Protease-stable polycationic photosensitizer conjugates between polyethyleneimine and chlorin(e6) for broad-spectrum antimicrobial photoinactivation.
We previously showed that covalent conjugates between poly-L-lysine and chlorin(e6) were efficient photosensitizers (PS) of both gram-positive and gram-negative bacteria. The polycationic molecular constructs increased binding and penetration of the PS into impermeable gram-negative cells. We have now prepared a novel set of second-generation polycationic conjugates between chlorin(e6) and three molecular forms of polyethyleneimine (PEI): a small linear, a small cross-linked, and a large cross-linked molecule. The conjugates were characterized by high-pressure liquid chromatography and tested for their ability to kill a panel of pathogenic microorganisms, the gram-positive Staphylococcus aureus and Streptococcus pyogenes, the gram-negative Escherichia coli and Pseudomonas aeruginosa, and the yeast Candida albicans, after exposure to low levels of red light. The large cross-linked molecule efficiently killed all organisms, while the linear conjugate killed gram-positive bacteria and C. albicans. The small cross-linked conjugate was the least efficient antimicrobial PS and its remarkably low activity could not be explained by reduced photochemical quantum yield or reduced cellular uptake. In contrast to polylysine conjugates, the PEI conjugates were resistant to degradation by proteases such as trypsin that hydrolyze lysine-lysine peptide bonds, The advantage of protease stability combined with the ready availability of PEI suggests these molecules may be superior to polylysine-PS conjugates for photodynamic therapy of localized infections.


[Cinematic Rendering in Cone Beam Computed Tomography: Advanced 3D Reconstructions of Dental and Maxillofacial Pathologies].
Cinematic rendering (CR) is a novel 3D visualisation technique, which provides photorealistic image reconstructions with a high level of image details. Aim of this case series is to show the application of CR in Cone Beam Computed Tomography (CBCT) in dentomaxillofacial pathologies. Four exemplary CBCTs of clinical dentomaxillofacial cases were selected. 3D CR reconstructions were generated from the CBCT by using a vendor-provided standard CR software. Cases include 1) external tooth resorption, 2) ankylosed maxillary molar tooth, 3) giant cell-associated osteolytic lesion of the mandible, 4) unilateral cleft lip/palate with additional skeletofacial deformity. CBCTs of four patients showing dental and osseous pathologies were successfully reconstructed. Overall, a subjectively improved 3D understanding of the presented pathologies was observed. The CR images seem to present more plasticity, giving a better feeling for the spatial depth of the tissue. CR can be applied to CBCT images in dentomaxillofacial patients. The photorealistic appearance might improve the understanding of complex anatomy or pathology, could facilitate patient communication, and might be helpful for advanced medical education. We see potential in the use of CR for additional 3D visualization. The actual image diagnosis is done in the classic sectional planes. The significance of CR reconstruction for image diagnostics must be investigated in appropriate studies.


End-Use Quality of Historical and Modern Winter Wheats Adapted to the Great Plains of the United States.
Improving milling and baking properties is important during wheat breeding. To determine changes in milling and baking quality of hard winter wheat, 23 adapted cultivars released in the Great Plains between 1870 and 2013 were grown in triplicate in a single location (Mead, NE, USA) over two crop years (2018 and 2019). Grain yield and kernel hardness index increased by release year (p < 0.05). The observed increase in hardness index was accompanied by a decrease in percent soft kernels (p < 0.05). Diameter and weight decreased with release year in 2019 (p < 0.05), and their standard deviation increased with the release year (p < 0.05). Flour protein content decreased with release year (p < 0.05) and dough mixing quality increased (p < 0.05). No significant relationship was found for baking property variables, but bran water retention capacity (BWRC), which is correlated with whole wheat bread quality, increased with release year (p < 0.05). In conclusion, wheat kernels have become harder but more variable in shape over a century of breeding. Mixing quality showed significant improvements, and loaf volume and firmness remained constant, even in the presence of a decrease in protein concentration. Bran quality decreased across release year, which may have implications for whole grain baking quality and milling productivity.


Use of Electromagnetic Device to Insert Postpyloric Feeding Tubes in a Pediatric Intensive Care Unit.
The preferred route for providing nutrition in the pediatric intensive care unit is enteral. Placement of postpyloric feeding tubes using an electromagnetic-tipped stylet that emits a signal detected by a device held over the patient's abdomen is effective in adult intensive care units, but has not been well studied in pediatric units. To determine the effectiveness of the electromagnetic device in reducing the numbers of radiation exposures, intrahospital transports, tubes used, and tube placement attempts in the pediatric intensive care unit. Data from a historical control group were compared with data from a prospective intervention group of patients less than 18 years of age and weighing at least 3 kg who required a postpyloric feeding tube in a 23-bed pediatric intensive care unit. Primary outcome was number of radiation exposures. Independent-samples Student t tests were used to compare the 2 study groups for mean equality; Pearson χ2 tests were used to compare categorical data. Statistical testing was 2-sided, and P less than .05 was considered statistically significant. Of 73 children (30 in control group, 43 in intervention group), those in the intervention group had a higher success rate at tube placement (P = .009) and fewer radiation exposures (P = .006), intrahospital transports (P = .004), and tubes used (P < .001). Successful placement of postpyloric feeding tubes by nurse practitioners was safely enhanced using an electromagnetic device. Establishing users' expertise with the device before studying outcomes may improve effectiveness.


Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit.
Proteins such as the product of the break-point cluster region, chimaerin, and the Src homology 3-binding protein 3BP1, are GTPase activating proteins (GAPs) for members of the Rho subfamily of small GTP-binding proteins (G proteins or GTPases). A 200-residue region, named the breakpoint cluster region-homology (BH) domain, is responsible for the GAP activity. We describe here the crystal structure of the BH domain from the p85 subunit of phosphatidylinositol 3-kinase at 2.0 A resolution. The domain is composed of seven helices, having a previously unobserved arrangement. A core of four helices contains most residues that are conserved in the BH family. Their packing suggests the location of a G-protein binding site. This structure of a GAP-like domain for small GTP-binding proteins provides a framework for analyzing the function of this class of molecules.


Plasma proteomics for biomarker discovery: a study in blue.
The performance of Cibacron Blue dye (HiTrapBlue or Affigel Blue) in depleting albumin from plasma, as a pre-treatment for biomarker searching in the low-abundance proteome, is here assessed. It is shown that (i) co-depletion of non-albumin species is an ever-present hazard; (ii) the only proper eluant able to release quantitatively the proteins bound to the dye is boiling 4% SDS-25 mM DTT, an ion shock (2 M NaCl) being quite ineffective in releasing the low-abundance species tightly bound to the dye moiety; (iii) the mechanism of dye-protein interaction, after an initial ion-ion docking, is a robust hydrophobic interaction, which progressively augments at lower and lower pH values; (iv) at pH 2.2 in the presence of 0.1% TFA, the blue resin behaves, for all practical purposes, just as a reverse-phase chromatography column, since all residual proteins present in plasma are completely harvested. However Cibacron Blue technology should not necessarily be discarded: As long as also the plasma fraction adsorbed is properly released and analyzed, together with the flow through, one should be able to perform a viable analysis of the low-abundance proteome.


[See the thinking brain: a story about water].
Among the astonishing Einstein's papers from 1905, there is one which unexpectedly gave birth to a powerful method to explore the brain. Molecular diffusion was explained by Einstein on the basis of the random translational motion of molecules which results from their thermal energy. In the mid 1980s it was shown that water diffusion in the brain could be imaged using MRI. During their random displacements water molecules probe tissue structure at a microscopic scale, interacting with cell membranes and, thus, providing unique information on the functional architecture of tissues. A dramatic application of diffusion MRI has been brain ischemia, following the discovery that water diffusion drops immediately after the onset of an ischemic event, when brain cells undergo swelling through cytotoxic edema. On the other hand, water diffusion is anisotropic in white matter, because axon membranes limit molecular movement perpendicularly to the fibers. This feature can be exploited to map out the orientation in space of the white matter tracks and image brain connections. More recently, it has been shown that diffusion MRI could accurately detect cortical activation. As the diffusion response precedes by several seconds the hemodynamic response captured by BOLD fMRI, it has been suggested that water diffusion could reflect early neuronal events, such as the transient swelling of activated cortical cells. If confirmed, this discovery will represent a significant breakthrough, allowing non invasive access to a direct physiological marker of brain activation. This approach will bridge the gap between invasive optical imaging techniques in neuronal cell cultures, and current functional neuroimaging approaches in humans, which are based on indirect and remote blood flow changes.


A tale of two symmetrical tails: structural and functional characteristics of palindromes in proteins.
It has been previously shown that palindromic sequences are frequently observed in proteins. However, our knowledge about their evolutionary origin and their possible importance is incomplete. In this work, we tried to revisit this relatively neglected phenomenon. Several questions are addressed in this work. (1) It is known that there is a large chance of finding a palindrome in low complexity sequences (i.e. sequences with extreme amino acid usage bias). What is the role of sequence complexity in the evolution of palindromic sequences in proteins? (2) Do palindromes coincide with conserved protein sequences? If yes, what are the functions of these conserved segments? (3) In case of conserved palindromes, is it always the case that the whole conserved pattern is also symmetrical? (4) Do palindromic protein sequences form regular secondary structures? (5) Does sequence similarity of the two "sides" of a palindrome imply structural similarity? For the first question, we showed that the complexity of palindromic peptides is significantly lower than randomly generated palindromes. Therefore, one can say that palindromes occur frequently in low complexity protein segments, without necessarily having a defined function or forming a special structure. Nevertheless, this does not rule out the possibility of finding palindromes which play some roles in protein structure and function. In fact, we found several palindromes that overlap with conserved protein Blocks of different functions. However, in many cases we failed to find any symmetry in the conserved regions of corresponding Blocks. Furthermore, to answer the last two questions, the structural characteristics of palindromes were studied. It is shown that palindromes may have a great propensity to form alpha-helical structures. Finally, we demonstrated that the two sides of a palindrome generally do not show significant structural similarities. We suggest that the puzzling abundance of palindromic sequences in proteins is mainly due to their frequent concurrence with low-complexity protein regions, rather than a global role in the protein function. In addition, palindromic sequences show a relatively high tendency to form helices, which might play an important role in the evolution of proteins that contain palindromes. Moreover, reverse similarity in peptides does not necessarily imply significant structural similarity. This observation rules out the importance of palindromes for forming symmetrical structures. Although palindromes frequently overlap with conserved Blocks, we suggest that palindromes overlap with Blocks only by coincidence, rather than being involved with a certain structural fold or protein domain.


