switch process.


Acoustic bubble for spheroid trapping, rotation, and culture: a tumor-on-a-chip platform (ABSTRACT platform).
Cancer is the leading cause of death globally, with 90% of deaths being caused by cancer metastasis. Circulating tumor cells (CTCs) play an important role in early diagnosis of cancer metastasis and in monitoring of therapeutic response. Therefore, reliable methods to isolate, collect and culture CTCs are required to obtain information on metastasis status and therapeutic treatment. In this work, we present a CTC-processing system: acoustic bubble for spheroid trapping, rotation, and culture: a tumor-on-a-chip platform (ABSTRACT). The platform consists of a main channel, several parallel sub-microchannels with microcavities and culture chambers. The microcavity is designed to trap a bubble with desired shape at the entrance of the sub-microchannel. Under the acoustic actuation, the trapped bubble oscillates and creates a secondary radiation force to trap and rotate CTCs at a desired location. By controlling the acoustic bubble, CTCs can be continuously trapped from the blood flow, rotated to form a spheroid, and released to the microchamber for culture. We systematically investigated the effects of device geometry, flow parameters, and input voltage on trapping of CTCs to optimize the performance. Additionally, the successful on-chip spheroid culture demonstrates the biocompatibility and the simplicity of this platform. Besides simplifying conventional complex CTC processing procedures, this ABSTRACT platform also shows great potential for downstream analysis of tumor cells, such as monitoring the progression of metastasis and personalized drug testing.


Variation in antibiotic treatment for diabetic patients with serious foot infections: a retrospective observational study.
Diabetic foot infections are common, serious, and diverse. There is uncertainty about optimal antibiotic treatment, and probably substantial variation in practice. Our aim was to document whether this is the case: A finding that would raise questions about the comparative cost-effectiveness of different regimens and also open the possibility of examining costs and outcomes to determine which should be preferred. We used the Veterans Health Administration (VA) Diabetes Epidemiology Cohorts (DEpiC) database to conduct a retrospective observational study of hospitalized patients with diabetic foot infections. DEpiC contains computerized VA and Medicare patient-level data for VA patients with diabetes since 1998, including demographics, ICD-9-CM diagnostic codes, antibiotics prescribed, and VA facility. We identified all patients with ICD-9-CM codes for cellulitis/abscess of the foot and then sub-grouped them according to whether they had cellulitis/abscess plus codes for gangrene, osteomyelitis, skin ulcer, or none of these. For each facility, we determined: 1) The proportion of patients treated with an antibiotic and the initial route of administration; 2) The first antibiotic regimen prescribed for each patient, defined as treatment with the same antibiotic, or combination of antibiotics, for at least 5 continuous days; and 3) The antibacterial spectrum of the first regimen. We identified 3,792 patients with cellulitis/abscess of the foot either alone (16.4%), or with ulcer (32.6%), osteomyelitis (19.0%) or gangrene (32.0%). Antibiotics were prescribed for 98.9%. At least 5 continuous days of treatment with an unchanged regimen of one or more antibiotics was prescribed for 59.3%. The means and (ranges) across facilities of the three most common regimens were: 16.4%, (22.8%); 15.7%, (36.1%); and 10.8%, (50.5%). The range of variation across facilities proved substantially greater than that across the different categories of foot infection. We found similar variation in the spectrum of the antibiotic regimen. The large variations in regimen appear to reflect differences in facility practice styles rather than case mix. It is unlikely that all regimens are equally cost-effective. Our methods make possible evaluation of many regimens across many facilities, and can be applied in further studies to determine which antibiotic regimens should be preferred.


Neonatal diaphragmatic hernia. An improving outlook with extracorporeal membrane oxygenation.
In a 15-year period, 89 newborns were treated for congenital diaphragmatic hernia. The patients were divided into three groups, depending on postoperative therapeutic support available: group 1, ventilator therapy only; group 2, ventilator therapy plus pulmonary vasodilators (tolazoline hydrochloride); and group 3, ventilators, tolazoline, and/or extracorporeal membrane oxygenation (ECMO). The three groups were identical for presenting symptoms, signs, and preoperative blood gas determinations. The survival for each group was as follows: group 1, 17 (40%) of 42; group 2, 14 (45%) of 31; and group 3, 12 (75%) of 16. Complications requiring further operations were identical. All survivors in groups 1 and 2 are normal developmentally, while one of five group 3 ECMO survivors has developmental delay and another has long-term ventilator dependence. These data suggest that ECMO, an invasive technique for newborn respiratory failure, improves survival in congenital diaphragmatic hernia.


Simple Structure Detection Through Bayesian Exploratory Multidimensional IRT Models.
In modern validity theory, a major concern is the construct validity of a test, which is commonly assessed through confirmatory or exploratory factor analysis. In the framework of Bayesian exploratory Multidimensional Item Response Theory (MIRT) models, we discuss two methods aimed at investigating the underlying structure of a test, in order to verify if the latent model adheres to a chosen simple factorial structure. This purpose is achieved without imposing hard constraints on the discrimination parameter matrix to address the rotational indeterminacy. The first approach prescribes a 2-step procedure. The parameter estimates are obtained through an unconstrained MCMC sampler. The simple structure is, then, inspected with a post-processing step based on the Consensus Simple Target Rotation technique. In the second approach, both rotational invariance and simple structure retrieval are addressed within the MCMC sampling scheme, by introducing a sparsity-inducing prior on the discrimination parameters. Through simulation as well as real-world studies, we demonstrate that the proposed methods are able to correctly infer the underlying sparse structure and to retrieve interpretable solutions.


Development and psychopathology of children with the fetal alcohol syndrome.
Extended psychiatric and pediatric examinations were performed on patients with the fetal alcohol syndrome (FAS). A subgroup of these patients underwent psychological testing to measure intelligence, visual perception, and psycholinguistic abilities. Psychopathology was also studied in a matched control group. The investigation revealed a broad scale of developmental hazards and psychopathologic symptoms indicating the negative long-range effects of alcohol abuse during pregnancy. The extent of morphologic damage was found to be a good predictor of psychopathology and mental impairment. Social environment and socioeconomic status appear less important as predictors.


