Risk factors for infective endocarditis and outcome of patients with Staphylococcus aureus bacteremia.
To investigate the risk factors for Staphylococcus aureus infective endocarditis (SAIE) and 6-month mortality in patients with S aureus bacteremia (SAB). This study consisted of patients who were diagnosed as having nosocomial or community-acquired SAB or SAIE between June 1, 2000, and December 31, 2005. Clinical characteristics of patients with SAB were compared with those of patients with SAIE, and predictors of mortality in patients with SAB were analyzed. The median age of the 132 randomly selected patients with SAB and the 66 patients with SAIE was 66 and 68 years, respectively. Univariable analysis showed that unknown origin of SAB, a valvular prosthesis, a pacemaker, persistent fever, and persistent bacteremia were significantly associated with SAIE. In multivariable analysis, unknown origin of SAB (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.9-9.3; P=.001), a valvular prosthesis (OR, 9.2; 95% CI, 3.2-26.2; P<.001), persistent fever (OR, 3.1; 95% CI, 1.0-9.0; P=.04), and persistent bacteremia (OR, 6.8; 95% CI, 2.3-20.2- P=.001) were independently associated with SAIE. Six- month mortality was 8% in patients with SAB vs 35% in patients with SAIE (OR, 6.5; 95% CI, 2.9- 14.8; P<.001). In univariable analysis, methicillin- resistant S aureus (OR, 7.2; 95% CI, 1.7 - 29.4; P=.005) was significantly associated with 6-month mortality in patients with SAB. Unknown origin of SAB, a valvular prosthesis, persistent fever, and persistent bacteremia were independently associated with SAIE in patients with SAB. In univariable analysis, methicillin-resistant S aureus was associated with 6-month mortality in patients with SAB. S aureus infective endocarditis had a significantly higher mortality than SAB. The optimal management of SAB and SAIE deserves further study.


In situ reversible tuning of chemical interface damping in mesoporous silica-coated gold nanorods via direct adsorption and removal of thiol.
Chemical interface damping (CID) is a recently proposed plasmon decay channel in gold nanoparticles. However, thus far, a very limited number of studies have focused on controlling CID in single gold nanoparticles. Herein, we describe a new simple method for reversible tuning of CID in single gold nanorods coated with a mesoporous silica shell (AuNRs@mSiO2). We used 1-alkanethiols with two different carbon chain lengths (1-butanethiol and 1-decanethiol) as adsorbates to induce CID. In addition, NaBH4 solution was used to remove the attached thiol from the AuNR surface. We confirmed the adsorption and removal of 1-alkanethiols on single AuNRs@mSiO2 and the corresponding changes in localized surface plasmon resonance (LSPR) peak wavelengths and linewidths. Furthermore, we investigated the effect of immersion time in NaBH4 solution on thiol removal from AuNRs@mSiO2. Therefore, the LSPR properties and CID can be controlled, thereby paving the way for in situ reversible tuning of CID by repeated adsorption and desorption of thiol molecules on single AuNRs@mSiO2.


Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase downregulation.
Gemcitabine is an antimetabolite drug used in the treatment of various solid tumours, including lung, pancreatic or gynaecological cancers. Innovative combinational strategies (e.g. gemcitabine+capecitabine or gemcitabine+oxaliplatin) make gemcitabine an extensively prescribed drug now. Gemcitabine is characterized by a narrow therapeutic index, and its liver elimination depends upon a key enzymatic step, driven by cytidine deaminase (CDA). CDA is prone to gene polymorphism, including the 208A>G mutation, which can result in marked enzymatic deficiency with subsequent impact on drug exposure levels and related toxicities. We have developed a simple and inexpensive method to determine phenotypically CDA status in cancer patients, as an attempt to detect those at risk upon gemcitabine intake. Conjointly to genotypic investigations, this method was used to phenotype, in a retrospective setting, a female patient displaying extremely severe, and eventually lethal, toxicities after administration of a standard gemcitabine/carboplatin protocol. Phenotypic investigation showed a marked CDA deficiency (-75%) in this patient when compared with a reference, nontoxic population. Genetic studies undertaken next to screen mutations, possibly at the origin of this deficiency, showed heterozygosity for the 79A>C single-point mutation, whereas surprisingly the canonical CDA 208A>G polymorphism was not found. Taken together, this case report demonstrates, for the first time, that CDA downregulation can lead to toxic-death in patients exposed to gemcitabine. Besides, we showed here that our cost-effective and simple phenotypic approach should enable, in the future, the detection of deficient patients at risk upon gemcitabine administration.


Characteristics and Outcomes of Critically Ill Patients With Pulmonary Hypertension Who Undergo Endotracheal Intubation and Mechanical Ventilation.
Background: Patients with pulmonary hypertension (PH) who undergo endotracheal intubation have an increased risk of adverse outcomes, but little is known regarding prognostic factors and there is limited evidence to guide management. We sought to define characteristics, prognostic factors, and outcomes of critically ill patients with PH who underwent intubation. Study Design: We performed a single-center retrospective cohort study of critically ill patients with group 1, 3 or 4 PH who underwent intubation. Results: Eighty-one patients were included. Patients had a median age of 56 years (interquartile range 44-65) and were predominantly female (n = 53, 65%) and Caucasian (n = 71, 88%). Forty-five (56%) had group 1 PH while 25 (31%) had group 3 PH and 11 (14%) had group 4 PH. Patients were admitted to the hospital for right ventricular failure (n = 21, 25.6%), sepsis (n = 18, 22.2%), and respiratory failure (n = 19, 23.1%). Hypoxemic respiratory failure (n = 54, 66.7%) was the most common indication for intubation. In-hospital mortality was 30.9% and 1-year mortality was 48.2%. All patients (11 of 11, 100%) intubated electively for intensive care unit procedures survived to hospital discharge while only 1 of 6 (16.7%) intubated in the setting of a cardiac arrest survived. After adjusting for right ventricular systolic pressure, pre-intubation PaO2 (odds ratio [OR] = 0.99, 95% confidence interval [CI] 0.97-1.00, P = .02) and postintubation PaO2 (OR = 0.97 per 1mm Hg, 95% CI 0.95 to 0.99, P = .003), pH (OR = 0.49 per 0.1 increase, 95% CI 0.29 to 0.80, P = .005) and PaCO2 (OR = 1.08 per 1mm Hg, 95% CI 1.02 to 1.14, P = .005) were significantly associated with in-hospital mortality. Results were similar when we excluded patients intubated electively or in the setting of cardiac arrest. Conclusions: Intubation in critically ill patients with PH is associated with significant in-hospital mortality and nearly 50% 1-year mortality. Potentially modifiable factors, such as peri-intubation gas exchange, are associated with an increased risk of death while other demographic and hemodynamic variables are not.


Yield gap analyses to estimate attainable bovine milk yields and evaluate options to increase production in Ethiopia and India.
Livestock provides an important source of income and nourishment for around one billion rural households worldwide. Demand for livestock food products is increasing, especially in developing countries, and there are opportunities to increase production to meet local demand and increase farm incomes. Estimating the scale of livestock yield gaps and better understanding factors limiting current production will help to define the technological and investment needs in each livestock sector. The aim of this paper is to quantify livestock yield gaps and evaluate opportunities to increase dairy production in Sub-Saharan Africa and South Asia, using case studies from Ethiopia and India. We combined three different methods in our approach. Benchmarking and a frontier analysis were used to estimate attainable milk yields based on survey data. Household modelling was then used to simulate the effects of various interventions on dairy production and income. We tested interventions based on improved livestock nutrition and genetics in the extensive lowland grazing zone and highland mixed crop-livestock zones of Ethiopia, and the intensive irrigated and rainfed zones of India. Our analyses indicate that there are considerable yield gaps for dairy production in both countries, and opportunities to increase production using the interventions tested. In some cases, combined interventions could increase production past currently attainable livestock yields.


Theory of the lattice Boltzmann method: acoustic and thermal properties in two and three dimensions.
The focus of the present work is to provide an analysis for the acoustic and thermal properties of the energy-conserving lattice Boltzmann models, and a solution to the numerical defects and instability associated with these models in two and three dimensions. We discover that a spurious algebraic coupling between the shear and energy modes of the linearized evolution operator is a defect universal to the energy-conserving Boltzmann models in two and three dimensions. This spurious mode coupling is highly anisotropic and may occur at small values of wave number k along certain directions, and it is a direct consequence of the following key features of the lattice Boltzmann equation: (1) its simple spatial-temporal dynamics, (2) the linearity of the relaxation modeling for collision operator, and (3) the energy-conservation constraint. To eliminate the spurious mode coupling, we propose a hybrid thermal lattice Boltzmann equation (HTLBE) in which the mass and momentum conservation equations are solved by using the multiple-relaxation-time model due to d'Humières, whereas the diffusion-advection equation for the temperature is solved separately by using finite-difference technique (or other means). Through the Chapman-Enskog analysis we show that the hydrodynamic equations derived from the proposed HTLBE model include the equivalent effect of gamma=C(P)/C(V) in both the speed and attenuation of sound. Appropriate coupling between the energy and velocity field is introduced to attain correct acoustics in the model. The numerical stability of the HTLBE scheme is analyzed by solving the dispersion equation of the linearized collision operator. We find that the numerical stability of the lattice Boltzmann scheme improves drastically once the spurious mode coupling is removed. It is shown that the HTLBE scheme is far superior to the existing thermal LBE schemes in terms of numerical stability, flexibility, and possible generalization for complex fluids. We also present the simulation results of the convective flow in a rectangular cavity with different temperatures on two opposite vertical walls and under the influence of gravity. Our numerical results agree well with the pseudospectral result.


