Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol.
Islet transplantation offers the prospect of good glycemic control without major surgical risks. After our initial report of successful islet transplantation, we now provide further data on 12 type 1 diabetic patients with brittle diabetes or problems with hypoglycemia previous to 1 November 2000. Details of metabolic control, acute complications associated with islet transplantation, and long-term complications related to immunosuppression therapy and diabetes were noted. Insulin secretion, both acute and over 30 min, was determined after intravenous glucose tolerance tests (IVGTTs). The median follow-up was 10.2 months (CI 6.5-17.4), and the longest was 20 months. Glucose control was stable, with pretransplant fasting and meal tolerance-stimulated glucose levels of 12.5+/-1.9 and 20.0+/-2.7 mmol/l, respectively, but decreased significantly, with posttransplant levels of 6.3+/-0.3 and 7.5+/-0.6 mmol/l, respectively (P < 0.006). All patients have sustained insulin production, as evidenced by the most current baseline C-peptide levels 0.66+/-0.06 nmol/l, increasing to 1.29+/-0.25 nmol/l 90 min after the meal-tolerance test. The mean HbA1c level decreased from 8.3+/-0.5% to the current level of 5.8+/-0.1% (P < 0.001). Presently, four patients have normal glucose tolerance, five have impaired glucose tolerance, and three have post-islet transplant diabetes (two of whom need oral hypoglycemic agents and low-dose insulin (<10 U/day). Three patients had a temporary increase in their liver-function tests. One patient had a thrombosis of a peripheral branch of the right portal vein, and two of the early patients had bleeding from the hepatic needle puncture site; but these technical problems were resolved. Two patients had transient vitreous hemorrhages. The two patients with elevated creatinine levels pretransplant had a significant increase in serum creatinine in the long term, although the mean serum creatinine of the group was unchanged. The cholesterol increased in five patients, and lipid-lowering therapy was required for three patients. No patient has developed cytomegalovirus infection or disease, posttransplant lymphoproliferative disorder, malignancies, or serious infection to date. None of the patients have been sensitized to donor antigen. In 11 of the 12 patients, insulin independence was achieved after 9,000 islet equivalents (IEs) per kilogram were transplanted. The acute insulin response and the insulin area under the curve (AUC) after IVGTT were consistently maintained over time. The insulin AUC from the IVGTT correlated to the number of islets transplanted, but more closely correlated when the cold ischemia time was taken into consideration (r = 0.83, P < 0.001). Islet transplantation has successfully corrected labile type 1 diabetes and problems with hypoglycemia, and our results show persistent insulin secretion. After a minimum of 9,000 IEs per kilogram are provided, insulin independence is usually attained. An elevation of creatinine appears to be a contraindication to this immunosuppressive regimen. For the subjects who had labile type 1 diabetes that was difficult to control, the risk-to-benefit ratio is in favor of islet transplantation.


The stability of ferricytochrome c. Temperature dependence of its NMR spectrum.
The temperature dependence of the nuclear magnetic resonance spectrum of horse ferricytochrome c is described. The protein maintains an ordered structure over the temperature range 20 degrees C to 77 degrees C. The temperature dependence of the spectrum of ferricytochrome c arises from a number of causes including the paramagnetism of the ferric ion and protein structural changes. Preliminary analysis of the data show that the region of the protein about Ile-57 is flexible. Comparison of the data with the analogous data for horse ferrocytochrome c reveals that there is a small difference in structure between cytochrome c in its two oxidation states in the region about Ile-57.


Testing differential expression in nonoverlapping gene pairs: a new perspective for the empirical Bayes method.
The currently practiced methods of significance testing in microarray gene expression profiling are highly unstable and tend to be very low in power. These undesirable properties are due to the nature of multiple testing procedures, as well as extremely strong and long-ranged correlations between gene expression levels. In an earlier publication, we identified a special structure in gene expression data that produces a sequence of weakly dependent random variables. This structure, termed the delta-sequence, lies at the heart of a new methodology for selecting differentially expressed genes in nonoverlapping gene pairs. The proposed method has two distinct advantages: (1) it leads to dramatic gains in terms of the mean numbers of true and false discoveries, and in the stability of the results of testing; and (2) its outcomes are entirely free from the log-additive array-specific technical noise. We demonstrate the usefulness of this approach in conjunction with the nonparametric empirical Bayes method. The proposed modification of the empirical Bayes method leads to significant improvements in its performance. The new paradigm arising from the existence of the delta-sequence in biological data offers considerable scope for future developments in this area of methodological research.


Cytonuclear theory for haplodiploid species and X-linked genes. I. Hardy-Weinberg dynamics and continent-island, hybrid zone models.
We develop models that describe the cytonuclear structure for either a cytoplasmic and nuclear marker in a haplodiploid species or a cytoplasmic and X-linked marker in a diploid species. Sex-specific disequilibrium statistics that summarize nonrandom cytonuclear associations in such systems are defined, and their basic Hardy-Weinberg dynamics and admixture formulae are delimited. We focus on the context of hybrid zones and develop continent-island models whereby individuals from two genetically differentiated source populations migrate into and mate within a single zone of admixture. We examine the effects of differential migration of the sexes, assortative mating by pure type females, and census time (relative to mating and migration), as well as special cases of random mating and migration subsumed under the general models. We show that pure type individuals and nonzero cytonuclear disequilibria can be maintained within a hybrid zone if there is continued migration from both source populations, and that females generally have a greater influence over these cytonuclear variables than males. The resulting theoretical framework can be used to estimate the rates of assortative mating and sex-specific gene flow in hybrid zones and other zones of admixture involving haplodiploid or sex-linked cytonuclear data.


Correlation of vascular smooth muscle cell morphology observed by scanning electron microscopy with transmission electron microscopy.
Smooth muscle cell (SMC) morphology was studied in rat large mesenteric artery using scanning electron microscopy (SEM), after removal of connective tissue elements with the OsO4/HCl method. Transmission electron microscopy (TEM) was used to correlate the findings of SEM and to assess the effects of digestion on cell ultrastructure. When viewed with SEM, relaxed SMC possessed a smooth, regular surface morphology with longitudinal striations or grooves. TEM examination of cross-sectional profiles of SMC suggested that these striations corresponded to the arrangement of membrane dense bodies within the SMC. The presence of cell contacts among SMC as observed with SEM were confirmed using TEM. Two types of SMC contacts were found: simple appositional contacts and interdigitations. Gap junctions were not observed between SMC in the media. Although structures suggesting nerve networks were observed in the medial-adventitial border with SEM, this could not be confirmed using TEM as a result of alteration in cell ultrastructure with the digestive method. We conclude that the OsO4/HCl method, although useful for SEM, is not suitable for TEM study, because it caused significant alterations of SMC ultrastructure such that organelles and other structures were no longer evident when viewed with TEM.


Hypofractionation: less is more?
One third of patients with bladder cancer present with muscle invasive bladder cancer (MIBC) which has a poor prognosis. International guidelines for the management of MIBC recommend radical cystectomy or bladder-preserving treatment based on radical radiotherapy with a form of radiosensitisation. In the UK, both conventional fractionation with 64 Gy in 32 fractions and hypofractionation with 55 Gy in 20 fractions are standard of care options with the choice varying between centres. A meta-analysis of individual patients with locally advanced bladder cancer from two UK multicentre phase 3 trials was published recently. This study evaluated the non-inferiority of a hypofractionated schedule compared to a conventional regime. This analysis confirmed the non-inferiority of the hypofractionated regimen, and noted superior locoregional control. We discuss the relevance of these findings to current practice while considering the radiobiology of hypofractionation, the role of systemic therapies and radiosensitisation, as well as the socioeconomic benefits.


Notch-mediated re-specification of neuronal identity during central nervous system development.
Neuronal identity has long been thought of as immutable, so that once a cell acquires a specific fate, it is maintained for life.1 Studies using the overexpression of potent transcription factors to experimentally reprogram neuronal fate in the mouse neocortex2,3 and retina4,5 have challenged this notion by revealing that post-mitotic neurons can switch their identity. Whether fate reprogramming is part of normal development in the central nervous system (CNS) is unclear. While there are some reports of physiological cell fate reprogramming in invertebrates,6,7 and in the vertebrate peripheral nervous system,8 endogenous fate reprogramming in the vertebrate CNS has not been documented. Here, we demonstrate spontaneous fate re-specification in an interneuron lineage in the zebrafish retina. We show that the visual system homeobox 1 (vsx1)-expressing lineage, which has been associated exclusively with excitatory bipolar cell (BC) interneurons,9-12 also generates inhibitory amacrine cells (ACs). We identify a role for Notch signaling in conferring plasticity to nascent vsx1 BCs, allowing suitable transcription factor programs to re-specify them to an AC fate. Overstimulating Notch signaling enhances this physiological phenotype so that both daughters of a vsx1 progenitor differentiate into ACs and partially differentiated vsx1 BCs can be converted into ACs. Furthermore, this physiological re-specification can be mimicked to allow experimental induction of an entirely distinct fate, that of retinal projection neurons, from the vsx1 lineage. Our observations reveal unanticipated plasticity of cell fate during retinal development.


[Effects of blood refluxes on formation of trophic ulcers in patients with postthrombotic disease].
The results of complex examination of 45 patients with chronic venous insufficiency having class C6 open trophic ulcers by CEAP classification due to postthrombotic disease were analyzed. The localization, intensity and duration of blood refluxes in the venous system of the injured extremity were determined using ultrasonic angioscanning. Highly intensive total reflux of blood in the popliteal and talocrural segments of the lower extremity venous system found in 68.9% of patients has most injuring effects on the microcirculatory bed of patients having postthrombotic disease with recanalization of the profound veins. The developing pathological cross-flow of blood from the musculo-venous pump of the shank into the foot profound veins gives rise to perforator vein incompetence on the foot and shank forming two zones of venous hypertension under and over the ankle-bone. The main factor of the developing trophic ulcers in patients with segmental obliteration (17.8%) and insufficient recanalization of the profound veins (13.3%) was venous hypertension in the distal parts of the injured extremity. Blood refluxes in the shank profound veins were weakly intensive and played a subsidiary role in the development of trophic disorders.