A modular system for the synchronized multimodal data acquisition during Awake Surgery: towards the emergence of a dedicated clinical database.
Awake Surgery (AS) is considered the best treatment for brain tumors located in or near eloquent areas. During this intervention, Direct Electrical Stimulations (DES) are delivered by the surgeon on the patient's brain in order to obtain an accurate brain mapping of the patient. The patient is asked to perform various tasks (e.g. counting, object naming, emotion recognition) through neuropsychological tests during these stimulations. These DES may cause a reversible lesion inducing deficits on the patient which can be observed during these tasks by the medical staff. The resection is then performed or not according to the patient's response. The intraoperative deficits can take several forms and can be difficult to analyze and identify. The development of new solutions allowing the automatic detection of these deficits could be therefore essential. However, still today, no structured and organized AS dedicated database is available that could be used to train and test these algorithms. We propose a modular system allowing the synchronized multimodal acquisition of various information including physiological measurements, DES signals and parameters, and task-related data to create such database.Clinical relevance- Acquiring synchronized multimodal data during AS will allow the creation of a dedicated database that could then be used to reveal new correlations between DES and the patient's response, and to develop and test new algorithms for the automatic detection of deficits.


[A simple highly sensitive recording microspectrophotometer].
A design of the recording microspectrophotometer is described. The instrument possesses an absolutely flat base line and quantum-noise limited detection threshold. Two principal elements of the design are the "jumping" stage, and the logarithmic amplifier with the phase-sensitive detector which converts the photomultiplier output into the optical density signal. The performance of the instrument is illustrated by the recordings of visual pigment spectra in single photoreceptors.


Receptive field center size decreases and firing properties mature in ON and OFF retinal ganglion cells after eye opening in the mouse.
Development of the mammalian visual system is not complete at birth but continues postnatally well after eye opening. Although numerous studies have revealed changes in the development of the thalamus and visual cortex during this time, less is known about the development of response properties of retinal ganglion cells (RGCs). Here, we mapped functional receptive fields of mouse RGCs using a Gaussian white noise checkerboard stimulus and a multielectrode array to record from retinas at eye opening, 3 days later, and 4 wk after birth, when visual responses are essentially mature. Over this time, the receptive field center size of ON and OFF RGC populations decreased. The average receptive field center size of ON RGCs was larger than that of OFF RGCs at eye opening, but they decreased to the same size in the adult. Firing properties were also immature at eye opening. RGCs had longer latencies, lower frequencies of firing, and lower sensitivity than in the adult. Hence, the dramatic maturation of the visual system during the first weeks of visual experience includes the retina.


The coverage of continuum of care in maternal, newborn and child health: a cross-sectional study of woman-child pairs in Ghana.
The continuum of care has recently received attention in maternal, newborn and child health. It can be an effective policy framework to ensure that every woman and child receives timely and appropriate services throughout the continuum. However, a commonly used measurement does not evaluate if a pair of woman and child complies with the continuum of care. This study assessed the continuum of care based on two measurements: continuous visits to health facilities (measurement 1) and receiving key components of services (measurement 2). It also explored individual-level and area-level factors associated with the continuum of care achievement and then investigated how the continuum of care differed across areas. In this cross-sectional study in Ghana in 2013, the continuum of care achievement and other characteristics of 1401 pairs of randomly selected women and children were collected. Multilevel logistic regression was used to estimate the factors associated with the continuum of care and its divergence across 22 areas. Throughout the pregnancy, delivery and post-delivery stages, 7.9% of women and children achieved the continuum of care through continuous visits to health facilities (measurement 1). Meanwhile, 10.3% achieved the continuum of care by receiving all key components of maternal, newborn and child health services (measurement 2). Only 1.8% of them achieved it under both measurements. Women and children from wealthier households were more likely to achieve the continuum of care under both measurements. Women's education and complications were associated with higher continuum of care services-based achievement. Variance of a random intercept was larger in the continuum of care services-based model than the visit-based model. Most women and children failed to achieve the continuum of care in maternal, newborn and child health. Those who consistently visited health facilities did not necessarily receive key components of services.


Meeting fisheries, ecosystem function, and biodiversity goals in a human-dominated world.
The worldwide decline of coral reefs necessitates targeting management solutions that can sustain reefs and the livelihoods of the people who depend on them. However, little is known about the context in which different reef management tools can help to achieve multiple social and ecological goals. Because of nonlinearities in the likelihood of achieving combined fisheries, ecological function, and biodiversity goals along a gradient of human pressure, relatively small changes in the context in which management is implemented could have substantial impacts on whether these goals are likely to be met. Critically, management can provide substantial conservation benefits to most reefs for fisheries and ecological function, but not biodiversity goals, given their degraded state and the levels of human pressure they face.


Physiology of weight-lifting exercise.
This review describes the major features of skeletal muscle adaptation to weight-lifting exercise. Changes in contraction time, fiber size, and possibly fiber number may result in response to prolonged weight-training. Effective strength-training programs, both for athletics and rehabilitation, require recognition of the concept of "specificity of training," realization of the tendency of human skeletal muscle to adapt differently to different forms of physiologic stress.


Does pravastatin promote cancer in elderly patients? A meta-analysis.
An increase in the incidence of cancer among elderly people assigned to pravastatin therapy has been reported in a randomized controlled trial; however, this finding has been attributed to chance. Our aim was to assess the effect of pravastatin therapy on cancer risk and to examine whether the effect varies according to age by performing a detailed meta-analysis and meta-regression analysis of randomized controlled trials. We performed a comprehensive literature search for relevant studies published before February 2006. Before analysis, the selected studies were evaluated for publication bias and heterogeneity. Pooled relative risk estimates with 95% confidence intervals (CIs) were calculated using fixed-and random-effects models. Meta-regression analysis was performed to examine the impact of age on the study estimates of the relative risk of cancer due to pravastatin therapy. Twelve trials that investigated the use of pravastatin therapy for cardiovascular outcomes were included in the analysis (n = 42 902). Although the overall association between pravastatin use and cancer was not statistically significant in the fixed-effects (risk ratio [RR] 1.06, 95% CI 0.99 - 1.13) or random-effects model (RR 1.06, 95% CI 0.97 - 1.14), the meta-regression analysis showed that the age of study participants significantly modified the effect of pravastatin therapy on cancer risk (p = 0.006). Specifically, this analysis showed that pravastatin therapy was associated with an increasing risk of cancer as age increased. This finding was remarkably robust in the sensitivity analysis. Our findings suggest an association between pravastatin therapy and cancer in elderly patients. However, given the importance of this potential association, further verification is warranted.


