Infrared Signatures for Phase Identification in Hafnium Oxide Thin Films.
Phase identification in HfO2-based thin films is a prerequisite to understanding the mechanisms stabilizing the ferroelectric phase in these materials, which hold great promise in next-generation nonvolatile memory and computing technology. While grazing-incidence X-ray diffraction is commonly employed for this purpose, it has difficulty unambiguously differentiating between the ferroelectric phase and other metastable phases that may exist due to similarities in the d-spacings, their low intensities, and the overlapping of reflections. Infrared signatures provide an alternative route. However, their use in phase identification remains limited because phase control has overwhelmingly been accomplished via substituents, thereby convoluting infrared signatures between the substituents and the phase changes that they induce. Herein, we report the infrared optical responses of three undoped hafnium oxide films where annealing conditions have been used to create films consisting primarily of the ferroelectric polar orthorhombic Pca21, antipolar orthorhombic Pbca, and monoclinic P21/c phases, as was confirmed via transmission electron microscopy (TEM), UV-visible optical properties, and electrical property measurements. Vibrational signatures acquired from synchrotron nano-Fourier transform infrared spectroscopy (nano-FTIR) are shown to be capable of differentiating between the phases in a nondestructive, rapid, and nanoscale manner. The utility of nano-FTIR is illustrated for a film exhibiting an antiferroelectric polarization response. In this sample, it is proven that this behavior results from the Pbca phase rather than the often-cited tetragonal phase. By demonstrating that IR spectroscopy can unambiguously distinguish phases in this material, this work establishes a tool needed to isolate the factors dictating the ferroelectric phase stability in HfO2-based materials.


The E3 ligase Itch in immune regulation and beyond.
Itch or itchy E3 ubiquitin ligase was initially discovered by genetic studies on the mouse coat color changes, and its deletion results in an itchy phenotype with constant skin scratching and multi-organ inflammation. It is a member of the homologous to E6-associated protein C-terminus (HECT)-type family of E3 ligases, with the protein-interacting WW-domains for the recruitment of substrate and the HECT domain for the transfer of ubiquitin to the substrate. Since its discovery, numerous studies have demonstrated that Itch is involved in the control of many aspects of immune responses including T-cell activation and tolerance and T-helper cell differentiation. Itch is also implicated in other biological contexts such as tumorigenesis, development, and stress responses. Many signaling pathways are regulated by Itch-promoted ubiquitylation of diverse target proteins. Itch is also involved in human diseases. Here, we discuss the major progress in understanding the biological significance of Itch-promoted protein ubiquitylation in the immune and other systems and in Itch-mediated regulation of signal transduction.


A swollen leg unmasks longstanding SLE.
We report a case of long-standing SLE which presented with symptomatic muscle vasculitis on a background of photosensitivity, arthralgia and myalgia. The diagnosis was complicated by cardiomyopathy, nephrotic syndrome and diabetes. We highlight the benefits of aggressive treatment in severe disease and the importance of recognising and treating comorbidity especially ih relation to atherosclerosis.


Photoemission Spectra and Electronic Properties of KxC60.
Photoemission spectra of vacuum deposited layers of C(60), before and after exposure to K vapor, show that the K donates its conduction electron into the band derived from the lowest unoccupied molecular orbital. A compound with composition of K(3)C(60), corresponding to the maximum conductivity, has been prepared. In it the potassium atoms presumably occupy both the octahedral and the two tetrahedral interstitial sites of the face-centered-cubic (fcc) C(60) structure.


[Antibiotic sensitivity of pneumococci isolated in chronic bronchitis and bronchial asthma].
Antibiotic sensitivity of 218 pneumococcal strains isolated from sputum of 140 patients with chronic bronchitis and 78 patients with infectious and allergic bronchial asthma in Tomsk at the period from September 1981 to March 1984 was studied by the agar diffusion method with the use of standard sensitivity disks. A significant number of the isolates were resistant or little sensitive to tetracycline (54 per cent) and monomycin (42 per cent). It should be noted that 5.5 per cent of the pneumococcal strains were resistant or little sensitive to benzylpenicillin. The decreased sensitivity of the pneumococcal strains to many of the widely used antibiotics and especially occurrence of benzylpenicillin resistant strains require determination of the sensitivity of the pneumococcal strains isolated from each patient with aggravation of chronic bronchitis and infectious and allergic bronchial asthma.


Impact of apexes on the resonance shift in double hole nanocavities.
The transmission of light through metallic films with periodic double nanoholes is studied using vectorial three-dimensional finite element method. Special emphasis is given on understanding different transmission resonances arising in gold and silver films with periodic sub-wavelength holes of different shapes. The spectral shift of the hole-shape resonance resulting from a variation of the hole refractive index is analyzed for a double nanohole geometry in the transmission mode using numerical simulations. Specifically, the role of field enhancement at the apexes of the double nanohole in the sensing of medium within the hole cavity is pointed out and discussed. The presence of sharp apexes within the double nanoholes significantly improves the resonance sensitivity as compared to rectangular holes of comparable area. Impact of possible manufacturing errors on the overall sensitivity is also characterized. Robustness and a relatively simple fabrication procedure make these kinds of refractive index sensors practically attractive.


Stress-protective signalling of prion protein is corrupted by scrapie prions.
Studies in transgenic mice revealed that neurodegeneration induced by scrapie prion (PrP(Sc)) propagation is dependent on neuronal expression of the cellular prion protein PrP(C). On the other hand, there is evidence that PrP(C) itself has a stress-protective activity. Here, we show that the toxic activity of PrP(Sc) and the protective activity of PrP(C) are interconnected. With a novel co-cultivation assay, we demonstrate that PrP(Sc) can induce apoptotic signalling in PrP(C)-expressing cells. However, cells expressing PrP mutants with an impaired stress-protective activity were resistant to PrP(Sc)-induced toxicity. We also show that the internal hydrophobic domain promotes dimer formation of PrP and that dimerization of PrP is linked to its stress-protective activity. PrP mutants defective in dimer formation did not confer enhanced stress tolerance. Moreover, in chronically scrapie-infected neuroblastoma cells the amount of PrP(C) dimers inversely correlated with the amount of PrP(Sc) and the resistance of the cells to various stress conditions. Our results provide new insight into the mechanism of PrP(C)-mediated neuroprotection and indicate that pathological PrP conformers abuse PrP(C)-dependent pathways for apoptotic signalling.


Association between Hypertension and Epistaxis: Systematic Review and Meta-analysis.
Objective Whether there is an association or a cause-and-effect relationship between epistaxis and hypertension is a subject of longstanding controversy. The objective of this systematic review and meta-analysis was to determine the association between epistaxis and hypertension and to verify whether hypertension is an independent risk factor of epistaxis. Data Sources A comprehensive search was performed using the MEDLINE, EMBASE, and Cochrane Library databases. Review Methods The review was performed according to the Meta-analysis of Observational Studies in Epidemiology guidelines and reported using the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Results We screened 2768 unique studies and selected 10 for this meta-analysis. Overall, the risk of epistaxis was significantly increased for patients with hypertension (odds ratio, 1.532 [95% confidence interval (CI), 1.181-1.986]; number needed to treat, 14.9 [95% CI, 12.3-19.0]). Results of the Q test and I2 statistics suggested considerable heterogeneity ([Formula: see text] = 0.038, I2 = 49.3%). The sensitivity analysis was performed by excluding 1 study at a time, and it revealed no change in statistical significance. Conclusion Although this meta-analysis had some limitations, our study demonstrated that hypertension was significantly associated with the risk of epistaxis. However, since this association does not support a causal relationship between hypertension and epistaxis, further clinical trials with large patient populations will be required to determine the impact of hypertension on epistaxis.


Case study of hypertriglyceridemia from COVID-19 Pfizer-BioNTech vaccination in a patient with familial hypercholesteremia.
The Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine is the first novel nucleoside-modified messenger ribonucleic acid (modRNA) vaccine to receive Emergency Use Authorization from the Food and Drug Administration in the United States. It is indicated to be used in patients ≥12 years-of-age as of May 25th, 2021, including populations with high atherosclerotic cardiovascular disease (ASCVD) burden. However, little is known about the potential impact this vaccine may have on serum lipoprotein levels in patients with familial hypercholesteremia (FH), who are predisposed to high ASCVD burden due to elevated low-density lipoprotein cholesterol (LDL-C). We present an interesting case where a patient with heterozygous FH (HeFH) and elevated triglycerides (TG)-controlled for years on medication and apheresis-experienced significantly elevated TG, one day after receiving his second Pfizer-BioNTech COVID-19 vaccine dose. It is not known whether this adverse event may be seen in other FH patients and may be worth assessing in such patients to determine the possibility of a rare adverse reaction from a COVID-19 vaccine.


Effects of Supercapacitor Physics on Its Charge Capacity.
This paper investigates the effects of three aspects of the supercapacitor physics on its charge capacity: porous electrode structure, charge redistribution, and self-discharge. The relationship between the delivered charge and the discharge current is examined for both the upper and lower bounds of the utilized charge capacity, which refers to the amount of charge delivered during a constant current discharge process. In the upper bound case, Peukert's law applies when the discharge current is above a certain threshold and does not apply anymore if the discharge current is below the threshold. In the lower bound case, if the discharge current is above the threshold, the delivered charge increases when the discharge current decreases although the increase rate is lower compared to that in the upper bound case. The individual and combined effects of supercapacitor physics are studied. The porous electrode structure and the charge redistribution process result in an increase in the delivered charge when a smaller discharge current is applied. The impact of self-discharge is negligible when the discharge current is relatively large. If the discharge current is sufficiently small, self-discharge results in a significant energy loss and consequently a drop in the delivered charge.


The dentist's role in reporting suspected child abuse and neglect.
While dentists are in a position to report suspected child abuse and neglect (SCAN), few reports are made by dentists. Evidence exists that dentists are not well-informed about SCAN, but even with education about SCAN, dentists continue to make few reports. Reasons for low reporting are noted. This article lists criteria which will be helpful in determining whether a traumatic injury to a child is accidental or intentional.