Towards improved coding of acute myocardial infarction in hospital discharge abstracts: a pilot project.
To pilot-test a simple checklist designed to improve coding of acute myocardial infarction (AMI) in hospital discharge abstracts. Health records technologists review hospital charts to code discharge diagnoses according to the International Classification of Diseases, 9th revision (ICD-9). Many studies have suggested that there is a high false positive rate in coding AMI, ie, ICD-9 410, on hospital discharge abstracts. The checklist required either at least two of suggestive symptoms, diagnostic electrocardiographic changes, or diagnostic rise in serum cardiac enzymes; or confirmation by autopsy. First case of use was confirmed-typical time to complete the checklist was 3 to 4 mins. Then 16 Ontario community hospitals were recruited to apply the checklist on a blinded basis to 1000 randomly drawn in-patient records-10% were audited for another study to confirm AMI; and 90% were originally coded with 'most responsible diagnosis' (MRD) of AMI, other cardiovascular diagnoses and various noncardiac conditions. Percentage agreement (95% CI) between the checklist and the confirmed or coded diagnosis was analyzed; coding of AMI as a secondary diagnosis was examined in further analyses. One hospital withdrew for logistical reasons; the final useable sample from 15 hospitals was 943 records. The checklist correctly identified 100% of AMIs independently confirmed for another study; usual coding identified 89.7% of cases (70 of 78; 95% CI 80.8 to 95.5). For cases not confirmed, but where the physician had nonetheless diagnosed AMI, six of 11 charts were miscoded as AMI in hospital records; none were miscoded by the checklist. For records with AMI as MRD, 11.6% (44 of 380; 95% CI 8.5 to 15.2) were classified as false positives by the checklist. Where an AMI was coded as a secondary diagnosis, 52.9% (36 of 68; 95% CI 40.5 to 65.2) met the checklist criteria for AMI. Finally, among records where the MRD was other than AMI, 6.8% (38 of 563; 95% CI 4.8 to 9.2) met checklist criteria for AMI during admission, but 94.7% had an ICD-9410 code as a secondary diagnosis. A simple checklist can be very easily applied, has extremely high sensitivity for confirming the presence of AMI, and identifies a clinically significant proportion of charts with false positive codes for AMI. Conversely, these findings support the high sensitivity (low false negative rates) of conventional coding practices for AMI in Canadian hospital records, be it as a primary or secondary diagnosis (eg, 95% detection rate). Usual coding, combined with the checklist for tentative ICD-9 410 diagnoses, would improve the accuracy of Canadian hospital records.


Rivaroxaban in the treatment of venous thromboembolism and the prevention of recurrences: a practical approach.
Anticoagulation therapy is the standard treatment of patients with symptomatic venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. Until recently, treatment of VTE was based on parenteral or low-molecular-weight heparin for initial therapy (5-10 days) and oral vitamin K antagonists for long-term therapy. Those treatments have some limitations, including parenteral administration (heparins), the need for frequent monitoring and dose adjustments, interactions with several medications, and dietary restrictions (vitamin K antagonists). Rivaroxaban is a new oral direct factor Xa inhibitor with a wide therapeutic window, predictable anticoagulant effect, no food interactions, and few drug interactions. Consequently, no periodic monitoring of anticoagulation is needed, and fixed doses can be prescribed. EINSTEIN program demonstrated that rivaroxaban was as effective as and significantly safer than standard therapy for treatment of VTE. Rivaroxaban was recently authorized so doubts exist about how to use it in daily clinical practice. This document aims to clarify common questions formulated by clinicians regarding the use of this new drug.


[The time-frequency analysis of the exercise ECG signal].
Exercise ECG indicates information about the heart load status in the exercise test. It is very significant to represent the characteristics of the exercise ECG for evaluating the exercise load test. This article introduces the principle of Winger-Ville Distribution time-frequency analysis and its implementation. By applying this method to analyse exercise ECG, some results were acquired. It is a promising method to do research of the exercise ECG in the time-frequency plane.


[Research research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal hypoxic-ischemic encephalopathy].
Neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of death and long-term neurodevelopmental disorders in full-term neonates, and there is currently no curative treatment. Therapeutic hypothermia is now a standard therapy for HIE in the neonatal intensive care unit, but its safety and efficacy in remote areas remains unclear. Melatonin is an indole endocrine hormone mainly produced by the pineal gland and it has the ability to easily penetrate the blood-brain barrier. Through receptor and non-receptor mechanisms, melatonin exerts anti-oxidative and anti-inflammatory effects and participates in the regulation of organelle function and the inhibition of cell death. Melatonin is considered one of the most promising drugs for the treatment of HIE based on its reliable safety profile and clinical/preclinical results. This article reviews the recent research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal HIE.


Generation of three-dimensional medical thermograms.
To visualise non-invasively human organs in their true form and shape has intrigued mankind for centuries. Three-dimensional (3D) imaging is one recent development that has brought us closer to fulfilling the age-old quest of non-invasive visualisation so that diagnoses by doctors can be efficiently enhanced. Nowadays, 3D CT and MRI images have been very popular. Thermography is an important medical imaging technique that displays the temperature distribution on the surface of a human organ and it has been proved to be significant in offering a unique physiological reflection of pathology that may confirm or enhance the anatomic findings of other diagnostic imaging modalities. It is the only imaging modality that can evaluate pain whereas plain radiographs, CT and MRI, etc. can only depict structural anatomic abnormalities that may not always coincide with patients' clinical complaints. It is against this background that 3D thermograms have been developed. A set of comprehensive calibration procedures for the 3-camera system have been designed based on different models for the optical and infrared cameras. The accuracy of the results is high enough to produce 3D thermograms that can be used to correlate with the 3D images from other medical imaging modalities. One important achievement of the system is that the resultant 3D images are absolutely dimensioned and hence, it is particularly favourable for fully autonomous applications with robots. The system can also provide an overall picture of both the structural abnormalities and nervous responses of patients.


Clinical significance of serum levels of a carbohydrate antigen, sialyl SSEA-1, in patients with fibrosing lung disease.
Serum levels of sialyl SSEA-1 antigen, a carbohydrate antigen, were measured by radioimmunoassay in 142 patients with nonmalignant lung diseases. In 20 of 41 patients with fibrosing lung disease, either idiopathic or associated with collagen disease, the serum sialyl SSEA-1 levels were abnormally elevated. In patients with other lung diseases, the serum levels were almost within normal limits, less than 38.0 units/ml. In fibrosing lung disease the serum levels ranged from 13.8 to 147.0 units/ml and were largely concurrent with the degree of disease activity. The therapeutic effects of corticosteroid, which were evaluated with clinical-radiographic-physiologic scores and survivals in the patients with elevated serum levels, were significantly lower than those of the patients with the normal range of antigen levels. An immunohistochemical study performed on autopsied lungs from five patients with fibrosing lung disease indicated that the antigen was selectively expressed in the pulmonary epithelial cells that covered the remodeling alveolar septi in the lungs. No antigen was detectable by immunostaining in normal pulmonary epithelium among five normal lungs. From these findings, it is thought that the elevated levels of serum sialyl SSEA-1 may be derived from proliferating epithelial cells that were dominant in the late stage of fibrosing lung disorders. The measurements of serum sialyl SSEA-1 in patients with fibrosing lung disease may be clinically useful in establishing the degree of disease activity that has an influence on patient prognosis and therapeutic response.


Organization of the human glucokinase regulator gene GCKR.
Glucokinase plays an important role in regulating insulin secretion in response to changes in blood glucose levels. As a result, one form of maturity onset diabetes of the young (MODY) results from haploinsufficiency of glucokinase. In both liver and pancreatic islet, glucokinase is allosterically regulated by an inhibitory protein (glucokinase regulatory protein, GCKR). GCKR has therefore become an important gene for functional analysis in type 2 diabetes. To allow genetic assessment of any such role, we have determined the structure of the human GCKR gene. Characterization of P1 and YAC clones containing GCKR shows it to consist of 19 exons spanning 27 kb. RT-PCR, RACE, and RNase protection experiments defined a transcriptional start site for GCKR 66 bp upstream of the initiation codon, but provided no evidence for islet cell specific alternative splicing in the rat. By SSCP screening, a common polymorphic sequence variant has been defined within exon 15 of human GCKR, at nt 1400 of the cDNA. This alters amino acid residue 446 from proline, conserved in rat and Xenopus, to leucine.


Structural characterization of photopolymerizable binary liposomes containing diacetylenic and saturated phospholipids.
The use of liposomes to encapsulate materials has received widespread attention for drug delivery, transfection, diagnostic reagent, and as immunoadjuvants. Phospholipid polymers form a new class of biomaterials with many potential applications in medicine and research. Of interest are polymeric phospholipids containing a diacetylene moiety along their acyl chain since these kinds of lipids can be polymerized by Ultra-Violet (UV) irradiation to form chains of covalently linked lipids in the bilayer. In particular the diacetylenic phosphatidylcholine 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC) can form intermolecular cross-linking through the diacetylenic group to produce a conjugated polymer within the hydrocarbon region of the bilayer. As knowledge of liposome structures is certainly fundamental for system design improvement for new and better applications, this work focuses on the structural properties of polymerized DC8,9PC:1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes. Liposomes containing mixtures of DC8,9PC and DMPC, at different molar ratios, and exposed to different polymerization cycles, were studied through the analysis of the electron spin resonance (ESR) spectra of a spin label incorporated into the bilayer, and the calorimetric data obtained from differential scanning calorimetry (DSC) studies. Upon irradiation, if all lipids had been polymerized, no gel-fluid transition would be expected. However, even samples that went through 20 cycles of UV irradiation presented a DSC band, showing that around 80% of the DC8,9PC molecules were not polymerized. Both DSC and ESR indicated that the two different lipids scarcely mix at low temperatures, however few molecules of DMPC are present in DC8,9PC rich domains and vice versa. UV irradiation was found to affect the gel-fluid transition of both DMPC and DC8,9PC rich regions, indicating the presence of polymeric units of DC8,9PC in both areas. A model explaining lipids rearrangement is proposed for this partially polymerized system.


Ultraviolet absorption studies of germanium silicate glasses.
The absorptions of pure and codoped germanium silicate preforms made by modified chemical vapor deposition (MCVD) have been studied from 170 to 400 nm. Three bands with maxima at 185, 242, and 325 nm have been observed. The shortest wavelength band is attributed to GeO(2), while the other bands are assigned to GeO. The 242- and 325-nm bands are correlated with a singlet-singlet and a triplet-singlet transition of GeO, respectively. The GeO content is found to increase with processing temperature, because higher temperature allows the greater dissociation of GeO(2) to GeO. The amount of GeO incorporated is determined to be of the order of 10(-2) wt. %. The 325-nm band of GeO should have no effect on fiber loss in the IR region.


Chemical Analysis of Water-accommodated Fractions of Crude Oil Spills Using TIMS-FT-ICR MS.
Multiple chemical processes control how crude oil is incorporated into seawater and also the chemical reactions that occur overtime. Studying this system requires the careful preparation of the sample in order to accurately replicate the natural formation of the water-accommodated fraction that occurs in nature. Low-energy water-accommodated fractions (LEWAF) are carefully prepared by mixing crude oil and water at a set ratio. Aspirator bottles are then irradiated, and at set time points, the water is sampled and extracted using standard techniques. A second challenge is the representative characterization of the sample, which must take into consideration the chemical changes that occur over time. A targeted analysis of the aromatic fraction of the LEWAF can be performed using an atmospheric-pressure laser ionization source coupled to a custom-built trapped ion mobility spectrometry-Fourier transform-ion cyclotron resonance mass spectrometer (TIMS-FT-ICR MS). The TIMS-FT-ICR MS analysis provides high-resolution ion mobility and ultrahigh-resolution MS analysis, which further allow the identification of isomeric components by their collision cross-sections (CCS) and chemical formula. Results show that as the oil-water mixture is exposed to light, there is significant photo-solubilization of the surface oil into the water. Over time, the chemical transformation of the solubilized molecules takes place, with a decrease in the number of identifications of nitrogen- and sulfur-bearing species in favor of those with a greater oxygen content than were typically observed in the base oil.