[Choriocarcinoma of the uterine cervix and cervical pregnancy].
Case report of a 20-year-old women with a chorionic carcinoma of the uterine cervix. Subsequently, the aspects of the disease of chorionic carcinoma and cervical pregnancy are discussed, including epidemiology, aetiology, diagnosis and management. Finally, the conclusions of this discussion are compared with the case report.


Dairy products and cancer.
Cancer is a group of more than 100 diseases in which cells display uncontrolled growth, invasion, and sometimes metastasis. Milk and dairy products contain micronutrients and several bioactive constituents that may influence cancer risk and progression. Much of the focus of human, population-based studies has been on the effects of intake of milk and total dairy products or of calcium intake. Based on a systematic review of the epidemiologic literature, the World Cancer Research Fund and American Institute for Cancer Research report concluded there was a probable association between milk intake and lower risk of colorectal cancer, a probable association between diets high in calcium and increased risk of prostate cancer, and limited evidence of an association between milk intake and lower risk of bladder cancer. For other cancers, the evidence was mixed or lacking. Since the 2007 report, several additional, large-cohort studies have been published, including two that show an inverse association between intake of cultured dairy products and bladder cancer. Little is known about the potential effect of various bioactives produced during rumen microbe metabolism on cancer risk. Furthermore, studies support a role of live microbes present in some dairy products in the modulation of the human gut microbial community and gut metabolism. Given the growing appreciation for the role of the gut microbial community in relation to immune function and health and disease, including cancer, the potential role of various dairy products in the modulation of the human gut microbiome warrants further evaluation. Key teaching points: As a dietary exposure, dairy products are a complex group of foods and composition varies by region, which makes evaluation of their association with disease risk difficult. For most cancers, associations between cancer risk and intake of milk and dairy products have been examined only in a small number of cohort studies, and data are inconsistent or lacking. Meta-analyses of cohort data available to date support an inverse association between milk intake and risk of colorectal and bladder cancer and a positive association between diets high in calcium and risk of prostate cancer. Other constituents of dairy products, such as rumen-derived metabolites, have not been evaluated extensively for cancer-preventive properties. The influence of live microbes in fermented dairy products and certain cheeses on the human gut microbiome and immune function is a growing area of study.


Anatomical and biomechanical traits of broiler chickens across ontogeny. Part I. Anatomy of the musculoskeletal respiratory apparatus and changes in organ size.
Genetic selection for improved meat yields, digestive efficiency and growth rates have transformed the biology of broiler chickens. Modern birds undergo a 50-fold multiplication in body mass in just six weeks, from hatching to slaughter weight. However, this selection for rapid growth and improvements in broiler productivity is also widely thought to be associated with increased welfare problems as many birds suffer from leg, circulatory and respiratory diseases. To understand growth-related changes in musculoskeletal and organ morphology and respiratory skeletal development over the standard six-week rearing period, we present data from post-hatch cadaveric commercial broiler chickens aged 0, 2, 4 and 6 weeks. The heart, lungs and intestines decreased in size for hatch to slaughter weight when considered as a proportion of body mass. Proportional liver size increased in the two weeks after hatch but decreased between 2 and 6 weeks. Breast muscle mass on the other hand displayed strong positive allometry, increasing in mass faster than the increase in body mass. Contrastingly, less rapid isometric growth was found in the external oblique muscle, a major respiratory muscle that moves the sternum dorsally during expiration. Considered together with the relatively slow ossification of elements of the respiratory skeleton, it seems that rapid growth of the breast muscles might compromise the efficacy of the respiratory apparatus. Furthermore, the relative reduction in size of the major organs indicates that selective breeding in meat-producing birds has unintended consequences that may bias these birds toward compromised welfare and could limit further improvements in meat-production and feed efficiency.


HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum.
Vascular endothelial growth factor (VEGF)-dependent angiogenesis is essential for normal luteal development. Although it is believed that hypoxia is the primary inducer of VEGF, in the corpus luteum it is up-regulated by human chorionic gonadotrophin (hCG). As hypoxia-inducible factor (HIF)1A has been shown to regulate VEGFA under ligand-stimulated conditions, we hypothesized that the effect of hCG on luteal VEGFA was mediated through HIF1A. We studied the effect of hCG on VEGFA and HIF1A expression in human luteinized granulosa cells in vitro and in human corpora lutea in vivo. HCG up-regulated VEGFA (P < 0.05) and HIF1A (P < 0.001) in vitro and VEGFA (P < 0.05) and HIF1A (P < 0.05) in vivo. There was a correlation between HIF1A and VEGFA in vivo (P < 0.005) and in vitro (P < 0.05). Nuclear HIF1A in granulosa-lutein cells was highest during luteal formation and absent from the fully functional corpus luteum (P < 0.05). Both VEGFA (P < 0.001) and HIF1A (P < 0.01) were up-regulated by dibutyryl-cAMP, through a PKA pathway. Hypoxia increased VEGFA (P < 0.001) and HIF1A (P < 0.05) expression and hCG further augmented VEGFA (P < 0.001) and HIF1A (P < 0.01) under hypoxic conditions. However, progesterone increased hCG-stimulated VEGFA but had no effect on HIF1A expression. The expression of HIF1A is therefore hormonally regulated in luteal cells in vitro and in vivo and may regulate VEGFA expression under normoxic and hypoxic conditions. However, the differential effects of progesterone suggest that not all regulation of VEGFA is associated with an up-regulation of HIF1A.