Polarization-insensitive silicon nitride Mach-Zehnder lattice wavelength demultiplexers for CWDM in the O-band.
Polarization-insensitive silicon nitride (SiN) 4-channel wavelength (de)multiplexers based on Mach-Zehnder interferometer lattice filters for coarse wavelength division multiplexing (CWDM) in the O-band are demonstrated in a SiN-on-silicon photonic platform. For the best-performing device, the insertion loss was < 2.8 dB, the inter-channel crosstalk was < -11.5 dB for a polarization scrambled input, and the passband shift between the orthogonal polarizations was < 1.5 nm. Across the 200mm wafer, the die-averaged insertion loss and maximum crosstalk were 3.1 dB and -10.6 dB, respectively. The higher-than-expected crosstalk was due to dimensional variations. This work shows the potential of SiN photonic circuits for CWDM without polarization diversity.


Interaction between the pili of Pseudomonas aeruginosa PAK and its carbohydrate receptor beta-D-GalNAc(1-->4)beta-D-Gal analogs.
Pseudomonas aeruginosa employs pili to mediate adherence to epithelial cell surface receptors. Previously, it has been shown that the pilus adhesin of P. aeruginosa PAK binds to the ganglioside asialo-GM1. In particular, it was found that the carbohydrate sequence beta-D-GalNAc(1-->4)beta-D-Gal is the minimal carbohydrate receptor sequence of asialo-GM1. To study the binding specificity of P. aeruginosa, O-modified and N-modified sugar analogs, where each hydroxyl group was substituted either by O-methyl or O-propyl and the acetamido group was changed to a propionamido group, were synthesized. The sugar analogs were evaluated as inhibitors in a competitive solid phase binding assay. The results demonstrate that the pili of P. aeruginosa PAK accepts a variety of sugar analogs possessing the sequence beta-D-GalNAc(1-->4)beta-D-Gal. Most sugar analogs bind with a similar order of magnitude (50% inhibitory concentration (IC50) = 60-130 microM) except for the 2-O-propyl derivative 7 (IC50 = 8 +/- 4 microM) compared with an IC50 of 79 +/- 18 microM for the native compound. The significant increase in binding affinity of 2-O-propyl derivative 7 suggests that improved inhibitors of adhesion may be prepared by introducing a hydrophobic side chain at the 2-position of galactose.


Golgi tubule traffic and the effects of brefeldin A visualized in living cells.
The Golgi complex is a dynamic organelle engaged in both secretory and retrograde membrane traffic. Here, we use green fluorescent protein-Golgi protein chimeras to study Golgi morphology in vivo. In untreated cells, membrane tubules were a ubiquitous, prominent feature of the Golgi complex, serving both to interconnect adjacent Golgi elements and to carry membrane outward along microtubules after detaching from stable Golgi structures. Brefeldin A treatment, which reversibly disassembles the Golgi complex, accentuated tubule formation without tubule detachment. A tubule network extending throughout the cytoplasm was quickly generated and persisted for 5-10 min until rapidly emptying Golgi contents into the ER within 15-30 s. Both lipid and protein emptied from the Golgi at similar rapid rates, leaving no Golgi structure behind, indicating that Golgi membranes do not simply mix but are absorbed into the ER in BFA-treated cells. The directionality of redistribution implied Golgi membranes are at a higher free energy state than ER membranes. Analysis of its kinetics suggested a mechanism that is analogous to wetting or adsorptive phenomena in which a tension-driven membrane flow supplements diffusive transfer of Golgi membrane into the ER. Such nonselective, flow-assisted transport of Golgi membranes into ER suggests that mechanisms that regulate retrograde tubule formation and detachment from the Golgi complex are integral to the existence and maintenance of this organelle.


Transoesophageal echocardiography of aortic atherosclerosis: the additive value of three-dimensional over two-dimensional imaging.
Complex aortic atherosclerotic plaques (AAPs) carry a significant risk of embolism. Currently, two-dimensional (2D) transoesophageal echocardiography (TOE) is the principal diagnostic tool of AAPs. However, we hypothesized that the data obtained from three-dimensional (3D) imaging may improve AAPs' spatial assessment. The study included 67 patients (aged 70 ± 15 years, 35 men), who had routine TEE studies. The thoracic aorta was studied from arch to distal descending aorta, using the x-plane mode (simultaneous short- and long-axis views). If focal intimal thickening (suggestive of AAP) was detected, the 3D zoom algorithm was exercised on the specific site with further post-processing on a Q-lab workstation to measure its thickness in the X, Y, and Z dimensions. The AAP contour was defined qualitatively as regular or irregular in each mode. A total of 100 AAPs were investigated. The AAP thickness estimation was significantly greater in the 3D mode than in the 2D mode (0.51 ± 0.33 vs. 0.28 ± 0.20 cm, P < 0.001). The rate of complex AAPs (defined by AAP thickness of ≥4 mm) was two-fold higher with 3D imaging than with 2D imaging (27% with 2D imaging alone vs. 53% with the addition of 3D imaging). The rate of irregular AAPs increased from 29 to 65% when assessed with 3D imaging compared with 2D imaging. This study has shown a significant difference in the estimation of AAPs between 2D and 3D TEE. The significant shift to a more complex AAPs profile may suggest that 3D imaging is preferable for the assessment of aortic atherosclerosis burden.


Reproductive tourism in Argentina: clinic accreditation and its implications for consumers, health professionals and policy makers.
A subcategory of medical tourism, reproductive tourism has been the subject of much public and policy debate in recent years. Specific concerns include: the exploitation of individuals and communities, access to needed health care services, fair allocation of limited resources, and the quality and safety of services provided by private clinics. To date, the focus of attention has been on the thriving medical and reproductive tourism sectors in Asia and Eastern Europe; there has been much less consideration given to more recent 'players' in Latin America, notably fertility clinics in Chile, Brazil, Mexico and Argentina. In this paper, we examine the context-specific ethical and policy implications of private Argentinean fertility clinics that market reproductive services via the internet. Whether or not one agrees that reproductive services should be made available as consumer goods, the fact is that they are provided as such by private clinics around the world. We argue that basic national regulatory mechanisms are required in countries such as Argentina that are marketing fertility services to local and international publics. Specifically, regular oversight of all fertility clinics is essential to ensure that consumer information is accurate and that marketed services are safe and effective. It is in the best interests of consumers, health professionals and policy makers that the reproductive tourism industry adopts safe and responsible medical practices.


[Inflammation, adaptive regeneration and dysregeneration (intercellular interaction analysis)].
Inflammation, regeneration and fibrosis are inseparable components of the adaptive tissue response to damage. Systemic analysis indicates that this reaction is brought about due to the cooperative interaction of the connective tissue and blood cells (neutrophils, labrocytes, thrombocytes, macrophages, lymphocytes, fibroblasts) between each other, with intercellular matrix (collagen, fibronectin, proteoglycans) and organ parenchyma on the basis of feedback mechanisms. The role of the "cell orchestra conductor" changes at different stage of reaction; macrophage-fibroblast interaction is the most important in the cooperation between inflammation and regeneration. The breakdown of the homeostatic autoregulatory mechanisms (particularly those of intercellular and intertissue interaction) results in the disturbance of standard reactions, disintegration of inflammation and regeneration, chronicity of inflammatory reactions, incomplete regeneration, progressing sclerosis, formation of deficient granulation and fibrous tissue, tendency to the secondary destruction. The process loses the adaptive character and the notion of "dysregeneration" is introduced for its characteristics.


Current Progress of Mo-Based Metal Organic Frameworks Derived Electrocatalysts for Hydrogen Evolution Reaction.
As an important half-reaction for electrochemical water splitting, electrocatalytic hydrogen evolution reaction suffers from sluggish kinetics, and it is still urgent to search high efficiency non-platinum-based electrocatalysts. Mo-based catalysts such as Mo2 C, MoO2 , MoP, MoS2 , and MoNx have emerged as promising alternatives to Pt/C owing to their similar electronic structure with Pt and abundant reserve of Mo. On the other hand, due to the adjustable topology, porosity, and nanostructure of metal organic frameworks (MOFs), MOFs are extensively used as precursors to prepare nano-electrocatalysts. In this review, for the first time, the progress of Mo-MOFs-derived electrocatalysts for hydrogen evolution reaction is summarized. The preparation method, structures, and catalytic performance of the catalysts are illustrated based on the types of the derived electrocatalysts including Mo2 C, MoO2 , MoP, MoS2 , and MoNx . Especially, the commonly used strategies to improve catalytic performance such as heteroatoms doping, constructing heterogeneous structure, and composited with noble metal are discussed. Moreover, the opportunities and challenges in this area are proposed to guide the designment and development of Mo-based MOF derived electrocatalysts.


Exploiting molecular virulence determinants in Burkholderia to develop vaccine antigens.
The Burkholderia genus is a highly diverse group of species that are distributed throughout a wide range of environments and habitats. Among this group, which is remarkable for its adaptability to a wider range of environmental conditions including disinfectants and organic solvents, are a subgroup that represents some of the most difficult to treat infections. This subgroup includes Burkholderia pseudomallei, the causative agent of melioidosis; B. mallei, the causative agent of glanders and B. cepacia complex (Bcc) which causes opportunistic infections in people with cystic fibrosis and immunocompromised patients. The latter pathogen is itself a group of 18 distinct, but, closely related species. The adaptability of this group allows the expression of a rich selection of molecular virulence determinants to facilitate its survival in the diverse habitats that it colonises. This review will describe a selection of these associated with human infection; comparing them across the three pathogens and highlighting their potential roles as vaccine candidates. Better integration of the knowledge on the pathogenesis and molecular determinants of virulence for these Burkholderia spp may allow the development of more efficacious vaccines.