Acquired resistance L747S mutation in an epidermal growth factor receptor-tyrosine kinase inhibitor-naïve patient: A report of three cases.
The purpose of the present study was to report cases of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-naïve patients carrying a mutation associated with acquired resistance to the drug. Gene alterations in 77 lung carcinoma patients were analyzed by collecting and studying curette lavage fluid at the time of diagnosis. PCRs were performed to amplify mutation hotspot regions in EGFR genes. The PCR products were direct-sequenced and the mutations confirmed by resequencing using different primers. Case 1 was a 78-year-old Japanese male diagnosed with stage IB lung adenocarcinoma who was found to have two EGFR mutations, G719S and L747S. Case 2 was a 73-year-old Japanese male diagnosed with stage IV squamous cell lung carcinoma and bone metastasis who had the EGFR mutation, L747S. Case 3 was an 82-year-old Japanese male diagnosed with hyponatremia due to inappropriate secretion of antidiuretic hormone and stage IIIB small cell lung carcinoma (SCLC) who had the EGFR mutation, L747S. Thus, the EGFR mutation L747S associated with acquired EGFR-TKI resistance was detected in two non-small cell lung carcinoma (NSCLC) patients and one SCLC patient, none of whom had ever received EGFR-TKI. The patients were current smokers with stages at diagnosis ranging from IB to IV, and their initial tumors contained resistant clones carrying L747S. L747S may be associated with primary resistance. To the best of our knowledge, this study is the first report of an EGFR mutation associated with resistance to EGFR-TKI in SCLC patients. The early detection of EGFR-TKI resistance mutations may be beneficial in making treatment decisions for lung carcinoma patients, including those with SCLC.


Comparison of methods for detection of vaccinia virus in patient specimens.
We analyzed a shell vial culture assay (SVA), real-time PCR, and a direct fluorescent antibody assay (DFA) for rapid detection of vaccinia virus from vaccination sites of Dryvax vaccine recipients. Of 47 samples assayed, 100% were positive by PCR, 89% were positive by SVA, and 40% were positive by DFA. DFA was limited by the need for adequate numbers of cells, with 32% of samples inadequate for interpretation. DFA performed better with specimens from patients who had not previously received the vaccine. PCR was positive for longer times postvaccination than was SVA. Infectious virus could be recovered after 45 min of acetone fixation of shell vial coverslips. Commercially available polyclonal antibodies cross-reacted with other orthopoxviruses and herpes simplex 1, but commercially available monoclonal antibodies were specific for vaccinia virus. In summary, PCR was the most sensitive test for detecting vaccinia virus in clinical specimens, while the DFA was the most rapid but the least sensitive test.


Optimal Hotspots of Dynamic Surfaced-Enhanced Raman Spectroscopy for Drugs Quantitative Detection.
Surface-enhanced Raman spectroscopy (SERS) as a powerful qualitative analysis method has been widely applied in many fields. However, SERS for quantitative analysis still suffers from several challenges partially because of the absence of stable and credible analytical strategy. Here, we demonstrate that the optimal hotspots created from dynamic surfaced-enhanced Raman spectroscopy (D-SERS) can be used for quantitative SERS measurements. In situ small-angle X-ray scattering was carried out to in situ real-time monitor the formation of the optimal hotspots, where the optimal hotspots with the most efficient hotspots were generated during the monodisperse Au-sol evaporating process. Importantly, the natural evaporation of Au-sol avoids the nanoparticles instability of salt-induced, and formation of ordered three-dimensional hotspots allows SERS detection with excellent reproducibility. Considering SERS signal variability in the D-SERS process, 4-mercaptopyridine (4-mpy) acted as internal standard to validly correct and improve stability as well as reduce fluctuation of signals. The strongest SERS spectra at the optimal hotspots of D-SERS have been extracted to statistics analysis. By using the SERS signal of 4-mpy as a stable internal calibration standard, the relative SERS intensity of target molecules demonstrated a linear response versus the negative logarithm of concentrations at the point of strongest SERS signals, which illustrates the great potential for quantitative analysis. The public drugs 3,4-methylenedioxymethamphetamine and α-methyltryptamine hydrochloride obtained precise analysis with internal standard D-SERS strategy. As a consequence, one has reason to believe our approach is promising to challenge quantitative problems in conventional SERS analysis.


Neurokinin 2 receptor-mediated activation of protein kinase C modulates capsaicin responses in DRG neurons from adult rats.
Patch-clamp techniques and Ca2+ imaging were used to examine the interaction between neurokinins (NK) and the capsaicin(CAPS)-evoked transient receptor potential vanilloid receptor 1 (TRPV1) responses in rat dorsal root ganglia neurons. Substance P (SP; 0.2-0.5 microM) prevented the reduction of Ca2+ transients (tachyphylaxis) evoked by repeated brief applications of CAPS (0.5 microM). Currents elicited by CAPS were increased in amplitude and desensitized more slowly after administration of SP or a selective NK2 agonist, [Ala8]-neurokinin A (4-10) (NKA). Neither an NK1-selective agonist, [Sar9, Met11]-SP, nor an NK3-selective agonist, [MePhe7]-NKB, altered the CAPS currents. The effects of SP on CAPS currents were inhibited by a selective NK2 antagonist, MEN10,376, but were unaffected by the NK3 antagonist, SB 235,375. Phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C(PKC), also increased the amplitude and slowed the desensitization of CAPS responses. Phosphatase inhibitors, decamethrin and alpha-naphthyl acid phosphate (NAcPh), also enhanced the currents and slowed desensitization of CAPS currents. Facilitatory effects of SP, NKA and PDBu were reversed by bisindolylmaleimide, a PKC inhibitor, and gradually decreased in magnitude when the agents were administered at increasing intervals after CAPS application. The decrease was partially prevented by prior application of NAcPh. These data suggest that activation of NK2 receptors in afferent neurons leads to PKC-induced phosphorylation of TRPV1, resulting in sensitization of CAPS-evoked currents and slower desensitization. Thus, activation of NK2 autoreceptors by NKs released from the peripheral afferent terminals or by mast cells during inflammatory responses may be a mechanism that sensitizes TRPV1 channels and enhances afferent excitability.


Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing.
Neurexins are neuron-specific vertebrate proteins with hundreds of differentially spliced isoforms that may function in synapse organization. We now show that Drosophila melanogaster and Caenorhabditis elegans express a single gene encoding only an alpha-neurexin, whereas humans and mice express three genes, each of which encodes alpha- and beta-neurexins transcribed from separate promoters. The neurexin genes are very large (up to 1.62 Mb), with the neurexin-3 gene occupying almost 2% of human chromosome 14. Although invertebrate and vertebrate neurexins exhibit a high degree of evolutionary conservation, only vertebrate neurexins are subject to extensive alternative splicing that uses mechanisms ranging from strings of mini-exons to multiple alternative splice donor and acceptor sites. Consistent with their proposed role in synapse specification, neurexins thus have evolved from relatively simple genes in invertebrates to diversified genes in vertebrates with multiple promoters and extensive alternative splicing.


Raised BMI is associated with fewer Type I endoleaks in patients treated with the Gore Excluder device: data from the Global Registry for Endovascular Aortic Treatment (GREAT).
Obesity is increasing in prevalence globally and within the cohort of vascular surgical patients, leading to poorer outcomes. There are few data on endoleak as a complication of AAA surgery in obese patients. The aim of this study was to use large scale registry data from the Global Registry for Endovascular Aortic Treatment (GREAT) to interrogate any relationship between obesity and endoleak following endovascular aneurysm repair (EVAR) using a Gore Excluder device (W. L. Gore & Associates, Newark, DE, USA), in order to guide treatment recommendations in the future. A retrospective review of the GREAT Registry was carried out and patients who were recorded as having a postoperative endoleak requiring intervention were included. Patient demographics including Body Mass Index (BMI), aneurysm parameters and on- or off-instructions for use (IFU) were recorded. Ruptured AAA were excluded. Data were obtained for 3326 patients with an operation date between August 25, 2010 and September 22, 2019. Obese patients were significantly less likely to have a Type 1 endoleak (Fisher's Exact P value=0.006), and the association was maintained in a multiple logistic regression model which controlled for age, gender, neck angulation and off IFU device use (OR=0.33, P=0.01). Among AAA patients treated with a Gore Excluder device (W. L. Gore & Associates), a higher BMI category was associated with a lower risk of Type 1 endoleak requiring reintervention. Further work needs to be carried out to assess our findings in other patient cohorts.


A systems biology approach to reconcile metabolic network models with application to Synechocystis sp. PCC 6803 for biofuel production.
Production of biofuels has been one of the promising efforts in biotechnology in the past few decades. The perspective of these efforts can be reduction of increasing demands for fossil fuels and consequently reducing environmental pollution. Nonetheless, most previous approaches did not succeed in obviating many big challenges in this way. In recent years systems biology with the help of microorganisms has been trying to overcome these challenges. Unicellular cyanobacteria are widespread phototrophic microorganisms that have capabilities such as consuming solar energy and atmospheric carbon dioxide for growth and thus can be a suitable chassis for the production of valuable organic materials such as biofuels. For the ultimate use of metabolic potential of cyanobacteria, it is necessary to understand the reactions that are taking place inside the metabolic network of these microorganisms. In this study, we developed a Java tool to reconstruct an integrated metabolic network of a cyanobacterium (Synechocystis sp. PCC 6803). We merged three existing reconstructed metabolic networks of this microorganism. Then, after modeling for biofuel production, the results from flux balance analysis (FBA) disclosed an increased yield in biofuel production for ethanol, isobutanol, 3-methyl-1-butanol, 2-methyl-1-butanol, and propanol. The numbers of blocked reactions were also decreased for 2-methyl-1-butanol production. In addition, coverage of the metabolic network in terms of the number of metabolites and reactions was increased in the new obtained model.