[Why do efforts toward theoretical synthesis prove so successful in biology but not in sociology?].
Rarely are efforts made to arrive at major theoretical syntheses in the realm of biology, while they are so often successful within the realm of sociology. Furthermore, though these efforts gain paradigmatic status in the former case, in the latter they lead to a 'Balkanization' of the discipline. The article explores what might account for this difference, seeking an answer through the reconstruction of one such effort in biology, which has covered more than two decades.


Changes in electrical perception threshold within the first 6 months after traumatic spinal cord injury: a multicenter responsiveness study.
To assess the reliability of the electrical perception threshold (EPT) in healthy participants and its responsiveness in patients for 6 months after traumatic spinal cord injury (SCI). The reliability of EPT measures was assessed in 15 healthy volunteers (from C3 to S2). EPT measures were assessed in 37 patients at 1, 3, and 6 months after SCI. EPT was determined in dermatomes at, above, and below the neurological level of lesion. Reliability was quantified with an intraclass correlation coefficient (ICC) and responsiveness with the standardized response mean (SRM). Dermatomes were classified as having normal or pathological sensory perception, based on both light touch (LT) and EPT testing. The percentage of agreement between LT and EPT classifications was determined. The ICCs varied considerably between dermatomes (0.00 ≤ ICC ≤ 0.86). Overall, EPTs changed little within the first 6 months after SCI, resulting in small SRM values. Agreement between classifications according to EPT or LT testing varied from 30% to 100%. The least agreement was observed in the first segment below the lesion. Future studies must note that the reliability of EPT differs between dermatomes in healthy participants. Furthermore, at and below the level of the lesion, spontaneous recovery of sensory perception is poor within the first 6 months after SCI. Based on subgroup analyses, if a translational trial aims to improve sensory perception around the level of the lesion, sensory-incomplete tetraplegic patients could be included. These patients show poor spontaneous recovery, and the EPT may detect subtle changes in perception.


Secretogranins I and II: two tyrosine-sulfated secretory proteins common to a variety of cells secreting peptides by the regulated pathway.
We report on the biochemical and immunological properties as well as on the cellular and subcellular distribution of two proteins, called secretogranins I and II. These proteins specifically occur in a wide variety of endocrine and neuronal cells that package and sort regulatory peptides into secretory granules. Both secretogranins take the same intracellular route as the peptides and are also sorted into secretory granules. Secretogranins I and II are biochemically and immunologically distinct proteins and differ from chromogranin A. Yet, these three proteins are similar to each other in many respects and therefore constitute one class of proteins. A remarkable feature of this protein class is a very acidic pI, brought about by a high content of acidic amino acids as well as by phosphorylation on serine and sulfation on tyrosine and O-linked carbohydrate. As a result, this class of proteins has a high net negative charge even at the acidic pH of the trans Golgi cisternae. We discuss the possibility that this property of the proteins may point to a role in the packaging of regulatory peptides into secretory granules.


The effect of qigong exercise on immunity and infections: a systematic review of controlled trials.
The objective of this review was to summarize and critically evaluate the clinical evidence of the effect of qigong exercise on immunity and its efficacy in the prevention or treatment of infectious diseases. Thirteen databases were searched from their respective inceptions through January 2011, and all controlled clinical trials of qigong exercise on immunity and infections were included. Quality and validity of the included studies were evaluated using standard scales. Seven studies including two randomized controlled trials (RCTs), two controlled clinical trials (CCTs) and three retrospective observational studies (ROSs) met the inclusion criteria. One study focused on functional measures of immunity (antigen-induced immunity) and six studies on enumerative parameters of immunity. No study on clinical symptoms relevant to infectious diseases could be identified. Overall, the included studies suggested favorable effects of qigong exercise on immunity, but the quality of research for most of the studies examined in this review was poor. Further rigorously designed studies are required, which should adhere to accepted standards of methodology for clinical trials.


[Recent data on the mechanism of action of prolactin].
Prolactin is a hormone involved in the control of many functions, from osmoregulation in fishes to lactation in mammals. For that reason, the control of its secretion by hypophysis is particularly complex. Multiple factors of hypothalamic origin (dopamine, GABA, VIP, etc . . .) and hormones (oestrogens, TRH, thyroxine, . . .) are involved in this control. Prolactin molecule contains about 200 aminoacids. It has three disulfide bridges, of which one, at the center of the molecule, is required for the lactogenic activity. The expression of prolactin gene is dependent upon oestrogens, TRH, Ca++ ion and cAMP which favour its transcription. In contrast, dopaminergics such as CB 154 lower the expression rate of this gene. Prolactin receptor is located essentially on the plasma and intracellular membranes of target cells. Its essential binding part has a molecular weight of about 40,000. In mammary gland and liver prolactin receptor is up-regulated following a slow process. It is also down-regulated following a rapid and reversible process. In mammary gland, prolactin controls the expression of milk protein genes by enhancing their transcription rate and also by increasing the stability and the translation rate of the mRNAs. The transfer of the prolactin information to genes takes place through a relay which is released from plasma membrane when the receptor is occupied by the hormone or by anti-prolactin receptor antibodies. This relay which seems to be a small peptide (less than 1000 daltons and inactivated by trypsin) acts directly and specifically on isolated mammary nuclei via a dephosphorylation of nuclear proteins.


The cost-effectiveness of metformin in the US diabetes prevention program trial: Simple interpretations need not apply.
Based on previously published US Diabetes Prevention Program (DPP) cost-effectiveness analyses (CEAs) metformin continues to be promoted as "cost-effective." We review the DPP within-trial CEA to assess this claim. Treatment alternatives included placebo (plus standard lifestyle advice), branded metformin and individual lifestyle modification. We added generic metformin as an alternative. Original published CEA data were taken as given and re-analyzed according to accepted principles for calculating incremental cost-effectiveness ratios (ICERs) in the economic evaluation field. With more than two treatments as in the DPP, these require attention to the rankings of interventions according to cost or effect prior to stipulating appropriate ICERs to calculate. With proper ICERs neither branded nor generic metformin was cost-effective, regardless of the value assumed for the willingness to pay for the quality-adjusted life year outcome assessed. Metformin alternatives were technically inefficient compared to placebo or the lifestyle modification alternative. Net loss calculations indicated substantial costs/health losses to using metformin instead of the optimal lifestyle alternative in response to metformin having been inaccurately labelled "cost-effective" in the original CEA. That CEA and subsequent analyses and citations of such analyses continue to claim that both metformin and lifestyle modification are cost-effective in diabetes prevention based on DPP data. Using metformin implies substantial costs and health losses compared to the cost-effective lifestyle modification. It may be that metformin has a role in cost-effective diabetes prevention, but this has yet to be shown based on DPP data.


Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity.
The microvasculature plays a key role in tissue perfusion and exchange of gases and metabolites. In this study we use human blood vessel organoids (BVOs) as a model of the microvasculature. BVOs fully recapitulate key features of the human microvasculature, including the reliance of mature endothelial cells on glycolytic metabolism, as concluded from metabolic flux assays and mass spectrometry-based metabolomics using stable tracing of 13C-glucose. Pharmacological targeting of PFKFB3, an activator of glycolysis, using two chemical inhibitors results in rapid BVO restructuring, vessel regression with reduced pericyte coverage. PFKFB3 mutant BVOs also display similar structural remodelling. Proteomic analysis of the BVO secretome reveal remodelling of the extracellular matrix and differential expression of paracrine mediators such as CTGF. Treatment with recombinant CTGF recovers microvessel structure. In this work we demonstrate that BVOs rapidly undergo restructuring in response to metabolic changes and identify CTGF as a critical paracrine regulator of microvascular integrity.


Determination of seventeen major and trace elements in new float glass standards for use in forensic comparisons using laser ablation inductively coupled plasma mass spectrometry.
Consensus concentration values for seventeen (17) major and trace elements typically present in soda-lime glass manufactured using the "float " process and used in the quantitative analysis and forensic comparison of glass samples were determined using laser ablation (LA) micro sampling coupled to inductively coupled plasma mass spectrometry (ICP-MS). This is the first reporting of the chemical characterization of a new set of float glass intended for use as matrix-matched calibration standards in the forensic analysis and comparison of glass by LA-ICP-MS using a standard test method (ASTM E2927-16e1). Three Corning Float Glass Standards (CFGS) were manufactured at low, medium, and high concentrations of 32 elements typically encountered in float glass samples as found in forensic casework. This work describes an international collaboration among seven (7) laboratories to evaluate the homogeneity of the three glass materials and reports the consensus concentrations values of 17 elements at three concentration levels. Eight (8) sets of independent results from LA-ICP-MS analysis using the standard test method of analysis and one set of micro-X-ray Fluorescence Spectrometry (μXRF) data (using method ASTM E2926-17) resulted in typically <3% relative standard deviation (RSD) within each lab and < 5% RSDs among all labs participating in the study for the concentration ranges using sampling spots between 50 μm - 100 μm in diameter. These results suggest that the new calibration standards are homogeneous for most elements at the small sampling volumes (~ 90 μm deep by ~80 μm in diameter) reported and show excellent agreement among the different participating labs. Consensus concentration values are determined using a previously reported calibration standard (FGS 2) and checked with a NIST 1831 SRM®. A collaboration with National Institute of Standards and Technology (NIST) scientists to certify these glasses as SRMs, including the certification of the quantitative analysis of the minor and trace element content, for future distribution by NIST is ongoing.