Cellulomonas telluris sp. nov., an endoglucanase-producing actinobacterium isolated from Badain Jaran desert sand.
A Gram-stain-positive, aerobic bacterium, designated CPCC 204705T, was isolated from a desert soil sample, collected from the Badain Jaran desert. Growth of strain CPCC 204705T was observed at pH 6.0-8.0 and 15-37 °C, with optimal growth at 28 °C and pH 7.0. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CPCC 204705T belonged to the genus Cellulomonas, showing the highest similarity (98.54 %) of 16S rRNA gene sequence to Cellulomonas oligotrophica JCM 17534T. The peptidoglycan type was A4β, containing d-ornithine and d-glutamic acids as diagnostic amino acids. Rhamnose and galactose were detected in the whole-cell hydrolysate as diagnostic sugars. The major cellular fatty acids were anteiso-C15 : 0, anteiso-C15 : 1A, C14 : 0 and C16 : 0. The major menaquinone was MK-9 (H4) and the polar lipid system contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol mannoside, one unidentified lipid, one unidentified aminolipid and two unidentified aminophospholipids. The DNA-DNA hybridization value between strain CPCC 204705T and C. oligotrophica JCM 17534T was 7.1±0.4 %, and the value of average nucleotide identity between these two strains was 79.8 %. The DNA G+C content of strain CPCC 204705T was 75.4 mol%. Based on the results of physiological experiments, chemotaxonomic data, phylogenetic analysis and DNA-DNA hybridization value, strain CPCC 204705T should be classified as a novel Cellulomonas species. The name Cellulomonas telluris sp. nov. is proposed, with strain CPCC 204705T (=DSM 105430T=KCTC 39974T) as the type strain.


Use of [3H]methylglucose and [14C]iodoantipyrine to determine kinetic parameters of glucose transport in rat brain.
Local maximal velocities of transport (Tmax) and the half-maximum transport constants (KT) for glucose transport across the blood-brain barrier have been determined in local regions of the brain in normal conscious rats. [14C]iodoantipyrine and [3H]methylglucose were infused together intravenously for 2 min in rats with plasma glucose concentrations maintained at different levels, and the time courses of the tracer levels in arterial blood were measured. Local 14C and 3H concentrations were then measured in tissue samples dissected from the frozen brains. By comparing the transport-limited uptake of [3H]methylglucose with the blood flow-limited uptake of [14C]iodoantipyrine, the value of m, a factor between 0 and 10 that accounts for diffusion and/or transport limitations, was derived, and from the equation, m = 1 - PS/F (where PS is capillary permeability-surface area product and F is cerebral blood flow), the permeability-capillary surface area for methylglucose was calculated (S. S. Kety. Pharmacol. Rev. 3: 1-41, 1951). Values for Tmax and KT for glucose were calculated by application of Michaelis-Menten kinetic relationships adapted for the competition for transport between glucose and methylglucose. Tmax was determined in three representative gray structures and one white structure of the brain: Tmax was 5.3 +/- 0.3 (SD) mumol.g-1.min-1 in the gray structures and 4.3 mumol.g-1.min-1 in the white structure. KT was 3.6 +/- 0.4 (SD) mM in the gray structures and 5.9 mM in the white structure. This approach allows the simultaneous determination of local values of Tmax and KT for glucose and the rates of blood flow in various regions of the brain in conscious animals.


Experimental realization of on-chip topological nanoelectromechanical metamaterials.
Guiding waves through a stable physical channel is essential for reliable information transport. However, energy transport in high-frequency mechanical systems, such as in signal-processing applications1, is particularly sensitive to defects and sharp turns because of back-scattering and losses2. Topological phenomena in condensed matter systems have shown immunity to defects and unidirectional energy propagation3. Topological mechanical metamaterials translate these properties into classical systems for efficient phononic energy transport. Acoustic and mechanical topological metamaterials have so far been realized only in large-scale systems, such as arrays of pendulums4, gyroscopic lattices5,6, structured plates7,8 and arrays of rods, cans and other structures acting as acoustic scatterers9-12. To fulfil their potential in device applications, mechanical topological systems need to be scaled to the on-chip level for high-frequency transport13-15. Here we report the experimental realization of topological nanoelectromechanical metamaterials, consisting of two-dimensional arrays of free-standing silicon nitride nanomembranes that operate at high frequencies (10-20 megahertz). We experimentally demonstrate the presence of edge states, and characterize their localization and Dirac-cone-like frequency dispersion. Our topological waveguides are also robust to waveguide distortions and pseudospin-dependent transport. The on-chip integrated acoustic components realized here could be used in unidirectional waveguides and compact delay lines for high-frequency signal-processing applications.


Prevalence, etiology, clinical features and management associated with impacted and transmigrated mandibular canines: a systematic review.
The occurrence of mandibular canine impaction and/ or transmigration is a rare clinical entity but diagnosis and treatment planning is of clinical significance. The associated etiological factors and the clinical guidelines for the management are still not clear. The aim of this systematic review was to summarize the available data to report the prevalence and identify the etiological factors, clinical features, and various treatment outcomes in patients with mandibular canine impaction and/or transmigration. The review protocol was registered in PROSPERO (CRD42021222566) and was conducted and reported according to the PRISMA and Cochrane Handbook / Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A computerized search of studies published up to April 30, 2023, was conducted using the following databases: Medline, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and Latin American and Caribbean Health Sciences Literature. A manual search of the reference and citation lists of eligible articles and existing systematic reviews for any additions were also conducted. The Newcastle-Ottawa Scale quality assessment tool was used to assess the studies' quality. After removing 6 duplicates, 3700 articles were identified. For the final analysis, 19 studies published between 1985 and 2023 met all the eligibility criteria and were included. A total of 7 studies presented as good and 12 studies presented as satisfactory. Patients were screened in ten studies and diagnostic records from archives were retrieved in nine studies. The total number of diagnostic records screened was 138.394, and the total number of patients from the included studies was 43.127. Based on the findings from this systematic review, the prevalence of mandibular canine impaction ranged from 0.008% to 1.29% while canine transmigration from 0.12% to 0.98%. Crowding of the mandibular arch, the presence of a retained deciduous canine, and odontoma or cyst are the etiological factors more commonly associated with mandibular canine impaction and or transmigration. Surgical extraction and surgical exposure followed by orthodontic traction are the two most frequently carried out treatment modalities in the management of mandibular canine impaction and or transmigration.


Climate and vegetation controls on boreal zone energy exchange.
The boreal forest, one of the world's larger biomes, is distinct from other biomes because it experiences a short growing season and extremely cold winter temperatures. Despite its size and impact on the earth's climate system, measurements of mass and energy exchange have been rare until the past five years. This paper overviews results of recent and comprehensive field studies conducted in Canada, Siberia and Scandinavia on energy exchanges between boreal forests and the atmosphere. How the boreal biosphere and atmosphere interact to affect the interception of solar energy and how solar energy is used to evaporate water and heat the air and soil is examined in detail. Specifically, we analyse the magnitudes, temporal and spatial patterns and controls of solar energy, moisture and sensible heat fluxes across the land-atmosphere interface. We interpret and synthesize field data with the aid of a soil-vegetation-atmosphere transfer model, which considers the coupling of the energy and carbon fluxes and nutrient status. Low precipitation and low temperatures limit growth of many boreal forests. These factors restrict photosynthetic capacity and lower root hydraulic conductivity and stomatal conductance of the inhabitant forests. In such circumstances, these factors interact to form a canopy that has a low leaf area index and exerts a significant resistance to evaporation. Conifer forests, growing on upland soils, for example, evaporate at rates between 25 and 75% of equilibrium evaporation and lose less than 2.5 mm day-1 of water. The open nature of many boreal conifer forest stands causes a disproportionate amount of energy exchange to occur at the soil surface. The climatic and physiological factors that yield relatively low rates of evaporation over conifer stands also cause high rates of sensible heat exchange and the diurnal development of deep planetary boundary layers. In contrast, evaporation from broad-leaved aspen stands and fen/wetlands approach equilibrium evaporation rates and lose up to 6 mm day-1 .


Estimates of Antibacterial Consumption in Timor-Leste Using Distribution Data and Variation in Municipality Usage Patterns.
The association between antimicrobial resistance and antimicrobial usage has become a growing global concern. Many lower-middle income countries including Timor-Leste (TL) have limited information on antimicrobial usage, although recent research suggests increasing resistance rates among human pathogens there. The aim of this study was to use distribution data to estimate antibiotic consumption at both the national and sub-national level in Timor-Leste, stratifying into resistance class and adherence to the national essential medicines list (EML) and WHO AWaRe guidelines. A retrospective review of distribution data from Timor-Leste central medical store (SAMES) was undertaken to give a defined daily dose (DDD)/1000 inhabitants/day using WHO methodology. National antibiotic distribution in the TL EML in 2019 was estimated at 11.1 DDD/1000 inhabitants/day, comparable to consumption rates observed in other lower-middle-income countries using similar methodology. Differences in distribution quantities were noted between municipalities, with 4 of the 13 municipalities notably above the national average and around 32% of listed restricted antimicrobials distributed incongruent with the EML. This study provides insights into estimated antimicrobial consumption in Timor-Leste that has previously been poorly defined. Estimates of consumption can be used to understand emerging resistance in this small island nation, add to the body of knowledge on antimicrobial use to advise policy and guideline development, and help with stewardship activities.


Characterization of the extracellular haemoglobin of Haemopsis sanguisuga (L.).
The haemoglobin from the blood of the horseleech, Haemopsis sanguisuga (L.), had a sedimentation coefficient, SO20, w, of 59.11 +/- 0.55 S, and a molecular weight as determined by sedimentation equilibrium of 3.71 X 10(6)+/-9904 X 10(6). In the electron microscope the molecule appeared to be made up of two hexagonal plates, as is found with other worm haemoglobins, with dimensions 24.4+/-2.0 nm (across the hexagon) and 15.2+/-1.4 nm (height). The amino acid composition and spectrum were closely similar to those of the haemoglobins of other annelids (e.g. Lumbricus). The alpha-helical content, calculated from circular-dichroism measurements in the far-u.v. region, was 56-63%. The haem content was 2.49%, corresponding to a minimum molecular weight per haem group of 24 800, but detergent-gel electrophoresis indicated the presence of polypeptide chains of mol.wts. 12 600, 14 800, 15 500 and 25 100. The pH-induced dissociation of the native molecule yielded compotosol of Soya-bean root nodules.