Once Weekly Low Dose Subcutaneous Erythropoietin: An Economic Solution for the Management of Anemia of End-stage Renal Disease.
Forty patients with end-stage renal disease on maintenance hemodialysis were categorized into three groups depending upon the route of administration of erythropoietin (EPO). Eighteen of these patients received i.v. EPO (group A), 11 were switched from i.v. to s.c. route (group B), and 11 other patients were started on s.c. EPO from the beginning of treatment (group C). They were studied to evaluate the efficacy of EPO and its dosage. The target hemoglobin was decided to be between 9 and 10.5 g/L. The hemogram of all these patients showed considerable improvement after EPO treatment. Mean hemoglobin level increased from 7.0 +/- 1.0 in all the groups to 9.0 + 1.0, 9.1 +/- 0.9 and 9.0 + 0.9 g/dl in groups A,B, and C respectively. Mean dose of EPO to achieve target hemoglobin was 120 +/- 42.2, 42.6 + 16.2 and 36.6 + 11.1 U/Kg/week in groups A, B, and C respectively. Our observation illustrates that once weekly s.c. EPO is equally effective as i.v. EPO albeit at reduced dose and hence saving costs substantially without compromising patient care. Also, it maintains hemoglobin in target range in patients already stabilized on i.v. EPO.


Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis.
Extracorporeal life-support as an adjunct to cardiac resuscitation has shown encouraging outcomes in patients with cardiac arrest. However, there is little evidence about the benefit of the procedure compared with conventional cardiopulmonary resuscitation (CPR), especially when continued for more than 10 min. We aimed to assess whether extracorporeal CPR was better than conventional CPR for patients with in-hospital cardiac arrest of cardiac origin. We did a 3-year prospective observational study on the use of extracorporeal life-support for patients aged 18-75 years with witnessed in-hospital cardiac arrest of cardiac origin undergoing CPR of more than 10 min compared with patients receiving conventional CPR. A matching process based on propensity-score was done to equalise potential prognostic factors in both groups, and to formulate a balanced 1:1 matched cohort study. The primary endpoint was survival to hospital discharge, and analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00173615. Of the 975 patients with in-hospital cardiac arrest events who underwent CPR for longer than 10 min, 113 were enrolled in the conventional CPR group and 59 were enrolled in the extracorporeal CPR group. Unmatched patients who underwent extracorporeal CPR had a higher survival rate to discharge (log-rank p<0.0001) and a better 1-year survival than those who received conventional CPR (log rank p=0.007). Between the propensity-score matched groups, there was still a significant difference in survival to discharge (hazard ratio [HR] 0.51, 95% CI 0.35-0.74, p<0.0001), 30-day survival (HR 0.47, 95% CI 0.28-0.77, p=0.003), and 1-year survival (HR 0.53, 95% CI 0.33-0.83, p=0.006) favouring extracorporeal CPR over conventional CPR. Extracorporeal CPR had a short-term and long-term survival benefit over conventional CPR in patients with in-hospital cardiac arrest of cardiac origin.


Identification of Organic Anion Transporter 2 Inhibitors: Screening, Structure-Based Analysis, and Clinical Drug Interaction Risk Assessment.
Organic anion transporter 2 (OAT2 or SLC22A7) plays an important role in the hepatic uptake and renal secretion of several endogenous compounds and drugs. The goal of this work is to understand the structure activity of OAT2 inhibition and assess clinical drug interaction risk. A single-point inhibition assay using OAT2-transfected HEK293 cells was employed to screen about 150 compounds; and concentration-dependent inhibition potency (IC50) was measured for the identified "inhibitors". Acids represented about 65% of all inhibitors, and the frequency of bases-plus-zwitterions approximately doubled for "non-inhibitors". Interestingly, 9 of 10 most potent inhibitors (low IC50) are acids (pKa ∼ 3-5). Additionally, inhibitors are significantly larger and lipophilic than non-inhibitors. In silico (binary) models were developed to identify inhibitors and non-inhibitors. Finally, in vivo risk assessed via static drug-drug interaction models identified several inhibitors with potential for renal and hepatic OAT2 inhibition at clinical doses. This is the first study assessing the global pattern of OAT2-ligand interactions.


Inducible nitric oxide synthase messenger RNA levels in hip periprosthetic tissue: a preliminary study.
Nitric oxide (NO) is a ubiquitous molecule that has been associated with inflammation, arthritis, autoimmune disease, bone resorption, and other biological processes. Elucidating the role of NO at the bone-implant interface may further our understanding of the biological processes of osseointegration, loosening, and osteolysis. This study demonstrates the use of a molecular biological technique to investigate the possible role of NO in prosthetic loosening and periprosthetic bone resorption following total hip arthroplasty. Periprosthetic tissue from 12 patients undergoing revision hip arthroplasty was harvested and total ribonucleic acid (RNA) was extracted. In six of the 12 patients, multiple samples from different anatomic locations along the same interface were studied. To estimate the amount of NO present in the tissues in vivo, the level of inducible NO synthase (iNOS) messenger RNA (mRNA) was determined using a ribonuclease (RNase) protection assay. Inducible NOS mRNA was detected in every tissue sample: there was no correlation between iNOS mRNA levels and clinical loosening or osteolysis. Analysis of multiple tissue samples from the same prosthetic component revealed that the levels of iNOS mRNA vary greatly, confirming the heterogeneous nature of the interface.


Endovascular exclusion of popliteal artery aneurysms with expanded polytetrafluoroethylene stent-grafts: early results.
There is increasing interest in using endovascular methods instead of surgical reconstruction to treat popliteal artery aneurysms. Exclusive use of the Viabahn stent-graft, a nitinol stent covered with expanded polytetrafluoroethylene, was assessed in the treatment of patients who presented with popliteal artery aneurysms in the absence of acute limb ischemia. Technical success, endoleaks, graft patency, freedom from amputation, and aneurysm sac flow and size changes were assessed by duplex ultrasound. From June 2004 to March 2006, 16 men (mean age, 76 years; range, 65-83) underwent endovascular exclusion of 23 popliteal artery aneurysms (mean diameter, 2.5 cm; range, 1.3-6.7 cm). Nine lesions had partial thrombus on preprocedural duplex imaging. Nineteen of the 23 limbs treated had at least 2-vessel tibial artery runoff. Procedures were performed under local anesthesia using ipsilateral percutaneous antegrade arterial access. All patients received 75 mg/day of clopidogrel afterward. Follow-up assessments included direct clinical examinations and duplex ultrasonography performed 1, 3, 6, and 12 months after the procedure. Primary patency and amputation-free survival were calculated using Kaplan-Meier analysis. Complete aneurysm exclusion (technical success) was achieved in all cases. During the mean follow-up of 7 months (range, 1-21 months), 22 of 23 treated limbs remained asymptomatic. One stent-graft thrombosis occurred 6 months after the procedure and was successfully treated with percutaneous mechanical thrombectomy, balloon angioplasty of a stent-graft stenosis, and insertion of an uncovered nitinol stent. No popliteal artery aneurysm sac size enlargements or endoleaks were detected. At 12 months, the treated limb mean ankle-brachial index was 1.0 (range, 0.82-1.31) and the primary and secondary patency rates were 93% and 100%, respectively. Early results with Viabahn endovascular stent-graft exclusion of asymptomatic popliteal artery aneurysms are promising. Patient selection for endovascular repair depends on suitable popliteal artery anatomy, extent of aneurysmal degeneration, and quality of tibial arterial runoff.


Immunohistochemical characterization of a pulmonary large-cell carcinoma in a dog.
Primary pulmonary tumors are less common in dogs than secondary (metastatic) tumors. Most primary tumors are malignant and of epithelial origin. Pulmonary large-cell carcinoma is considered extremely rare in domestic animals, and some of the few reported cases actually may have been cases of malignant pulmonary histiocytosis. An 8-year-old female Wire Fox Terrier with diffuse alveolar pattern radiographically was euthanatized when it failed to respond to antibiotic therapy. Histologically, pulmonary alveolar spaces contained clusters of large round anaplastic cells with ample eosinophilic cytoplasm and large irregularly shaped nuclei with prominent nucleoli. Immunohistochemistry was used to distinguish large-cell carcinoma from malignant pulmonary histiocytosis. Tumor cells had strong immunoreactivity for cytokeratin, consistent with epithelial origin. However, a substantial percentage of the neoplastic cells co-expressed vimentin and MHC-II. The type II alveolar epithelial cell was considered the cell of origin of the neoplasm based on the presence of lamellar bodies in some neoplastic cells and immunoreactivity for surfactant protein A and thyroid transcription factor-1.


Synergistic antitumor activity of low-dose c-Met tyrosine kinase inhibitor and sorafenib on human non-small cell lung cancer cells.
Sorafenib is a multikinase inhibitor that is frequently used to treat various types of malignant tumors. However, it has been demonstrated that Sorafenib only has a moderate antitumor efficacy and is associated with numerous side effects in non-small cell lung cancer (NSCLC), which greatly limits its clinical application. The present study aimed to examine the effects of a combination of Sorafenib and low-dose PF-2341066, a selective c-Met tyrosine kinase inhibitor, on the proliferation, apoptosis and migration of the NSCLC cell line NCI-H1993. The data indicated that treatment with a combination of Sorafenib and low-dose PF-2341066 was able to significantly inhibit the proliferation and migration as well as promote the apoptosis, of NCI-H1993 cells, compared with treatment with Sorafenib or low-dose PF-2341066 alone. Further experiments indicated that the levels of phosphorylated epidermal growth factor receptor and c-Met were significantly decreased following the combined treatment of Sorafenib and PF-2341066, compared with the treatment with Sorafenib or PF-2341066 alone. The findings of the present study indicated that using a low-dose c-Met inhibitor enhances the antitumor activity of Sorafenib in NSCLC and may provide a novel strategy for the treatment of NSCLC.


[The first treatise on diet: the Kitāb Hawāss al-agdiyah de Yūhannā ibn Māsawayh].
The article presents the first treatise concerning dietetics, written in Arabic in the first half of the IX century by one of the most ancient doctors of Bagdād, Yūhannā ibn Māsawayh, known in the western world as Jean Mésué. Ibn Māsawayh, basing his work on Galen's Properties of Foods, describes the properties of 140 foodstuffs from the vegetable and animal kingdom, and their good or bad effects on the human body. The translation of this treatise has been made from the only manuscript surviving, in the National Library of Madrid.


Traumatic haemorrhagic optic neuropathy: case report.
We report a case of visual loss following haemorrhage into the optic nerve sheath following head trauma. The patient showed improvement in visual function following decompression of the optic nerve sheath and evacuation of the haematoma.