Inhibition of motor cortex excitability with 15Hz transcranial alternating current stimulation (tACS).
There remains a lack of solid evidence showing whether transcranial stimulation with weak alternating current (transcranial alternating current stimulation, tACS) can in fact induce significant neurophysiological effects. Previously, a study in which tACS was applied for 2 and 5min with current density=0.16-0.25A/m(2) was unable to show robust effects on cortical excitability. Here we applied tACS at a significantly higher current density (0.80A/m(2)) for a considerably longer duration (20min) and were indeed able to demonstrate measurable changes to cortical excitability. Our results show that active 15Hz tACS of the motor cortex (electrodes placed at C3 and C4) significantly diminished the amplitude of motor evoked potentials and decreased intracortical facilitation (ICF) as compared to baseline and sham stimulation. In addition, we show that our method of sham tACS is a reliable control condition. These results support the notion that AC stimulation with weak currents can induce significant changes in brain excitability; in this case, 15Hz tACS led to a pattern of inhibition of cortical excitability. We propose that tACS may have a dampening effect on cortical networks and perhaps interfere with the temporal and spatial summation of weak subthreshold electric potentials.


Renal handling of magnesium: drug and hormone interactions.
Magnesium is the fourth most abundant cation in the human body and the second most common cation in the intracellular fluid. The abundance and distribution of this divalent cation implies an essential role of magnesium in intracellular metabolism. Although no single homeostatic control has been demonstrated for magnesium, the cellular availability of this cation is closely regulated by the gastrointestinal tract, kidney and bone. The purpose of this review is to survey some of the events involved in renal magnesium handling. The excretory side of magnesium balance involves appropriate changes in renal magnesium handling. Present evidence suggests that the renal handling of magnesium is normally a filtration-reabsorption process. Experimental support for secretion remains unconvincing. Renal magnesium reabsorption has distinctive features when compared with that of sodium and calcium. The concentration of magnesium in the proximal tubule rises 1.5 times greater than the glomerular filtrate. Some 20-30% of the filtered magnesium is reabsorbed in the proximal tubule compared to the fractional absorption of sodium or calcium of 50-60%. Although the fractional reabsorption of magnesium is only half that of sodium, it changes in parallel with that of sodium in response to changes in extracellular fluid volume. The major portion of filtered magnesium (some 65%) is reabsorbed in the loop of Henle, mainly in the thick ascending limb. Recent evidence suggests that magnesium reabsorption in the ascending limb may be voltage-dependent and secondary to active sodium chloride reabsorption. Evidence also suggests an important competition between magnesium and calcium for transport at the basolateral surface of the ascending limb cell. The loop of Henle appears to be the major nephron site where magnesium reabsorption is controlled. The principal factors which alter magnesium reabsorption in the loop include parathyroid hormone, changes in plasma magnesium and calcium concentration and the loop diuretics. About 10% of the filtered magnesium is delivered into the distal nephron where only a small fraction of the filtered magnesium is reabsorbed and the transport capacity is readily exceeded with increased magnesium delivery. A number of drugs have been shown to alter magnesium handling; these include antibiotics such as gentamicin, antineoplastic agents such as cisplatin and immunological suppressive drugs such as cyclosporin. The cellular alterations of these diverse drugs leading to renal magnesium wasting are not well understood.


Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response.
To evaluate efficacy, serological responses, and predictors of response in patients with severe and refractory systemic lupus erythematosus (SLE) treated with rituximab plus cyclophosphamide. 16 patients entered a treatment protocol using rituximab plus cyclophosphamide. Disease activity was assessed by the SLE disease activity index (SLEDAI) and by the British Isles Lupus Assessment Group (BILAG) index. At six months follow up, mean SLEDAI values decreased significantly from (mean (SD)) 12.1 (2.2) to 4.7 (1.1). Clinical improvement (50% reduction in SLEDAI) occurred in all but three patients. All but one patient responded according to BILAG. Remission defined as SLEDAI <3 was achieved in nine of 16 patients. Isotype analysis of anti-dsDNA antibodies revealed preferential decreases of IgG and IgA, but not IgM. Higher absolute numbers of CD19+ cells at baseline were correlated with shorter depletion time (r = -0.6). The majority of patients improved following rituximab plus cyclophosphamide. The differential downregulation of anti-DNA of the IgG and IgA but not the IgM isotypes supports the hypothesis that cells producing pathogenic autoantibodies are preferentially targeted by the treatment. The fact that greater absolute numbers of CD19+ cells at baseline predict a less impressive clinical and serological response suggests that more flexible dosing could be advantageous.


CERES: a cryo-EM re-refinement system for continuous improvement of deposited models.
The field of electron cryomicroscopy (cryo-EM) has advanced quickly in recent years as the result of numerous technological and methodological developments. This has led to an increase in the number of atomic structures determined using this method. Recently, several tools for the analysis of cryo-EM data and models have been developed within the Phenix software package, such as phenix.real_space_refine for the refinement of atomic models against real-space maps. Also, new validation metrics have been developed for low-resolution cryo-EM models. To understand the quality of deposited cryo-EM structures and how they might be improved, models deposited in the Protein Data Bank that have map resolutions of better than 5 Å were automatically re-refined using current versions of Phenix tools. The results are available on a publicly accessible web page (https://cci.lbl.gov/ceres). The implementation of a Cryo-EM Re-refinement System (CERES) for the improvement of models deposited in the wwPDB, and the results of the re-refinements, are described. Based on these results, contents are proposed for a `cryo-EM Table 1', which summarizes experimental details and validation metrics in a similar way to `Table 1' in crystallography. The consistent use of robust metrics for the evaluation of cryo-EM models and data should accompany every structure deposition and be reported in scientific publications.


Buffered diffusion around a spherical proton pumping cell: a theoretical analysis.
H(+) ions are a substrate of many active and passive membrane transporters in all cells. Absolute proton fluxes are often quantified using intracellular pH sensitive microelectrodes or pH sensitive dyes. These measurements, however, rely on a priori estimates of the intracellular buffer capacity and on the assumption of diffusive equilibrium inside the cell. Here, assuming local equilibrium of protons with a single mobile buffer, we model the diffusion of H(+) in the extracellular medium around an H(+) pumping cell to estimate the expected pH changes as a function of time, distance from the cell, extracellular buffer capacity, and the absolute proton flux across the membrane. In particular, using accurate numerical simulation, we gauge the range of validity of an explicit, analytical solution of the linearized, nonstationary diffusion equation. Our results provide a framework to quantify the absolute membrane proton flux, if spatiotemporal information about the extracellular pH change is available, e.g., using imaging of pH dependent fluorescent dyes.


A comparative map viewer integrating genetic maps for Brassica and Arabidopsis.
Molecular genetic maps provide a means to link heritable traits with underlying genome sequence variation. Several genetic maps have been constructed for Brassica species, yet to date, there has been no simple means to compare this information or to associate mapped traits with the genome sequence of the related model plant, Arabidopsis. We have developed a comparative genetic map database for the viewing, comparison and analysis of Brassica and Arabidopsis genetic, physical and trait map information. This web-based tool allows users to view and compare genetic and physical maps, search for traits and markers, and compare genetic linkage groups within and between the amphidiploid and diploid Brassica genomes. The inclusion of Arabidopsis data enables comparison between Brassica maps that share no common markers. Analysis of conserved syntenic blocks between Arabidopsis and collated Brassica genetic maps validates the application of this system. This tool is freely available over the internet on http://bioinformatics.pbcbasc.latrobe.edu.au/cmap. This database enables users to interrogate the relationship between Brassica genetic maps and the sequenced genome of A. thaliana, permitting the comparison of genetic linkage groups and mapped traits and the rapid identification of candidate genes.


Ultrafast dynamics of liquid water: frequency fluctuations of the OH stretch and the HOH bend.
Frequency fluctuations of the OH stretch and the HOH bend in liquid water are reported from the third-order response function evaluated using the TTM3-F potential for water. The simulated two-dimensional infrared spectra of the OH stretch are similar to previously reported theoretical results. The present study suggests that the frequency fluctuation of the HOH bend is faster than that of the OH stretch. The ultrafast loss of the frequency correlation of the HOH bend is due to the strong couplings with the OH stretch as well as the intermolecular hydrogen bond bend.


An experimental method to facilitate the identification of hybrid sporophytes in the moss Physcomitrella patens using fluorescent tagged lines.
• The sequencing of the Physcomitrella patens genome, combined with the high frequency of gene targeting in this species, makes it ideal for reverse genetic studies. For forward genetic studies, experimental crosses and genetic analysis of progeny are essential. • Since P. patens is monoicous, producing both male and female gametes on the same gametophore, and undergoing self-fertilization at a high frequency, the identification of crossed sporophytes is difficult. Usually spores from many sporophytes from a mixed culture must be tested for the production of recombinant progeny. • Here, we describe the use of transgenic lines that express a fluorescent transgene constitutively, to provide a direct visual screen for hybrid sporophytes. • We show that segregations in crosses obtained with this technique are as expected, and demonstrate its utility for the study of the rate of outcrossing between three isolates of P. patens.


THINGS: A database of 1,854 object concepts and more than 26,000 naturalistic object images.
In recent years, the use of a large number of object concepts and naturalistic object images has been growing strongly in cognitive neuroscience research. Classical databases of object concepts are based mostly on a manually curated set of concepts. Further, databases of naturalistic object images typically consist of single images of objects cropped from their background, or a large number of naturalistic images of varying quality, requiring elaborate manual image curation. Here we provide a set of 1,854 diverse object concepts sampled systematically from concrete picturable and nameable nouns in the American English language. Using these object concepts, we conducted a large-scale web image search to compile a database of 26,107 high-quality naturalistic images of those objects, with 12 or more object images per concept and all images cropped to square size. Using crowdsourcing, we provide higher-level category membership for the 27 most common categories and validate them by relating them to representations in a semantic embedding derived from large text corpora. Finally, by feeding images through a deep convolutional neural network, we demonstrate that they exhibit high selectivity for different object concepts, while at the same time preserving variability of different object images within each concept. Together, the THINGS database provides a rich resource of object concepts and object images and offers a tool for both systematic and large-scale naturalistic research in the fields of psychology, neuroscience, and computer science.