Low temperature formation of calcium-deficient hydroxyapatite-PLA/PLGA composites.
Hydroxyapatite-biodegradable polymer composites have been formed by a low temperature chemical route. Precomposite structures were prepared by combining alpha-Ca(3)(PO(4))(2) (alpha-tricalcium phosphate or alpha-TCP) with poly(L-lactic) acid and poly(DL-lactide-co-glycolide) copolymers. The final composite structure was achieved by in situ hydrolysis of alpha-TCP to Ca(9)(HPO(4))(PO(4))(5)OH (calcium deficient hydroxyapatite or CDHAp) either in solvent cast or pressed precomposites. Hydrolysis was performed at 56 degrees C-a temperature slightly above the glass transition of the polymers. The effects of polymer chemistry, composite formation technique, and porosity on hydrolysis kinetics and degree of transformation were examined with isothermal calorimetry, X-ray diffraction (XRD), Fourier transform infrared spectroscopy, and scanning electron microscopy. Calorimetric data and XRD analyses revealed that hydrolysis reactions were inhibited in the presence of the polymers. Isothermal calorimetry indicated the extent of the alpha-TCP to CDHAp transformation in 24 h to be 85% in the solvent cast composites containing PLGA (85:15) copolymer; however, XRD analyses suggested almost complete reaction. The CDHAp formation extent was 26% for the pressed composites containing the same polymer. In the presence of NaCl as a pore generator, 81% transformation was observed for the pressed composites. This transformation occurred without any chemical reaction between the polymer-inorganic components, as determined by Fourier transform infrared spectroscopy. Minimal transformation to CDHAp occurred in composites containing poly(L-lactic) acid.


Nitrogen-Regulated Theanine and Flavonoid Biosynthesis in Tea Plant Roots: Protein-Level Regulation Revealed by Multiomics Analyses.
Theanine and flavonoids (especially proanthocyanidins) are the most important and abundant secondary metabolites synthesized in the roots of tea plants. Nitrogen promotes theanine and represses flavonoid biosynthesis in tea plant roots, but the underlying mechanism is still elusive. Here, we analyzed theanine and flavonoid metabolism in tea plant roots under nitrogen deficiency and explored the regulatory mechanism using proteome and ubiquitylome profiling together with transcriptome data. Differentially expressed proteins responsive to nitrogen deficiency were identified and found to be enriched in flavonoid, nitrogen, and amino acid metabolism pathways. The proteins responding to nitrogen deficiency at the transcriptional level, translational level, and both transcriptional and translational levels were classified. Nitrogen-deficiency-responsive and ubiquitinated proteins were further identified. Our results showed that most genes encoding enzymes in the theanine synthesis pathway, such as CsAlaDC, CsGDH, and CsGOGATs, were repressed by nitrogen deficiency at transcriptional and/or protein level(s). While a large number of enzymes in flavonoid metabolism were upregulated at the transcriptional and/or translational level(s). Importantly, the ubiquitylomic analysis identified important proteins, especially the hub enzymes in theanine and flavonoid biosynthesis, such as CsAlaDC, CsTSI, CsGS, CsPAL, and CsCHS, modified by ubiquitination. This study provided novel insights into the regulation of theanine and flavonoid biosynthesis and will contribute to future studies on the post-translational regulation of secondary metabolism in tea plants.


Extracellular matrix containing mutated fibrillin-1 (Fbn1) down regulates Col1a1, Col1a2, Col3a1, Col5a1, and Col5a2 mRNA levels in Tsk/+ and Tsk/Tsk embryonic fibroblasts.
It is known that the extracellular matrix (ECM) is able to signal to cells and thereby direct or modulate the transcription of certain mRNAs. This signaling plays an important role in tumor invasion and metastasis, wound healing, remodeling of the ECM and cell differentiation. There are several mechanisms whereby the ECM signals cells to change their metabolism: (1) receptor molecules binding to specific domains in the ECM, (2) direct phagocytosis of the ECM molecules or domains into the cell, (3) structural changes of the ECM domains. We report the effect of an ECM containing either mutant or normal Fbn1 on the transcription levels of several collagen mRNAs. Tsk/Tsk, Tsk/+ and +/+ mouse embryonic fibroblast cell lines were used. Tsk/Tsk cells produce only mutated fibrillin-1 which arises from mRNA containing an in-frame duplication of exons 17-40. To test the effect of the ECM containing mutant Fbn1, cells of the Tsk/Tsk, Tsk/+ and the wild-type (+/+) genotype were each grown on an ECM produced by either Tsk/Tsk, Tsk/+ cells or by wild-type cells (+/+). The embryonic cells were genotyped by Northern analyses for Fbn1 and grown to confluence. The cultures were then harvested and the cells removed, leaving the matrix in the flasks. Matrices produced from Tsk/Tsk, Tsk/+ and from +/+ cells were reseeded with Tsk/Tsk cells, Tsk/+ cells or +/+ cells. The cells were plated at a confluent concentration and incubated on the matrices for 48 h, after which total RNA was harvested and cDNA generated. Real-time PCR using cDNA or Northern analyses using RNA were performed for Fbn1 and Types I, III and V collagens. The PCR and Northern results were normalized using beta-actin and GAPDH, respectively. The Northern analyses showed that the steady state levels of mRNA for Col1a1 were depressed in both Tsk/Tsk and +/+ cells when grown on the matrix produced by Tsk/Tsk cells. Real-time PCR was then performed with primers specific for Col1a2, Col3a1, Col5a1 and Col5a2. The results showed that cells with the Tsk/Tsk, Tsk/+, and +/+ genotype all had lower steady-state levels of the above 4 collagen mRNAs when grown on the matrix produced by homozygous Tsk/Tsk cells or the matrix produced by heterozygous Tsk/+ cells compared with those grown on a matrix produced by +/+ cells. We hypothesize that the mutated Fbn1 molecules with many additional EGF-calcium binding regions and TGF-beta binding domains may (1) change the homeostasis of the ECM by binding additional growth factors and/or (2) present a radically different ECM 3-dimensional architecture. Either or both of these changes could signal the cell to produce less collagen.


Comparative study of friction between metallic and conventional interactive self-ligating brackets in different alignment conditions.
The aim of this study was to compare the friction between three bracket models: conventional stainless steel (Ovation, Dentsply GAC), self-ligating ceramic (In-Ovation, Denstply GAC) and self-ligating stainless steel brackets (In-Ovation R, Dentsply GAC). Five brackets were used for each model. They were bonded to an aluminum prototype that allowed the simulation of four misalignment situations (n = 10). Three of these situations occured at the initial phase (in which a 0.016-in nickel-titanium wire was used): 1. horizontal; 2. vertical; and 3. simultaneous horizontal/vertical. One of the situations occurred at the final treatment phase: 4. no misalignment (in which a 0.019 x 0.025-inch stainless steel rectangular wire was used). The wires slipped through the brackets and friction was measured by a Universal Testing Machine. Analysis of variance followed by Tukey's Test for multiple comparisons (α = 0.05) were applied to assess the results. Significant interaction (p < 0.01) among groups was found. For the tests that simulated initial alignment, Ovation® bracket produced the highest friction. The two self-ligating models resulted in lower and similar values, except for the horizontal situation, in which In-Ovation C® showed lower friction, which was similar to the In-Ovation R® metallic model. For the no misalignment situation, the same results were observed. The self-ligating system was superior to the conventional one due to producing less friction. With regard to the material used for manufacturing the brackets, the In-Ovation C® ceramic model showed less friction than the metallic ones.


Sap Pressure in Vascular Plants: Negative hydrostatic pressure can be measured in plants.
A method is described which permits measurement of sap pressure in the xylem of vascular plants. As long predicted, sap pressures during transpiration are normally negative, ranging from -4 or -5 atmospheres in a damp forest to -80 atmospheres in the desert. Mangroves and other halophytes maintain at all times a sap pressure of -35 to -60 atmospheres. Mistletoes have greater suction than their hosts, usually by 10 to 20 atmospheres. Diurnal cycles of 10 to 20 atmospheres are common. In tall conifers there is a hydrostatic pressure gradient that closely corresponds to the height and seems surprisingly little influenced by the intensity of transpiration. Sap extruded from the xylem by gas pressure on the leaves is practically pure water. At zero turgor this procedure gives a linear relation between the intracellular concentration and the tension of the xylem.


Development of a more accurate Geant4 quantum molecular dynamics model for hadron therapy.
Objective. Although in heavy-ion therapy, the quantum molecular dynamics (QMD) model is one of the most fundamental physics models providing an accurate daughter-ion production yield in the final state, there are still non-negligible differences with the experimental results. The aim of this study is to improve fragment production in water phantoms by developing a more accurate QMD model in Geant4.Approach. A QMD model was developed by implementing modern Skyrme interaction parameter sets, as well as by incorporating with an ad hocα-cluster model in the initial nuclear state. Two adjusting parameters were selected that can significantly affect the fragment productions in the QMD model: the radius to discriminate a cluster to which nucleons belong after the nucleus-nucleus reaction, denoted byR, and the squared standard deviation of the Gaussian packet, denoted byL. Squared Mahalanobis's distance of fragment yields and angular distributions with 1, 2, and the higher atomic number for the produced fragments were employed as objective functions, and multi-objective optimization (MOO), which make it possible to compare quantitatively the simulated production yields with the reference experimental data, was performed.Main results. The MOO analysis showed that the QMD model with modern Skyrme parameters coupled with the proposedα-cluster model, denoted as SkM*α, can drastically improve light fragments yields in water. In addition, the proposed model reproduced the kinetic energy distribution of the fragments accurately. The optimizedLin SkM*αwas confirmed to be realistic by the charge radii analysis in the ground state formation.Significance. The proposed framework using MOO was demonstrated to be very useful in judging the superiority of the proposed nuclear model. The optimized QMD model is expected to improve the accuracy of heavy-ion therapy dosimetry.


Breast cancer surgery with augmented reality.
Innovations in 3D spatial technology and augmented reality imaging driven by digital high-tech industrial science have accelerated experimental advances in breast cancer imaging and the development of medical procedures aimed to reduce invasiveness. A 57-year-old post-menopausal woman presented with screen-detected left-sided breast cancer. After undergoing all staging and pre-operative studies the patient was proposed for conservative breast surgery with tumor localization. During surgery, an experimental digital and non-invasive intra-operative localization method with augmented reality was compared with the standard pre-operative localization with carbon tattooing (institutional protocol). The breast surgeon wearing an augmented reality headset (Hololens) was able to visualize the tumor location projection inside the patient's left breast in the usual supine position. This work describes, to our knowledge, the first experimental test with a digital non-invasive method for intra-operative breast cancer localization using augmented reality to guide breast conservative surgery. In this case, a successful overlap of the previous standard pre-operative marks with carbon tattooing and tumor visualization inside the patient's breast with augmented reality was obtained. Breast cancer conservative guided surgery with augmented reality can pave the way for a digital non-invasive method for intra-operative tumor localization.