Co-delivery of VEGF siRNA and Etoposide for Enhanced Anti-angiogenesis and Anti-proliferation Effect via Multi-functional Nanoparticles for Orthotopic Non-Small Cell Lung Cancer Treatment.
Targeting tumor angiogenesis pathway via VEGF siRNA (siVEGF) has shown great potential in treating highly malignant and metastatic non-small cell lung cancer (NSCLC). However, anti-angiogenic monotherapy lacked sufficient antitumor efficacy which suffered from malignant tumor proliferation. Therefore, the combined application of siVEGF and chemotherapeutic agents for simultaneous targeting of tumor proliferation and angiogenesis has been a research hotspot to explore a promising NSCLC therapy regimen. Methods: We designed, for the first time, a rational therapy strategy via intelligently co-delivering siVEGF and chemotherapeutics etoposide (ETO) by multi-functional nanoparticles (NPs) directed against the orthotopic NSCLC. These NPs consisted of cationic liposomes loaded with siVEGF and ETO and then coated with versatile polymer PEGylated histidine-grafted chitosan-lipoic acid (PHCL). We then comprehensively evaluated the anti-angiogenic and anti-proliferation efficiency in the in vitro tumor cell model and in bioluminescent orthotopic lung tumor bearing mice model. Results: The NPs co-delivering siVEGF and ETO exhibited tailor-made surface charge reversal features in mimicking tumor extracellular environment with improved internal tumor penetration capacity and higher cellular internalization. Furthermore, these NPs with flexible particles size triggered by intracellular acidic environment and redox environment showed pinpointed and sharp intracellular cargo release guaranteeing adequate active drug concentration in tumor cells. Enhanced VEGF gene expression silencing efficacy and improved tumor cell anti-proliferation effect were demonstrated in vitro. In addition, the PHCL layer improved the stability of these NPs in neutral environment allowing enhanced orthotopic lung tumor targeting efficiency in vivo. The combined therapy by siVEGF and ETO co-delivered NPs for orthotopic NSCLC simultaneously inhibited tumor proliferation and tumor angiogenesis resulting in more significant suppression of tumor growth and metastasis than monotherapy. Conclusion: Combined application of siVEGF and ETO by the multi-functional NPs with excellent and on-demand properties exhibited the desired antitumor effect on the orthotopic lung tumor. Our work has significant potential in promoting combined anti-angiogenesis therapy and chemotherapy regimen for clinical NSCLC treatment.


Population Dynamics and Parasite Load of a Foraminifer on Its Antarctic Scallop Host with Their Carbonate Biomass Contributions.
We studied the population dynamics and parasite load of the foraminifer Cibicides antarcticus on its host the Antarctic scallop Adamussium colbecki from three localities differing by sea ice cover within western McMurdo Sound, Ross Sea, Antarctica: Explorers Cove, Bay of Sails and Herbertson Glacier. We also estimated CaCO3 biomass and annual production for both species. Cibicides populations varied by locality, valve type, and depth. Explorers Cove with multiannual sea ice had larger populations than the two annual sea ice localities, likely related to differences in nutrients. Populations were higher on Adamussium top valves, a surface that is elevated above the sediment. Depth did not affect Cibicides distributions except at Bay of Sails. Cibicides parasite load (the number of complete boreholes in Adamussium valves) varied by locality between 2% and 50%. For most localities the parasite load was < 20%, contrary to a previous report that ~50% of Cibicides were parasitic. The highest and lowest parasite load occurred at annual sea ice localities, suggesting that sea ice condition is not important. Rather, the number of adults that are parasitic could account for these differences. Cibicides bioerosion traces were categorized into four ontogenetic stages, ranging from newly attached recruits to parasitic adults. These traces provide an excellent proxy for population structure, revealing that Explorers Cove had a younger population than Bay of Sails. Both species are important producers of CaCO3. Cibicides CaCO3 biomass averaged 47-73 kg ha(-1) and Adamussium averaged 4987-6806 kg ha(-1) by locality. Annual production rates were much higher. Moreover, Cibicides represents 1.0-2.3% of the total host-parasite CaCO3 biomass. Despite living in the coldest waters on Earth, these species can contribute a substantial amount of CaCO3 to the Ross Sea and need to be incorporated into food webs, ecosystem models, and carbonate budgets for Antarctica.


Alterations in intrahepatic hemodynamics of the harvested porcine liver.
Hemodynamic properties of a donor liver, during initial reperfusion, are associated with the degree of graft preservation injury and have been proposed to correlate with subsequent markers of liver function. In the present study, hepatic hemodynamics, that is, portal venous pressure, hepatic vascular resistance, and compliance (vascular distensibility), were characterized (1) in situ before porcine livers were manipulated, (2) after these same livers were isolated and perfused within a bypass circuit, and (3) on reperfusion after 2 hours of cold ischemia. Hepatic vascular resistance was determined in each of these three states from the portal vein pressure response to differing hepatic blood flows. In addition, the response of the same livers to norepinephrine and nitroprusside was evaluated in each condition. In the in situ and isolated perfused liver, portal venous pressure increased only modestly despite doubling of hepatic flows. After cold ischemia, the pressure response to higher flows was significantly greater and much less of a reduction in hepatic vascular resistance was noted than in studies prior to cold ischemia. Unlike livers prior to cold ischemia, the pressure response to norepinephrine was attenuated following cold ischemia. The response to nitroprusside, however, remained intact reducing the portal pressure to that of in situ livers. Therefore the portal hypertension that follows cold ischemia appears to be largely provoked by the preservation injury and not by surgical manipulation or the bypass circuit. This increment in portal pressure is responsive to a nitric oxide donor.


The shaping and functional consequences of the dosage effect landscape in multiple myeloma.
Multiple myeloma (MM) is a malignant proliferation of plasma B cells. Based on recurrent aneuploidy such as copy number alterations (CNAs), myeloma is divided into two subtypes with different CNA patterns and patient survival outcomes. How aneuploidy events arise, and whether they contribute to cancer cell evolution are actively studied. The large amount of transcriptomic changes resultant of CNAs (dosage effect) pose big challenges for identifying functional consequences of CNAs in myeloma in terms of specific driver genes and pathways. In this study, we hypothesize that gene-wise dosage effect varies as a result from complex regulatory networks that translate the impact of CNAs to gene expression, and studying this variation can provide insights into functional effects of CNAs. We propose gene-wise dosage effect score and genome-wide karyotype plot as tools to measure and visualize concordant copy number and expression changes across cancer samples. We find that dosage effect in myeloma is widespread yet variable, and it is correlated with gene expression level and CNA frequencies in different chromosomes. Our analysis suggests that despite the enrichment of differentially expressed genes between hyperdiploid MM and non-hyperdiploid MM in the trisomy chromosomes, the chromosomal proportion of dosage sensitive genes is higher in the non-trisomy chromosomes. Dosage-sensitive genes are enriched by genes with protein translation and localization functions, and dosage resistant genes are enriched by apoptosis genes. These results point to future studies on differential dosage sensitivity and resistance of pro- and anti-proliferation pathways and their variation across patients as therapeutic targets and prognosis markers. Our findings support the hypothesis that recurrent CNAs in myeloma are selected by their functional consequences. The novel dosage effect score defined in this work will facilitate integration of copy number and expression data for identifying driver genes in cancer genomics studies. The accompanying R code is available at http://www.canevolve.org/dosageEffect/.