A journey to becoming: the student nurse in transition.
The study reported in this paper explored the nature of the transition experienced by student nurses in their journey to becoming qualified nurses. In keeping with the developing relationship between the disciplines of anthropology and nursing, the methodology of choice was ethnography. Data were collected by open-ended questionnaires and interviews with key informants from one English College of Nursing undertaking Diploma level Project 2000 Adult Branch Studies. Thematic analysis of the data revealed an ill-defined transition for the student nurse and this lack of clarity was being perpetuated for many by their dual role as both student nurse and worker. This was also creating a potential role conflict and a blurring of the boundaries between professional nursing and skilled health care work. The data also revealed two 'in limbo' states, a ritualized transition phase, and that the rationale for 'learning to become a nurse' retains the idealized and vocational imagery of nursing as helping and caring for sick people.


Preference of sheep and goats for extracts from high-grain concentrate.
Appetite stimulants were extracted and partially isolated from high-grain concentrate. The stimulants were fed daily and were palatable to sheep and goats used in the experiments. The stimulative effects were tested by comparing the intake of two types of hay: with or without the extracts. Diethylether and n-pentane extracts of the concentrate stimulated feeding in sheep (P < .01 and P < .05, respectively). However, methanol extracts had no significant stimulative effect on selective feeding in sheep. Goats also preferentially fed on hay sprayed with the diethyl ether extracts (P < .01). The diethyl ether extracts were divided into acid, neutral, and basic fractions. Sheep and goats had a marked preference for the acid fraction only (P < .01 and P < .05, respectively). These results suggest that specific chemicals to increase palatability of hay are present in high-grain concentrate and that the chemical are nonpolar, acidic substances.


First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a meta-relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue.


Secondary prophylaxis of esophageal variceal treatment: Endoscopic sclerotherapy, band ligation and combined therapy--long-term results.
To evaluate the long-term results of endoscopic sclerotherapy and endoscopic band ligation in secondary prophylaxis on variceal eradication and to evaluate the effectiveness of endoscopic sclerotherapy and endoscopic band ligation combination in resistant cases. The results of the patients who underwent endoscopic sclerotherapy (n=47 31M/16F, 49.9+/-16.1 years) and endoscopic band ligation (n=72 56M/16F, 46.6+/-14.1 years) were compared. The results of patients whose varices could not be eradicated who were treated with endoscopic band ligation and combined endoscopic sclerotherapy (combined group, n=62 49M/13F, 48.8+/-12.7 years) are also given. Patients were evaluated for portal hypertension etiology, Child score, fundal varices-portal hypertensive gastropathy presence according to first and last endoscopic findings, varices eradication, rebleeding, recurrence and complication rates. 181 patients were followed for 35.2+/- 25.6 (6-123) months. Varices eradication and recurrence rates were 93.6% and 44.7% for endoscopic sclerotherapy, and 90.3% and 47.2% for endoscopic band ligation (p>0.05). The number of sessions for eradication were 6.6+/-4.0 and 2.5+/-1.6 for endoscopic sclerotherapy and endoscopic band ligation groups, respectively (p<0.05). Rebleeding rates were 16.3% for endoscopic sclerotherapy and 6.1% for endoscopic band ligation (p>0.05). In the combined group, although the rebleeding rate was 34.4%, which was as expected significantly higher than that of endoscopic sclerotherapy and endoscopic band ligation, variceal eradication and the recurrence rates were 82.3% and 50.0%, similar to endoscopic sclerotherapy and endoscopic band ligation, and the number of sessions for eradication was 6.8+/-3.5. Endoscopic band ligation is the most suitable method for varices eradication, but there is a group of patients resistant to endoscopic band ligation. In this patient group, the addition of endoscopic sclerotherapy to endoscopic band ligation was a suitable and effective technique in order to achieve variceal eradication.


Trends in civilian penetrating brain injury: A review of 26,871 patients.
The aim of our study is to analyze the 5 years' trends, mortality rate, and factors that influence mortality after civilian penetrating traumatic brain injury (pTBI). We performed a 5-year-analysis of all trauma patients diagnosed with pTBI in the TQIP. Our outcome measures were trends of pTBI. A total of 26,871 had penetrating brain injury over the 5-year period. Mean age was 36.2 ± 18 years. Overall 55% of the patients had severe TBI and mortality rate was 43.8%. There was an increase in the rate of pTBI from 3042/100,000 (2010) to 7578/100,000 trauma admissions (2014) (p < 0.001). The mortality rate has increased from 35% (2010) to 48% (2011) (p < 0.001) followed by a linear decrease in mortality to 40% (2014). Independent predictors of mortality were age, pre-hospital intubation, suicide attempt, and craniotomy/craniectomy. Incidence and mortality for patients who are brought to hospitals following pTBI have gradually increased over the five-year period. Self-inflicted injury and prehospital intubation were the two most significant predictors of mortality.


Work ability in vibration-exposed workers.
Hand-arm vibration exposure may cause hand-arm vibration syndrome (HAVS) including sensorineural disturbances. To investigate which factors had the strongest impact on work ability in vibration-exposed workers. A cross-sectional study in which vibration-exposed workers referred to a department of occupational and environmental medicine were compared with a randomized sample of unexposed subjects from the general population of the city of Gothenburg. All participants underwent a structured interview, answered several questionnaires and had a physical examination including measurements of hand and finger muscle strength and vibrotactile and thermal perception thresholds. The vibration-exposed group (47 subjects) showed significantly reduced sensitivity to cold and warmth in digit 2 bilaterally (P < 0.01) and in digit 5 in the left hand (P < 0.05) and to warmth in digit 5 in the right hand (P < 0.01), compared with the 18 referents. Similarly, tactilometry showed significantly raised vibration perception thresholds among the workers (P < 0.05). A strong relationship was found for the following multiple regression model: estimated work ability = 11.4 - 0.1 × age - 2.3 × current stress level - 2.5 × current pain in hands/arms (multiple r = 0.68; P < 0.001). Vibration-exposed workers showed raised vibrotactile and thermal perception thresholds, compared with unexposed referents. Multiple regression analysis indicated that stress disorders and muscle pain in hands/arms must also be considered when evaluating work ability among subjects with HAVS.


Supracondylar nail failure: two case reports.
We describe two case reports of supracondylar nail failure in young patients who had sustained high energy, closed, comminuted supracondylar femoral fractures. These injuries had been successfully treated using retrograde intramedullary nails which failed several months later because of excessive activity on the part of the patient without the presence of full flexion at the knee. The failed implants were removed and dynamic condylar screws were inserted with bone graft to the fracture site. This revision procedure produced solid bony union. We recommend that these patients should not fully weight bear, or engage in strenuous physiotherapy after nailing, until the fracture has consolidated and a functional range of knee motion has been obtained. Failed implants should be managed by nail removal, bone grafting and insertion of a dynamic condylar screw.


Kmer-Node2Vec: a Fast and Efficient Method for Kmer Embedding from the Kmer Co-occurrence Graph, with Applications to DNA Sequences.
Learning low-dimensional continuous vector representation for short k-mers divided from long DNA sequences is key to DNA sequence modeling that can be utilized in many bioinformatics investigations, such as DNA sequence retrieval and classification. DNA2Vec is the most widely used method for DNA sequence embedding. However, it poorly scales to large data sets due to its extremely long training time in kmer embedding. In this paper, we propose a novel efficient graph-based kmer embedding method, named Kmer-Node2Vec, to tackle this concern. Our method converts the large DNA corpus into one kmer co-occurrence graph, and extracts kmer relation on the graph by random walks to learn fast and high-quality kmer embedding. Extensive experiments show that our method is faster than DNA2Vec by 29 times for training on a 4GB data set, and on par with DNA2Vec in terms of task-specific accuracy of sequence retrieval and classification.


Uptake, tissue distribution, and fate of inhaled carbon tetrachloride: comparison of rat, mouse, and hamster.
Carbon tetrachloride is hepatotoxic in rats, mice, and hamsters. However, rats are less sensitive to the hepatotoxic effects of CCl(4) than the other two species. The purpose of this study was to compare the uptake, tissue distribution, and elimination of CCl(4) by these three rodent species. Groups of 20 F344/Crl BR rats, B6C3F(1) mice, and Syrian hamsters were exposed by nose-only inhalation for 4 h to 20 ppm (14)C-labeled CCl(4). The fate of (14)C was followed in tissues, excreta, and exhaled breath for 48 h after the exposure. At the end of the exposure, concentrations of CCl(4) equivalents (CE) in tissue were highest in liver of rats and mice, but highest in fat for rats. The liver received the highest dose of CCl(4) equivalents with the following species ranking: mouse > hamster > rat. Patterns of CE elimination were species and tissue dependent, with the majority of elimination occurring within 48 h after exposure. Rats eliminated less radioactivity associated with metabolism ((14)CO(2), urine and feces) and more radioactivity associated with parent compound (exhaled activity trapped on charcoal) than did mice or hamsters. The results indicate that ranking of species sensitivity to the hepatotoxic effects of inhaled CCl(4) correlates with CE dose to liver and with the ability to metabolize CCl(4).


Role of the cerebellum in time perception: a TMS study in normal subjects.
The aim of this study was to investigate the role of the cerebellum in a temporal-discrimination task without movement production in healthy subjects. Ten healthy subjects underwent a time-perception task with somatosensory stimuli. Two pairs of electrical stimuli: the first considered the reference pair (rp) with a standard interval of 400 ms and the second, the test pair (tp), with variable intervals ranging from 300 to 500 ms, were applied by surface electrodes on the right forearm. Subjects were instructed to compare time intervals of rp and tp and to estimate whether the tp interval was shorter than, equal to, or longer than that of rp. The task was performed in baseline and after 1 Hz rTMS over the right and left cerebellar hemisphere. The right cerebellar rTMS worsened temporal discrimination of cutaneous somatosensory electrical stimuli on the ipsilateral hand. rTMS of the left cerebellar hemisphere did not determine significant changes in the subjects' performance with respect to the baseline. These findings suggest that the cerebellum plays a role in merely perceptive aspects of temporal information processing.