Human Beings as Evolved Nepotists : Exceptions to the Rule and Effects of Cost of Help.
Inclusive fitness theory provides a compelling explanation for the evolution of altruism among kin. However, a completely satisfactory account of non-kin altruism is still lacking. The present study compared the level of altruism found among siblings with that found among friends and mates and sought to reconcile the findings with an evolutionary explanation for human altruism. Participants (163 males and 156 females) completed a questionnaire about help given to a sibling, friend, or mate. Overall, participants gave friends and mates as much or more help than they gave siblings. However, as the cost of help increased, siblings received a progressively larger share of the help, whereas friends and mates received a progressively smaller share, despite the fact that participants were closer emotionally to friends and mates than they were to siblings. These findings help to explain the relative standing of friends and mates as recipients of altruistic aid.


Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer.
Using a polyclonal antibody that is monospecific for the erbB-2 oncogene product, an immunohistochemical study of the expression of erbB-2 protein was performed in formalin-fixed paraffin-embedded tissue sections from 260 primary gastric cancers. erbB-2 protein expression in which the reaction was localized to the cell membranes was observed in 31 (11.9%) cancers. All nontumor cells and normal gastric epithelium were negative for membrane staining. There was not a significant association between erbB-2 staining and histological type or venous invasion. erbB-2 protein expression was associated with serosal invasion, lymph node metastasis, and lymphatic invasion. In addition, erbB-2 protein expression correlated with a high number of lymph node metastases. Furthermore, the risk of recurrence in lymph node was over 3 times higher in patients with erbB-2 protein-positive tumors than in those with erbB-2 protein-negative ones. When erbB-2 protein expression and the clinical parameters were entered simultaneously into the Cox regression model, erbB-2 protein expression emerged as an independent prognostic indicator. Patients with erbB-2 protein-positive tumors had 5-fold greater relative risk of death, as compared with those with erbB-2 protein-negative tumors. These results indicate that erbB-2 protein expression is an important independent prognostic indicator in gastric cancer. The high malignant potential of erbB-2 protein-positive tumors may be associated with the very high potential for lymph node metastasis.


Indolent B-cell non-Hodgkin's lymphomas.
The indolent B-cell non-Hodgkin's lymphomas are a diverse group of disorders that differ markedly with respect to presenting features and natural history. This article reviews entities that have generally been encompassed under the category of indolent lymphomas in various classifications, including the Working Formulation, although many were not specifically identified or labeled as separate entities. These include small-lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma, the follicle center cell lymphomas, mantle cell lymphoma, and nodal and extranodal marginal zone lymphomas, including mucosa-associated lymphoid tissue (MALT) lymphoma. There is still a great deal to be learned about the basic biology and treatment of these disorders. Numerous variables influence the type of management used for each individual case, including the disease entity and stage, symptoms and real or threatened organ dysfunction, patient age, and medical condition, as well as the preferences of the patient and practitioner. Unfortunately, because of the inadequacy of current treatment, the majority of patients with indolent lymphoma will not be cured. Thus, continued investigation in the laboratory and through carefully designed clinical trials is essential.


Antibacterial and hemostatic chitin sponge directly constructed from Pleurotus Eryngii via top-down approach.
Chitin, the second most abundant polysaccharide on earth, possesses unique characteristics, including biosafety, biodegradability, and procoagulant activity, making it an attractive material for hemostasis. However, the conventional bottom-up construction of chitin-based materials is intricate and time-consuming. In this study, we have developed a top-down strategy to prepare a 3D porous chitin-based hemostatic sponge with exceptional hemostatic properties and antibacterial activity, directly from the spongy Pleurotus eryngii. The top-down method involves deproteinization, in situ quaternization, and tannin acid crosslinking. The obtained sponge has an interconnected microporous structure with high porosity (89.7 ± 3.2 %), endowing it with high water absorption (2047 ± 105 %) and rapid water-triggered shape-memory behavior (< 2 s). The sponge exhibits superior blood coagulant activity and outperforms standard medical gauze, gelatin sponge, and chitosan sponge in both topical artery and non-compressive liver puncture wound. In addition, the sponge exhibited significant antibacterial activity against both gram-positive Staphylococcus aureus and gram-negative Escherichia coli. In summary, this study provides a straightforward and practical approach for constructing an antibacterial and hemostatic chitin sponge that could be a valuable option for treating bleeding wounds.


Saudi neurology residents' knowledge and attitudes toward intravenous thrombolysis in patients with acute ischemic stroke.
Although intravenous (IV) thrombolysis is an effective treatment for patients with acute ischemic stroke (AIS), it remains underused by neurologists worldwide. This study assessed the knowledge and attitudes toward IV thrombolysis in patients with AIS among neurology residents in Saudi Arabia. An online survey was conducted using a sample of 81 neurology residents in and around Saudi Arabia. Statistical analysis included descriptive studies and Chi-square or Fisher's exact test. Of the 81 respondents, 50 (61.7%) were males and 31 (38.3%) females. Regarding IV thrombolysis use in AIS patients; 61.7% thought that they would consider it, a vast majority about 72.8% showed positive attitudes toward performing IV thrombolysis for AIS patients, 69.1% thought that IV thrombolysis is safe, 79.0% did not think that they have good knowledge about IV thrombolysis, and 53.1% felt not confident about their ability to employ IV thrombolysis. Confidence with knowledge was associated with the residency stage (P = 0.000). Attitudes toward IV thrombolysis was found associated with sex (P = 0.044) and residency stage (P = 0.002). Residents from the central region were more likely to have positive attitudes (P = 0.043). The surveyed neurology residents showed a positive attitude towards the safety and use of IV thrombolysis for AIS patients. However, knowledge and confidence along with knowledge about the treatment are lacking. Therefore, theoretical and practical training is warranted to improve knowledge about IV thrombolysis.


Control of viremia and prevention of AIDS following immunotherapy of SIV-infected macaques with peptide-pulsed blood.
Effective immunotherapies for HIV are needed. Drug therapies are life-long with significant toxicities. Dendritic-cell based immunotherapy approaches are promising but impractical for widespread use. A simple immunotherapy, reinfusing fresh autologous blood cells exposed to overlapping SIV peptides for 1 hour ex vivo, was assessed for the control of SIV(mac251) replication in 36 pigtail macaques. An initial set of four immunizations was administered under antiretroviral cover and a booster set of three immunizations administered 6 months later. Vaccinated animals were randomized to receive Gag peptides alone or peptides spanning all nine SIV proteins. High-level, SIV-specific CD4 and CD8 T-cell immunity was induced following immunization, both during antiretroviral cover and without. Virus levels were durably approximately 10-fold lower for 1 year in immunized animals compared to controls, and a significant delay in AIDS-related mortality resulted. Broader immunity resulted following immunizations with peptides spanning all nine SIV proteins, but the responses to Gag were weaker in comparison to animals only immunized with Gag. No difference in viral outcome occurred in animals immunized with all SIV proteins compared to animals immunized against Gag alone. Peptide-pulsed blood cells are an immunogenic and effective immunotherapy in SIV-infected macaques. Our results suggest Gag alone is an effective antigen for T-cell immunotherapy. Fresh blood cells pulsed with overlapping Gag peptides is proceeding into trials in HIV-infected humans.


Cucumber mosaic virus satellite RNA (Y strain): analysis of sequences which affect yellow mosaic symptoms on tobacco.
Plants infected with cucumber mosaic virus (CMV) (KIN strain) produce a mild mosaic disease on tobacco whereas infections of CMV with satellite RNA (strain Y) cause a severe yellow mosaic. Analysis of recombinant and mutant forms of satellite RNA identified a site (nucleotides 185/186) in the Y satellite RNA that affects the ability to induce the yellow mosaic in combination with CMV but not with tomato aspermy virus. The location of this site with respect to other mutations in the satellite RNA indicated that polypeptides, which may be encoded by the satellite RNA, have no role in induction of yellow mosaic symptoms. The symptom induction is therefore an effect of the satellite RNA on the host plant with the intervention of the helper virus. In the course of the mutation analysis of satellite RNA we detected several secondary mutations which arose in planta. Two of these were deletions of more than 80 nucleotides. Other forms of mutant satellite RNA were non-functional even though the modifications involved nucleotides completely within the large secondary deletions. These data imply complex intramolecular interactions in the satellite RNA.


Pediatric emergency care in europe: a descriptive survey of 53 tertiary medical centers.
To examine determinants of quality of care provided by pediatric emergency departments (PEDs) in tertiary European centers. Analysis of questionnaires was sent to directors of PEDs. Questionnaires were sent through the pediatric research group of the European Society for Emergency Medicine. Three major descriptive categories were included in a 28-point questionnaire: institution's pediatric inpatient capabilities, scope of services, and medical staff education and structure. Sixty-five questionnaires were completed in full. Fifty-three tertiary medical centers from 14 countries were included in the study. In 86.8% of these institutions, the PED is separated from the adult emergency department; 91% have a pediatric intensive care unit, and 72% have an in-patient pediatric trauma service. Eighty-eight percent of the PEDs have incorporated triage protocols. Social service was not available in 17% of the departments. Sedation for painful procedures is provided by the staff in 77% of the PEDs. Only 24% of the PED medical directors have been formally trained in pediatric emergency medicine. In 17% of the departments, there is a 24-hour 7-day residents' coverage with no attending pediatrician or pediatric emergency medicine-trained physician. According to this pilot study, the basic services provided by tertiary PEDs in Europe appear to be appropriate. Physicians training level and staffing may not be adequate to achieve optimal patient outcome.


Strategies for reversing the effects of metabolic disorders induced as a consequence of developmental programming.
Obesity and the metabolic syndrome have reached epidemic proportions worldwide with far-reaching health care and economic implications. The rapid increase in the prevalence of these disorders suggests that environmental and behavioral influences, rather than genetic causes, are fueling the epidemic. The developmental origins of health and disease hypothesis has highlighted the link between the periconceptual, fetal, and early infant phases of life and the subsequent development of metabolic disorders in later life. In particular, the impact of poor maternal nutrition on susceptibility to later life metabolic disease in offspring is now well documented. Several studies have now shown, at least in experimental animal models, that some components of the metabolic syndrome, induced as a consequence of developmental programming, are potentially reversible by nutritional or targeted therapeutic interventions during windows of developmental plasticity. This review will focus on critical windows of development and possible therapeutic avenues that may reduce metabolic and obesogenic risk following an adverse early life environment.