Efficient amidation of weak amines: synthesis, chiral separation by SFC, and antimicrobial activity of N-(9,10-dioxo-9,10-dihydroanthracen-1-yl) carboxamide.
An effective and straightforward method for the synthesis of 1-aminoanthracene-9,10-dione carboxamides by coupling a weakly reactive amine, 1-aminoanthracene-9,10-dione, and sterically hindered carboxylic acids was achieved using COMU as the coupling agent. Furthermore, making use of the advantages associated with the super-critical fluid chromatography (SFC) technique, a simplified and straightforward method for the chiral separation of optically active amide derivatives from the impurities associated with the reaction mixture, in a single step, was demonstrated. The antimicrobial activity of selected 1-aminoanthracene-9,10-dione carboxamides was studied. Advanced NMR and other spectral techniques were used for the thorough characterization of all the compounds. This study provides a general and simplified method for coupling a weak amine with a sterically hindered acid using COMU as a coupling agent, and demonstrates the separation of optically pure compounds from reaction related impurities in a single step using SFC, and identification of amide derivatives of 1-aminoanthracene-9,10-dione as potential antimicrobial agents.


Feasibility Evaluation of Online Classification-based Control for Gross Movement in a 2-DoF Prosthetic Arm.
Regression and classification models have been extensively studied to exploit the myoelectric and kinematic input information from the residual limb for the control of multiple degree-of-freedom (DoF) powered prostheses. The gross movement control of above-elbow prostheses is mainly based on regression models which map the available inputs to continuous prosthetic poses. However, the regression output is sensitive to the variation in the input signal. The myoelectric signal variation is usually large due to unintentional muscle contractions, which can deteriorate the user-in-the-loop performance with respect to the offline analysis. Alternatively, the classification models offer the advantage of being more robust to the input signal variation, but they were predominantly used for fine motor functions such as grasping. For gross motor functions, the discrete output may cause issues. Therefore, this work attempts to investigate the feasibility of utilising the classification model to control a 2-DoF transhumeral prosthesis for gross movement. The performance of 6 able-bodied subjects was evaluated in performing reaching and orientation matching tasks with a prosthetic arm in a virtual reality environment. The results were compared with the case of using their intact arms and existing results using the regression model. Our findings indicate that the classification-based method provides comparable performance to the regression model, making it a potential alternative for gross arm movement in multi-DoF prosthetic arms.


Bronchopleural Fistula Resolution with Endobronchial Valve Placement and Liberation from Mechanical Ventilation in Acute Respiratory Distress Syndrome: A Case Series.
Patients who have acute respiratory distress syndrome (ARDS) with persistent air leaks have worse outcomes. Endobronchial valves (EBV) are frequently deployed after pulmonary resection in noncritically ill patients to reduce and eliminate bronchopleural fistulas (BPFs) with persistent air leak (PAL). Information regarding EBV placement in mechanically ventilated patients with ARDS and high volume persistent air leaks is rare and limited to case reports. We describe three cases where EBV placement facilitated endotracheal extubation in patients with severe respiratory failure on prolonged mechanical ventilation with BPFs. In each case, EBV placement led to immediate resolution of PAL. We believe endobronchial valve placement is a safe method treating persistent air leak with severe respiratory failure and may reduce days on mechanical ventilation.


Multi-Modal Data Correspondence for the 4D Analysis of the Spine with Adolescent Idiopathic Scoliosis.
Adolescent idiopathic scoliosis is a three-dimensional spinal deformity that evolves during adolescence. Combined with static 3D X-ray acquisitions, novel approaches using motion capture allow for the analysis of the patient dynamics. However, as of today, they cannot provide an internal analysis of the spine in motion. In this study, we investigated the use of personalized kinematic avatars, created with observations of the outer (skin) and internal shape (3D spine) to infer the actual anatomic dynamics of the spine when driven by motion capture markers. Towards that end, we propose an approach to create a subject-specific digital twin from multi-modal data, namely, a surface scan of the back of the patient and a reconstruction of the 3D spine (EOS). We use radio-opaque markers to register the inner and outer observations. With respect to the previous work, our method does not rely on a precise palpation for the placement of the markers. We present the preliminary results on two cases, for which we acquired a second biplanar X-ray in a bending position. Our model can infer the spine motion from mocap markers with an accuracy below 1 cm on each anatomical axis and near 5 degrees in orientations.


Management of colitis caused by irradiation.
Radiation therapy has assumed a role of primary importance in the management of gynecologic and other malignant growths. To be effective, the treatment dosage must be adequate. However, with higher dosages for curative radiation therapy, damage from the treatment may promote prolonged morbidity and even death. The effects of this treatment may be intensified by predisposing conditions within the patient, but the damage seems to be related to the insertion of radium. Prior to therapy, each patient must be individualized, and any predisposing factors should be kept in mind during treatment to recognize and treat these complications early. Once complications have arisen, the most conservative modality of dealing with the irradiated tissue is best, since these areas of intestinal injury do not heal. This requires early diversion or resection as conservative therapy, because fistulas and bleeding will become recurrent and intractable. If diversion fails to control bleeding, resection is necessary, even if it involves an abdominoperineal resection. Therefore, conservative can become radical for this supposedly benign illness.


Pharmacologic activation of the innate immune system to prevent respiratory viral infections.
Drugs that can rapidly inhibit respiratory infection from influenza or other respiratory pathogens are needed. One approach is to engage primary innate immune defenses against viral infection, such as activating the IFN pathway. In this study, we report that a small, cell-permeable compound called 5,6-di-methylxanthenone-4-acetic acid (DMXAA) can induce protection against vesicular stomatitis virus in vitro and H1N1 influenza A virus in vitro and in vivo through innate immune activation. Using the mouse C10 bronchial epithelial cell line and primary cultures of nasal epithelial cells, we demonstrate DMXAA activates the IFN regulatory factor-3 pathway leading to production of IFN-β and subsequent high-level induction of IFN-β-dependent proteins, such as myxovirus resistance 1 (Mx1) and 2',5'-oligoadenylate synthetase 1 (OAS1). Mice treated with DMXAA intranasally elevate mRNA/protein expression of Mx1 and OAS1 in the nasal mucosa, trachea, and lung. When challenged intranasally with a lethal dose of H1N1 influenza A virus, DMXAA reduced viral titers in the lungs and protected 80% of mice from death, even when given at 24 hours before infection. These data show that agents, like DMXAA, that can directly activate innate immune pathways, such as the IFN regulatory factor-3/IFN-β system, in respiratory epithelial cells can be used to protect from influenza pneumonia and potentially in other respiratory viral infections. Development of this approach in humans could be valuable for protecting health care professionals and "first responders" in the early stages of viral pandemics or bioterror attacks.