An application of a computational ecology model to a routing method in computer networks.
The paper proposes a network routing method based on a computational ecology model. The computational ecology model is a mathematical model proposed by B.A. Huberman and T. Hogg (1988), which represents a macro action of multi-agent systems. We formulate routing on a computer network as a resource allocation problem, where packets and links are regarded as agents and resources, respectively. Then, we apply an extended computational ecology model for this problem. Agents conflict so as to get more payoffs from links. As a result, they get the same payoffs, and a good resource allocation is achieved. In each node, each packet selects a link according to the selection rate decided through conflicts, and routing is accomplished autonomously with adaptability on the computer network. Moreover, we improve fault-tolerance of the system by local information exchanges. Finally, we examine the efficiency of the proposed method by computer simulation.


Gene expression analysis of energy metabolism mutants of Desulfovibrio vulgaris Hildenborough indicates an important role for alcohol dehydrogenase.
Comparison of the proteomes of the wild-type and Fe-only hydrogenase mutant strains of Desulfovibrio vulgaris Hildenborough, grown in lactate-sulfate (LS) medium, indicated the near absence of open reading frame 2977 (ORF2977)-coded alcohol dehydrogenase in the hyd mutant. Hybridization of labeled cDNA to a macroarray of 145 PCR-amplified D. vulgaris genes encoding proteins active in energy metabolism indicated that the adh gene was among the most highly expressed in wild-type cells grown in LS medium. Relative to the wild type, expression of the adh gene was strongly downregulated in the hyd mutant, in agreement with the proteomic data. Expression was upregulated in ethanol-grown wild-type cells. An adh mutant was constructed and found to be incapable of growth in media in which ethanol was both the carbon source and electron donor for sulfate reduction or was only the carbon source, with hydrogen serving as electron donor. The hyd mutant also grew poorly on ethanol, in agreement with its low level of adh gene expression. The adh mutant grew to a lower final cell density on LS medium than the wild type. These results, as well as the high level of expression of adh in wild-type cells on media in which lactate, pyruvate, formate, or hydrogen served as the sole electron donor for sulfate reduction, indicate that ORF2977 Adh contributes to the energy metabolism of D. vulgaris under a wide variety of metabolic conditions. A hydrogen cycling mechanism is proposed in which protons and electrons originating from cytoplasmic ethanol oxidation by ORF2977 Adh are converted to hydrogen or hydrogen equivalents, possibly by a putative H(2)-heterodisulfide oxidoreductase complex, which is then oxidized by periplasmic Fe-only hydrogenase to generate a proton gradient.


A quantitative analysis of leptomeric fibrils in an adriamycin/carnitine chronic mouse model.
A quantitative ultrastructural analysis of leptomeres in cardiac muscle was performed using an adriamycin/carnitine chronic mouse model. Five animals from each of the following four groups were sacrificed for evaluation by electron microscopy: the control group received saline injections only; the carnitine group received carnitine orally; the adriamycin group received a chronic dose of adriamycin (10 mg/kg over 4 weeks); the adriamycin/carnitine group received both the adriamycin and carnitine dosage regimens. The leptomeres were quantitated using a double-blind method. The total number of leptomeres were scored for 20 random low-power electron micrographs from each of 5 animals within each group. The adriamycin group contained 3 of the 4 lowest leptomere scores. The relationships between myofibrillar disruption (MD) and the number of leptomeres found in an intramyofibrillar location(IML) were then determined for each of the four groups using linear regression analysis. In the control group, increased MD was associated with a decrease in the number of IML. In the carnitine group, increased MD was associated with an increase in IML. In the adriamycin group, no significant change in the number of IML occurred with increasing levels of MD. The adriamycin/carnitine group was similar to the control group. It was concluded from this study that 1) a relationship exists between MD and the number of IML in normal murine cardiac muscle; 2) carnitine produces an inverse effect on this normal relationship; 3) adriamycin disturbs the normal relationship between IML and MD; and 4) the administration of carnitine to adriamycin-treated animals restored the normal relationship. The physiological significance of the leptomere to the cardiac cell is then discussed.


Fibroscan detection of fatty liver and liver fibrosis in patients with systemic lupus erythematosus.
Although liver dysfunction is not considered the main organ involvement in Systemic Lupus Erythematosus (SLE), the frequency of liver dysfunction or abnormal liver enzyme values may be observed in 50-60% of patients. The aim of this study was to assess fatty liver and liver fibrosis in SLE patients using Fibroscan as well as determine associated factors such as immunosuppressive medications. Sixty SLE patients and 30 healthy controls were included. Patients with HBV, HCV or cirrhosis, malignancy, cardiac disease, or patients on dialysis were excluded. All participants underwent Fibroscan measurements. The prevalence of fatty liver disease was similar between SLE patients and healthy controls (21.7 vs 26.7%, p = .597). Liver fibrosis was also similar between the two groups (26.7 vs 10.0%, p = .069). Since the majority of SLE patients were female, we performed a subgroup analysis in female patients (n = 51) and controls (n = 25). Fatty liver disease was similar between female SLE patients and controls (23.5 vs 24.0%, p = .964). However, liver fibrosis in female patients with SLE was increased compared to female controls (29.4 vs 4.0%, p = .011) and was associated with age (Exp (B) 95% CI: 1.083 (1.006-1.166), p = .034) and low-dose cumulative glucocorticoid use (Exp (B) 95% CI: 14.116 (1.213-164.210), p = .034). The prevalence of fatty liver was similar between SLE patients and controls, while liver fibrosis was increased in the female patient group as compared to controls. Furthermore, liver fibrosis was associated with age and low dose cumulative glucocorticoid use. Interestingly, fatty liver did not precede liver fibrosis in the majority of cases, contrary to what is observed in the general population. Larger studies are needed to confirm our findings and determine whether immunosuppressive use has any impact on the development of liver fibrosis in SLE patients.


Associations among cytoplasmic molecular markers, gender, and components of fitness in Silene vulgaris, a gynodioecious plant.
It has been suggested that the dynamics of chloroplast DNA (cpDNA) or mitochondrial DNA (mtDNA) genetic markers used in studies of plant populations could be influenced by natural selection acting elsewhere in the genome. This could be particularly true in gynodioecious plants if cpDNA or mtDNA genetic markers are in gametic disequilibrium with genes responsible for sex expression. In order to investigate this possibility, a natural population of the gynodioecious plant Silene vulgaris was used to study associations among mtDNA haplotype, cpDNA haplotype, sex and some components of fitness through seed. Individuals were sampled for mtDNA and cpDNA haplotype as determined using restriction fragment length polymorphism (RFLP) methods, sex (female or hermaphrodite), fruit number, fruit set, seeds/fruit and seed germination. The sex of surviving germinating seeds was also noted. All individuals in the population fell into one of two cytoplasmic categories, designated haplotypes f and g by a unique electrophoretic signature in both the mtDNA and cpDNA. The subset of the population carrying haplotype g included a significantly higher proportion of females when compared with the sex ratio of the subset carrying the f haplotype. Haplotype g had a significantly higher fitness when measured by fruit number, fruit set and seeds/fruit, whereas haplotype f had significantly higher fitness when measured by seed germination. Offspring of individuals carrying haplotype g included a significantly greater proportion of females when compared with offspring of individuals carrying the f haplotype. Other studies of gynodioecious plants have shown that females generally have higher fitness through seed than hermaphrodites, but in this study not all fitness differences between haplotypes could be predicted from differences in haplotype-specific sex ratio alone. Rather, some differences in haplotype-specific fitness were due to differences in fitness between individuals of the same sex, but carrying different haplotypes. The results are discussed with regard to the potential for hitchhiking selection to influence the dynamics of the noncoding regions used to designate the cpDNA and mtDNA haplotypes.


An Atomistic Model of a Precursor State of Light-Induced Channel Opening of Channelrhodopsin.
Channelrhodopsins (ChRs) are microbial light-gated ion channels with a retinal chromophore and are widely utilized in optogenetics to precisely control neuronal activity with light. Despite increasing understanding of their structures and photoactivation kinetics, the atomistic mechanism of light gating and ion conduction remains elusive. Here, we present an atomic structural model of a chimeric ChR in a precursor state of the channel opening determined by an accurate hybrid molecular simulation technique and a statistical theory of internal water distribution. The photoactivated structure features extensive tilt of the chromophore accompanied by redistribution of water molecules in its binding pocket, which is absent in previously known photoactivated structures of analogous photoreceptors, and widely agrees with structural and spectroscopic experimental evidence of ChRs. The atomistic model manifests a photoactivated ion-conduction pathway that is markedly different from a previously proposed one and successfully explains experimentally observed mutagenic effects on key channel properties.


Isolation and structure elucidation of the compounds from Teucrium hyrcanicum L. and the investigation of cytotoxicity, antioxidant activity, and protective effect on hydrogen peroxide-induced oxidative stress.
Teucrium hyrcanicum L. (family Lamiaceae) is widely distributed in the North and Northwest of Iran. It has been used in the form of tea, tonic, and tincture for the treatment of various diseases such as cough, rheumatism, and fever. In this study, the total phenolic and flavonoid contents, antioxidant and cytotoxic activities of methanol extract and different fractions of T. hyrcanicum were measured. Furthermore, the potential ability of T. hyrcanicum to protect against H2O2-induced oxidative stress was tested on the NIH3T3 cell line. Then, the isolation and structure elucidation of the compounds were performed on the most potent fractions. Finally, the quantification of isolated compounds in methanol extract (ME) was done by the HPLC method. Isolated phytochemicals were assessed for the cytotoxic and antioxidant activities. The results indicated that the methanol fraction (MF) had the highest amount of phenolic and flavonoid contents (69.36 mg GAE/g extract and 68.95 mg QE/g extract). The highest radical scavenging activities were observed from MF and ME (IC50 44.32 and 61.12 μg.ml-1, respectively). The best cytotoxicity was obtained by ethyl acetate fraction (EF) against A431 and MCF7 cell lines (IC50 values of 235.4and 326.6 μg.ml-1, respectively). The pretreatment with MF exerts the highest reduction in malondialdehyde (MDA) formation (IC50 2.51 μM, p < 0.001) compared to the H2O2 group (5.77 μM). Also, MF significantly inhibited H2O2-induced Glutathione (GSH) oxidation (p < 0.001). Furthermore, two phenolic compounds, acteoside and quercetin, were isolated and identified in MF and EF, respectively. The IC50 values of acteoside and quercetin in the DPPH assay were 7.19 and 5.56 µg.ml-1, respectively. Both quercetin and acteoside significantly reduced the MDA formation and inhibited GSH oxidation, which was comparable with BHA (as a standard antioxidant) (p < 0.05). Acteoside demonstrated significant cytotoxicity against all tested cell lines (IC50 = 32 to 145 μg.ml-1). The HPLC quantification of isolated compounds revealed that the quantity of acteoside and quercetin in ME were 93.31 and 16.87 μg.mg-1, respectively. The isolated compounds (quercetin and acteoside) had significant antioxidant activities and revealed a protective effect on H2O2-induced oxidative stress which was comparable with BHA.