Evaluation of carbocyanine-labeled erythrocytes for microvascular measurements.
Red blood cells labeled with the carbocyanine dyes, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO), were evaluated for use in making microvascular measurements in rat small intestine and spinotrapezius muscle. We determined the minimum concentration of each dye which produced near maximal fluorescent intensity and labeled cell fraction. These dyes, which have excitation and emission spectra similar to fluorescein and rhodamine derivatives, have a number of advantages over the isothiocyanates: (1) the labeling procedure is quicker, easier, and less expensive; (2) the labeled cell fraction and the fluorescent intensity of DiI and DiO cells are stable for long periods of time in the rat circulation; and (3) DiI-labeled cells are brighter and transmit light through overlying erythrocytes better than rhodamine X isothiocyanate. However, in vitro and in vivo evaluations illustrate the potential limiting effects of vessel diameter and cell velocity on the accuracy of microvascular measurements made using this technique. In the small intestine and spinotrapezius muscle preparations, measurements of labeled cell flux were readily reproducible and could be partly automated with image analysis only in capillaries and small venules. Counting labeled cells in larger vessels by human observation or with automation was not reproducible, presumably due to absorption and dispersion of the fluorescent signal by overlying erythrocytes and smearing of the cell image at high cell velocities.


Estimation and Inference for the Mediation Proportion.
In epidemiology, public health and social science, mediation analysis is often undertaken to investigate the extent to which the effect of a risk factor on an outcome of interest is mediated by other covariates. A pivotal quantity of interest in such an analysis is the mediation proportion. A common method for estimating it, termed the "difference method", compares estimates from models with and without the hypothesized mediator. However, rigorous methodology for estimation and statistical inference for this quantity has not previously been available. We formulated the problem for the Cox model and generalized linear models, and utilize a data duplication algorithm together with a generalized estimation equations approach for estimating the mediation proportion and its variance. We further considered the assumption that the same link function hold for the marginal and conditional models, a property which we term "g-linkability". We show that our approach is valid whenever g-linkability holds, exactly or approximately, and present results from an extensive simulation study to explore finite sample properties. The methodology is illustrated by an analysis of pre-menopausal breast cancer incidence in the Nurses' Health Study. User-friendly publicly available software implementing those methods can be downloaded from the last author's website (SAS) or from CRAN (R).


"Glandular intoxication" following emergent tracheotomy during transsphenoidal surgery for acromegaly: Cushing's 1910 unrecognized case of thyroid storm?
Harvey Cushing's monograph The Pituitary Body and Its Disorders describes Case XXXVIII, H. M. B., a 33 year-old man who presented with acromegaly in 1910. The detailed operative note reports an emergency tracheotomy performed following induction of anesthesia, and immediately prior to a naso-labial approach to a suspected sellar lesion. Cushing's post-operative notes document a significant increase in temperature prior to the patient's death. Cushing offered an explanation for the patient's symptoms immediately pre-mortem, which is largely unsatisfying. Following institutional review board approval, and through the courtesy of the Alan Mason Chesney Archives, the surgical records from the Johns Hopkins Hospital, 1896-1912, were reviewed. A review of the original surgical file revealed a more extensive description of the emergent tracheotomy required following induction of anesthesia, and provided additional information regarding the patient's symptoms in the immediate pre-mortem period. Namely, the urgent tracheotomy transected the thyroid gland, and post-operatively the patient experienced significant tachycardia and hyperthermia, consistent with thyroid storm. The new information regarding the hospital course of H. M. B. offers insight into the previously incompletely described circumstances surrounding his emergent tracheotomy, and subsequent death. Additionally, the case underscores the clinical importance of recognizing and appropriately treating thyroid storm.


A flow cytometry assay to quantify intercellular exchange of membrane components.
Membrane-compound exchange is vital for cell-to-cell communication, yet quantification of this process is difficult. Here we present a method using flow cytometry in combination with bioorthogonal and fluorescent labelling techniques to quantify the amount of exchange of cholesterol and sialylated compounds between cells. We demonstrate that direct cell-cell contact is the likely mechanism of sterol-exchange and show that by manipulating the contact time between cells using complementary coiled-coil peptides results in an enhanced exchange rate of membrane components between cells.


Copper binding in IscA inhibits iron-sulphur cluster assembly in Escherichia coli.
Among the iron-sulphur cluster assembly proteins encoded by gene cluster iscSUA-hscBA-fdx in Escherichia coli, IscA has a unique and strong iron binding activity and can provide iron for iron-sulphur cluster assembly in proteins in vitro. Deletion of IscA and its paralogue SufA results in an E. coli mutant that fails to assemble [4Fe-4S] clusters in proteins under aerobic conditions, suggesting that IscA has a crucial role for iron-sulphur cluster biogenesis. Here we report that among the iron-sulphur cluster assembly proteins, IscA also has a strong and specific binding activity for Cu(I) in vivo and in vitro. The Cu(I) centre in IscA is stable and resistant to oxidation under aerobic conditions. Mutation of the conserved cysteine residues that are essential for the iron binding in IscA abolishes the copper binding activity, indicating that copper and iron may share the same binding site in the protein. Additional studies reveal that copper can compete with iron for the metal binding site in IscA and effectively inhibits the IscA-mediated [4Fe-4S] cluster assembly in E. coli cells. The results suggest that copper may not only attack the [4Fe-4S] clusters in dehydratases, but also block the [4Fe-4S] cluster assembly in proteins by targeting IscA in cells.


Accuracy and cost-effectiveness of exercise echocardiography for detection of coronary artery disease in patients with mitral valve prolapse.
Mitral valve prolapse is sometimes associated with chest pain, but this symptom may also be caused by coexisting coronary disease. The accuracy of exercise echocardiography in diagnosing coronary disease in these patients and the most cost-efficient diagnostic approach are unclear. We studied 96 patients (aged 59 +/- 12 years; 70 men) with mitral valve prolapse who underwent exercise electrocardiography, exercise echocardiography, and coronary angiography. The accuracies of seven diagnostic strategies based on the current and expected use of exercise electrocardiography and exercise echocardiography in patients with mitral valve prolapse were examined, with the costs calculated based on Medicare reimbursement. Thirteen (13.5%) patients had significant coronary artery disease. The sensitivity and specificity of exercise electrocardiography in the 71 patients with interpretable electrocardiograms were 50% and 72%, respectively. For the 73 patients who achieved >85% of maximal heart rate, 52 had interpretable exercise electrocardiograms (sensitivity 50%; specificity 69%). Exercise echocardiography had a sensitivity of 69% and a specificity of 98% in the 96 patients and a sensitivity of 82% and a specificity of 96% in patients who achieved >85% of maximal heart rate. Approaches adopting Bayes' theorem and restricting further investigation to patients with at least intermediate pretest probability of coronary disease were the least costly. When combined with exercise echocardiography as the initial test, clinical stratification was associated with a false-negative rate of 21%. The utility of exercise electrocardiography is limited by the high prevalence of resting electrocardiographic abnormalities and suboptimal sensitivity and specificity. The best balance of cost and diagnostic accuracy is to perform exercise echocardiography in patients with at least intermediate probability of coronary artery disease.


The water footprint of California's energy system, 1990-2012.
California's energy and water systems are interconnected and have evolved in recent decades in response to changing conditions and policy goals. For this analysis, we use a water footprint methodology to examine water requirements of energy products consumed in California between 1990 and 2012. We combine energy production, trade, and consumption data with estimates of the blue and green water footprints of energy products. We find that while California's total annual energy consumption increased by just 2.6% during the analysis period, the amount of water required to produce that energy grew by 260%. Nearly all of the increase in California's energy-related water footprint was associated with water use in locations outside of California, where energy products that the state consumes were, and continue to be, produced. We discuss these trends and the implications for California's future energy system as it relates to climate change and expected water management challenges inside and outside the state. Our analysis shows that while California's energy policies have supported climate mitigation efforts, they have increased vulnerability to climate impacts, especially greater hydrologic uncertainty. More integrated analysis and planning are needed to ensure that climate adaptation and mitigation strategies do not work at cross purposes.


Genetic diversity of Leishmania tropica: Unexpectedly complex distribution pattern.
In this study, we characterized a collection of clinical samples obtained from Syrian and Turkish patients with cutaneous leishmaniasis using internal transcribed spacer 1 (ITS1) sequences. All obtained sequences belonged to Leishmania tropica. Combining them with those available from GenBank allowed us performing a broad-scale analysis of genetic diversity for this species. We demonstrated that L. tropica has a complex phylogeographic pattern with some haplotypes being widespread across endemic countries and others restricted to particular regions. We hypothesize that at least some of them may be associated with alternative vectors or animal reservoirs.


A clinical study of culture-negative endocarditis.
Culture-negative infective endocarditis (CNE) is a diagnostic problem in spite of improved echocardiographic and blood culturing techniques. We conducted the present study to estimate the proportion of CNE in patients with infective endocarditis, to investigate data regarding risk factors, and to evaluate the Duke and the modified Beth Israel criteria in patients with CNE. We evaluated 820 consecutive suspected episodes of infective endocarditis in adults at the Departments of Infectious Diseases in Göteborg and Borås, Sweden (1984-1996). All patients were diagnosed and treated according to a protocol; 487 episodes were identified as infective endocarditis. Episodes with absence of bacterial growth at blood culture were defined as CNE and were classified with the Duke and the modified Beth Israel criteria. We identified 116 CNE episodes (median age, 67 yr). Mortality was 7%, and in 15%, cardiac surgery was performed. The Duke criteria classified 20 definite, 80 possible, and 16 reject episodes. The modified Beth Israel criteria distinguished 13 definite, 15 probable, 27 possible, and 61 reject episodes. The proportion of CNE among patients with infective endocarditis varied from 19% to 27% at the 2 departments. Antibiotic treatment preceded blood culture in 45% of the CNE episodes. About 20% in a Scandinavian population of infective endocarditis patients have CNE. Antibiotic pretreatment explains less than 50% of all CNE episodes. The Duke criteria are more sensitive but less specific than the modified Beth Israel criteria in classifying patients with CNE.