Species distinction of the ascomycetous heterothallic yeast-like fungus Stephanoascus ciferrii complex: description of Candida allociferrii sp. nov. and reinstatement of Candida mucifera Kocková-Kratochvílová et Sláviková.
The nucleotide sequences of the 18S rRNA gene (rDNA) from nine strains of the heterothallic ascomycetous Stephanoascus ciferrii complex were determined and the strains were separated into three groups according to their sequences. 18S rDNA sequences were identical within the same group. In group A the 18S rDNA sequences had no introns; in group B there was one group I intron, Sc1506-1 at position 1506; and in group C there were two group I introns, Sc943 at position 943 and Sc1506-2 at position 1506. Sc1506-1 and Sc1506-2 at position 1506 exhibited 19 base differences but were very similar. Therefore, it is suggested that these introns existed in the common ancestor of groups B and C, and that they were vertically inherited. DNA similarity values showed that the strains within the same group were of identical species. Group B included the isotype strains of Stephanoascus ciferrii and the type strains of Candida ciferrii and Sporothrix catenata; this confirmed that group B strains correspond to Stephanoascus ciferrii and that Candida ciferrii and Sporothrix catenata are synonyms of Stephanoascus ciferrii. The single member of group C, strain IFO 10918T, corresponds to the type strain of Candida mucifera and was independent of the other tested strains. Thus, Candida mucifera should be regarded as an independent species from Stephanoascus ciferrii. It is suggested that group A strains might comprise a new Stephanoascus species, but since group A strains could not form asci by themselves in this study they are described as a new species for which the name Candida allociferrii sp. nov. (type strain IFO 10194T) is proposed.


Target size analysis of neurotensin receptors.
The neurotensin receptors from rat brain synaptosomal membranes differed in subunit structure from those in rat gastric fundus smooth muscle plasma membranes when studied following photoaffinity labelling or after exposure to cross-linking reagents. However, these two receptors were similar in their recognition properties. In this study we compared the target size of the two receptors by radiation inactivation and observed that the receptors in both tissues had similar target sizes (mean values 103,000 and 108,000 daltons). This suggests that the differences in size observed in biochemical studies may reflect changes occurring during the isolation procedures, or, on the other hand, there might be inherent difference in the subunit structure of these receptors.


If the Objective is Herd Immunity, on Whom Should it be Built?
Assuming that there is no other solution than herd immunity in front of the current pandemic, on which groups of citizens should we build this herd immunity? Given the fact that young people face a mortality rate which is at least a thousand times smaller than people aged 70 years and more, there is a simple rational to build it on these younger generations. The transfer of some mortality risk from the elderly to younger people raises difficult ethical issues. However, none of the familiar moral or operational guidelines (equality of rights, VSL, QALY, ...) that have been used in the Western world over the last century weights the value of young lives 1000 times or more than the lives of the elders. This suggests that Society could offer covid protection to the elders by recommending them to remain confined as long as this herd immunity has not been attained by the younger generations. This would be a potent demonstration of intergenerational solidarity towards the most vulnerable people in our community. The welfare gain of this age-specific deconfinement strategy is huge, as it can reduce the global death toll by more than 80% as compared to a strategy of non-targeted herd immunity.


Simple adherence assessments to predict virologic failure among HIV-infected adults with discordant immunologic and clinical responses to antiretroviral therapy.
We evaluated the association between two antiretroviral therapy (ART) adherence measurements--the medication possession ratio (MPR) and patient self-report--and detectable HIV viremia in the setting of rapid service scale-up in Lusaka, Zambia. Drug adherence and outcomes were assessed in a subset of patients suspected of treatment failure based on discordant clinical and immunologic responses to ART. A total of 913 patients were included in this analysis, with a median time of 744 days (Q1, Q3: 511, 919 days) from ART initiation to viral load (VL) measurement. On aggregate over the period of follow-up, 531 (58%) had optimal adherence (MPR > or =95%), 306 (34%) had suboptimal adherence (MPR 80-94%), and 76 (8%) had poor adherence (MPR <80%). Of the 913 patients, 238 (26%) had VL > or =400 copies/ml when tested. When compared to individuals with optimal adherence, there was increasing risk for virologic failure in those with suboptimal adherence [adjusted relative risk (ARR): 1.3; 95% confidence interval (CI): 1.0, 1.6] and those with poor adherence (ARR: 1.7; 95% CI: 1.3, 2.4) based on MPR. During the antiretroviral treatment course, 676 patients (74%) reported no missed doses. The proportion of patients with virologic failure did not differ significantly among those reporting any missed dose from those reporting perfect adherence (26% vs. 26%, p = 0.97). Among patients with suspected treatment failure, a lower MPR was associated with higher rates of detectable viremia. However, the suboptimal sensitivity and specificity of MPR limit its utility as a sole predictor of virologic failure.


[Use of amniotic drop-volume determination in estimating fetal lung maturity].
The value of amniotic fluid drop-volume determination with a self-made Fetal Lung Maturity Apparatus in the analysis of fetal lung maturity is studied with 148 samples. The results were compared with those of L/S ratios, it shows that this method has a sensitivity of 95%, specificity 91% and accuracy 93%, if a falling-drop-interval of less than or equal to 85 seconds was taken as the defining point for lung maturity. The mean falling drop-interval was 89.0 +/- 12.3 seconds in the 18-30 th week pregnancy samples, 72.7 +/- 9.4 seconds in the 36-42 nd week samples and 81.4 +/- 9.9 seconds in the 31-35 th week samples. (P less than 0.001). The effects of blood and meconium on the testing were also studied. The drop-volume test is recommended as an accurate, rapid and easy method in predicting fetal lung maturity.


Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability.
While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails.


Control of vancomycin-resistant enterococci at a community hospital: efficacy of patient and staff cohorting.
To evaluate the efficacy of patient and staff cohorting to control vancomycin-resistant enterococci (VRE) at an Indianapolis community hospital. To interrupt transmission of VRE, a VRE point-prevalence survey of hospital inpatients was conducted, and VRE-infected or -colonized patients were cohorted on a single ward with dedicated nursing staff and patient-care equipment. To assess the impact of the intervention, staff compliance with contact isolation procedures was observed, and the VRE point-prevalence survey was repeated 2 months after the cohort ward was established. Following the establishment of the cohort ward, VRE prevalence among all hospitalized inpatients decreased from 8.1% to 4.7% (25 positive cultures among 310 patients compared to 13 positive cultures among 276 patients, P=.14); VRE prevalence among patients whose VRE status was unknown before cultures were obtained decreased from 5.9% to 0.8% (18 positive cultures among 303 patients compared to 2 positive cultures among 262 patients, P=.002); and observed staff-patient interactions compliant with published isolation recommendations increased (5 [22%] of 23 interactions compared to 36 [88%] of 41 interactions, P<.0001). Our data suggest that, in hospitals with endemic VRE or continued VRE transmission despite implementation of contact isolation measures, establishing a VRE cohort ward may be a practical and effective method to improve compliance with infection control measures and thereby to control epidemic or endemic VRE transmission.


Talen-mediated girdin knockout downregulates cell proliferation, migration and invasion in human esophageal carcinoma ECA109 cells.
Girdin is an actin-binding Akt substrate that is involved in the regulation of cell migration. Accumulating evidence has revealed that girdin has regulatory effects on invasion and metastasis in several types of cancer. However, the role of girdin in esophageal squamous cell carcinomas (ESCCs) is yet to be investigated. In the present study, tissue microarray data revealed that among 95 cases of ESCC, 27 cases (28.7%) exhibited a low expression of girdin, while 67 cases (71.3%) had an enhanced expression of girdin. However, among 78 cases of adjacent tissues, 64 cases (82.1%) did not express girdin and 14 cases (17.9%) exhibited a low expression of girdin. Furthermore, the expression of girdin was significantly associated with the tumor stage, lymph node metastasis stage, and tumor, lymph node and metastasis stage. Of note, the mean survival time of girdin-positive cases was only 30.62±2.99 months, while it was 53.37±5.02 months in girdin-negative cases, indicating that girdin protein expression is an independent prognostic factor of poor survival. Talen-mediated girdin knockout (KO) significantly suppressed cellular proliferation, migration and invasion in ESCC ECA109 cells. In conclusion, the present study suggested that girdin protein expression was significantly correlated with cancer progression and poor prognosis in ESCCs, and that girdin had a positive role in the regulation of cell proliferation, migration and invasion in ESCC cells. Therefore, girdin may be a potential candidate for the development of novel prognostic tools and therapeutic strategies for ESCCs.


The effectiveness of brief interventions in the clinical setting in reducing alcohol misuse and binge drinking in adolescents: a critical review of the literature.
To investigate the effectiveness of brief interventions for adolescent alcohol misuse and to determine if these interventions are useful in reducing alcohol consumption. To determine if brief interventions could be used successfully by nurses in the clinical setting. Australian adolescents are consuming risky levels of alcohol in ever increasing numbers. The fiscal, health-related and social costs of this alcohol misuse are rising at an alarming rate and must be addressed as a matter of priority. Brief interventions have been used with some success for adult problem drinkers in the clinical setting. Brief interventions delivered in the clinical setting by nurses who are 'on the scene' are therefore a potential strategy to redress the epidemic of adolescent alcohol misuse. Literature review. Multiple databases were searched to locate randomised controlled trials published within the past 10 years, with participants aged 12-25 years. Included studies used brief intervention strategies specific to alcohol reduction. Fourteen studies met these criteria and were reviewed. A range of different interventions, settings, participant age-ranges and outcome measures were used, limiting generalisability to the studied populations. No trials were carried out by nurses and only one took place in Australia. Motivational interviewing (one form of brief intervention) was partially successful, with the most encouraging results relating to harm minimisation. Long-term follow-up trials using motivational interviewing reported significant reductions in alcohol intake and harmful effects, but this may be partially attributed to a normal maturation trend to a steady reduction in alcohol consumption. No single intervention could be confidently recommended due to confounding evidence. However, successful elements of past studies warrant further investigation. These include face-to-face, one-session, motivational interviewing-style brief interventions, focusing on harm minimisation and all with long-term follow-up. The introduction of brief interventions in the hospital setting has the potential to address the epidemic of adolescent alcohol misuse. Nurses are well placed to deliver these interventions, but a standardised approach is required to ensure consistency. Further research is urgently needed to ensure clinical practice is based on the best available evidence and to ensure findings are more relevant to Australian adolescents and to nurses in a clinical setting.


Moraxella caprae sp. nov., a new member of the classical Moraxellae with very close affinity to Moraxella bovis.
Eight phenotypically homogeneous Moraxella-like strains were isolated from the nasal flora of healthy goats. Total genomic DNA-DNA hybridization, DNA base composition determination, and genetic transformation studies were performed to determine the relationships of these bacteria to the classical moraxellae. The eight new isolates exhibited very high levels of genetic affinity to Moraxella bovis, as shown by quantitative and qualitative genetic transformation data, and exhibited high DNA-DNA relative binding ratios to each other (63% or more) but lower levels of DNA homology with all of the other species investigated, including the closely related classical moraxellae. Our results, combined with the general morphologic and phenotypic profiles of these organisms, indicate that they should be classified with the classical moraxellae, and we propose the name Moraxella caprae for them. Strain 8897 (= CCUG 33296 [corrected] = NCTC 12877) is the type strain of M. caprae.