A new antifouling bioassay monitoring brown algal spore swimming behaviour in the presence of echinoderm extracts.
Epibiosis, the colonization of biogenic surfaces by epibiotic organisms such as bacteria, filamentous algae, and sessile invertebrates, poses a major threat to the fitness and survival of macroorganisms which could potentially be fouled. Fouling of artificial submerged structures can also cause severe economic problems, making the need for refined bioassays to determine the efficacy of potential antifouling compounds even more important. The aim of this study was to use the distinct swimming behaviour of zoospores of the fouling brown alga Hincksia irregularis to develop a new laboratory antifouling bioassay to test the effect of marine natural products. Spores were exposed to different concentrations of aqueous and organic extracts from body walls of sympatric echinoderms (Asteroidea: Luidia clathrata, Astropecten articulatus; Ophiuroidea: Astrocyclus caecilia). Computer-assisted motion analysis was used to distinguish between the straight and fast swimming movements of undisturbed spores (controls) and the helical and erratic swimming patterns of chemically irritated spores, using the quantitative parameters rate of direction change (RCD) and swimming speed (SPD). The ratio RCD/SPD of spore swimming paths at extract treatments compared to controls can be used to quantify the detrimental effect of echinoderm extracts. Echinoderm extracts had significant effects on spore swimming behaviour at concentrations three orders of magnitude lower than that present naturally in the echinoderm body walls (mg extract/dry weight echinoderm body wall). Comparative studies on spore settlement and germination under similar treatment conditions show that changes in spore swimming behaviour reflect decreased fitness and survivourship of algal spores. It is suggested that this bioassay can be used to screen potential antifouling extracts and compounds at very low concentrations, making this assay particularly suitable for detection of concentration dependent effects and for bioassay-guided fractionation of extracts to identify active compounds.


Biomass derived from transgenic tobacco expressing the Arabidopsis CESA3ixr1-2 gene exhibits improved saccharification.
Studies in Arabidopsis thaliana and Nicotiana tabacum L. variety Samsun NN demonstrated that expression of the CESA3 cellulose synthase gene that contains a point mutation, named ixr1-2, results in greater conversion of plant-derived cellulose to fermentable sugars. The present study was designed to examine the improved enzymatic saccharification efficiency of lignocellulosic biomass of tobacco plants expressing AtCESA3ixr1-2. Three-month-old AtCESA3ixr1-2 transgenic and wild-type tobacco plants (Nicotiana tabacum L. variety Samsun NN) were grown in the presence and absence of isoxaben. Biomass obtained from leaf, stem, and root tissues were analyzed for enzymatic saccharification rates. During enzymatic saccharification, 45% and 25% more sugar was released from transgenic leaf and stem samples, respectively, when compared to the wild-type samples. This gain in saccharification efficiency was achieved without chemical or heat pretreatment. Additionally, leaf and stem biomass from transgenic AtCESA3ixr1-2 requires a reduced amount of enzyme for saccharification compared to biomass from wild-type plants. From a practical standpoint, a similar strategy could be employed to introduce the mutated CESA into energy crops like poplar and switchgrass to improve the efficiency of biomass conversion.


Direct speech quotations promote low relative-clause attachment in silent reading of English.
The implicit prosody hypothesis (Fodor, 1998, 2002) proposes that silent reading coincides with a default, implicit form of prosody to facilitate sentence processing. Recent research demonstrated that a more vivid form of implicit prosody is mentally simulated during silent reading of direct speech quotations (e.g., Mary said, "This dress is beautiful"), with neural and behavioural consequences (e.g., Yao, Belin, & Scheepers, 2011; Yao & Scheepers, 2011). Here, we explored the relation between 'default' and 'simulated' implicit prosody in the context of relative-clause (RC) attachment in English. Apart from confirming a general low RC-attachment preference in both production (Experiment 1) and comprehension (Experiments 2 and 3), we found that during written sentence completion (Experiment 1) or when reading silently (Experiment 2), the low RC-attachment preference was reliably enhanced when the critical sentences were embedded in direct speech quotations as compared to indirect speech or narrative sentences. However, when reading aloud (Experiment 3), direct speech did not enhance the general low RC-attachment preference. The results from Experiments 1 and 2 suggest a quantitative boost to implicit prosody (via auditory perceptual simulation) during silent production/comprehension of direct speech. By contrast, when reading aloud (Experiment 3), prosody becomes equally salient across conditions due to its explicit nature; indirect speech and narrative sentences thus become as susceptible to prosody-induced syntactic biases as direct speech. The present findings suggest a shared cognitive basis between default implicit prosody and simulated implicit prosody, providing a new platform for studying the effects of implicit prosody on sentence processing.


"Medical tourism" and the global marketplace in health services: U.S. patients, international hospitals, and the search for affordable health care.
Health services are now advertised in a global marketplace. Hip and knee replacements, ophthalmologic procedures, cosmetic surgery, cardiac care, organ transplants, and stem cell injections are all available for purchase in the global health services marketplace. "Medical tourism" companies market "sun and surgery" packages and arrange care at international hospitals in Costa Rica, India, Mexico, Singapore, Thailand, and other destination nations. Just as automobile manufacturing and textile production moved outside the United States, American patients are "offshoring" themselves to facilities that use low labor costs to gain competitive advantage in the marketplace. Proponents of medical tourism argue that a global market in health services will promote consumer choice, foster competition among hospitals, and enable customers to purchase high-quality care at medical facilities around the world. Skeptics raise concerns about quality of care and patient safety, information disclosure to patients, legal redress when patients are harmed while receiving care at international hospitals, and harms to public health care systems in destination nations. The emergence of a global market in health services will have profound consequences for health insurance, delivery of health services, patient-physician relationships, publicly funded health care, and the spread of medical consumerism.


Medical student's perspective on preceptors in family practice.
Preceptorships have become an important means by which medical students are exposed to family practice. In order for a preceptor to be successful in nurturing student interest in family practice, he must have a good understanding of certain characteristics of today's medical students. Important differences exist between preclinical and clinical students, and the preceptorship must be designed accordingly. Unless preceptors are carefully selected and trained, they may have a negative influence on student interest in family practice.


Studies of human seminal parameters with frequent ejaculation II. Spermatozoal vitality and storage.
The hypothesis that the percentage of dead spermatozoa in an ejaculate is related to their storage time in the extra-gonadal reserve was tested using a protocol where men followed a set ejaculatory pattern. Semen samples were requested as follows: abstinence from ejaculation for at least 3 days (not more than 7 days) followed by production of the first sample, then one ejaculation per day for 4 consecutive days before the second sample; and, lastly, abstinence for a further 4 days and production of the final sample. Within the time scale of the experiment there was no relationship between the percentage of dead spermatozoa in the ejaculate and the preceding period of abstinence, nor was the percentage of dead spermatozoa related to the total number of spermatozoa present. The percentage of non-motile, but vital, spermatozoa similarly exhibited a random pattern. Thus whatever mechanisms are contributing to the mortality of spermatozoa, they are independent of storage time in the extra-gonadal reserve, and total spermatozoal count. Therefore, in the absence of necrozoospermia, this parameter probably contributes little to the overall diagnosis of infertility, but does allow assessment of the functional spermatozoa present.


Frequent recognition of BCRF1, a late lytic cycle protein of Epstein-Barr virus, in the HLA-B*2705 context: evidence for a TAP-independent processing.
Using a transient COS transfection assay, allowing a rapid estimation of the dominant CD8(+) T cell responses against a large number of HLA/viral protein combinations within polyclonal cell lines, we searched for HLA-B*2705-restricted CD8 T cell responses to Epstein-Barr virus (EBV) within T cell samples enriched for EBV-reactive cells. Among the 18 EBV proteins tested, only 2, the latent protein EBNA3A and the late lytic protein BCRF1 (viral IL-10), appeared dominant in the B27 context, as they triggered significant TNF and cytolytic responses in some donors. We provide evidence that the B27/BCRF1 epitope (RRLVVTLQC) is located in the signal sequence and that it can be presented in a TAP-independent manner. Using B27/BCRF1 monomeric complexes coated on immunomagnetic beads, we sorted out BCRF1-specific CD8 T cells from 8 of 15 HLA-B27(+) donors. This is, to our knowledge, the first demonstration of a recognition of BCRF1, suggesting that some immune control against EBV exists even during the late stage of the lytic cycle. This result also strengthens the unusual ability of HLA-B*2705 to present peptide in a TAP-independent manner.


Nudging Toward Sustainable Food Consumption at University Canteens: A Systematic Review and Meta-Analysis.
This systematic literature review and meta-analysis investigated the effectiveness of the nudging approach toward sustainable food consumption in the university canteen context. The systematic literature search was carried out in 5 databases, Web of Science, PubMed, Scopus, ProQuest, and the Royal Library, identifying 14 eligible studies and selecting 9 articles containing adequate information for meta-analysis. The nudging strategies were classified using the typology of interventions in the proximal physical microenvironments framework that resulted in 5 different intervention types: availability, position, size, presentation, and information that belonged to either intervention class-altering properties or placement. The study identified presentation, availability, and information as the most promising nudge intervention for achieving sustainable food consumption at the university canteen or similar settings. Nudging by altering the properties had a small effect size (d = 0.16), and nudging by altering placement showed a medium effect size (d = 0.21). Nudging interventions implemented after understanding consumers' current behavior showed positive effectiveness toward sustainable food consumption rather than implementing random nudges. It is important that future studies aim to achieve sustainable food consumption by understanding canteen user food preferences and food choice motives before designing a nudging strategy.