Curcumin suppresses Janus kinase-STAT inflammatory signaling through activation of Src homology 2 domain-containing tyrosine phosphatase 2 in brain microglia.
Curcumin has been strongly implicated as an anti-inflammatory agent, but the precise mechanisms of its action are largely unknown. In this study, we show that the inhibitory action of curcumin on Janus kinase (JAK)-STAT signaling can contribute to its anti-inflammatory activity in the brain. In both rat primary microglia and murine BV2 microglial cells, curcumin effectively suppressed the ganglioside-, LPS-, or IFN-gamma-stimulated induction of cyclooxygenase-2 and inducible NO synthase, important enzymes that mediate inflammatory processes. These anti-inflammatory effects appear to be due, at least in part, to the suppression of the JAK-STAT inflammatory signaling cascade. Curcumin markedly inhibited the phosphorylation of STAT1 and 3 as well as JAK1 and 2 in microglia activated with gangliosides, LPS, or IFN-gamma. Curcumin consistently suppressed not only NF binding to IFN-gamma-activated sequence/IFN-stimulated regulatory element, but also the expression of inflammation-associated genes, including ICAM-1 and monocyte chemoattractant protein 1, whose promoters contain STAT-binding elements. We further show that activation of Src homology 2 domain-containing protein tyrosine phosphatases (SHP)-2, a negative regulator of JAK activity, is likely to be one of the mechanisms underlying the curcumin-mediated inhibition of JAK-STAT signaling. Treatment of microglial cells with curcumin led to an increase in phosphorylation and association with JAK1/2 of SHP-2, which inhibit the initiation of JAK-STAT inflammatory signaling in activated microglia. Taken together, these data suggest curcumin suppresses JAK-STAT signaling via activation of SHP-2, thus attenuating inflammatory response of brain microglial cells.


Elucidation of the Differences in Cinobufotalin's Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein.
Cinobufotalin is one of the major anti-tumor components isolated from toad venom and has been used in the clinical therapy of hepatocellular carcinoma (HCC), known as Cinobufacini injection. However, the pharmacokinetic (PK) behaviors of cinobufotalin in vivo with HCC are still unknown. Hence, we have established a HCC model in Sprague Dawley (SD) rats induced by diethylnitrosamine (DEN), named as DEN-injured rats. Then, we developed and validated a sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify cinobufotalin in rat plasma. This UPLC-MS/MS method was successfully used to characterize the PK behaviors of cinobufotalin in normal and DEN-injured rats after intravenous (i.v.) injection at a dosage of 2.5 mg/kg. Cinobufotalin pharmacokinetics was well described by the two-compartment pharmacokinetic model and the PK parameters were calculated using WinNonlin 3.3 software. The transfer rate constant of cinobufotalin from the central compartment to the peripheral compartment (k12) in DEN-injured rats was significantly greater than that in normal rats (p < 0.01), accompanied by the shorter half-life for the distribution phase (t1/2α). Additionally, the elimination rate constant (K10) and clearance (CL) values in DEN-injured rats were significantly higher than that in normal rats (p < 0.05 for K10 and p < 0.001 for CL, respectively). Therefore, the values of areas under concentration - time curve (AUC) and the liver concentration of cinobufotalin in DEN-injured rats was obviously lower than that in normal rats (p < 0.001 and p < 0.01, respectively). This indicated that the PK behaviors of cinobufotalin will be altered in rats with HCC. In addition, P-glycoprotein (P-gp) has shown higher expression in live tissues of DEN-injured rats. Furthermore, cinobufotalin was identified as the substrate of P-gp using MDCK II and MDCK-MDR1 cell models for the first time. Consequently, P-gp will play an important role in the disposition of cinobufotalin in vivo, which provided a new combination therapy for the clinical treatment of HCC.


GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity.
Intrahepatic cholangiocarcinoma (iCCA) is rising in incidence, and at present, there are limited effective systemic therapies. iCCA tumours are infiltrated by stromal cells, with high prevalence of suppressive myeloid populations including tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Here, we show that tumour-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) and the host bone marrow is central for monopoiesis and potentiation of TAMs, and abrogation of this signalling axis facilitates antitumour immunity in a novel model of iCCA. Blood and tumours were analysed from iCCA patients and controls. Treatment and correlative studies were performed in mice with autochthonous and established orthotopic iCCA tumours treated with anti-GM-CSF monoclonal antibody. Systemic elevation in circulating myeloid cells correlates with poor prognosis in patients with iCCA, and patients who undergo resection have a worse overall survival if tumours are more infiltrated with CD68+ TAMs. Mice with spontaneous iCCA demonstrate significant elevation of monocytic myeloid cells in the tumour microenvironment and immune compartments, and tumours overexpress GM-CSF. Blockade of GM-CSF with a monoclonal antibody decreased tumour growth and spread. Mice bearing orthotopic tumours treated with anti-GM-CSF demonstrate repolarisation of immunosuppressive TAMs and MDSCs, facilitating T cell response and tumour regression. GM-CSF blockade dampened inflammatory gene networks in tumours and TAMs. Human tumours with decreased GM-CSF expression exhibit improved overall survival after resection. iCCA uses the GM-CSF-bone marrow axis to establish an immunosuppressive tumour microenvironment. Blockade of the GM-CSF axis promotes antitumour T cell immunity.


Socioeconomic differences in recruitment and sickness absence in a large NHS health organisation: a cross-sectional study.
This study investigates the distribution of the workforce of one large National Health Service (NHS) employer in relation to socioeconomic deprivation and how sickness absence rates varied across these levels of deprivation. Share of the working age population that was employed at the NHS organisation mapped by area deprivation. The study used negative binomial regression models to investigate the extent to which wage level, occupational group and area deprivation were associated with sickness absence among employees. The study used electronic staff records (2018-2019) of a large NHS organisation in the North West of England. In the most deprived areas, an additional person per 1000 working age population were employed at this NHS organisation compared with the most affluent areas. Employees from the most deprived quintile had 1.41 (95% CI 1.16 to 1.70) times the higher sickness rates than the employees from the least deprived quintile, when adjusting for age and sex. These differences were largely explained by differences in wage levels and occupation groups, with the lowest wage employees having 2.5 (95% CI 1.87 to 3.42) times the sickness absence rate as the highest wage group and the nursing and midwifery employees having 1.8 (95% CI 1.50 to 2.24) times the sickness absence rate as the administrative and clerical group. This large NHS organisation employed people disproportionately from deprived areas. They were considerably more likely to experience sickness absence compared with people from affluent areas. This appears to be because they were more likely to be in lower wage employment and employed in nursing and nursing assistant. Workplace health policies need to target these workers, adapting to their needs while enabling improvements in their working conditions, pay and career progression.


Case reviews of infections of the spine in patients with a history of solid organ transplantation.
Retrospective clinical case series. To report on the epidemiological, microbiological, and clinical characteristics of spinal infections in patients who have undergone solid organ transplantation. Spine infections remain a therapeutic challenge, particularly in patients who are immunocompromised. Solid organ transplant patients represent a growing population of immunocompromised hosts. To our knowledge, no previous reports have examined the clinical characteristics spinal infections in this at-risk population in a systematic fashion. The records of patients with a history of solid organ transplantation from January 2007 through December 2012 were identified using Current Procedural Terminology procedure codes. Patients with spine infections who have received transplants were then identified using International Classification of Diseases, Ninth Revision codes for spine infection. In addition to demographic data, we recorded medical comorbidities, immunosuppressant medications, laboratory results, culture data, treatment received, and short-term results. During this 6-year period, 2764 solid organ transplants were performed at our institution. Of this cohort, 6 patients (0.22%) were treated for a spinal infection. Patient's age ranged from 51 to 80 years (mean, 63 yr). All spine infections occurred within 1 year after organ transplantation. All patients had an elevated erythrocyte sedimentation rate. Only 1 patient had an elevated white blood cell count. The most common organisms were Escherichia coli and Staphylococcus. Four patients required surgical treatment. All patients had complete resolution of symptoms. Our data suggest that patients with a history of solid organ transplantation may be more susceptible to developing spine infections than the general population. The most common organisms in our cohort were E. coli and Staphylococcus. Spine infections caused by atypical organisms do also occur in the organ transplant population, as is the case in other immunocompromised patients. The identification of these organisms and timely institution of treatment remains critical in the management of this at-risk population. 4.


Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice.
Interleukin-10 knockout (IL-10(-/-)) mice spontaneously develop colitis characterized by T-helper cell type 1-polarized inflammation. We tested the possible therapeutic activity of the peroxisome proliferator-activated receptor alpha (PPARalpha) ligand fenofibrate, and the PPARdelta ligand GW0742, in IL-10(-/-) mice and investigated the cellular/molecular mechanisms for fenofibrate action. The effect of fenofibrate or GW0742 on the progression of colitis in C3H.IL-10(-/-) mice was evaluated. Effects of fenofibrate on cytokine and chemokine gene expression were studied in cultured splenocytes, pathogenic T cells isolated from C3H/HeJBir mice, and HT-29 colorectal cancer cells. Treatment of C3H.IL-10(-/-) mice with fenofibrate delayed the onset of colitis, decreased the colonic histopathology score, and decreased colonic expression of genes encoding the inflammatory cytokines interferon-gamma and interleukin (IL)-17. The target for fenofibrate, PPARalpha, was expressed in lymphocytes, macrophages, and crypt and surface epithelial cells of the colon. The mean number of lymphocytes was decreased by more than 75% in colonic sections of fenofibrate-treated as compared with control IL-10(-/-) mice, and fenofibrate repressed interferon-gamma and IL-17 expression in isolated T cells. Fenofibrate also repressed the expression of the genes encoding 3 chemokines, CXCL10, CCL2, and CCL20, and repressed CXCL10 gene promoter activity in tumor necrosis factor-alpha-treated HT-29 cells. In contrast to the beneficial effect of fenofibrate, the PPARdelta ligand GW0742 accelerated the onset of colitis in IL-10(-/-) mice. The immunopathology observed in IL-10(-/-) mice resembles that seen in Crohn's disease. The novel therapeutic activity of fenofibrate in this mouse model suggests that it may also have activity in Crohn's disease.