Lifestyle-related risks: are trends in Europe converging?
What has become of lifestyle differences in a united Europe, where member states become more and more similar on aspects such as welfare systems and population dynamics? In this paper, we try to answer the question whether the gap in lifestyle-related risk factors in Europe has narrowed over the past 30-40 years. Smoking, alcohol consumption, physical activity, obesity and food consumption all have an impact on cancer, cardiovascular disease and other non-communicable diseases. Databases of Eurostat, OECD (Organisation for Economic Co-operation and Development) and the World Health Organisation were screened for data on lifestyle-related risk factors in the European Union, and a literature search was performed for studies that collected international comparable data about the selected factors. The gap in European lifestyle has narrowed over the past 30-40 years for smoking (women), alcohol consumption and total fat intake. For fruit and vegetable consumption, convergence is not occurring. For some risk factors, such as smoking and obesity, intranational differences surpass the international differences. The results support the notion of convergent lifestyles among Europeans over time. We also found that there is a serious lack of reliable data on lifestyle-related risk factors that are suitable for international comparison. It is essential to invest in reliable and internationally comparable data, obtained according to best evidence, to get more insight into real differences regarding risk factors in Europe. The European Public Health programme may be an opportunity to realize these goals.


Evaluation of the Emergency Severity Index in US Emergency Departments for the Rate of Mistriage.
Accurate emergency department (ED) triage is essential to prioritize the most critically ill patients and distribute resources appropriately. The most used triage system in the US is the Emergency Severity Index (ESI). To derive and validate an algorithm to assess the rate of mistriage and to identify characteristics associated with mistriage. This retrospective cohort study created operational definitions for each ESI level that use ED visit electronic health record data to classify encounters as undertriaged, overtriaged, or correctly triaged. These definitions were applied to a retrospective cohort to assess variation in triage accuracy by facility and patient characteristics in 21 EDs within the Kaiser Permanente Northern California (KPNC) health care system. All ED encounters by patients 18 years and older between January 1, 2016, and December 31, 2020, were assessed for eligibility. Encounters with missing ESI or incomplete ED time variables and patients who left against medical advice or without being seen were excluded. Data were analyzed between January 1, 2021, and November 30, 2022. Assigned ESI level. Rate of undertriage and overtriage by assigned ESI level based on a mistriage algorithm and patient and visit characteristics associated with undertriage and overtriage. A total of 5 315 176 ED encounters were included. The mean (SD) patient age was 52 (21) years; 44.3% of patients were men and 55.7% were women. In terms of race and ethnicity, 11.1% of participants were Asian, 15.1% were Black, 21.4% were Hispanic, 44.0% were non-Hispanic White, and 8.5% were of other (includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, and multiple races or ethnicities), unknown, or missing race or ethnicity. Mistriage occurred in 1 713 260 encounters (32.2%), of which 176 131 (3.3%) were undertriaged and 1 537 129 (28.9%) were overtriaged. The sensitivity of ESI to identify a patient with high-acuity illness (correctly assigning ESI I or II among patients who had a life-stabilizing intervention) was 65.9%. In adjusted analyses, Black patients had a 4.6% (95% CI, 4.3%-4.9%) greater relative risk of overtriage and an 18.5% (95% CI, 16.9%-20.0%) greater relative risk of undertriage compared with White patients, while Black male patients had a 9.9% (95% CI, 9.8%-10.0%) greater relative risk of overtriage and a 41.0% (95% CI, 40.0%-41.9%) greater relative risk of undertriage compared with White female patients. High relative risk of undertriage was found among patients taking high-risk medications (30.3% [95% CI, 28.3%-32.4%]) and those with a greater comorbidity burden (22.4% [95% CI, 20.1%-24.4%]) and recent intensive care unit utilization (36.7% [95% CI, 30.5%-41.4%]). In this retrospective cohort study of over 5 million ED encounters, mistriage with ESI was common. Quality improvement should focus on limiting critical undertriage, optimizing resource allocation by patient need, and promoting equity.


[Physicians' strikes--ethical considerations].
Strikes in general represent a solution based on a form of coercion. Historically, the striker caused direct damage to his employer, who was responsible for the perceived unfair treatment of the employee. In the case of strikes in the public sector, the employer is generally not harmed, but innocent citizens suffer in order to pressure the government agencies, a questionable practice from an ethical viewpoint. Physicians' strikes have more serious ethical problems. They cause suffering and death to innocent citizens. They violate the ethical codes to which physicians have committed themselves as professionals, and they seriously impair the trust of the public in physicians. Better and more ethical ways to provide fair compensation for physicians must be employed, perhaps like those used for judges and members of the IDF.


Importance of a Fluorine Substituent for the Preparation of meta- and para-Pentafluoro-λ(6) -sulfanyl-Substituted Pyridines.
Although there are ways to synthesize ortho-pentafluoro-λ(6) -sulfanyl (SF5 ) pyridines, meta- and para-SF5 -substituted pyridines are rare. We disclose herein a general route for their synthesis. The fundamental synthetic approach is the same as reported methods for ortho-SF5 -substituted pyridines and SF5 -substituted arenes, that is, oxidative chlorotetrafluorination of the corresponding disulfides to give pyridylsulfur chlorotetrafluorides (SF4 Cl-pyridines), followed by chloride/fluoride exchange with fluorides. However, the trick in this case is the presence on the pyridine ring of at least one fluorine atom, which is essential for the successful transformation of the disulfides into m-and p-SF5 -pyridines. After enabling the synthesis of an SF5 -substituted pyridine, ortho-F groups can be efficiently substituted by C, N, S, and O nucleophiles through an SN Ar pathway. This methodology provides access to a variety of previously unavailable SF5 -substituted pyridine building blocks.


Schwannoma of the medial cutaneous nerve of the arm: a rare location with concomitant compression neuropathy of the ulnar nerve.
The objective of this paper is to present a case of rare location of schwannoma in the medial cutaneous nerve of the arm at the level of the axilla. Preliminary diagnostic examination of the tumour was carried out in another hospital by means of open biopsy. In the preoperative period symptoms of ulnar nerve dysfunction (paraesthesias, positive Hoffmann-Tinel sign) dominated the clinical picture. After having performed imaging studies and electromyographic (EMG) examination, the patient was scheduled for an operation. The tumour, measuring 3.5 × 3.0 × 1.5 cm, was resected without damage to the fascicular structure. Presence of paraesthesias in the distribution of the medial cutaneous nerve of the arm, which was first noted in the postoperative period, persists in moderate severity until now. As a result of the performed operative treatment, such symptoms as palpable tumour mass, pain, paraesthesias in the ulnar nerve distribution and positive Hoffmann-Tinel sign resolved. On the basis of histopathological examination results the final diagnosis of classical schwannoma was established.


Venous disease and ergonomics of female employment.
The aim of this study was to describe the employment conditions of women with chronic venous disorders of the lower limbs. Cross sectional study conducted by general practitioners who describe the first 3 women, between 18 and 65 years of age, who were employed and who presented with at least CEAP stage I venous disorders. Occupations held by these women indicate significant departures from the general population with an over representation of industrial workers (18.6% vs 11.9%) and an under representation of intermediate professions (12.5% vs 26.6%), (P<0.001). At work, 78.2% (n=4,143) of the women remained standing for 6.2+/-2.4 hours per day and/or 52.3% (n=2,771) were seated for prolonged periods, 28.9% (n=1 503) were exposed to sources of high heat on the legs and 18.2% (n=947) wore garments that compressed the abdomen Conditions favorable to the ergonomic evolution of their workstation are limited: only 9.2% (n=397) thought it possible to reduce the time they spend standing; 10.1% (n=319) the time they spend sitting; 12.9% (n=189) their exposure to heat. Combating these factors appears difficult: 74.3% (n=3 883) state that they do not have sufficient breaks to rest their legs, 38.9% (n=2,053) that they do not have the opportunity to stretch their legs and 42.5% (n=1,395) that compression stockings would be permitted, but would be a hindrance in their work (85.6%, n=4,503). For 27% (n=1,424) of respondents, these problems significantly increase the arduousness of their work and 73.7% (n=3,870) think their working conditions have worsened their venous distress. Women who consult for venous problems are employed in work which are characterized by unavoidable conditions constituting undeniable venous risk factors for venous disease and occupational medicine does not pay enough attention to the ''ladies legs'' at work.


Single-Walled Carbon Nanotubes in Highly Viscous Media: A Comparison between the Dispersive Agents [BMIM][BF4 ], L121, and Triton X-100.
Dispersions of single-walled carbon nanotubes (SWNTs) have been prepared by using the room-temperature ionic liquid [BMIM][BF4 ] (1-butyl-3-methylimidazolium tetrafluoroborate), the triblock copolymer Pluronic L121 [poly(ethylene oxide)5 -poly(propylene oxide)68 -poly(ethylene oxide)5 ] and the non-ionic surfactant Triton X-100 (TX100) in the pure state. The size of the SWNTs aggregates and the dispersion degree in the three viscous systems depend on the sonication time, as highlighted by UV/Vis/NIR spectroscopy and optical microscopy analysis. A nonlinear increase in conductivity can be observed as a function of the SWNTs loading, as suggested by electrochemical impedance spectroscopy. The generation of a three-dimensional network of SWNTs showing a viscoelastic gel-like behavior above a critical percolation concentration has been found at 25 °C in all the investigated systems by oscillatory rheology measurements.


Identification of resistance gene analogs of the NBS-LRR family through transcriptome probing and in silico prediction of the expressome of Dalbergia sissoo under dieback disease stress.
Dalbergia sissoo is an important timber tree, and dieback disease poses a dire threat to it toward extinction. The genomic record of D. sissoo is not available yet on any database; that is why it is challenging to probe the genetic elements involved in stress resistance. Hence, we attempted to unlock the genetics involved in dieback resistance through probing the NBS-LRR family, linked with mostly disease resistance in plants. We analyzed the transcriptome of D. sissoo under dieback challenge through DOP-rtPCR analysis using degenerate primers from conserved regions of NBS domain-encoded gene sequences. The differentially expressed gene sequences were sequenced and in silico characterized for predicting the expressome that contributes resistance to D. sissoo against dieback. The molecular and bioinformatic analyses predicted the presence of motifs including ATP/GTP-binding site motif A (P-loop NTPase domain), GLPL domain, casein kinase II phosphorylation site, and N-myristoylation site that are the attributes of proteins encoded by disease resistance genes. The physicochemical characteristics of identified resistance gene analogs, subcellular localization, predicted protein fingerprints, in silico functional annotation, and predicted protein structure proved their role in disease and stress resistance.