Emerging source of infection - Mycobacterium tuberculosis in rescue dogs: a case report.
Rescue dog activity is a heavily increasing form of dog charity. Imported homeless dogs represent a reservoir of zoonotic diseases putting owners, veterinarians and pathologists repeatedly at risk. The clinical signs of tuberculosis in a dog are non-specific and diagnosis is often delayed or dismissed. We present a case of 9 months of possible exposure at home and definite exposure at laparotomy and autopsy to intestinal tuberculosis in a family dog imported from Romania to Finland. Persistent gastrointestinal symptoms started 2 years after the import. Abdominal pain, diarrhoea and vomiting proceeded and led to spontaneous death. Mycobacterium tuberculosis was identified in the liver, lymph nodes and intestine at autopsy. Exposed persons were notified and follow-up was provided, and no further infections were identified within 12 months of follow-up. The heavily increasing import of companion animals presents unexpected public health risks, such as prolonged exposure to tuberculosis, of which the general public is not aware. The dramatic consequences and high costs of tuberculosis could be reduced through accessible information of the risks of imported animals to both the general public and veterinarians, in addition to availability of rapid diagnostics and proper personal protection.


The 1978 Italian mental health law--a personal evaluation: a review.
"The author discusses the sociopsychiatric consequences of the 1978 Italian mental health law. He also reviews the international scientific ideas that led up to it. The sociopolitical psychiatric views of the late Franco Basaglia, pioneer of the change in the mental health system of the Italian Republic, are described. Statistical reports and critical analyses are reported. Objective data, based on the author's personal experience as a practising psychiatrist in Rome, Italy, from 1969 to 1987, are given."


[Yoke technique for severe proximal hypospadias].
PROPOSED: Various techniques have so far been reported for the repair of hypospadias, however, a one-stage procedure for the repair of severe proximal hypospadias still remains difficult to perform. We recently have begun to use the Yoke hypospadias repair technique for the treatment of severe proximal hypospadias. As the chief surgeon, I performed a one-stage hypospadias repair on 40 proximal hypospadiac patients with severe fibrous chordee between July 1992 and December 2004. During the early period, eleven patients underwent urethroplasty by the Transverse Preputial Island Flap techinique (TPIF). Next, 10 patients underwent One-stage Urethroplasty with Parameatal Foreskin flap technique (OUPF IV). Finally, the most recent 19 had their hypospadias repaired by the Yoke technique. With the TPIF technique in the early periods, only 6 out of 11 patients underwent a successful repair (54.5%). With the OUPF IV technique, the success rate was only 60.0% (6 out of 10 cases). In contrast, 17 out of 19 cases treated by the Yoke technique in the most recent period had a successful repair, although proximal urethrocutaneous fistula and urethral stenosis occurred in one patient, respectively. A relatively high success rate was therefore obtained using the Yoke technique for the repair of severe proximal hypospadias. The Yoke techniques for the repair of hypospadias is therefore considered to be a safe and effective technique for the repair of proximal hypospadias because of the continuous skin flap of the ventral urethral plate and the prepuce with a blood supply from the circumferential vascular pedicle. We consider this technique to be very useful for the treatment of severe proximal hypospadias.


Sex-Specific Effects of Incubation Temperature on Embryonic Development of Zebra Finch (Taeniopygia guttata) Embryos.
In oviparous species, the embryonic environment-particularly temperature-can alter phenotype and survival of an individual by affecting its size as well as its metabolic rate. Previous studies have shown that incubation temperatures can affect sex ratio in birds; specifically, low incubation temperatures were shown to produce a male-biased sex ratio in zebra finches (Taeniopygia guttata) possibly because of a higher pre- or postnatal mortality rate in females. We hypothesized that sexes respond differently to suboptimal incubation temperature, leading to a male-biased sex ratio. To test this hypothesis, zebra finch eggs were incubated at 36.1°, 37.5°, or 38.5°C and hatching success, hatchling mass, residual yolk mass, and pectoralis mass were measured. We found that while hatchling mass was similar between the sexes at 37.5°C, female hatchlings were heavier at 36.1°C, and male hatchlings were heavier at 38.5°C. Pectoralis muscle mass was similar between the sexes at 36.1°C; however, at 37.5°C, female pectoralis mass was heavier at hatching than that of males. Females at 37.5°C also had lower residual yolk at hatching compared with males, reflecting a higher use of energy by female embryos compared with male embryos at this temperature. In contrast, residual yolk was similar between the sexes at 36.1° and 38.5°C. Our results suggest that there are sex differences in how incubation temperature alters organ mass and yolk energy reserve; this can lead to a difference in survival at different incubation temperatures between the sexes. Taken together with previous studies showing that females alter incubation behavior with ambient temperature, rising ambient temperatures could impact phenotype and survival of avian offspring in a sex-specific manner.


A cross-study analysis of drug response prediction in cancer cell lines.
To enable personalized cancer treatment, machine learning models have been developed to predict drug response as a function of tumor and drug features. However, most algorithm development efforts have relied on cross-validation within a single study to assess model accuracy. While an essential first step, cross-validation within a biological data set typically provides an overly optimistic estimate of the prediction performance on independent test sets. To provide a more rigorous assessment of model generalizability between different studies, we use machine learning to analyze five publicly available cell line-based data sets: National Cancer Institute 60, ancer Therapeutics Response Portal (CTRP), Genomics of Drug Sensitivity in Cancer, Cancer Cell Line Encyclopedia and Genentech Cell Line Screening Initiative (gCSI). Based on observed experimental variability across studies, we explore estimates of prediction upper bounds. We report performance results of a variety of machine learning models, with a multitasking deep neural network achieving the best cross-study generalizability. By multiple measures, models trained on CTRP yield the most accurate predictions on the remaining testing data, and gCSI is the most predictable among the cell line data sets included in this study. With these experiments and further simulations on partial data, two lessons emerge: (1) differences in viability assays can limit model generalizability across studies and (2) drug diversity, more than tumor diversity, is crucial for raising model generalizability in preclinical screening.


Prevalence of self-reported allergic conditions in an adult population in Israel.
Asthma, allergic rhinitis, and atopic dermatitis are leading causes of chronic diseases in developed countries, with at least one allergic condition troubling 10 to 20% of the general population. The few studies performed in Israel determined the prevalence of allergic conditions in selected populations (schoolchildren and soldiers); no study representative of the general population has previously been done. To determine the prevalence of allergic conditions in the general population in Israel and the differences between ethnic and socioeconomic groups. Using a computer-assisted telephone interview, a telephone questionnaire was conducted in a representative sample of the general Israeli population. Of the population studied, 14% claimed to have bronchial asthma, 14% allergic rhinitis, and 6% other allergic conditions. Prevalence rates were higher in the Israeli Arab population and in those with low income and low education levels. Of those with allergic conditions, 58% were treated by a primary physician, 32% were not treated at all, and only 10% were treated by a different specialist physician. The prevalence of allergic conditions in this study concurs with that found by other studies in developed countries. Allergic conditions are higher in the Israeli Arab population and in those with low income and low education level.


Estimation of polio infection prevalence from environmental surveillance data.
A major obstacle to eradicating polio is that poliovirus from endemic countries can be reintroduced to polio-free countries. Environmental surveillance (ES) can detect poliovirus from sewage or wastewaters samples, even in the absence of patients with paralysis. ES is underused, in part because its sensitivity is unknown. We used two unique data sets collected during a natural experiment provided by the 2013 polio outbreak in Israel: ES data from different locations and records of supplemental immunization with the live vaccine. Data from the intersecting population between the two data sets (covering more than 63,000 people) yielded a dose-dependent relationship between the number of poliovirus shedders and the amount of poliovirus in sewage. Using a mixed-effects linear regression analysis of these data, we developed several quantitative tools, such as (i) ascertainment of the number of infected individuals from ES data for application during future epidemics elsewhere, (ii) evaluation of the sensitivity of ES, and (iii) determination of the confidence level of the termination of poliovirus circulation after an outbreak. These results will be valuable in monitoring future outbreaks with ES, and this approach could be used to certify poliovirus elimination or to validate the need for more containment efforts.


Posttraumatic empyema. Risk factor analysis.
Empyema remains a distressing complication after thoracic injury. To identify high-risk factors associated with the development of empyema. Retrospective cohort review. University hospital, level I trauma center. Trauma patients who required tube thoracostomy (TT) between January 1, 1991, and November 31, 1993 (n = 584). Data (demographic characteristics, injuries, chest x-ray film reports, and setting of TT) were assessed using a stepwise logistic regression analysis to identify risk factors associated with the development of post-traumatic empyema. Empyema that required decortication developed in 25 patients (4%). Factors predictive of development of empyema were retained hemothorax (odds ratio, 12.5; 95% confidence interval, 0.96-163), pulmonary contusion (odds ratio, 6.3; 95% confidence interval, 1.53-25.8), and multiple chest tube placement (odds ratio, 2.5; 95% confidence interval, 1.91-3.28); factors not predictive of empyema were severity of injury, mechanism of injury, setting in which TT was performed, number of days chest tubes were in place, and antibiotic drugs at the time of TT. The extent of pulmonary injury (pulmonary contusion) is an important predictor of empyema development. Previously implicated factors such as setting in which a TT was performed and mechanism of injury did not correlate with the development of posttraumatic empyema. Based on the results of our study, we recommend early drainage of the pleural space with video-assisted thoracoscopic techniques in patients at risk of empyema, which may spare them the morbidity of a thoracotomy.