Sedentary behaviour levels in adults with an intellectual disability: a systematic review protocol.
Background: Sedentary behaviour contributes to non-communicable diseases, which account for almost 71% of world deaths. Of these, cardiovascular disease is one of the largest causes of preventable death. It is not yet fully understood what level of sedentary behaviour is safe. People with an intellectual disability have poorer health than the general population with higher rates of multi-morbidity, obesity and inactivity. There is a paucity of evidence on whether this poorer health is due to sedentary behaviour or physical inactivity. This systematic review will investigate the sedentary behaviour levels of adults with an intellectual disability. Method: The PRISMA-P framework will be applied to achieve high-quality articles. An extensive search will be conducted in Medline, Embase, psycINFO and Cinahl and grey literature sources. All articles will be independently reviewed by two reviewers and a third to resolve disputes. Initially, the articles will be reviewed by title and abstract and then the full article will be reviewed using stringent inclusion criteria. All article data will be summarised in a standardised tabular format. The National Institute of Health's quality assessment tool will be used to assess article quality. GRADE will be used to assess the quality of the evidence. The primary outcome of interest is the prevalence of sedentary behaviour levels for people with an intellectual disability. The definition of sedentary behaviour to be used for the purposes of this study is: 'low physical activity as identified by metabolic equivalent (MET) or step levels or as measured by the Rapid Assessment of Physical activity questionnaire (RAPA) or the International Physical Activity questionnaire (IPAQ) or sitting for more than 3 hours per day'. Conclusion: This systematic review will provide a critical insight into the prevalence of sedentary behaviour in adults with an intellectual disability.


The influence of religiosity and spirituality on adolescent mothers and their teenage children.
This project assessed the influence of religiosity and spirituality on the socioemotional and behavioral adjustment of 110 adolescent mothers and their teenage offspring at age 14. Maternal religiosity, measured prenatally and when children were 3, 5, and 8 years of age, was defined as involvement in church as well as contact with and dependence on church officials and members. Levels of spirituality, defined as religious practices and beliefs, were assessed for both mothers and their children at 14 years postpartum. Hierarchical regression analyses suggested that maternal religiosity was a strong predictor of maternal and child adjustment; children's own spirituality served as a predictor of their socioemotional adjustment as well. Furthermore, child spirituality mediated the relationship between maternal religiosity and children's externalizing behavior. Implications for designing intervention programs with high risk families are discussed.


Pitfall in assessing the size of tumor phantoms on mammograms.
Tumor size is crucial for clinical management and prognosis of breast malignancies. The gold standard-size of 12 tumor phantoms was assessed at The Department of Production Engineering. Subsequently, with a conventional ruler, seven experienced mammographers measured the largest diameter of the 12 devices in two independent trials. In the first trial, 30% (n=25) of the 84 values given by the seven mammographers failed to recreate the gold standard size by >1 mm and in the second, by 37% (31/84). Size was overestimated (>1 mm) in 9.5% (n=8) of 84 measurements in the first trial, and in 15.5% (14/84) in the second. Conversely, size was underestimated (>1 mm) in 20% (n=17) of 84 measurements in the first trial, and in 21% (18/84) in the second. Neither the age of the participants, nor their years of experience improved the obtained results. The method used here raised doubts concerning the ability of discriminating size among subgroups of T1 breast tumors in mammograms. According to the TNM staging system, T1 tumors (≤2.0 cm in greatest dimension) are subdivided into T1mic: microinvasion (≤0.1 cm), T1a (>0.1 cm but not more than 0.5 cm), T1b (>0.5 cm but not more than 1.0 cm) and T1c (>1.0 cm but not more than 2.0 cm in their greatest dimension). Since the TNM staging system for breast tumors is important in therapeutic decision making, it is crucial to develop a more reliable method for tumor size assessment.


A dynamically reconfigurable Fano metamaterial through graphene tuning for switching and sensing applications.
We report on a novel electrically tunable hybrid graphene-gold Fano resonator. The proposed metamaterial consists of a square graphene patch and a square gold frame. The destructive interference between the narrow- and broadband dipolar surface plasmons, which are induced respectively on the surfaces of the graphene patch and the gold frame, leads to the plasmonic equivalent of electromagnetically induced transparency (EIT). The response of the metamaterial is polarization independent due to the symmetry of the structure and its spectral features are shown to be highly controllable by changing a gate voltage applied to the graphene patch. Additionally, effective group index of the device is retrieved and is found to be very high within the EIT window suggesting its potential use in slow light applications. Potential outcomes such as high sensing ability and switching at terahertz frequencies are demonstrated through numerical simulations with realistic parameters.


Modeling the Health and Economic Burden of Chronic Obstructive Pulmonary Disease in China From 2020 to 2039: A Simulation Study.
Despite a growing prevalence of respiratory diseases in recent decades in China, limited evidence is available on the health and economic burden of chronic obstructive pulmonary disease (COPD). We estimated the 20-year health and economic burden of COPD in China from 2020 to 2039. We created a probabilistic dynamic open-cohort Markov model of COPD for the Chinese population aged ≥40 years. Projections of population growth and urbanization rates were obtained from the United Nations Population Division. Other parameter inputs including smoking prevalence, COPD prevalence and severity distributions, disease-related costs, and utility weights were obtained from the most recent published literature. We modeled number of COPD patients, excess mortality due to COPD, exacerbations, COPD-attributable losses of quality-adjusted life-years, and direct and indirect COPD costs over the 20 years. The number of COPD patients was projected to increase from 88.3 million in 2020 to 103.3 million in 2039. The projected total losses of quality-adjusted life-years and the excess mortality due to COPD were, respectively, estimated to be 253.6 million and 3.9 million over the 20 years. The projected 20-year total discounted direct and indirect costs of COPD were, respectively, $3.1 trillion and $360.5 billion. The projected health and economic burden was higher in males and urban areas. COPD is projected to inflict a substantial burden to the society and the health care system in China. Effective strategies for prevention and early management of COPD are needed to mitigate the forthcoming disease burden.


Observer variability of lung function measurements in 2-6-yr-old children.
The aim of this study was to assess the within-observer and between-observer variability of lung function measurements in children aged 2-6 yrs. Two observers examined 22 asthmatic children independently according to a predefined protocol. Each observer obtained duplicate measurements of respiratory resistance by the interrupter technique (Rint), respiratory resistance (Rrs,5) and reactance (Xrs,5) at 5 Hz by the impulse oscillation technique and the specific airway resistance (sRaw) by whole body plethysmography. The within-subject SD (SDw) was not significantly different in the two observers. The ratio SDw between observers/mean SDw within observers was 0.94, 1.25, 1.35 and 2.86 for Xrs,5, Rrs,5, sRaw and Rint, respectively, indicating greater between-observer variability of the latter. The systematic difference between observers assessed by the difference between observer means (expressed as a percentage of their mean value) was 11, 7, 6 and 2% for Xrs,5, sRaw, Rrs,5 and Rint, respectively. These differences were statistically significant, except that for Rint. In conclusion, specific airway resistance, impulse oscillation technique and respiratory resistance assessed by the interrupter technique measurements in young children are subject to influence by the observer, and the random variability between observers appears to be particularly great for respiratory resistance assessed by the interrupter technique. The authors suggest that the between-observer variability should be investigated when evaluating novel methods for testing lung function.


Autoradiographic localization of beta-adrenergic receptors in rat kidney slices using [125I]iodocyanopindolol.
We have used autoradiography of [125I]iodocyanopindolol [( 125I]-ICYP) to define the distribution and localization of beta-adrenergic receptors in the rat kidney. [125I]ICYP, a radiolabeled beta-adrenergic antagonist, proved to be an excellent probe to identify these receptors in kidney slices in that specific [125I]ICYP binding was 1) saturable, 2) competed stereoselectively by the agonist isoproterenol and the antagonist propranolol, and 3) competed by agonists in a classical rank order of potency for beta 1-adrenergic receptors (isoproterenol greater than epinephrine congruent to norepinephrine). Autoradiographic studies demonstrated that specific [125I]ICYP sites were present exclusively in the cortex and outer medulla and were localized in glomeruli, ascending limb, and distal tubule-cortical collecting duct. Autoradiography of probes like [125I]ICYP appears to offer a simple and rapid method to assess distribution of adrenergic receptors in the kidney and presumably in other tissues as well.


Currents evoked in Bergmann glial cells by parallel fibre stimulation in rat cerebellar slices.
1. Whole-cell recordings were obtained from Bergmann glial cells in rat cerebellar slices. 2. The cells had low input resistances (70 +/- 38 M omega; n = 13) and a mean resting potential of -82 +/- 6 mV (n = 12) with a potassium-based internal solution. Electrical and dye coupling between Bergmann glia were confirmed. 3. Stimulation of parallel fibres induced a complex, mostly inward current which could be decomposed pharmacologically. 4. The ionotropic glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM), but not DL-2-amino-5-phosphonopentanoic acid (DL-APV; 100 microM) consistently blocked an early inward current component that may reflect synaptic activation of AMPA/kainate receptors in Bergmann glia. 5. Addition of cadmium ions (100 microM) to inhibit transmitter release blocked most of the CNQX-APV-insensitive current. This component probably reflects electrogenic uptake of the synaptically released glutamate. 6. Tetrodotoxin (TTX; 1 microM) blocked the remaining inward current: a slow component, possibly produced by the potassium ion efflux during action potential propagation in parallel fibres. An initial triphasic component of the response was also TTX sensitive and reflected passage of the parallel fibre action potential volley. 7. The putative glutamate uptake current was further characterized; it was blocked by the competitive uptake blockers D-aspartate (0.5 mM) and L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC; 0.5 mM), and by replacement of sodium with lithium. Monitoring the triphasic TTX-sensitive component showed that this inhibition did not result from changes of action potential excitation and propagation. 8. Intracellular nitrate ions increased the putative uptake current, consistent with the effect of this anion on glutamate transporters. 9. The putative uptake current was reduced by depolarization, consistent with the voltage dependence of glutamate uptake. 10. It is concluded that a large fraction of the current induced by parallel fibre stimulation reflects the uptake of synaptically released glutamate. The uptake current activated rapidly, with a 20-80% rise time of 2.3 +/- 0.7 ms (n = 10), and decayed with a principal time constant of 25 +/- 6 ms (n = 10).