Method of obtaining drug-macromolecule binding parameters directly from dynamic dialysis data.
A new method of treating dynamic dialysis data to obtain binding parameters for drug-macromolecule interactions is presented. This method allows the determination of binding parameters directly from dialysis data according to a theoretical model. It is not necessary to determine the dialysis rate constant accurately in a separate experiment, and bias is not introduced due to differentiation. The proposed method should be applicable where the drug is substantially bound to the dialysis membrane.


Perceived threat of Alzheimer's disease and related dementias among older Chinese Americans in subsidized housing: Through a cultural lens.
Low socioeconomic status and limited social support may put older residents in subsidized housing at high risk for developing fears of Alzheimer's disease or related dementias. This study examined the perceived threat of Alzheimer's disease or related dementias among older Chinese Americans in subsidized housing facilities in Phoenix, Arizona of the United States, and focused on the effect of cultural beliefs (i.e., beliefs toward Alzheimer's disease or related dementias, and beliefs toward intergenerational support) on the perceived threat of Alzheimer's disease or related dementias. Analyses were based upon a survey of 207 Chinese American older adults (Mage = 75.37, SD = 7.47) living in subsidized housing facilities in the Phoenix metropolitan area. Standardized survey questionnaires were delivered through face-to-face interviews. Multivariate analyses suggest that fatalism related beliefs about Alzheimer's disease or related dementias, rather than stigmatization, were related to higher levels of concerns for developing Alzheimer's disease or related dementias, while beliefs in intergenerational support were related to lower levels of perceived threat of Alzheimer's disease or related dementias. However, the protective effect of beliefs in intergenerational support tended to diminish in those living with higher levels of depressive symptoms. Cultural beliefs can entail both risks and strengths when low-income Chinese American elders attempt to comprehend the implications of Alzheimer's disease or related dementias. Health education or intervention programs need to address their fatalism beliefs toward Alzheimer's disease or related dementias, and facilitate the accessibility of intergenerational support for this group.


A model of the early mineralization process of mantle dentin.
The aim of this study was to investigate the relationship between proteoglycans (PGs) and collagen fibrils at the early mineralization process of mantle dentin. Ten first molar dental germs of rats were removed and fixed in glutaraldehyde/formaldehyde in cacodylate buffer and post-fixed in osmium tetroxide. The samples were dehydrated and embedded in epoxy resin. Ultrathin sections were contrasted and analyzed in TEM before and after treatment with EDTA, chondroitinases AC and ABC. After EDTA treatment, a electrondense substance associated with collagen fibril was removed, and did not stain again. A high magnification of these areas showed globular structures with 15 nm diameter surrounding collagen fibrils. In advanced mineralization areas, collagen fibrils showed a banded pattern and at high magnification the fibrils presented a light 10 nm ring inside and a dark 10 nm ring outside. After chondroitinase treatment, the electrondense substance associated with collagen fibrils was removed, showing a banded pattern of clear and dark areas along them. From morphological data, the authors proposed a model of interaction between PGs and collagen fibrils, where glicosaminoglycans chains are inside the fibrils, while the protein core remains outside. That stereochemical arrangement would start the crystal nucleation.


Pharmacokinetics of daclatasvir in Egyptian adolescents with genotype-4 HCV infection.
Daclatasvir has potent antiviral activity against HCV infection when used in combination with sofosbuvir, however, its pharmacokinetics have not been described in adolescents. The aim is to determine the pharmacokinetic parameters of daclatasvir in adolescents, and to develop a population pharmacokinetic (PopPK) model. Seventeen adolescent patients with genotype-4 chronic HCV infection received once daily oral daclatasvir 60 mg in combination with 400 mg sofosbuvir for 12 weeks. Steady state concentrations were determined. Non-compartmental and population PK were determined. The average PK parameters calculated by non-compartmental analysis (NCA): maximum plasma concentration (Cmax), area under the curve (AUC), apparent oral volume of distribution (V/F), apparent oral clearance (CL/F) and half-life (T1/2) were 1,092 ng/ml, 11,178 ng/ml•h, 55 l, 4.5 l/h and 8.5 h, respectively. Daclatasvir was best described by one compartment structural PK model with zero order absorption and first-order elimination. The absorption rate constant (K0), V/F, and CL/F of the final PopPK model of daclatasvir were 1.5/h, 52 l and 4.7 l/h, respectively. Body weight and serum albumin had significant effect on the V/F parameter. Body weight and serum albumin were the major determinants of daclatasvir V/F in this population. PK parameters were comparable to those reported in adult HCV patients, demonstrating that 60 mg daclatasvir is an appropriate dose for adolescents. ClinicalTrials.gov NCT03540212.


Type 1 responses of human Vγ9Vδ2 T cells to influenza A viruses.
γδ T cells are essential constituents of antimicrobial and antitumor defenses. We have recently reported that phosphoantigen isopentenyl pyrophosphate (IPP)-expanded human Vγ9Vδ2 T cells participated in anti-influenza virus immunity by efficiently killing both human and avian influenza virus-infected monocyte-derived macrophages (MDMs) in vitro. However, little is known about the noncytolytic responses and trafficking program of γδ T cells to influenza virus. In this study, we found that Vγ9Vδ2 T cells expressed both type 1 cytokines and chemokine receptors during influenza virus infection, and IPP-expanded cells had a higher capacity to produce gamma interferon (IFN-γ). Besides their potent cytolytic activity against pandemic H1N1 virus-infected cells, IPP-activated γδ T cells also had noncytolytic inhibitory effects on seasonal and pandemic H1N1 viruses via IFN-γ but had no such effects on avian H5N1 or H9N2 virus. Avian H5N1 and H9N2 viruses induced significantly higher CCL3, CCL4, and CCL5 production in Vγ9Vδ2 T cells than human seasonal H1N1 virus. CCR5 mediated the migration of Vγ9Vδ2 T cells toward influenza virus-infected cells. Our findings suggest a novel therapeutic strategy of using phosphoantigens to boost the antiviral activities of human Vγ9Vδ2 T cells against influenza virus infection.


Evaluating Neck Circumference as an Independent Predictor of Metabolic Syndrome and Its Components Among Adults: A Population-Based Study.
Background Metabolic syndrome (MetS), a public health problem worldwide, represents a high-risk condition for cardiovascular disease and diabetes. The reserve of subcutaneous fat in the upper torso is an important factor in the development of MetS and its risk factors. As neck circumference (NC) is a simple and reliable index that indicates upper-body subcutaneous fat accumulation, this study was conducted to investigate the association between NC with MetS and its components in a large population-based sample of Iranian adults. Methods The present cross-sectional study was conducted among 2094 individuals aged 20-70 years from Yazd Health Study (YaHS). MetS was defined based on the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. NC more than 40.25 cm for men and more than 35.75 cm for women was considered a high-risk NC. Logistic regression analysis was applied to obtain the associations of NC with MetS and its component. Results After adjusting for age, BMI, energy intake, physical activity, and smoking in those whose NC was higher than normal, the risk of the MetS (odds ratio {OR}: 2.32; 95%CI: 1.55-3.46, P<0.001 in men and OR: 2.56; 95%CI: 1.76-3.74, P<0.001 in women), abdominal obesity (OR: 4.39; 95%CI: 2.67-7.23, P<0.001 in men and OR: 1.92; 95%CI: 1.27-2.90, P=0.002 in women), high blood pressure (OR: 1.54; 95%CI: 1.07-2.21, P=0.02 in men and OR: 1.51; 95%CI: 1.06-2.14, P=0.02 in women), low high-density lipoprotein cholesterol (HDL-C) (OR: 1.47; 95%CI: 1.01-2.15, P=0.04 in men and OR: 1.69; 95%CI: 1.23-2.32, P=0.001 in women), and hypertriglyceridemia (OR: 1.41; 95%CI: 1.03-1.99, P=0.04 in men and OR: 1.68; 95%CI: 1.17-2.41, P=0.005 in women) were higher. There was no significant difference in the risk of hyperglycemia between the two NC groups in both sexes. The Pearson's correlation coefficients of NC with waist circumference, hip circumference, body mass index, and waist-to-height ratio were 0.52, 0.43, 0.41, and 0.31, respectively (P<0.001). Moreover, NC had a considerable correlation with serum triglyceride, high-density lipoprotein, systolic blood pressure, and diastolic blood pressure (0.27, -0.30, 0.29, 0.25, P<0.001), respectively. Conclusion Increased NC was significantly associated with higher odds of MetS and its components. Since NC measurement is simple, inexpensive, reliable, and less invasive, it can be used as a complementary tool in the screening and diagnosis of MetS and its risk factors in clinical and community programs especially in developing countries.


Triggering a [2]Rotaxane Molecular Shuttle by a Photochemical Bond-Cleavage Strategy.
The successful triggering of ring-shuttling motion between two stations in a [2]rotaxane is demonstrated by employing a photochemical bond-cleavage strategy. A photolabile bulk barrier is covalently introduced into two identical stations of the thread to prevent dynamic shuttling of the macrocycle, resulting in a "gated" state. Irradiation of UV light (λ = 365 nm) results in the complete removal of the bulk barrier and the balanced shuttling motion of the macrocycle, indicating an "open" state of the rotaxane. In addition, the process from the "open" rotaxane to the "gated" rotaxane was executed by a chemical-rebonding method.


The impact of financial circumstances on student health.
To explore the impact of students' financial circumstances on their mental and physical health. The study employed a correlational design. An opportunity sample of 89 British students and 98 Finnish students completed a questionnaire which assessed their amount of debt, financial concerns, mental and physical health, smoking and drinking behaviours, work in addition to study, and perceptions of control. British students reported greater levels of debt and financial concern than Finnish students. They also reported significantly worse mental and physical health on a variety of dimensions. Financial concern was a significant linear predictor of mental and physical health, with increased financial concern being consistently associated with worse health. There was no evidence that students' smoking or drinking behaviour, work in addition to study, or perceptions of control substantially mediated the relationship between financial concern and health. The results support the position that students' financial circumstances might have serious implications for their health. It is proposed, therefore, that recent changes in government funding policies for students could have a negative impact on student health and exacerbate finance-related health inequalities. Further research is required to identify factors that may mediate or moderate the impact of financial concern on health.


[A new case of perforation of the esophagus during intraoperative transesophageal echocardiography].
We describe a novel case of peroperative oesophageal perforation following insertion of a transoesophageal echocardiography probe. Histories of left pneumonectomy and oesophageal fragility probably explained this complication. The perforation was stitched and the coronary artery bypass graft surgery was delayed by a few days. Early postoperative period was not marked by infectious complication but the patient could not weaned from ventilatory support. She died 6 months later.