Minaprine, a new drug with antidepressant properties.
Minaprine is a new psychotropic drug which has recently proved to be effective in the treatment of various depressive states. In rodents, minaprine exhibits an atypical spectrum of antidepressant and dopaminomimetic activities. Thus in mice minaprine antagonizes the effects of reserpine, decreases immobility time in the behavioural despair test and potentiates the effects of 5-HTP; in rats it antagonizes muricidal behaviour (blocked by PCPA or raphectomy). However, minaprine does not affect yohimbine lethality and does not induce anticholinergic effects in mice. Minaprine also activates central dopaminergic transmission. Thus at low doses the drug antagonizes neuroleptic-induced catalepsy and induces stereotypies in rats. These stereotypies are blocked by neuroleptics. In addition, minaprine (like apomorphine) induces contralateral turning in mice with a unilateral lesion of the striatum, whereas d-amphetamine induces ipsilateral rotations. Unlike classical dopaminomimetic drugs, minaprine does not stimulate locomotor activity in rats. The mechanisms by which minaprine exerts its effects are still unclear, since in vitro minaprine does not affect monoamine uptake or release and does not interact with monoamine receptors. In vivo, minaprine (acute doses) increases 5-HT, decreases 5-HIAA levels in various brain areas and weakly and reversibly inhibits type A MAO; subacute treatments lead to a decrease in the number of 5-HT1 and 5-HT2 receptors. In addition, in the striatum the drug decreases HVA and DOPAC, and increases 3-MT levels, without affecting DA levels. Minaprine also weakly displaces (3H)-spiperone from striatal D2 receptors and increases striatal ACh levels. Finally, minaprine fails to affect brain NA or MHPG levels in acute doses and does not modify beta receptor density in subacute treatment. Thus minaprine appears to be a chemically and pharmacologically original antidepressant drug which activates both 5-HT- and DA-mediated transmission but which is devoid of NAergic and anticholinergic effects. This latter statement is confirmed by the good cardiovascular tolerance of minaprine in dog, monkey and humans, and by the lack of "tricyclic-like" anticholinergic side-effects in man.


Definition of the ostium (neck) of an aneurysm revealed by intravascular sonography: an experimental study in canines.
The major factor influencing the effectiveness of Guglielmi detachable coils (GDCs) in the treatment of saccular aneurysms is the size of the aneurysm's ostium (neck). Current imaging techniques often do not allow accurate assessment of aneurysm neck morphology. The primary purpose of this study was to determine the feasibility of using intravascular sonography to provide this information. Lateral and bifurcation aneurysms were created in each of six adult mongrel dogs by using a well-established surgical technique. Aneurysms were evaluated with digital subtraction angiography and intravascular sonography before (n = 12) and after (n = 6) treatment with GDCs. Angiography was performed using standard techniques. Sonography was performed using both a commercially available 2.6F 40-MHz catheter and a preproduction 0.014-inch 40-MHz imaging core wire housed in a Tracker catheter. Angiograms and sonograms were reviewed independently by two observers to assess the clarity and accuracy with which they depicted the size of each aneurysm's ostium. Posttreatment intravascular sonograms were evaluated for the extent to which they depicted the completeness of aneurysm obliteration. Two-dimensional reformatted images were made of the intravascular sonographic pullback sequences. In all instances, intravascular sonography provided clear definition of the aneurysm's neck (ostium) morphology as well as its relationship to the parent artery and adjacent branches, especially when 2D reformatted images were obtained. The position of coils in aneurysms was also clearly defined. Intravascular sonography is a novel technique for viewing the ostium (neck) of an aneurysm. It provides information not available with current angiographic methods.


The psychotherapeutic effects of estrogens.
The effect of estrogens on the central nervous system, particularly mood and behavior, remains a controversial area which needs clarification, not just for understanding of depression in women but to ensure that such commonplace problems in women have efficient and appropriate therapy. There is now good evidence that estrogens are rapidly effective in the treatment of depression in many women but this information has not found its way through to those health care personnel, psychiatrists and psychologists who are principally involved in the treatment of depression. There is also strong evidence for the benefits of estrogens on cognitive functioning, not only in preventing the onset of dementia but also in improving the symptoms in the established condition. Recent work has also suggested a benefit for estrogens on mood in women diagnosed as suffering from chronic fatigue syndrome. This article reviews the effect of endogenous estrogen on the female central nervous system and the ever increasing evidence for the diverse psychotherapeutic effects of exogenous estrogens.


Implications of maternal vitamin D deficiency for the fetus, the neonate and the young infant.
It has recently been demonstrated that vitamin D (VD) deficiency during pregnancy and lactation can give rise to problems in mothers and their children. To discuss the implications of VD deficiency during pregnancy and the best VD supplementation to use in order to avoid risks for the mother and child. PubMed was used to select all of the clinical studies published in the last 15 years concerning VD deficiency in pregnant women and its impact on the fetuses, neonates and infants, as well as the use of VD supplementation during pregnancy. Several studies have suggested that VD deficiency is associated with possible major outcomes in the preconception period, during pregnancy, perinatally and in childhood. A 25(OH)D concentration of >32 and <50-60 ng/mL seems to be associated with the lowest risk of disease, and the administration of 2,000 IU/day to pregnant and breastfeeding women seems to maintain adequate 25(OH)D levels. However, not all the experts agree with these conclusions because some of them do not think that VD deficiency can really cause extraskeletal manifestations and consider that the traditionally suggested 400-600 IU/day can be enough to permit an adequate bone development. Despite an increasing amount of data seems to suggest that pregnant women need a greater amount of VD than recommended in the past, further studies are needed to determine how much VD has to be given to assure a regular evolution of the pregnancy and an adequate development of the fetus and the young child.


HIV-1 Nef triggers macrophage fusion in a p61Hck- and protease-dependent manner.
Macrophages are a major target of HIV-1 infection. HIV-1-infected macrophages form multinucleated giant cells (MGCs) using poorly elucidated mechanisms. In this study, we show that MGC formation was reduced when human macrophages were infected with nef-deleted HIV-1. Moreover, expression of Nef, an HIV-1 protein required in several aspects of AIDS, was sufficient to trigger the formation of MGCs in RAW264.7 macrophages. Among Nef molecular determinants, myristoylation was dispensable, whereas the polyproline motif was instrumental for this phenomenon. Nef has been shown to activate hematopoietic cell kinase (Hck), a Src tyrosine kinase specifically expressed in phagocytes, through a well-described polyproline-SH3 interaction. Knockdown approaches showed that Hck is involved in Nef-induced MGC formation. Hck is expressed as two isoforms located in distinct subcellular compartments. Although both isoforms were activated by Nef, only p61Hck mediated the effect of Nef on macrophage fusion. This process was abolished in the presence of a p61Hck kinase-dead mutant or when p61Hck was redirected from the lysosome membrane to the cytosol. Finally, lysosomal proteins including vacuolar adenosine triphosphatase and proteases participated in Nef-induced giant macrophage formation. We conclude that Nef participates in HIV-1-induced MGC formation via a p61Hck- and lysosomal enzyme-dependent pathway. This work identifies for the first time actors of HIV-1-induced macrophage fusion, leading to the formation of MGCs commonly found in several organs of AIDS patients.


The impact of primary open-angle glaucoma: Comparison of vision-specific (National Eye Institute Visual Function Questionnaire-25) and disease-specific (Glaucoma Quality of Life-15 and Viswanathan 10) patient-reported outcome (PRO) instruments.
To compare a general vision-specific patient-reported outcomes (PRO) instrument, National Eye Institute Visual Function Questionnaire-25 (NEIVFQ-25) with two disease-specific PRO instruments, Glaucoma Quality of Life-15 (GQL-15), and Viswanathan 10 in patients with varying severity of primary open angle glaucoma (POAG). This hospital-based, prospective study enrolled 140 glaucoma patients. The patients were classified into mild, moderate, and severe glaucoma based on visual field defects. All these patients were administered the three PRO instruments and the results were statistically analyzed. All the three instruments showed high internal consistency (Cronbach's alpha for GQL-15, NEIVFQ-25, and Viswanathan 10 were 0.918, 0.937, and 0.929, respectively) There was a statistically significant difference between patients with mild, moderate, and severe POAG with all instruments (P ≤ 0.001). The instruments correlated well across several parameters especially the peripheral vision and glare/dark adaptation. The disease-specific scales however are simpler and faster to administer. All three instruments were reliable in assessment of mild, moderate, and severe glaucoma. They correlated strongly with each other in most of the related subscales, domains, and questions. NEIVFQ-25 additionally gave information regarding the general, psychological, and social effects of the disease.


Culture-independent analysis of bacterial species from an anaerobic mat from Lake Fryxell, Antarctica: prokaryotic diversity revisited.
Using a lake sediment mat sample from Lake Fryxell, Antarctica, different DNA extraction and purification methods were compared by denaturing gradient gel electrophoresis (DGGE). Based on the analyses of cloned 16S rRNA gene sequences a high degree of as yet uncultured prokaryotes have been reported in this sample. Although the vast majority of these as yet uncultured organisms seem to be classified as representatives of Firmicutes, Proteobacteria and Bacteriodetes, many of these taxa should be regarded novel species as judged from the distance of their gene sequences to those of their nearest cultured phylogenetic neighbours. The physiological properties of cultured strains from Lake Fryxell and of those of described species that are phylogenetically affiliated to the as yet uncultured species from this environment, suggest the presence of a well developed food web of primary producers, anaerobic degraders and fermenters, and aerobes. The few novel species described from this sample add to the increasing number of species characterized from various Antarctic habitats. Determination of the phylogenetic relatedness of the mat clone sequences of Clostridia with recent entries into public databases revealed that many of the putative species are closely related to other putative species detected in a broad range of environments, ranging from rumen and gut, anaerobic and polluted soil to sediment and groundwater samples.


Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process.
Alzheimer disease is characterized by the accumulation of abnormally folded protein fragments, i.e., amyloid beta peptide (Abeta) and tau that precipitate in amyloid plaques and neuronal tangles, respectively. In this review we discuss the complicated proteolytic pathways that are responsible for the generation and clearance of these fragments, and how disturbances in these pathways interact and provide a background for a novel understanding of Alzheimer disease as a multifactorial disorder. Recent insights evolve from the static view that the morphologically defined plaques and tangles are disease driving towards a more dynamic, biochemical view in which the intermediary soluble Abeta oligomers and soluble tau fragments are considered as the main mediators of neurotoxicity. The relevance of proteolytic pathways, centered on the generation and clearance of toxic Abeta, on the cleavage and nucleation of tau, and on the general proteostasis of the neurons, then becomes obvious. Blocking or stimulating these pathways provide, or have the potential to provide, interesting drug targets, which raises the hope that we will be able to provide a cure for this dreadful disorder.