Inserting a Neuropixels probe into awake monkey cortex: two probes, two methods.
Neuropixels probes have revolutionized neurophysiological studies in the rodent, but inserting these probes through the much thicker primate dura remains a challenge. Here we describe two methods we have developed for the insertion of two types of Neuropixels probes acutely into the awake macaque monkey cortex. For the fine rodent probe (Neuropixels 1.0, IMEC), which is unable to pierce native primate dura, we developed a dural-eyelet method to insert the probe repeatedly without breakage. For the thicker short NHP probe (Neuropixels NP1010), we developed an artificial dura system to insert the probe. We have now conducted successful experiments in 3 animals across 7 recording chambers with the procedures described here and have achieved recordings with similar yields over several months in each case. We hope that our hardware, surgical preparation, methods for insertion and methods for removal of broken probe parts are of value to primate physiologists everywhere.


Virus-induced gene silencing (VIGS) analysis shows involvement of the LsSTPK gene in lettuce (Lactuca sativaL.) in high temperature-induced bolting.
To determine the effect of the serine/threonine protein kinase (STPK) gene on leaf lettuce bolting, we utilized virus-induced gene silencing (VIGS) using the TRV vector to silence the target gene. The 'GB30' leaf lettuce cultivar was the test material, and the methods included gene cloning, bioinformatics analysis, quantitative real-time PCR (qRT-PCR) and VIGS. LsSTPK, was cloned from the 'GB30' leaf lettuce cultivar via reverse transcription-polymerase chain reaction (RT-PCR). qRT-PCR analysis showed that the expression of LsSTPK in the stem of leaf lettuce was significantly greater than that in the roots and leaves, and after high-temperature treatment, the gene expression in the stems in the experimental group was markedly lower than that in the control groups. Following LsSTPK silencing via the VIGS method, the stem length in the treatment group was significantly greater than that in the blank and negative control groups, and the contents of auxin (IAA), GA3 and abscisic acid (ABA) in the treatment group were greater than those in the other two groups. Flower bud differentiation occurred in the treatment group but not in the control group. The above findings suggested that LsSTPK inhibits the bolting of leaf lettuce under high-temperature conditions.


Comparison of the treatment methods efficiency for decolorization and mineralization of Reactive Black 5 azo dye.
Degradation of Reactive Black 5 (RB5), a well-known non-biodegradable disazo dye, has been studied using UV/TiO2, wet-air oxidation (WAO), electro-Fenton (EF) and UV/electro-Fenton (UV/EF) advanced oxidation processes (AOPs). The efficiency of substrate decolorization and mineralization in each process has been comparatively discussed by decreases in concentration and total organic carbon content of RB5 solutions. The most efficient method on decolorization and mineralization was observed to be WAO process. Mineralization efficiency was observed in the order of WAO>UV/TiO2>UV/EF>EF. Final solutions of AOPs applications after 90 min treatment can be disposed safely to environment. Photocatalytic degradation kinetics of RB5 successfully fitted to Langmuir-Hinshelwood (L-H) kinetics model. The values of second order degradation rate constant (k'') and adsorption constant (K) were determined as 5.085 mg L(-1)min(-1) and 0.112 L mg(-1), respectively.


miR-15b inhibits cancer-initiating cell phenotypes and chemoresistance of cisplatin by targeting TRIM14 in oral tongue squamous cell cancer.
Oral tongue squamous cell carcinoma (TSCC) is one of the most lethal cancers within the oral cavity and its prognosis remains dismal due to the paucity of effective therapeutic targets. The formation of cancer-initiating cells (CICs) and epithelial-mesenchymal transition (EMT) are pivotal events involved in the dismal prognosis. They have been shown to be related to the resistance to cisplatin treatment. In the present study, we showed that TRIM14 induced formation of cancer-initiating cells and EMT in TSCC SCC25 cells. Its overexpression promoted cisplatin resistance in the SCC25 cells. We found that overexpression of miR-15b suppressed TRIM14 and inhibited CIC phenotypes in the SCC25 cells. Moreover, overexpression of miR-15b promoted mesenchymal-epithelial transition (MET) in the SCC25 cells and sensitized cisplatin-resistant SCC25 (SCC25-res) cells to cisplatin. Thus, we conclude that miR-15b inhibited cancer stem cell phenotypes and its restoration reversed the chemoresistance of cisplatin by targeting TRIM14 in TSCC. Elucidating the molecular mechanism of EMT and cancer stem cells in TSCC may further aid in the understanding of the pathogenesis and progression of the disease, and offer novel targets for the discovery of new drugs.


The landscape of vascularized composite allograft donation in the United States.
Vascularized composite allograft (VCA) donation and transplantation has now demonstrated feasibility and impact to the lives of patients suffering from devastating and traumatic injury. This review summarizes the current landscape of VCA donation in the United States. VCA donations are nonlife-saving allografts, for nonlife-saving transplants - and therefore, conservative donor selection focused on the optimization of donors for the lowest risk to transplant recipients is paramount. VCA donors in the United States are a demographically and clinically diverse group that largely reflects the characteristics of the VCA candidates waiting for transplants. Public opinion about VCA donation is generally supportive, but has lower support for VCA transplants than for solid organ transplants. As an emerging area of transplantation, VCA donation is evolving in the United States with growing interest by the public, and those suffering from catastrophic injury for which reconstructive transplantation may offer excellent outcomes and a high quality of life.


Microbiological effectiveness and cost of boiling to disinfect drinking water in rural Vietnam.
Despite certain shortcomings, boiling is still the most common means of treating water in the home and the benchmark against which alternative household-based disinfection and filtration methods must be measured. We assessed the microbiological effectiveness and cost of boiling among a vulnerable population relying on unimproved water sources and commonly practicing boiling as a means of disinfecting water. In a 12 week study among 50 households from a rural community in Vietnam, boiling was associated with a 97% reduction in geometric mean thermotolerant coliforms (TTCs) (p < 0.001). Despite high levels of faecal contamination in source water, 37% of stored water samples from self-reported boilers met the WHO standard for safe drinking water (0 TTC/100 mL), and 38.3% fell within the low risk category (1--10 TTC/100 mL). Nevertheless, 60.5% of stored drinking water samples were positive for TTC, with 22.2% falling into the medium risk category (11--100 TTC/100 mL). The estimated cost of wood used to boil water was US$ 0.272 per month for wood collectors and US$ 1.68 per month for wood purchasers, representing approximately 0.48% to 1.04%, respectively, of the average monthly income of participating households.


Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia.
Cell death induced by cisplatin was studied in Chinese hamster ovary cell lines, one proficient and the other deficient (100-fold sensitive) in DNA excision repair. Previous experiments demonstrated that cells progressed to and arrested in the G2 phase of the cell cycle before dying. DNA double-strand breaks were detected following G2 arrest and prior to loss of membrane integrity. These DNA breaks have been studied in more detail. DNA fragments were observed consisting of multimers of approximately 180 base pairs. These fragments are consistent with internucleosomal cleavage of chromatin by an endonuclease. At LC90 concentrations, DNA digestion began 48 hr cisplatin treatment followed by loss of membrane integrity and cell shrinkage 24 hr later. High concentrations of cisplatin (170 logs of kill) induced DNA digestion 12 hr after drug treatment but loss of membrane integrity occurred 12 hr later. Both cell death and DNA fragmentation were inhibited by cycloheximide, suggesting the requirement for new protein synthesis. Cells incubated with many other agents demonstrated the same characteristic pattern of DNA degradation. At 90% lethal conditions, DNA digestion was induced within 30 min by hyperthermia, 18 hr by methotrexate, and 48-72 hr by all other agents tested. DNA digestion always preceded loss of membrane integrity and cell shrinkage. These observations are consistent with cell death occurring by the process of apoptosis, or prorammed cell death, and demonstrate the importance of DNA digestion as an early and presumably essential step in cell death. The results suggest that, irrespective of the primary site of action of a drug, cell death by most pharmacologic agents is mediated by activation of the signal transduction pathway for apoptosis. The results also suggest two signal pathways for apoptosis, one directly associated with drug action and a second that requires cell cycle-related events.


Frederick Knox, younger brother and assistant of Dr Robert Knox: his contribution to "Knox's Catalogues".
Analysis of the material written in the two manuscript volumes known as the "Old" and "New" Knox Catalogues has revealed that most of their contents are in the hand of Frederick Knox, younger brother of Dr Robert Knox. Frederick was employed by Dr Knox as his research assistant, and prepared detailed lists of the items in his brother's museum collection. He also dissected and prepared human and non-human specimens, many of which were described by Dr Knox in his numerous publications. As relatively little is known about Frederick Knox, this seemed a timely opportunity to evaluate his contribution to Knox's anatomy class in the extra-mural school. When in due course Dr Knox's success as a teacher of anatomy gradually declined, he decided to leave Edinburgh to pursue his career in London. It was at about this time that his brother Frederick also decided to leave Edinburgh to establish a new career for himself in the Antipodes. The present whereabouts of the majority of Knox's enormous teaching collection of anatomical preparations and his comparative anatomy collection are unknown, and suggestions are made as to their possible whereabouts.


Modelling the role of tissue heterogeneity in epileptic rhythms.
Epileptic seizure activity manifests as complex spatio-temporal dynamics on the clinically relevant macroscopic scale. These dynamics are known to arise from spatially heterogeneous tissue, but the relationship between specific spatial abnormalities and epileptic rhythm generation is not well understood. We formulate a simplified macroscopic modelling framework with which to study the role of spatial heterogeneity in the generation of epileptiform spatio-temporal rhythms. We characterize the overall model dynamics in terms of spontaneous activity and excitability and demonstrate normal and abnormal spreading of activity. We introduce a means to systematically investigate the topology of abnormal sub-networks and explore its impact on spontaneous and stimulus-evoked rhythmic dynamics. This computationally efficient framework complements results from detailed biophysical models, and allows the testing of specific hypotheses about epileptic dynamics on the macroscopic scale.