Sex, survival bias, and mortality following acute myocardial infarction.
Several though not all studies have found an up to 2-fold increase in 30-day mortality in women compared to men admitted to hospital for ST-elevation myocardial infarction (MI), even after adjustment for baseline variables. These data however do not take into account the pre-hospital period. Indeed, three large WHO MONICA reports that included out-of-hospital events found no significant gender difference in overall 28-day mortality from MI, with more men dying before reaching the hospital (presumably of ventricular tachyarrhythmias) and more women dying after hospital admission (presumably of heart failure). Women compared to men exhibit enhanced vagal activity, both under basal conditions and during angioplasty-induced coronary occlusion, and this may afford protection against malignant ventricular arrhythmias. Epidemiological data indicate that women dying of ischemic heart disease are less prone to sudden death than men. Taken together, the above findings suggest that, following acute MI, significant gender differences lie not so much in overall mortality, but in the timing and mechanisms of death.


Laparoscopic spleen-preserving distal pancreatectomy for a primary hydatid cyst mimicking a mucinous cystic neoplasia.
Pancreatic hydatid cysts are fairly rare. The disease can be encountered concurrently with systemic involvement or as an isolated pancreatic involvement. We report the first case of spleen-preserving laparoscopic distal pancreatectomy for a pancreatic hydatid cyst. There was no complication or recurrence. A 55-year-old woman was admitted to our centre with epigastric and back pain. Upper abdominal magnetic resonance imaging revealed a solitary cystic lesion with septations at the pancreatic tail level measuring 24 mm × 18 mm, which was initially thought to be a pancreatic mucinous cystic neoplasia. She underwent laparoscopic spleen-preserving distal pancreatectomy and cholecystectomy. Her post-operative course was uneventful and histopathological examination revealed a hydatid cyst in the pancreatic tail.


Aromatase inhibition abolishes LTP generation in female but not in male mice.
Inhibitors of aromatase, the final enzyme of estradiol synthesis, are suspected of inducing memory deficits in women. In previous experiments, we found hippocampal spine synapse loss in female mice that had been treated with letrozole, a potent aromatase inhibitor. In this study, we therefore focused on the effects of letrozole on long-term potentiation (LTP), which is an electrophysiological parameter of memory and is known to induce spines, and on phosphorylation of cofilin, which stabilizes the spine cytoskeleton and is required for LTP in mice. In acute slices of letrozole-treated female mice with reduced estradiol serum concentrations, impairment of LTP started as early as after 6 h of treatment and progressed further, together with dephosphorylation of cofilin in the same slices. Theta-burst stimulation failed to induce LTP after 1 week of treatment. Impairment of LTP was followed by spine and spine synapse loss. The effects were confirmed in vitro by using hippocampal slice cultures of female mice. The sequence of effects in response to letrozole were similar in ovariectomized female and male mice, with, however, differences as to the degree of downregulation. Our data strongly suggest that impairment of LTP, followed by loss of mushroom spines and spine synapses in females, may have implications for memory deficits in women treated with letrozole.


Translucency of glass-fibre-reinforced composite materials.
summary The purpose of this study was to examine the translucency of glass-fibre-reinforced composite framework materials. Vectris and FibreKor, as well as an experimental material, were the glass-fibre-reinforced framework materials used. Targis, Sculpture and Estenia were the types of particulate filler composites veneered onto frameworks. Specimens were fabricated from each material, 0.5 and 1.0 mm thick. In addition, laminate specimens, 1.5 mm thick, were fabricated. The translucency of each specimen was evaluated by determining its contrast ratio. The laminate specimens were examined for colour differences. The experimental framework material was more translucent than the enamel composite when it was not coloured, and was nearly as translucent as the dentine composite when coloured. The commercial tooth-coloured framework materials were nearly as translucent as the dentine composite. It was found that it was possible to reproduce the same colour as the veneering dentine composite, when the framework thickness was 0.5 mm, except in the case of FibreKor. Within the limitations of this study, tooth-coloured, glass-fibre-reinforced framework materials are nearly as translucent as the veneering dentine composite, but these materials affect the colour of the prosthesis if the thickness of the framework material is increased beyond a certain point.


Identity Disturbance, Feelings of Emptiness, and the Boundaries of the Schizophrenia Spectrum.
Historical and current research on borderline personality disorder reveal certain affinities with schizophrenia spectrum psychopathology. This is also the case for the borderline criteria of "identity disturbance" and "feelings of emptiness," which reflect symptomatology frequently found in schizophrenia and schizotypal personality disorder. Unfortunately, the diagnostic manuals offer limited insight into the nature of these criteria, including possible deviations and similarities with schizophrenia spectrum symptomatology. In this article, we attempt to clarify the concepts of identity disturbance and feelings of emptiness with an emphasis on the criteria's differential diagnostic significance. Drawing on contemporary philosophy, we distinguish between a "narrative" self and a "core" self, suggesting that this distinction may assist differential diagnostic efforts and contribute to mark the psychopathological boundaries of these disorders.


Methane emission from global livestock sector during 1890-2014: Magnitude, trends and spatiotemporal patterns.
Human demand for livestock products has increased rapidly during the past few decades largely due to dietary transition and population growth, with significant impact on climate and the environment. The contribution of ruminant livestock to greenhouse gas (GHG) emissions has been investigated extensively at various scales from regional to global, but the long-term trend, regional variation and drivers of methane (CH4 ) emission remain unclear. In this study, we use Intergovernmental Panel on Climate Change (IPCC) Tier II guidelines to quantify the evolution of CH4 emissions from ruminant livestock during 1890-2014. We estimate that total CH4 emissions in 2014 was 97.1 million tonnes (MT) CH4 or 2.72 Gigatonnes (Gt) CO2 -eq (1 MT = 1012 g, 1 Gt = 1015 g) from ruminant livestock, which accounted for 47%-54% of all non-CO2 GHG emissions from the agricultural sector. Our estimate shows that CH4 emissions from the ruminant livestock had increased by 332% (73.6 MT CH4 or 2.06 Gt CO2 -eq) since the 1890s. Our results further indicate that livestock sector in drylands had 36% higher emission intensity (CH4 emissions/km2 ) compared to that in nondrylands in 2014, due to the combined effect of higher rate of increase in livestock population and low feed quality. We also find that the contribution of developing regions (Africa, Asia and Latin America) to the total CH4 emissions had increased from 51.7% in the 1890s to 72.5% in the 2010s. These changes were driven by increases in livestock numbers (LU units) by up to 121% in developing regions, but decreases in livestock numbers and emission intensity (emission/km2 ) by up to 47% and 32%, respectively, in developed regions. Our results indicate that future increases in livestock production would likely contribute to higher CH4 emissions, unless effective strategies to mitigate GHG emissions in livestock system are implemented.


Successful rehabilitation after hip fracture to a patient with previous above-elbow amputation.
We experienced successful rehabilitation of an elderly man after hip fracture (HF) who had had ipsilateral above-elbow amputation. He was a wounded soldier whose right arm had been amputated more than 60 yrs ago, and he had never used a prosthesis. He had been admitted to our hospital because of exacerbation of chronic obstructive pulmonary disease. During his admission, he had a fall-related hip fracture. We devised a special upper-limb prosthesis so that he could hold an ipsilateral crutch to enable appropriate acute-phase rehabilitation for HF. As a result, effects of disuse were prevented and he gained improvement of lower-limb function. The specialized upper-limb prosthesis also reduced his anxiety regarding walking. It can be considered that the prosthesis contributed to his quality of life with regard to activities of daily living after discharge.


5-Methylcytosine content in the vertebrate deoxyribonucleic acids: species specificity.
RNA-free native DNA samples, isolated by four methods, from different vertebrate tissues and species, were hydrolyzed chemically and enzymatically and analyzed by paper chromatography to estimate the base composition. It was noted that (i) all the DNA preparations analyzed contained 5-methylcytosine, (ii) on the basis of mole percent of 5-methylcytosine, the composition of DNA varied in different species, but not so much in different tissues of the same species, (iii) the method of DNA hydrolysis, but not the method of deproteinization, affected the mole percent of 5-methylcytosine, and (iv) no 5-hydroxymethylcytosine (5-HMC) was detected in any of the DNA preparations analyzed.


Extramedullary acute myeloid leukemia (granulocytic sarcoma) with arm paresis, maculopapular exanthema and organ involvement.
Granulocytic sarcoma (extramedullary myelosarcoma, chloroma) is a rare extramedullary myeloid tumor which can occur at any anatomical site as isolated finding or associated with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). In this case, we describe a 71-year-old man who presented with incomplete paresis of the left arm, periorbital swelling, a maculopapular exanthema and organ involvement including testis and stomach. The tumors responded to combination chemotherapy and the patient fully recovered. However, after five months the patient relapsed and died quickly. This case confirms the importance of including granulocytic sarcoma in the differential diagnoses of a variety of diseases. In AML, the presence of granulocytic sarcoma is associated with worse overall survival. When diagnosed, it should be treated with intensive chemotherapy as soon as possible.


POLYPHYLETIC ORIGINS OF ASEXUALITY IN DAPHNIA PULEX. II. MITOCHONDRIAL-DNA VARIATION.
Allozyme studies of the cladoceran Daphnia pulex have shown that most populations reproduce by obligate parthenogenesis, although some cyclically parthenogenetic populations remain throughout the southern portion of its range. Clonal diversity within the obligate parthenogens is extremely high and has been attributed to the polyphyletic origin of asexuality. Specifically, it has been proposed that the clonal diversity in the obligate parthenogens was generated via the spread of a sex-limited meiosis suppressor through populations of a cyclically parthenogenetic ancestor. In this study, analysis of polymorphism of restriction-endonuclease sites in the mitochondrial genome, in conjunction with allozyme analysis, was used to determine whether obligate parthenogenesis has a monophyletic or polyphyletic origin in D. pulex. An allozyme survey of 77 populations from Ontario and Michigan was first conducted to determine breeding systems and levels of clonal diversity (Hebert et al., 1989). Mitochondrial-DNA variation was then surveyed in one isolate of each clone from each population reproducing by obligate parthenogenesis and in 2-4 isolates from each population reproducing by cyclic parthenogenesis. Seventeen restriction enzymes were used in this analysis. Thirty-five mitochondrial genotypes were found among the 36 obligate clones (as identified by allozyme analysis), while 17 mitochondrial genotypes were identified among 40 cyclic isolates from 14 populations. Five mitochondrial genotypes were found in both groups. Parsimony and phenetic-clustering methods were used to construct trees showing the genetic relationship among mitochondrial genotypes. The results clearly show that obligate parthenogenesis had a polyphyletic origin in this species. The close relationship between cyclic and obligate parthenogens in the Great Lakes region suggests that many obligate clones have recently been derived from cyclic populations and that the generation of clones is still occurring in this area. Patterns of clonal diversity based on the joint consideration of allozyme and mitochondrial-DNA data are discussed.