[Research in alternative medicine. What is documented, and what is documentation?].
A study of the literature describing research on alternative medicine showed that, in general, the research was of poor quality. Any clinical effect of kinesiology had not been documented. Only few studies on reflexology had been controlled. Several controlled studies on healing showed significant effect, mainly in patients with psychosomatic disorders, or when the patient had great faith in the healer. Acupuncture seems to be effective against nausea, in patients with chronic pain and in patients who have had stroke. The data do not support the claim that acupuncture is effective for asthma or addiction. In the case of homeopathy the evidence from clinical trials is positive but not sufficient to draw a definite conclusion, for example, is it better than placebo? The majority of studies seems to disregard the principle of homeopathy, i.e. that the treatment should be individualised. Even if the documented effect of alternative medicine is not convincing, the effect is favourable empirically and may in itself be sufficient to give practitioners of alternative medicine an authorization. The term "alternative medicine" should be replaced by "complementary medicine".


Treatments for women with gestational diabetes mellitus: an overview of Cochrane systematic reviews.
Successful treatments for gestational diabetes mellitus (GDM) have the potential to improve health outcomes for women with GDM and their babies. To provide a comprehensive synthesis of evidence from Cochrane systematic reviews of the benefits and harms associated with interventions for treating GDM on women and their babies. We searched the Cochrane Database of Systematic Reviews (5 January 2018) for reviews of treatment/management for women with GDM. Reviews of pregnant women with pre-existing diabetes were excluded.Two overview authors independently assessed reviews for inclusion, quality (AMSTAR; ROBIS), quality of evidence (GRADE), and extracted data. We included 14 reviews. Of these, 10 provided relevant high-quality and low-risk of bias data (AMSTAR and ROBIS) from 128 randomised controlled trials (RCTs), 27 comparisons, 17,984 women, 16,305 babies, and 1441 children. Evidence ranged from high- to very low-quality (GRADE). Only one effective intervention was found for treating women with GDM.EffectiveLifestyle versus usual careLifestyle intervention versus usual care probably reduces large-for-gestational age (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.50 to 0.71; 6 RCTs, N = 2994; GRADE moderate-quality).PromisingNo evidence for any outcome for any comparison could be classified to this category.Ineffective or possibly harmful Lifestyle versus usual careLifestyle intervention versus usual care probably increases the risk of induction of labour (IOL) suggesting possible harm (average RR 1.20, 95% CI 0.99 to 1.46; 4 RCTs, N = 2699; GRADE moderate-quality).Exercise versus controlExercise intervention versus control for return to pre-pregnancy weight suggested ineffectiveness (body mass index, BMI) MD 0.11 kg/m², 95% CI -1.04 to 1.26; 3 RCTs, N = 254; GRADE moderate-quality).Insulin versus oral therapyInsulin intervention versus oral therapy probably increases the risk of IOL suggesting possible harm (RR 1.3, 95% CI 0.96 to 1.75; 3 RCTs, N = 348; GRADE moderate-quality).Probably ineffective or harmful interventionsInsulin versus oral therapyFor insulin compared to oral therapy there is probably an increased risk of the hypertensive disorders of pregnancy (RR 1.89, 95% CI 1.14 to 3.12; 4 RCTs, N = 1214; GRADE moderate-quality).InconclusiveLifestyle versus usual careThe evidence for childhood adiposity kg/m² (RR 0.91, 95% CI 0.75 to 1.11; 3 RCTs, N = 767; GRADE moderate-quality) and hypoglycaemia was inconclusive (average RR 0.99, 95% CI 0.65 to 1.52; 6 RCTs, N = 3000; GRADE moderate-quality).Exercise versus controlThe evidence for caesarean section (RR 0.86, 95% CI 0.63 to 1.16; 5 RCTs, N = 316; GRADE moderate quality) and perinatal death or serious morbidity composite was inconclusive (RR 0.56, 95% CI 0.12 to 2.61; 2 RCTs, N = 169; GRADE moderate-quality).Insulin versus oral therapyThe evidence for the following outcomes was inconclusive: pre-eclampsia (RR 1.14, 95% CI 0.86 to 1.52; 10 RCTs, N = 2060), caesarean section (RR 1.03, 95% CI 0.93 to 1.14; 17 RCTs, N = 1988), large-for-gestational age (average RR 1.01, 95% CI 0.76 to 1.35; 13 RCTs, N = 2352), and perinatal death or serious morbidity composite (RR 1.03; 95% CI 0.84 to 1.26; 2 RCTs, N = 760). GRADE assessment was moderate-quality for these outcomes.Insulin versus dietThe evidence for perinatal mortality was inconclusive (RR 0.74, 95% CI 0.41 to 1.33; 4 RCTs, N = 1137; GRADE moderate-quality).Insulin versus insulinThe evidence for insulin aspart versus lispro for risk of caesarean section was inconclusive (RR 1.00, 95% CI 0.91 to 1.09; 3 RCTs, N = 410; GRADE moderate quality).No conclusions possibleNo conclusions were possible for: lifestyle versus usual care (perineal trauma, postnatal depression, neonatal adiposity, number of antenatal visits/admissions); diet versus control (pre-eclampsia, caesarean section); myo-inositol versus placebo (hypoglycaemia); metformin versus glibenclamide (hypertensive disorders of pregnancy, pregnancy-induced hypertension, death or serious morbidity composite, insulin versus oral therapy (development of type 2 diabetes); intensive management versus routine care (IOL, large-for-gestational age); post- versus pre-prandial glucose monitoring (large-for-gestational age). The evidence ranged from moderate-, low- and very low-quality. Currently there is insufficient high-quality evidence about the effects on health outcomes of relevance for women with GDM and their babies for many of the comparisons in this overview comparing treatment interventions for women with GDM. Lifestyle changes (including as a minimum healthy eating, physical activity and self-monitoring of blood sugar levels) was the only intervention that showed possible health improvements for women and their babies. Lifestyle interventions may result in fewer babies being large. Conversely, in terms of harms, lifestyle interventions may also increase the number of inductions. Taking insulin was also associated with an increase in hypertensive disorders, when compared to oral therapy. There was very limited information on long-term health and health services costs. Further high-quality research is needed.


The effect of chronic hypoxia on the number and nuclear diameter of type I cells in the carotid bodies of rats.
We measured the number and nuclear diameter of type I cells in the carotid bodies of 10 normal rats and in 10 rats living in a hypobaric chamber at a pressure of 460 mm Hg for 25 to 96 days. In normal rats, the number of type I rats, the number ranged from 15.92 to 30.77 times 10-3 with a mean of 40.79 times 10-3 which differed significantly from that in the control group. In 5 hypoxic rats the number of type I cells was less than the highest figure in the control group. The mean diameter of the nuclei of type I cells of hypoxic rats (5.5 mu) was greater than that of the controls (5.0 mu). The largest type I nuclei were seen in those rats which had been subjected to hypoxia for the shortest time.


Efficacy and safety of arachidonic acid for treatment of school-age children in Schistosoma mansoni high-endemicity regions.
Arachidonic acid (ARA), an omega-6 fatty acid, is a potent schistosomicide that displayed significant and safe therapeutic effects in Schistosoma mansoni-infected schoolchildren in S. mansoni low-prevalence regions. We here report on ARA efficacy and safety in treatment of schoolchildren in S. mansoni high-endemicity areas of Kafr El Sheikh, Egypt. The study was registered with ClinicalTrials.gov (NCT02144389). In total, 268 schoolchildren with light, moderate, or heavy S. mansoni infection were assigned to three study arms of 87, 91, and 90 children and received a single dose of 40 mg/kg praziquantel (PZQ), ARA (10 mg/kg per day for 15 days), or PZQ combined with ARA, respectively. The children were examined before and after treatment for stool parasite egg counts and blood biochemical, hematological, and immunological parameters. ARA, like PZQ, induced moderate cure rates (50% and 60%, respectively) in schoolchildren with light infection and modest cure rates (21% and 20%, respectively) in schoolchildren with high infection. PZQ and ARA combined elicited 83% and 78% cure rates in children with light and heavy infection, respectively. Biochemical and immunological profiles were either unchanged or ameliorated after ARA therapy. Combination of PZQ and ARA might be useful for treatment of children with schistosomiasis in high-endemicity regions.


Adding medical cannabis to standard analgesic treatment for fibromyalgia: a prospective observational study.
To assess any clinical improvement attributable to the addition of medical cannabis treatment (MCT) to the stable (>3 months) standard analgesic treatment of fibromyalgia (FM) patients, the retention rate and any changes in the concomitant analgesic treatment over a period of six months. The study involved 102 consecutive FM patients with VAS scores ≥4 despite standard analgesic treatment. Patients were prescribed two oil-diluted cannabis extracts: Bedrocan (22% THC, <1% CBD), and Bediol (6.3% THC, 8% CBD). FM severity was periodically assessed using Fibromyalgia Impact Questionnaire (FIQR), Fibromyalgia Assessment Scale (FAS), FACIT-Fatigue score, Pittsburgh Sleep Quality Index (PSQI), and Zung Depression and Anxiety Scales. During the study, patients were allowed to reduce or stop their concomitant analgesic therapy. The 6-month retention rate was 64%. A significant improvement in the PSQI and FIQR was observed in respectively 44% and 33% of patients. 50% showed a moderate improvement in the anxiety and depression scales. Multiple regression analysis showed a correlation between the body mass index (BMI) and FIQR improvement (p=0.017). Concomitant analgesic treatment was reduced or suspended in 47% of the patients. One-third experienced mild adverse events, which did not cause any significant treatment modifications. This observational study shows that adjunctive MCT offers a possible clinical advantage in FM patients, especially in those with sleep dysfunctions. The clinical improvement inversely correlated with BMI. The retention rate and changes in concomitant analgesic therapy reflect MCT efficacy of the improved quality of life of patients. Further studies are needed to confirm these data, identify MCT-responsive sub-groups of FM patients, and establish the most appropriate posology and duration of the therapy.