A case of esophageal squamous cell intraepithelial neoplasia with positivity for type 16 human papillomavirus successfully treated with radiofrequency ablation.
Esophageal cancer is the eight most common cancer worldwide and the sixth cause of cancer related death with squamous cell carcinoma (SCC) accounting for almost half of all esophageal cancers. Persistent human papilloma virus (HPV) infection has been suspected to play an active role in esophageal carcinogenesis but a clear association has not still been proven and no specific indications or guidelines for possible endoscopic and surgical therapeutic approaches to this clinical scenario are available. We report a case of a 62-year-old woman with histological diagnosis of high-grade intraepithelial squamous neoplasia of distal esophagus associated with cytological modifications resembling cervical HPV infection and with a positive INNO-LiPA assay for genotype 16 HPV. A single session of radiofrequency ablation (RFA) was performed on the dysplastic esophageal area with complete endoscopic eradication as confirmed by the following endoscopic, histologic and microbiologic examinations. Our report might give further strength to the hypothesis of an etiological role of HPV in selected cases of esophageal carcinogenesis and opens a discussion on the possible use of Radio Frequency Ablation as an effective and safe endoscopic treatment for both early squamous cell neoplasia and HPV esophageal colonization.


Liberation of the patient from mechanical ventilation.
Discontinuation of mechanical ventilation is too frequently difficult and frustrating for the patient and the clinician alike. With the view that expeditious withdrawal of mechanical support is often a mirror-image exercise requiring reversal of the factors that led to respiratory failure, we begin with a discussion of the various pathophysiologies of respiratory failure. We then describe an approach emphasizing assessment of respiratory load and neuromuscular function at the bedside, with strategies outlined for diminishing mechanical load while conditioning and strengthening respiratory muscles to the point that spontaneous ventilation can be sustained.


Prospective study of centipede bites in Australia.
There are limited reports of definite bites by centipedes with expert identification, which are required for attribution of particular clinical effects to different species. To describe the clinical effects of centipede bites in Australia. Prospective study of calls regarding centipede exposures to a state poison information center, from December 2000 to March 2002. Information collected included demographics, details of the exposure, local effects, systemic effects, and treatment. Collected centipedes were identified by an expert. All subjects were followed until clinical effects had resolved. Of 48 centipede exposures, 3 were centipede ingestions with no adverse effects and one was a contact reaction to the centipede that resulted in erythema and delayed itchiness. Of 44 definite centipede bites, the centipedes obtained and formally identified in 14 cases were from the genera Scolopendra (5), Cormocephalus (6), and Ethmostigmus (3). Of these 14 bites, 13 occurred distally (hands or feet). Pain occurred in all 14 cases and was severe in 7 patients. Redness/red mark occurred in 53%, swelling/raised area in 43%, and itchiness in 14%. No systemic effects were reported. Ethmostigmus spp. and Scolopendra spp. caused more severe effects. Of the bites, 57% occurred indoors and 50% at night. Treatment consisted of supportive measures including ice packs and simple analgesia, and 4 patients reported pain relief after immersing the bite area in hot water. Similar clinical effects were reported in the other 30 definite centipede bites. Australian centipede bites cause minor effects with moderate to severe pain, associated with localized swelling and erythema in bites by the genera Ethmostigmus and Scolopendra. Hot water immersion may potentially be beneficial for centipede bites. The genus Scolopendra occurs worldwide and the results may have international applicability.


De novo transcriptome sequencing of the northern fowl mite, Ornithonyssus sylviarum, shed light on parasitiform poultry mites evolution and its chemoreceptor repertoires.
The northern fowl mite (NFM), Ornithonyssus sylviarum, and the poultry red mite (PRM), Dermanyssus gallinae, are the most serious pests of poultry, both of which have an expanding global prevalence. Research on NFM has been constrained by a lack of genomic and transcriptomic data. Here, we report and analyze the first global transcriptome data across all mite live stages and sexes. A total of 28,999 unigenes were assembled, of which 19,750 (68.10%) were annotated using seven functional databases. The biological function of these unigenes was classified using the GO, KOG, and KEGG databases. To gain insight into the chemosensory receptor-based system of parasitiform mites, we furthermore assessed the gene repertoire of gustatory receptors (GRs) and ionotropic receptors (IRs), both of which encode putative ligand-gated ion channel proteins. While these receptors are well characterized in insect model species, our understanding of chemosensory detection in mites and ticks is in its infancy. To address this paucity of data, we identified 9 IR/iGluRs and 2 GRs genes by analyzing transcriptome data in the NFM, while 9 GRs and 41 IR/iGluRs genes were annotated in the PRM genome. Taken together, the transcriptomic and genomic annotation of these two species provide a valuable reference for studies of parasitiform mites and also help to understand how chemosensory gene family expansion/contraction events may have been reshaped by an obligate parasitic lifestyle compared with their free-living closest relatives. Future studies should include additional species to validate this observation and functional characterization of the identified proteins as a step forward in identifying tools for controlling these poultry pests.


Update of safety of cefotaxime.
Adverse reactions to various antibacterial drugs were compared in a review of the following: multiple-dose studies of cefotaxime (n = 3,463), cefazolin (n = 554), the combination gentamicin-clindamycin (n = 163), and cefoxitin (n = 18); prophylactic studies of cefotaxime (n = 300) and cefazolin (n = 149); and single-dose studies of cefotaxime (n = 314) and penicillin G procaine (n - 265). The demographic and background characteristics of the groups were similar. Results of extensive pretreatment and posttreatment laboratory tests, measures of vital signs, and physical examinations revealed no clinically important intergroup differences. In the multiple-dose studies, side effects were reported in 9.8% of the cefotaxime, 3.8% of the cefazolin, 17.2% of the gentamicin-clindamycin, and 16.7% of the cefoxitin patients. The most frequent side effects were reactions at the injection site, of the skin and appendages, and of the digestive and urogenital systems, the only significant difference being fewer injection-site reactions in the cefazolin group than in the other three groups. In the prophylactic studies one cefotaxime patient reported rash and pruritus. In the single-dose studies, side effects were reported in 1.6% of the cefotaxime and 4.2% of the penicillin patients. Side effects sufficiently severe to warrant drug discontinuation were reported in 2.1% of the cefotaxime, 0.7% of the cefazolin, 1.8% of the gentamicin-clindamycin, and in none of the cefoxitin patients. Posttreatment prolongation of prothrombin time was found in one cefotaxime patient, whose pretreatment value was also abnormal, and in two gentamicin-clindamycin patients. No patient deaths were attributed to any of the drugs.


Sexual deprivation increases ethanol intake in Drosophila.
The brain's reward systems reinforce behaviors required for species survival, including sex, food consumption, and social interaction. Drugs of abuse co-opt these neural pathways, which can lead to addiction. Here, we used Drosophila melanogaster to investigate the relationship between natural and drug rewards. In males, mating increased, whereas sexual deprivation reduced, neuropeptide F (NPF) levels. Activation or inhibition of the NPF system in turn reduced or enhanced ethanol preference. These results thus link sexual experience, NPF system activity, and ethanol consumption. Artificial activation of NPF neurons was in itself rewarding and precluded the ability of ethanol to act as a reward. We propose that activity of the NPF-NPF receptor axis represents the state of the fly reward system and modifies behavior accordingly.


Segmental enhancement inversion at biphasic multidetector CT: characteristic finding of small renal oncocytoma.
To retrospectively determine the usefulness of segmental enhancement inversion during the corticomedullary phase (CMP) and early excretory phase (EEP) of biphasic multidetector computed tomography (CT) in differentiating small renal oncocytoma from renal cell carcinoma (RCC). This retrospective study was institutional review board approved; informed consent was waived. Between January 2004 and December 2006, 98 patients with pathologically confirmed renal masses smaller than 4 cm (10 renal oncocytomas and 88 RCCs) were included in this study. Segmental enhancement inversion was defined as follows: In a mass with two segments showing different degrees of enhancement during CMP, the relatively highly enhanced segment became less enhanced during EEP, whereas the less-enhanced segment during CMP became highly enhanced during EEP. Two experienced radiologists retrospectively assessed the presence of segmental inversion in all masses and measured attenuation with consensus. The Fisher exact test was used to determine the significance of segmental enhancement inversion in differentiating small renal oncocytoma from RCC. Eight of 10 renal oncocytomas and only one of 88 RCCs showed segmental inversion during CMP and EEP, which significantly differentiated small renal oncocytomas and RCCs (P < .0001). For differentiating oncocytoma from RCC, segmental inversion was found to have a sensitivity of 80% (eight of 10), a specificity of 99% (87 of 88), a positive predictive value of 89% (eight of nine), and a negative predictive value of 98% (87 of 89). The mean values of the attenuation differences shown by two segments during CMP and EEP were 62.75 HU +/- 36.96 (standard deviation) and -36.88 HU +/- 20.02, respectively. Segmental enhancement inversion during CMP and EEP was found to be a characteristic enhancement pattern of small renal oncocytoma at biphasic multidetector CT and it may help in differentiating small oncocytoma from RCC. http://radiology.rsnajnls.org/cgi/content/full/2522081180/DC1.


NLOS Identification and Mitigation Using Low-Cost UWB Devices.
Indoor location systems based on ultra-wideband (UWB) technology have become very popular in recent years following the introduction of a number of low-cost devices on the market capable of providing accurate distance measurements. Although promising, UWB devices also suffer from the classic problems found when working in indoor scenarios, especially when there is no a clear line-of-sight (LOS) between the emitter and the receiver, causing the estimation error to increase up to several meters. In this work, machine learning (ML) techniques are employed to analyze several sets of real UWB measurements, captured in different scenarios, to try to identify the measurements facing non-line-of-sight (NLOS) propagation condition. Additionally, an ulterior process is carried out to mitigate the deviation of these measurements from the actual distance value between the devices. The results show that ML techniques are suitable to identify NLOS propagation conditions and also to mitigate the error of the estimates when there is LOS between the emitter and the receiver.