[Relationship between child day-care attendance and acute infectious disease. A systematic review].
Child day-care attendance is considered to be an acute early childhood disease risk factor, the studies available however not affording the possibility of fully quantifying this risk. A systematic review of clinical trials and cohort studies was conducted, in which the effects child day-care attendance had on the health of young children based on the Cochrane Collaboration, PubMed and Spanish Medical Index databases, without any time or language-related limits, were analyzed and rounded out with analyses of referenced works and an additional EMBASE search. The methodological quality was evaluated by means of personalized criteria. Pooling measures (relative risks, incidence density ratios and weighted mean differences) were calculated with their confidence intervals, assuming random effects models. A significant increase was found to exist of a risk consistent over time and among different social and geographical environments. Considering the most methodologically-stringent studies with adjusted effect estimates, child day-care attendance was related to an increased risk of upper respiratory tract infection (RR=1,88), acute otitis media (RR=1,58), otitis media with fluid draining (RR=2,43), lower respiratory tract infections (overall RR=210; acute pneumonia RR=1.70; broncholitis RR=1,80; bronchitis RR=2,10) and gastroenteritis (RR=1,40). Child day-care attendance could be responsible for 33%-50% of the episodes of respiratory infection and gastroenteritis among the exposed population. In conclusion, it can be said that the risk for childhood health attributable to the child day-care attendance is discreet but of high-impact. This information has some major implications for research, clinical practice, healthcare authorities and society as a whole.


Evaluation of the in vitro effects of commercial herbal preparations significant in African traditional medicine on platelets.
Commercial herbal medicines (CHMs) marketed as immune boosters are gaining wide popularity in South Africa, in the absence of control and regulatory guidelines. These commercially packaged and labelled herbal preparations, acquired in various retail outlets, are used without consulting either a conventional health provider or a traditional health practitioner. Although they are indicated for immune-boosting purposes, they might exert many other beneficial and unwanted effects on physiological systems. Platelets are crucial in haemostasis and important for the immunological system. The aim was to investigate the effect of the CHMs used to strengthen the immune system on the activity of human platelets. Six CHMs commonly used as African traditional medicines in Pretoria, South Africa, were tested for their effects on healthy, isolated human platelets, using a bioluminescence method. The tested herbal medicines were Intlamba Zifo™, Maphilisa™ Herbal medicine, Matla™ African medicine for all diseases, Ngoma™ Herbal Tonic Immune Booster, Stametta™ Body Healing Liquid, and Vuka Uphile™ Immune Booster and serial-diluted standards of each from 10 to 10,000 times. The luminol-enhanced luminescence activity of the platelets was measured after incubation with the herbal medicines and activation with phorbol myristate acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP). Five herbal medicines, namely Intlamba Zifo™, Maphilisa™ Herbal medicine, Matla™ African medicine for all diseases, Stametta™ Body Healing Liquid, and Vuka Uphile™ Immune Booster exerted comparable weak inhibitory effects on both PMA and fMLP-induced platelets, which were concentration dependent at high doses, and inversely related to concentration at low doses. Intlamba Zifo™, Matla™ African medicine for all diseases, Stametta™ Body Healing Liquid, and Vuka Uphile™ exhibited weak, but non-systematic stimulatory effects at low doses, which were not statistically significant. Ngoma™ Herbal Tonic Immune Booster had weak, inhibitory effects at high doses and weak stimulatory effects that were inversely related to concentration at low doses. The findings suggest a potential beneficial role of the CHMs in the suppression of platelets' reactivity and in enhancing the immune system. Caution, however, should be exercised as platelet inhibition and stimulation predispose to the risk of bleeding and thrombosis, respectively.


[Acute and chronic toxicity of psychotropic drugs].
Within psychotropic drugs acute toxicity is highest in antidepressants (thymoleptics, MAO-inhibitors, lithium), lower in neuroleptics, and very low in anxiolytics. The order of decreasing chronic toxicity is: neuroleptics, antidepressants, anxiolytics. Each class of psychotropic drugs has a specific toxicological problem. With anxiolytics the major problems stem from their misuse and overuse. With neuroleptics tardive dyskinesia is a serious threat to longterm therapy. Finally, antidepressants are characterized by a low therapeutic index and a resulting high incidence of severe and fatal poisoning cases, both intentional and accidental.


Effect of pre-infusion of hypertonic saline on postoperative delirium in geriatric patients undergoing shoulder arthroscopy: a randomized controlled trial.
Neuroinflammation may be a potential mechanism of postoperative delirium (POD) in geriatric patients, and hypertonic saline (HS) has immunomodulatory properties. The purpose of this study was to investigate whether HS could reduce the incidence of POD in elderly patients and its effect on neutrophil activation and inflammatory cytokine expression. We studied the effect of pre-infusion of 4 mL/kg 3% hypertonic saline vs. 4 mL/kg 0.9% normal saline on POD in patients undergoing shoulder arthroscopy in a prospective, randomized, double-blind, controlled trial. Neutrophil surface molecules (CD11b, CD66b and CD64) were analyzed by flow cytometry. Circulating concentrations of inflammatory factors IL-1β, IL-6, TNF-α and neurological damage factor S100β were assessed by enzyme immunoassay. The Confusion Assessment Method-Chinese Revision (CAM-CR) was applied for the assessment of POD 1-3 days after surgery. The incidence of POD in group H was significantly lower than that in group N (7.14% vs 26.83%, P = 0.036). The expression levels of inflammatory cytokines ( IL-6 and TNF-α) and neutrophil surface markers (CD11b and CD66b) were significantly lower in group H than in group N at 24 h after surgery (P = 0.018, P < 0.001, P < 0.001, P = 0.024). There were no significant differences in postoperative pain, nausea and vomiting, infection, phlebitis, and patients satisfaction between the two groups. Pre-infusion of HS can reduce the incidence of POD and the immune-inflammatory response. Chinese Clinical Trial Registry (14/4/2022, registration number: ChiCTR2200058681.


Effects of ochratoxin A on membrane phospholipids of the intestine of broiler chickens, practical consequences.
Ochratoxin A (OTA) is a mycotoxin produced by various species of Aspergillus and Penicillium. Ochratoxin A was classified as a group 2B carcinogen and is one of the major intestinal pathogenic mycotoxins. One of the most frequent modes of intoxication is consumption of contaminated food with mycotoxins. Feed represents the major cost and has a direct impact on the economical viability of broiler's production system, since it must contain the necessary elements that allow the animal to express the maximum genetic potential while providing its nutritional requirements. Thus, the animal has to digest the feed and absorb its nutrients, which is in direct correlation with the gastrointestinal tract, especially the small intestine and the development of the mucosal surface area. Once ingested, OTA is absorbed by passive diffusion, mainly the jejunum. Ochratoxin A's presence affects lipid membranes and could lead to the degradation of their normal structure and functionality. All of these effects contribute to the development of malabsorption. It was very interesting to study the effect of OTA on the layer of phospholipids of the bowel. The experimental group received OTA (0.05 to mg/kg BW) through an intra-peritoneal injection, every other day for 21 days. We noted that feed conversion ratio and average daily gain were reduced. Histological studies showed important alterations at the level of the mucosal membrane of the intestine (villosities, crypts) following intra-peritoneal administration of the mycotoxin. Thinning and enlargement at the base of the villosities, hyperplasia and crypts in irregular forms, blunting and denudation were observed through the examination of intestinal morphology. Biochemical studies, such as total lipid and phospholipid compositions, allowed us to have more detailed results. All identified mucosal phospholipids were modified, particularly the phosphatidylcholine (PC) and the phosphatidylethanolamine (PE) in the jejunum mucosa. In fact, there was a decrease by 55.81% for PC, 56.66% for PE, while a significant increase by 32.91% was noted for phosphatidylserine in the jejunum. It was very interesting to study the effect of OTA on the phospholipids layer of the bowel, as the mucous membrane of the small intestine represents the main site of absorption and transformation of nutriments. To avoid such disturbances and prevent the effects of the OTA, precautions must be taken to inhibit mold growth at the level of the feed manufactory units. Phosphatidylcholine and PE administrations may represent an option that could allow reestablishment of phospholipid equilibrium in the intestine.


Ionic liquid-enhanced photooxidation of water using the polyoxometalate anion [P2W18O62](6-) as the sensitizer.
Simple polyoxometalate anions are known to be photoreduced in molecular solvents in the presence of 2-propanol or benzyl alcohol. The use of ionic liquids (ILs) as the solvent is now reported to also allow the photooxidation of water to be achieved. In particular, the photochemistry of the classic Dawson polyoxometalate salt K(6)[P(2)W(18)O(62)] has been studied in detail when water is present in the aprotic IL, 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF(4)]) and the protic IL, diethanolamine hydrogen sulfate (DEAS). In these and other ILs, irradiation with white light (wavelength 275-750 nm) or UV light (wavelength 275-320 nm) leads to overall reduction of the [P(2)W(18)O(62)](6-) anion to [P(2)W(18)O(62)](7-) and concomitant oxidation of water to dioxygen and protons. The modified structure of bulk water present in ILs appears to facilitate its oxidation. Analogous results were obtained in aqueous solutions containing the protic IL as an electrolyte. The photoproducts (reduced polyoxometalate anion, dioxygen, and protons) were identified by, respectively, voltammetry, a Clark electrode, and monitoring of pH. The formal reversible potentials E(0)(F) for [P(2)W(18)O(62)](6-/7-/8-/9-/10-) couples are much more positive than in molecular solvents. The [P(2)W(18)O(62)](8-) and more reduced anions, if formed as intermediates, would efficiently reduce photoproducts H(+) or dioxygen to produce [P(2)W(18)O(62)](7-), rather than reform to [P(2)W(18)O(62)](6-). Thus, under photoirradiation conditions [P(2)W(18)O(62)](7-) acts as a kinetic sink so that in principle indirect splitting of water to produce dioxygen and dihydrogen can be achieved. The equivalent form of photooxidation does not occur in liquid water or in molecular solvents such as MeCN and MeCN/CH(2)Cl(2) containing added water, but does occur for solid K(6)[P(2)W(18)O(62)] in contact with water vapor.