Effects of Phosphoryl Guanidine Modification of Phosphate Residues on the Structure and Hybridization of Oligodeoxyribonucleotides.
Phosphoryl guanidine oligonucleotides (PGOs) are promising tools for biological research and development of biosensors and therapeutics. We performed structural and hybridization analyses of octa-, deca-, and dodecamers with all phosphate residues modified by 1,3-dimethylimidazolidine-2-imine moieties. Similarity of the B-form double helix between native and modified duplexes was noted. In PGO duplexes, we detected a decrease in the proportion of C2'-endo and an increased proportion of C1'-exo sugar conformations of the modified chain. Applicability of the two-state model to denaturation transition of all studied duplexes was proved for the first time. Sequence-dependent effects of this modification on hybridization properties were observed. The thermal stability of PGO complexes is almost native at 100 mM NaCl and slightly increases with decreasing ionic strength. An increase in water activity and dramatic changes in interaction with cations and in solvation of PGOs and their duplexes were noted, resulting in slight elevation of the melting temperature after an ionic-strength decrease from 1 M NaCl down to deionized water. Decreased binding of sodium ions and decreased water solvation were documented for PGOs and their duplexes. In contrast to DNA, the PGO duplex formation leads to a release of several cations. The water shell is significantly more disordered near PGOs and their complexes. Nevertheless, changes in solvation during the formation of native and PGO complexes are similar and indicate that it is possible to develop models for predictive calculations of the thermodynamic properties of phosphoryl guanidine oligomers. Our results may help devise an approach for the rational design of PGOs as novel improved molecular probes and tools for many modern methods involving oligonucleotides.


Multipronged Therapeutic Effects of Chinese Herbal Medicine Qishenyiqi in the Treatment of Acute Myocardial Infarction.
Background: Based on global gene expression profile, therapeutic effects of Qishenyiqi (QSYQ) on acute myocardial infarction (AMI) were investigated by integrated analysis at multiple levels including gene expression, pathways involved and functional group. Methods: Sprague-Dawley (SD) rats were randomly divided into 3 groups: Sham-operated, AMI model (left anterior descending coronary artery ligation) and QSYQ-treated group. Cardiac tissues were obtained for analysing digital gene expression. Sequencing and transcriptome analyses were performed collaboratively, including analyses of differential gene expression, gene co-expression network, targeted attack on network and functional grouping. In this study, a new strategy known as keystone gene-based group significance analysis was also developed. Results: Analysis of top keystone QSYQ-regulated genes indicated that QSYQ ameliorated ventricular remodeling (VR), which is an irreversible process in the pathophysiology of AMI. At pathway level, both well-known cardiovascular diseases and cardiac signaling pathways were enriched. The most remarkable finding was the novel therapeutic effects identified from functional group analysis. This included anti-inflammatory effects mediated via suppression of arachidonic acid lipoxygenase (LOX) pathway and elevation of nitric oxide (NO); and amelioration of dyslipidaemia mediated via fatty acid oxidation. The regulatory patterns of QSYQ on key genes were confirmed by western blot, immunohistochemistry analysis and measurement of plasma lipids, which further validated the therapeutic effects of QSYQ proposed in this study. Conclusions: QSYQ exerts multipronged therapeutic effects on AMI, by concurrently alleviating VR progression, attenuating inflammation induced by arachidonic acid LOX pathway and NO production; and ameliorating dyslipidaemia.


Thriving public-private partnership to fortify cooking oil in the West African Economic and Monetary Union (UEMOA) to control vitamin A deficiency: Faire Tache d'Huile en Afrique de l'Ouest.
In sub-Saharan Africa, more than 42% of children are at risk for vitamin A deficiency, and control of vitamin A deficiency will prevent more than 600,000 child deaths annually. In the West African Economic and Monetary Union (UEMOA), an estimated 54.3% of preschool-age children are vitamin A deficient and 13% of pregnant women have night blindness. To project the achievements of this West African coalition. This article documents the achievements, challenges, and lessons learned associated with the development of a public-private partnership to fortify vegetable oil in West Africa through project reports and industry assessments. National-level food consumption surveys identified cooking oil as a key vehicle for vitamin A. Stakeholders therefore advocated for the production of fortified vegetable oil at large scale, supported industrial assessments, and reinforced the capacity of cooking oil industries to implement vitamin A fortification through effective coordination of public and private partnerships tied with standards, regulations, and social marketing. Strong alliances for food fortification were established at the regional and national levels. Stakeholders also developed policies, adopted directives, built capacity, implemented social marketing, and monitored quality enforcement systems to sustain fortification for maximum public health impact. The synergy created resulted from the unique and complementary core competencies of all the partners under effective coordination. The initiative began with the 8 UEMOA member countries and now includes all 15 countries of the Economic Community of West African States (ECOWAS), plus Cameroon, Tanzania, and Mozambique, forming a sub-Saharan Africa-wide initiative on food fortification. All members of the Professional Association of Cooking Oil Industries of the West African Economic and Monetary Union (AIFO-UEMOA) now fortify edible oil with vitamin A. Through multisector cooperation, an estimated 70% of the population has access to vitamin A-fortified edible oil in participating countries. Sustainable fortification of cooking oil is now a reality in all UEMOA countries.


[Contemporary methods of non-drug therapy for depression].
The review presents information on the most effective current non-drug methods of treatment of depression used in practice. A review of publications in PubMed and PsycINFO and Cochrane Library over the past 10 years was conducted. Non-drug biological therapies demonstrate high efficacy in the reduction of depressive symptoms in patients with recurrent depressive disorder. The use of non-drug therapy does not preclude the continuation of pharmacological therapy. In order to choose an optimal method of treatment, the psychophysical state of a patient, severity of depressive symptoms, response to drug therapy, and possibility of prescribing pharmacological therapy should be taken into account, and the principles of evidence-based medicine should be taken into consideration when making a decision.


Hemodynamic and perioperative management in two different preclinical pig-to-baboon cardiac xenotransplantation models.
The perioperative phase of preclinical cardiac xenotransplantations significantly affects the experimental outcome. Moderate or even severe hemodynamic and respiratory impairment occurs frequently in baboons after receiving a cardiac transplant. The perioperative management of such postoperative instability is very demanding, especially in the experimental setting. We compared perioperative changes of hemodynamic and laboratory findings during orthotopic and heterotopic thoracic cardiac xenotransplantations and describe our monitoring, treatment and intensive care. Twenty-eight pig-to-baboon cardiac xenotransplantations were performed using either the orthotopic (oHTx, n=5) or heterotopic thoracic (htHTx; n=23) technique. In both techniques, cardioplegia and an intraoperative cardiopulmonary bypass (CPB) were required. Preoperatively, intensive care (eg, transfusions, catecholamine therapy) was provided and fast extubation was targeted. A central venous catheter, a femoral arterial thermodilution catheter, a telemetric pressure transmitter and transthoracic echocardiography were used to monitor the animal. Baboon jackets with a tethering system were used to continuously apply medication postoperatively and permit blood sampling, also after extubation of the animal and transfer into the cage. Perioperative survival, hemodynamics, catecholamine doses, respiratory function and weaning from respirator were compared. Perioperative organ damage was evaluated based on laboratory findings 12 hours after transplantation. Recipients could be weaned from CPB in the 20 htHTx and all five oHTx experiments, and three htHTx procedures were terminated during the operation. The time of cardiopulmonary bypass was significantly lower in the heterotopic group (oHTx median 171 [157-193] minutes; htHTx median 144 [100-190] minutes; P=.02). In 17 htHTx procedures, no inotropics were used, whereas epinephrine had to be administered in four of the five oHTx experiments; the mean time of catecholamine support was longer in the oHTx group (oHTx 972±348 minutes vs htHTx 111±92 minutes; P<.01). After htHTx, weaning off the respirator was possible in 19 of 20 cases (one died due to pneumothorax). After oHTx, three of the five baboons could be weaned off the respirator; in these cases, the arterial saturation was higher compared with the extubated baboons after htHTx (oHTx 99±1% vs htHTx 91±4%, P=.01). Intraoperative blood loss was similar between the two groups, and hemostasis was impaired after all procedures, but relevant postoperative bleeding never occurred. Intensive intra- and postoperative monitoring and care is required in both transplantation techniques as a requirement for successful weaning from CPB and respirator. After htHTx, the animals needed less catecholamines and were hemodynamically more stable. Even though pulmonary function was often impaired after htHTx, weaning from the respirator and extubation was more successful in this group.


Inflammation is associated with increased energy expenditure in patients with chronic kidney disease.
Inflammation, a clinical condition observed in patients with chronic kidney disease (CKD), may be related to increased resting energy expenditure (REE). The main objective was to investigate the relation between inflammation and REE in patients with CKD who are not undergoing dialysis. We also aimed to analyze whether a decrease in C-reactive protein (CRP) would result in a reduction in REE. This study enrolled 132 patients with CKD who were not undergoing dialysis, who had creatinine clearance from 5 to 65 mL.min(-1).1.73 m(-2), and who were 53.6 +/- 16 y old; 82 (62.1%) were men. Twenty-nine patients had clinical signs of infection. REE was measured by using indirect calorimetry, and inflammation was evaluated by using high-sensitivity CRP measurement. Patients were divided according to tertiles of CRP with the following intertertile ranges: first tertile, CRP < or = 0.14 mg/dL (n = 43); second tertile, CRP 0.15-0.59 mg/dL (n = 46); and third tertile, CRP > or = 0.60 mg/dL (n = 43). REE was measured before and after treatment in 10 patients who had inflammation or infection. After adjustment for age, sex, and lean body mass, the REE of the third (1395 kcal/d; P = 0.02) and second (1355 kcal/d; P = 0.04) tertiles was significantly higher than that of the first tertile (1286 kcal/d). In the multiple linear regression analysis (n = 132), the independent determinants of REE were lean body mass, CRP, and age (R2 = 0.55). After treatment of infection in a subgroup of 10 patients, it was observed that a significant reduction in CRP concentration was accompanied by a significant reduction of 174 +/- 165 kcal that accounted for 13% of the initial REE. This study showed that inflammation is associated with increased REE in patients with CKD.