Low-dose in vivo pharmacokinetic and deuterium isotope effect studies of N-nitrosodimethylamine in rats.
The rates of elimination of N-nitrosodimethylamine (NDMA) and its fully deuterated analogue (N-nitrosodi[2H6]methylamine, [2H6]NDMA) were studied in vivo to explore the origins of the difference in their carcinogenicity. Male Fischer 344 rats, 7.5 weeks of age, were given nitrosamine bolus doses of 1.35 mumol/kg by tail vein injection and 2.02 or 4.05 mumol/kg by p.o. gavage. Animals were sacrificed at various time points from 2.5 to 180 min after i.v. administration or 5 to 120 min after p.o. dosage, and their blood was analyzed for NDMA by gas chromatography-high resolution mass spectrometry. After i.v. injection, blood nitrosamine concentrations declined in an apparently biexponential manner with a terminal half-life of 10 min for NDMA and 12 min for [2H6]NDMA. The apparent total systemic blood clearances for NDMA and [2H6]NDMA were 39 and 26 ml/min/kg, respectively. The apparent steady-state volumes of distribution were nearly identical (297 and 309 ml/kg, respectively). The areas under the curve after 2.02- and 4.05-mumol/kg p.o. doses were proportional to dose. The apparent bioavailability of NDMA was 8%, while that of [2H6]NDMA was 21%. Isotope effects calculated as the ratios of first-pass metabolism, total systemic clearances, bioavailabilities, and intrinsic hepatic clearances were 1.2, 1.5, 2.6, and 3.2, respectively. The isotope effect determined from blood concentrations measured after simultaneous administration of NDMA and [2H6]NDMA by steady-state infusion (each at 1.5 mumol/kg/h) was 2.6 +/- 0.9 (SD). This study thus provides quantitative reference data on the time course of the disappearance of both N-nitrosodimethylamine and its deuterated analogue from blood (over 5 to 8 half-lives) after doses similar to those used to elicit liver tumors in chronic feeding studies, confirms the first-pass effect on their metabolism using direct blood measurements, and permits estimation of their bioavailabilities from actual blood concentrations. The results suggest that elimination pathways not involving alpha-hydroxylation are more important than is currently recognized.


Detection of Borrelia burgdorferi DNA in granulomatous tissues from patients with sarcoidosis using polymerase chain reaction in situ technique.
To investigate the correlation between sarcoidosis and Borrelia burgdorferi (Bb) infection, flagella DNA of Bb were detected in 23 granulomatous tissue specimens from patients with confirmed sarcoidosis using polymerase chain reaction in situ technique (in situ PCR) and the antibodies to Bb were examined in 55 serum samples obtained from the patients by indirect immunoflurescence assays. Our data presented that: (1) None of granulomatous tissues was found to have Bb DNA in 23 tissue samples. (2) Thirty of 55 (54.6%) patients with sarcoidosis were found antibodies to Bb positive, in contrast, six of 60 (10%) normal subjects had antibodies against Bb, the positive rate was remarkably higher in patient group than that in healthy group (P < 0.005). The results suggest that Bb might not be the causative agent of sarcoidosis, the elevated titres of serum antibodies against Bb in patients with sarcoidosis is a nonspecific response.


Role of methionine in the active site of alpha-galactosidase from Trichoderma reesei.
alpha-Galactosidase from Trichoderma reesei when treated with H2O2 shows a 12-fold increase in activity towards p-nitrophenyl alpha-D-galactopyranoside. A similar effect is produced by the treatment of alpha-galactosidase with other non-specific oxidants: NaIO4, KMnO4 and K4S4O8. In addition to the increase in activity, the Michaelis constant rises from 0.2 to 1.4 mM, the temperature coefficient decreases by a factor of 1.5 and the pH-activity curve falls off sharply with increasing pH. Galactose (a competitive inhibitor of alpha-galactosidase; Ki 0.09 mM for the native enzyme at pH 4.4) effectively inhibits oxidative activation of the enzyme, because the observed activity changes are related to oxidation of the catalytically important methionine in the active site. NMR measurements and amino acid analysis show that oxidation to methionine sulphoxide of one of five methionines is sufficient to activate alpha-galactosidase. Binding of galactose prevents this. Oxidative activation does not lead to conversion of other H2O2-sensitive amino acid residues, such as histidine, tyrosine, tryptophan and cysteine. The catalytically important cysteine thiol group is quantitatively titrated after protein oxidative activation. Further oxidation of methionines (up to four of five residues) can be achieved by increasing the oxidation time and/or by prior denaturation of the protein. Obviously, a methionine located in the active site of alpha-galactosidase is more accessible. The oxidative-activation phenomenon can be explained by a conformational change in the active site as a result of conversion of non-polar methionine into polar methionine sulphoxide.


Osseointegration in osteoporotic-like condition: A systematic review of preclinical studies.
Osteoporosis is one of the most common skeletal disorders affecting a significant percentage of people worldwide. Research data suggested that systemic diseases such as osteoporosis could act as risk factors for osseointegration, jeopardizing the healing process and thus the predictability of dental implant success on compromised patients. It is well accepted that preclinical studies in animal models reproducing the osteoporotic condition are one of the most important stages in the research of new biomaterials and therapeutic modalities. The aim of this systematic review was to investigate whether osteoporosis compromises dental implant osseointegration in experimental osteoporotic-like conditions. A 3-stage systematic literature research was conducted in MEDLINE via OVID and EMBASE up to and including March 2017. Experimental studies reporting on dental implant osseointegration on different osteoporotic animal models were assessed. The studies had to report on the percentage of bone-to-implant contact (%BIC) as the primary outcome. ARRIVE guidelines for reporting on animal research were applied to evaluate the methodological quality and risk of bias of the studies. Fifty-seven studies met the inclusion criteria and were assessed qualitatively. The most adopted animal model was the rat. A variability of %BIC values was observed, ranging from 30% to 99% and from 26% to 94% for the healthy and osteoporotic group, respectively. The great majority (47) of the included studies concluded that estrogen deficiency significantly affects BIC values, 9 studies stated that it was not possible to observe statistical differences in BIC between ovariectomized and healthy groups and 1 study did not provide a comparison between the healthy and osteoporotic group. Owing to the great heterogeneity in implant surface, study design, observation time-points, site of implant placement and reported outcomes, a meta-analysis could not be performed. An overall high risk of bias was observed, owing to the limited information on animal housing and husbandry, baseline characteristics and health status, ethical statement and allocation to the experimental groups provided. Although the available studies seem to suggest a lower osseointegration in osteoporotic-like conditions, no robust conclusions can be drawn due to the great heterogeneity and overall low quality of the available studies. Future studies with emphasis on minimizing the possible sources of bias and evaluating osseointegration of dental implants placed into jawbones instead of long bones are warranted.