Is COVID-19 Keeping us Up at Night? Stress, Anxiety, and Sleep Among Adult Twins.
In response to the COVID-19 pandemic, a variety of social distancing measures to mitigate the virus outbreak have been implemented. These measures may have unintended consequences on individuals' well-being, such as increased stress, anxiety, and sleep disruptions. We investigated the extent to which individuals' mental health status is associated with perceived changes in sleep amount and sleep quality among a sample of adult twin pairs (N = 909 pairs; 77% MZ, 23% DZ), less than a month after the outbreak was declared a pandemic by the World Health Organization. About half of participants reported no change in sleep amount (50.1%) or sleep quality (55.6%). Approximately one-third of the participants had increased amount of sleep (29.8%), and 32.9% reported a decrease in sleep quality. We found that stress and anxiety levels were associated with sleep reduction (ORs = 2.36 and 3.12 for stress and anxiety, respectively) and poorer sleep quality (ORs = 2.45 and 3.73 for stress and anxiety, respectively), even after taking into account between-family confounds. A much smaller association was observed between levels of stress and anxiety and increased sleep amount (ORs = 1.42 and 1.60 for stress and anxiety, respectively) and sleep quality (OR = 1.21 and 1.29 for stress and anxiety, respectively), which was no longer significant after controlling for between-family confounds. Our results demonstrate that stress and anxiety associated with the COVID-19 pandemic and social distancing measures may be linked to reduced sleep amount and quality.


[Climacteric arthralgia and hand arthrosis].
This study aimed at a possible classification of climacteric arthroses of the hand. 132 females suffering from arthralgias of the wrist and finger joints who had consulted our outpatient department originally because of climacteric complaints, were examined while asking them to complete a questionnaire with clinical criteria for classifying arthroses of the hand. The requisite number of criteria required for classification as ¿arthrosis of the hand¿ were attained in all three groups of females (premenopausal and postmenopausal women without operation, as well as hysterectomised and/or ovarectomised women¿, although the ex-ray showed no signs of degenerative arthritis. The subjective complaints voiced by the patients are opposed to the x-ray finding, so that it is not permissible to classify climacteric arthralgias of the wrist and finger joints as ¿arthritis¿.


Supporting rural midwifery practice using a mobile health (mHealth) intervention: a qualitative descriptive study.
Hypertensive disorders in pregnancy account for 12% of all maternal deaths globally. The risks of suboptimal outcomes from these disorders might be greater in rural and remote locations. These potential risks might be related to poor intra- and interprofessional communications due to geographic and digital isolation. Studies in low- and middle-income countries suggest that improving communications is essential and that mobile health (m-health) interventions can improve outcomes. However, for such interventions to be successful they must involve midwives in any design and software development. This study explored how an m-health intervention might support midwives in the management of women with pre-eclampsia in Scottish rural and remote locations. A qualitative descriptive approach was adopted. Rural and remote practising community midwives (n=18) were recruited to participate in three focus groups. The data were gathered through digital recordings of conversations at these focus groups. Recordings were transcribed and thematically analysed. Themes were agreed by consensus with the research team in an iterative process. Five principal themes were identified: 'working in isolation', 'encountering women with pre-eclampsia in rural and remote settings', 'learning on the move', 'using audio-visual resources' and 'unease with advances in technology'. Geographic and digital isolation pose significant challenges to rural midwifery practice in a high income country such as Scotland. Midwives need to be involved in the development of m-health interventions for them to be acceptable and tailored to their needs in a rural and remote context. The study highlights how m-health interventions can support continuous professional development whilst on the move with no internet connectivity. However, pride in current practice and unease with advances in mobile technology are barriers to the adoption of an m-health intervention. M-health interventions could be of value to other specialised healthcare practitioners in these regions, including general practitioners, to manage women with complications in their pregnancies.


[Relationship between digestive repletion state and hepatic composition in gavaged mule ducks].
Two batches of male mule ducks were constituted on the basis of the filling state of the crop at slaughter, after being over-fed twice a day for 5 days: no corn in the crop defined 'OV' birds, and corn in the crop defined 'OP' birds. 'OP' animals presented significantly lower daily consumption during the last 3 days of force-feeding. They had a lighter liver weight than 'OV' ducks (178 versus 197 g), lower hepatic lipid percentages (25.0 versus 33.0%), and enhanced hepatic glycogen rates (4.7 versus 2.4%). Metabolic state of animals might explain these variations in hepatic composition. Unadaptation to force-feeding modifies the metabolic inbalance of the overfed animals and consequently induces higher levels of carbohydrate. These results suggest that similar differences between crude fatty livers could be reflected in the quality of the cooked products.


Transurethral Unroofing of a Symptomatic Imperforate Cowper's Syringocele in an Adult Male.
Cystic dilatation of bulbourethral gland ducts (Cowper's gland syringocele) is a rare abnormality. The condition has been described among pediatric populations, but it is uncommon in adults. It can be asymptomatic or present with obstructive and irritative urinary symptoms. We report a case of a symptomatic imperforate Cowper's syringocele in a young patient that was successfully managed with transurethral unroofing of the cyst.


Modulating neural networks with transcranial magnetic stimulation applied over the dorsal premotor and primary motor cortices.
Our study uses the combined transcranial magnetic stimulation/positron emission tomography (TMS/PET) method for elucidating neural connectivity of the human motor system. We first altered motor excitability by applying low-frequency repetitive TMS over two cortical motor regions in separate experiments: the dorsal premotor and primary motor cortices. We then assessed the consequences of modulating motor excitability by applying single-pulse TMS over the primary motor cortex and measuring: 1) muscle responses with electromyography and 2) cerebral blood flow with PET. Low-frequency repetitive stimulation reduced muscle responses to a similar degree in both experiments. To map networks of brain regions in which activity changes reflected modulation of motor excitability, we generated t-statistical maps of correlations between reductions in muscle response and differences in cerebral blood flow. Low-frequency repetitive stimulation altered neural activity differently in both experiments. Neural modulation occurred in multiple brain regions after dorsal premotor cortex stimulation; these included motor regions in the frontal cortex as well as more associational regions in the parietal and prefrontal cortices. In contrast, neural modulation occurred in a smaller number of brain regions after primary motor cortex stimulation, many of these confined to the motor system. These findings are consistent with the known differences between the dorsal premotor and primary motor cortices in the extent of cortico-cortical anatomical connectivity in the monkey.


Manganese(I)-Catalyzed Direct C-H Allylation of Arenes with Allenes.
Polysubstituted allyl groups, for example, the prenyl group, are valuable synthetic handles and widely encountered in bioactive compounds. Reported herein is a manganese(I)-catalyzed direct C-H coupling with allenes for the efficient assembly of allylated arenes. The protocol offers an extremely high level of atom-economy and is particularly suited for the introduction of 1,1-disubstitiuted allyl groups, as exemplified by the quantitative syntheses of a variety of prenylated indoles. The practicality of this method was evidenced by a gram-scale synthesis with a lower catalyst loading of manganese(I) (2.5 mol %, 95% yield). Experimental mechanistic studies were conducted, and a possible reaction mechanism was proposed.


[Malignant tumors of the mouth and pharynx--MR tomography with surface coils].
The place of MRT, using surface coils, has been evaluated retrospectively in 27 patients with clinically confirmed malignant tumours of the mouth and pharynx. The extent of the tumour and its relationship to neighbouring structures is well demonstrated. The resolution obtainable by using surface coils is almost as good as that of CT. Soft tissue contrast is better in showing the spread and size of the tumour. A disadvantage of MRT is the inability in most cases to demonstrate bone destruction. Differentiation between residual tumour, recurrence and scarring is possible only occasionally. Quantitative MRT may be expected to lead to improved diagnosis during the course of following up.


Selenium and selenoproteins role in Parkinson's disease: Is there a link between selenoproteins and accumulated alpha-synuclein?
While Parkinson's disease (PD) etiology is not clear yet, accumulated alpha-synuclein is proposed to induce neurodegeneration. Selenium (Se) and its functional proteins play a key role in aggregation of misfolded proteins. However, their implications in neurodegenerative process are unclear. Diagnosing Se and selenoprotein P (SelP), selenoprotein S (SelS) proportions in serum of PD patients to compare with healthy controls, whether the changes in their concentration could be a biomarker for PD. Se concentration was investigated in 30 PD patients and 30 controls using atomic absorption spectrometry. Also, alpha-Synuclein, SelP, and SelS levels were evaluated by ELISA. The parameters were compared in PD patients and controls. Also, the variations within the case group according to their age, disorder stage, and drug administration were evaluated. PD subjects had higher Se concentration. The mean SelP in PD patients was lower from controls, whilst SelS levels were higher. Also, the concentration of alpha-synuclein was higher in PD patients. However, age, stage (except UPDRS III), and disorder duration had no influence on the Se and selenoproteins level, whilst there was a direct association between alpha-synuclein levels and disorder stage. Also, alpha-synuclein proportions in subjects using levodopa was significantly higher. Our results suggest that serum levels of Se and SelP could be a biomarker or risk factor for PD. Although SelS interferes to reduce aggregated proteins, its pathway in PD is not clearly understood. Future studies could focus on how SelS can reduce on alpha-synuclein aggregation. Thus, other studies should be performed on this issue to induce the selenoproteins in PD.


Pre- and post-natal exposure to antibiotics and the development of eczema, recurrent wheezing and atopic sensitization in children up to the age of 4 years.
Little data are available on the relationship between indirect antibiotic exposure of the child in utero or during lactation and allergic diseases. On the other hand, several studies have been conducted on the association with direct post-natal antibiotic exposure, but the results are conflicting. The aim of this study was to investigate pre- and post-natal antibiotic exposure and the subsequent development of eczema, recurrent wheeze and atopic sensitization in children up to the age of 4 years. We conducted an aetiologic study in 773 children based on a prospective birth cohort project in which environmental and health information were collected using questionnaires. Antibiotic exposure was assessed as maternal antibiotic intake during pregnancy and during lactation and as medication intake of the child. The chronology of exposures and outcomes was taken into account during the data processing. At the age of 1 and 4 years, a blood sample was taken for the quantification of specific IgE. Prenatal antibiotic exposure was significantly positively associated with eczema, whereas no association was found with recurrent wheeze and atopic sensitization. We found a positive, although statistically not significant, association between antibiotic exposure through breastfeeding and recurrent wheeze. Neither eczema nor atopic sensitization was significantly associated with antibiotic exposure through breastfeeding. Finally, we observed a negative association between the use of antibiotics in the first year of life and eczema and atopic sensitization, and also between antibiotic use after the first year of life and recurrent wheeze, eczema and atopic sensitization. Indirect exposure to antibiotics (in utero and during lactation) increases the risk for allergic symptoms in children, while direct exposure to antibiotics appears to be protective. The biological mechanisms underlying these findings still need to be elucidated.