Condylar penetration into the middle cranial fossa.
This article describes two cases of condylar penetration into the middle cranial fossa in which a similar surgical procedure is used, namely, a rib graft for closure of the fossa. The rib graft, being an autogenous substance, does not present the problems associated with alloplastic materials. If care is taken not to contaminate the graft, and if the bone used has adequate thickness to prevent penetration and resorption, the graft will prove a superior option to repair damage in the middle cranial fossa.


Effects of GABA-mediated inhibition on direction-dependent frequency tuning in the frog inferior colliculus.
Earlier studies from our laboratory have shown that the frequency selectivity of neurons in the frog inferior colliculus is direction dependent. The goal of this study was to test the hypotheses that gamma-aminobutyric acid or GABA (but not glycine)-mediated synaptic inhibition was responsible for the direction-dependence in frequency tuning, and that GABA acted through creation of binaural inhibition. We performed single unit recordings and investigated the unit's free-field frequency tuning, and/or the unit's response to the interaural level differences (under dichotic stimulation), before and during local applications of antagonists specific to gamma-aminobutyric acid A and glycine receptors. Our results showed that application of bicuculline produced a broadening of free-field frequency tuning depending on sound direction, i.e., more pronounced at azimuths at which the unit exhibited narrower frequency tuning under the pre-drug condition, thereby typically abolishing direction dependence in tuning. Application of strychnine produced no change in frequency tuning. The results from dichotic stimulation further revealed that bicuculline typically elevated and/or flattened the unit's interaural-level-difference response function, indicating a reduction in the strength of binaural inhibition. Our study provides evidence that gamma-aminobutyric acid-mediated binaural inhibition is important for direction dependence in frequency tuning.


Dysregulation of the autonomic nervous system and its association with the presence and intensity of chronic widespread pain.
To test the hypotheses that dysregulation of the autonomic nervous system (ANS) is associated with the presence of chronic widespread pain (CWP), and that dysregulation of the ANS is associated with higher pain intensity in CWP. Cross-sectional data were obtained from 1,574 subjects (healthy controls as well as persons with depressive and anxiety disorders) participating in The Netherlands Study of Depression and Anxiety. The Chronic Pain Grade was used to assess pain intensity and pain-related disability. Heart rate (HR), SD of the normal-to-normal interval (SDNN), the preejection period (PEP), and respiratory sinus arrhythmia (RSA) were used to assess the ANS. Logistic regression analyses and linear regression analyses were conducted with adjustment for potential confounders. No differences in HR, PEP, SDNN, or RSA values were found between CWP subjects and controls after adjustment for confounders. However, lower SDNN and lower RSA were associated with higher pain intensity in subjects with CWP. Lower parasympathetic activity, as assessed with SDNN and RSA, is associated with higher pain intensity in subjects with CWP. This large and well-controlled study does not provide evidence for an association between dysregulation of the ANS and the presence of CWP.


Computational Structural Pharmacology and Toxicology of Voltage-Gated Sodium Channels.
Voltage-gated sodium channels are targets for many toxins and medically important drugs. Despite decades of intensive studies in industry and academia, atomic mechanisms of action are still not completely understood. The major cause is a lack of high-resolution structures of eukaryotic channels and their complexes with ligands. In these circumstances a useful approach is homology modeling that employs as templates X-ray structures of potassium channels and prokaryotic sodium channels. On one hand, due to inherent limitations of this approach, results should be treated with caution. In particular, models should be tested against relevant experimental data. On the other hand, docking of drugs and toxins in homology models provides a unique possibility to integrate diverse experimental data provided by mutational analysis, electrophysiology, and studies of structure-activity relations. Here we describe how homology modeling advanced our understanding of mechanisms of several classes of ligands. These include tetrodotoxins and mu-conotoxins that block the outer pore, local anesthetics that block of the inner pore, batrachotoxin that binds in the inner pore but, paradoxically, activates the channel, pyrethroid insecticides that activate the channel by binding at lipid-exposed repeat interfaces, and scorpion alpha and beta-toxins, which bind between the pore and voltage-sensing domains and modify the channel gating. We emphasize importance of experimental data for elaborating the models.


Dietary Habits and Cardiometabolic Health in Obese Children.
Prevalence rates of cardiometabolic risk factors vary largely among overweight children. This study investigated the relationships between dietary habits and cardiometabolic health among obese children living in a city of Northern Italy. Dietary habits were collected in 448 obese subjects aged 6-18 years, attending an obesity outpatient center in Milan. Anthropometry, blood pressure (BP), lipids, fasting and post-load glucose, and insulin were measured. Physical activity was assessed in adolescents using a questionnaire. Frequency of glucose intolerance, hypertension and dyslipidemia was 0.7%, 13% and 27.2%, respectively. Plausible reporters consumed more animal protein and sodium and less legumes than recommended in nutritional recommendations and adequate amounts of fiber mainly derived from whole grains. Subjects skipping breakfast had unhealthy diets and greater body fatness. After adjustment for confounders, waist/height and fasting glucose were associated with sodium intake (r =0.149 and r = 0.142, respectively; p < 0.05), 2-hour glucose with fiber (r = -0.172; p < 0.01), and BP with vegetable protein intake (systolic r = -0.120 (p < 0.05); diastolic r = -0.267 (p < 0.01)). Hypertensive children consumed less vegetable protein than normotensive children. The cardiometabolic health of obese children improves with vegetable protein and whole grain intake, whereas dysglycemia and adiposity increase with sodium intake.


Fixation of metatarsal osteotomies in the treatment of hallux valgus.
Osteotomies as a treatment for hallux valgus require careful preoperative planning and meticulous attention to surgical technique. The procedure selected should be tailored to fit the deformity. For a patient with mild hallux valgus, the chevron osteotomy is the most intrinsically stable of the distal osteotomies and has the least potential for complications. Interest in the Ludloff osteotomy has had a resurgence because of its improved stability compared with more traditional osteotomies for correction of metatarsus primus varus. This osteotomy, however, is less forgiving and more dependent on technique than other procedures. The proximal chevron osteotomy, with plantar-to-dorsal screw placement, is easier to perform than the Ludloff and provides excellent stability. Regardless of the osteotomy used, screw fixation has been shown to be mechanically superior to all other modes of fixation (K-wire, staples, or no fixation). Postoperatively, a hard-soled postoperative shoe that permits weight-bearing on the heel and lateral foot is recommended; however, for the more unstable osteotomies and for those performed in patients with poor bone quality, a period of non-weight-bearing should be considered. Future studies with cyclic loading may help modify these current postoperative restrictions.


Mendelian randomization of serum urate and parkinson disease progression.
Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach. The study was conducted among participants in DATATOP and PRECEPT, 2 randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for 3 SLC2A9 single nucleotide polymorphisms (SNPs) that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. An SLC2A9 score was created based on the total number of minor alleles at the 3 SLC2A9 loci. Primary outcome was disability requiring dopaminergic treatment. Serum urate concentrations were 0.69mg/dl lower among individuals with ≥4 SLC2A9 minor alleles as compared to those with ≤2 (p = 0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR = 1.16, 95% confidence interval [CI] = 1.00-1.35, p = 0.056). In a comparative analysis, the HR was 1.27 (95% CI = 1.00-1.61, p = 0.0497) for a 0.5mg/dl genetically conferred decrease in serum urate, and 1.05 (95% CI = 1.01-1.10, p = 0.0133) for a 0.5mg/dl decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression. This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels.


Cell cycle arrest and astrocytic differentiation resulting from PTEN expression in glioma cells.
Genetic alterations of the PTEN gene (also known as MMAC1 or TEP1) have frequently been identified in high-grade gliomas, indicating that inactivation of PTEN plays a crucial role in human glioma progression. The aim of this study was to assess the biological significance of PTEN inactivation in the development of glioma. The authors introduced wild-type PTEN complementary DNA into four human glioma cell lines (T98G, U-251MG, U-87MG, and A172) containing endogenous aberrant PTEN alleles. The number of colonies transfected with the wild-type PTEN was reduced to 15 to 32% of those found after transfection of a control vector, suggesting growth suppression by the exogenous PTEN. To analyze phenotypic alterations produced by PTEN expression, T98G-derived clones with inducible PTEN expression were further established using a tetracycline-regulated inducible gene expression system. Induction of PTEN expression suppressed the in vitro growth of T98G cells with accumulation of G1 phase cells. Furthermore, when cells were cultured in the presence of the extracellular matrix (ECM), PTEN expression caused distinct morphological changes, with multiple and elongated cytoplasmic processes similar to those of normal astrocytes. The level of glial fibrillary acidic protein, an intermediate protein specifically expressed in differentiated astrocytes, was upregulated concomitantly. These findings strongly indicate that exogenous PTEN expression inhibits the proliferation of glioma cells by inducing G1 arrest and elicits astrocytic differentiation in the presence of the ECM. Inactivation of PTEN would play an important role in the enhancement of unregulated growth of undifferentiated glioma cells.


The relevance of iron overload and the appropriateness of iron chelation therapy for patients with myelodysplastic syndromes: a dialogue and debate.
Accumulation of excessive amounts of iron in vulnerable organs and tissues, together with elevated plasma and intracellular concentrations of reactive iron molecules, are likely to be harmful to some patients with myelodysplastic syndromes (MDS) who have received numerous red blood cell transfusions. But what is the real magnitude of risks related to iron overload in MDS, and how strong is the evidence that reducing total body iron and labile plasma iron through treatment with chelating drugs is beneficial to patients? Available data can be interpreted in different ways, and as a result, these topics continue to be areas of heated debate among physicians who care for patients with MDS. Using the traditional but rarely employed format of a classical dialogue, I explore here the potential dangers of iron overload and the risks and benefits of iron chelation therapy for patients with MDS.