Radioautographic studies of the initial site of formation of protein-bound iodine in the rat thyroid gland.
1. Predominantly cellular labelling was observed in radioautographs of rat thyroid glands fixed by perfusion from the aorta at intervals between 5 and 55s after [(125)I]iodide administration via the aorta. 2. When perfusion was delayed for 2min, or if immersion fixation was used, the labelling was predominantly over the peripheral portion of the follicular lumen, in agreement with the observations of other investigators. 3. The findings support the concept that the initial site of binding of iodine to protein is intracellular, but the nature of this protein has not been established.


N400 abnormalities in late life schizophrenia and related psychoses.
The N400, an event-related brain potential (ERP) sensitive to semantic congruity, has been reported to have increased latency and/or reduced amplitude in young adults with schizophrenia. Little is known, however, regarding the N400 in older schizophrenia patients, especially those with late onset. We studied 18 middle-aged and elderly patients with schizophrenia and related psychoses (nine with early-onset psychosis (EOP) and nine with late-onset psychosis (LOP)), and nine normal comparison (NC) subjects. Subjects read words which were semantically incongruent (50%) or congruent (50%) with a preceding spoken phrase which defined either an antonymic or categorical relationship. The LOP group had a significantly later peak latency of the N400 congruity effect compared to the NC group. Seven of 18 psychosis patients, but none (0/9) of the normal subjects, had an abnormal latency or amplitude (p = 0.04), measured at T6 (right temporal). Smaller amplitudes were associated with more severe negative symptoms (rp = 0.58; p = 0.01). N400 abnormalities in older schizophrenia patients likely reflect abnormal processing of semantic information.


Leber Hereditary Optic Neuropathy (LHON) in Patients with Presumed Childhood Monocular Amblyopia.
Most Leber hereditary optic neuropathy (LHON) cases are bilateral and sequential; however, there are rare unilateral examples, or those in which the delay of onset of vision loss between one and the other eye is longer. In the case of presumed childhood amblyopia in one eye, vision loss in the good eye may be the only symptom of bilateral disease, which was unnoticed in the previously amblyopic eye, or a preexisting episode of LHON in the "amblyopic" eye. The clinical decision in such cases may be difficult and suggestive of other forms of atypical optic neuropathy until confirmed by genetic testing. We present three genetically confirmed (MT-ND1:m.3700G>A, MT-ND6:m14484 T>C, and MT-ND4:m.11778G>A) patients with subacute vision loss in the previously good eye, with the other eye believed to be amblyopic from childhood and their features different from what would be expected in true amblyopia. In all, electrophysiology testing showed a bilaterally reduced amplitude of PERG with low VEP P100 wave amplitudes and prolonged peak time in both eyes, also unusual for amblyopia. During follow-up, the pallor of the optic discs progressed in all eyes. Significant thinning of the peripapillary retinal nerve fiber layer (pRNFL; retinal nerve fiber layer around the optic disc) and ganglion cell complex (GCC) in the macular region was present. All three patients had a peculiar history. The first patient was treated for presumed hyperopic amblyopia that did not improve since childhood, experienced visual loss in the good eye at the age of 17, and was negative for the three typical LHON mutations. Extended testing confirmed an atypical pathogenic variant MT-ND1:m.3700G>A in homoplasmy. The second patient with presumed strabismic amblyopia had an unusual presentation of vision loss only at the age of 61, and after the exclusion of other causes, a typical MT-ND4:m.11778G>A pathogenic variant was found in homoplasmy. The third case was peculiar as he had presumed strabismic amblyopia since childhood and had some degree of disc pallor in the amblyopic eye upon presenting with loss of vision in the good eye at the age of 21, and a typical pathogenic variant m14484 T>C, p.Met64Val was subsequently confirmed. However, one year after disease onset, he started to experience significant spontaneous functional improvement in the non-amblyopic up to 1.0 Snellen whilst improvement in the presumed amblyopic eye was modest, suggesting preexisting amblyopia. This interestingly extensive improvement was carefully followed by electrophysiology as well as visual acuity and fields. This report shows three different scenarios of presentation of LHON in patients with presumed uniocular amblyopia from childhood. In such cases, the diagnosis may be difficult, and detailed structural and functional evaluation of the optic nerve head is necessary to assess whether an earlier LHON episode was misdiagnosed as amblyopia or whether LHON presented bilaterally on both eyes whilst only being noticed in the previously good eye.


Motion-based threat detection using microrods: experiments and numerical simulations.
Motion-based chemical sensing using microscale particles has attracted considerable recent attention. In this paper, we report on new experiments and Brownian dynamics simulations that cast light on the dynamics of both passive and active microrods (gold wires and gold-platinum micromotors) in a silver ion gradient. We demonstrate that such microrods can be used for threat detection in the form of a silver ion source, allowing for the determination of both the location of the source and concentration of silver. This threat detection strategy relies on the diffusiophoretic motion of both passive and active microrods in the ionic gradient and on the speed acceleration of the Au-Pt micromotors in the presence of silver ions. A Langevin model describing the microrod dynamics and accounting for all of these effects is presented, and key model parameters are extracted from the experimental data, thereby providing a reliable estimate for the full spatiotemporal distribution of the silver ions in the vicinity of the source.


Sociodemographic factors associated with suicidal behavior at a federal public university in the Western Brazilian Amazon.
to determine risk factors for suicidal behavior among students and employees of a federal public university in the Brazilian Western Amazon. an analytical cross-sectional study of survey and association between variables with a sample of 475 participants. Statistical analyzes were performed using the Mann-Whitney test, Pearson's chi-square test, likelihood ratio test or Fisher's exact test and a logistic regression model. A significance level of 5% was used (p-value< 0.05). a higher proportion of suicidal behavior was found in younger participants, females, who had no religion or had one, but were non-practicing, who did not have children and/or had a monthly family income of less than two minimum wages. Lower proportions of suicidal behavior were identified in heterosexuals and/or married or in a stable relationship. the study suggests a relationship between sociodemographic factors and suicidal behavior in the studied academic community.


Experimental evolution of a microbial predator's ability to find prey.
Foraging theory seeks to explain how the distribution and abundance of prey influence the evolution of predatory behaviour, including the allocation of effort to searching for prey and handling them after they are found. While experiments have shown that many predators alter their behaviour phenotypically within individual lifetimes, few have examined the actual evolution of predatory behaviour in light of this theory. Here, we test the effects of prey density on the evolution of a predator's searching and handling behaviours using a bacterial predator, Myxococcus xanthus. Sixteen predator populations evolved for almost a year on agar surfaces containing patches of Escherichia coli prey at low or high density. Improvements in searching rate were significantly greater in those predators that evolved at low prey density. Handling performance also improved in some predator populations, but prey density did not significantly affect the magnitude of these gains. As the predators evolved greater foraging proficiency, their capacity diminished to produce fruiting bodies that enable them to survive prolonged periods of starvation. More generally, these results demonstrate that predators evolve behaviours that reflect at least some of the opportunities and limitations imposed by the distribution and abundance of their prey.


Cellular and molecular characterization of a feline insulinoma.
Insulinoma is an autonomous insulin-secreting islet cell neoplasm that is rarely diagnosed in cats. The clinical and pathological aspects of feline insulinoma have been described previously, but the molecular characteristics of these tumors have not been investigated. The study objectives were to characterize peptide hormone production and determine expression of selected genes involved in glucose metabolism and insulin secretion in a feline insulinoma. Immunohistochemistry and RT-PCR were used to examine hormone and gene expression, respectively, by insulinoma cells. Immunohistochemistry examination indicated that the tumor cells expressed insulin, chromogranin A, and somatostatin but not glucagon or pancreatic polypeptide. The tumor expressed several genes characteristic of pancreatic beta cells (beta cells) including insulin (INS), glucose transporter 2 (GLUT2), and glucokinase (GCK). The tumor also expressed hexokinase 1 (HK1), a glycolytic enzyme not normally expressed in beta cells. GCK expression was higher in the insulinoma than in normal pancreas from the same cat. The GCK : HK1 ratio was >20-fold higher in insulinoma tissue than in normal pancreas. The feline insulinoma produced several peptide hormones and expressed genes consistent with a beta-cell phenotype. The pattern of hexokinase gene expression in tumor cells differed from that of normal pancreas. These findings suggest insulinoma cells may have an increased sensitivity to glucose that could contribute to the abnormal insulin secretory response observed at low serum glucose concentrations.


Electrophysiological characteristics and radiofrequency ablation of accessory pathways with slow conductive properties.
Atrioventricular accessory pathways (AP) with unusually long ventriculo-atrial (VA) conduction times are present in a significant subset of patients with the Wolff-Parkinson-White (WPW) syndrome, not including patients with the permanent form of atrioventricular junctional reciprocating tachycardia. We compared the electrophysiological characteristics and outcomes after radiofrequency (RF) ablation in 34 patients with the WPW syndrome, a VA interval >80 ms, and paroxysmal tachycardia with an RP/PR ratio <1 (the slow group), vs 80 patients with WPW syndrome and a VA interval <80 ms (the fast group). AP were found in the posteroseptal region significantly more often in the slow than in the fast group. In addition, the decremental conductive properties of the AP were more common in the slow than in the fast group. Catheter ablation of AP was highly successful in both groups, although ablation required a greater number of RF applications and longer procedure times in the slow group, especially for AP with decremental conductive properties. A posteroseptal AP location was more common in AP associated with long conduction times than in AP with typical conductive properties. Both types of AP were successfully ablated, although the slow group required longer procedures and more RF energy deliveries.