Interleukin-12: role of interferon-gamma in IL-12 adverse effects.
Interleukin 12 (IL-12) activates natural killer and T cells with the secondary synthesis and release of interferon-gamma (IFN-gamma) and therefore enhances a Th1- or cell-mediated immune response. The immunostimulatory property of IL-12 may be used clinically in cancer and viral diseases. Safety studies in rodents and primates demonstrated a rather small therapeutic window with hepato- and splenomegaly, myelodepression, and lung edema. Investigations in mutant mice deficient for the IFN-gamma receptor (IFN-gamma R-/-) revealed that both the biologic and toxic effects are indirect and largely due to IL-12-induced IFN-gamma. The significance of these findings for the safety in man needs to be explored.


Chronic Discharging Sinus of Upper Lid Due to the Missed Wooden Foreign Body.
Foreign bodies of the orbit can have a diverse range of clinical presentations, which may be perplexing to the most Ophthalmologists. Wooden foreign bodies can remain quiescent for a long time, before presenting with various complications. We report a case of Post-traumatic chronic non-healing discharging sinus in the left upper lid, which on exploration revealed the presence of the missed wooden foreign body. A 48-year-old male, presented to Ophthalmic OPD with a complaint of discharge from the left upper eyelid for 18 months. The patient had a history of minor trauma to the left upper eyelid while collecting wood in the forest, 18 months back. The patient was misdiagnosed on previous examinations elsewhere. The diagnosis of retained wooden foreign body was made at our center and surgical exploration was done to remove the same. On clinical examination, there was a 2-3mm long sinus in the left upper eyelid with purulent discharge and granulation tissue. Surrounding skin showed hyperpigmentation and excoriation. CT scan orbit was inconclusive. MRI orbit revealed a peripherally enhancing extraconal/conal collection in the left orbit with a central hypo intense structure suggestive of a foreign body. Surgical exploration of the wound was done and a small wooden foreign body measuring 9mm was removed with excision of the sinus tract. A history of trauma followed by chronic discharging sinus should evoke suspicion of a retained foreign body. Prompt imaging, followed by surgical exploration should be done to prevent misdiagnosis and inappropriate management.


Regional TMPRSS2 V197M Allele Frequencies Are Correlated with COVID-19 Case Fatality Rates.
Coronavirus disease, COVID-19 (coronavirus disease 2019), caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has a higher case fatality rate in European countries than in others, especially East Asian ones. One potential explanation for this regional difference is the diversity of the viral infection efficiency. Here, we analyzed the allele frequencies of a nonsynonymous variant rs12329760 (V197M) in the TMPRSS2 gene, a key enzyme essential for viral infection and found a significant association between the COVID-19 case fatality rate and the V197M allele frequencies, using over 200,000 present-day and ancient genomic samples. East Asian countries have higher V197M allele frequencies than other regions, including European countries which correlates to their lower case fatality rates. Structural and energy calculation analysis of the V197M amino acid change showed that it destabilizes the TMPRSS2 protein, possibly negatively affecting its ACE2 and viral spike protein processing.


Prevalence of mutations in GJB2, SLC26A4, and mtDNA in children with severe or profound sensorineural hearing loss in southwestern China.
To study the distribution characteristics of common mutations in the GJB2, SLC26A4, and mtDNA genes in children with severe or profound sensorineural hearing loss (SNHL) in southwestern China. A total of 1,164 individuals were recruited to screen for the common GJB2, SLC26A4, and mtDNA mutations by microarrays. Subsequencing for the coding region of the GJB2 gene in the samples without the GJB2 hotspot mutations as well as subsequencing for the exon 1 of the TRMU gene in those samples with the mtDNA hotspot mutations was performed by Sanger sequencing. All mutations were analyzed in association with medical imaging. In this study, 28.43% of all subjects carried mutations. The mutation frequencies in the GJB2, SLC26A4, and mtDNA genes were 17.27%, 7.04%, and 4.12%, respectively. No TRMU mutation was found in the study. The frequency of the mtDNA mutations in the multiethnic minorities was six times that in the Han (11.23% vs. 1.91%; p approaches 0.000) and in the urban group was one-third of that in the suburban group(1.49% vs. 4.47%; p=0.047). The frequency of the GJB2 mutations in urban and suburban groups was 23.38% and 15.99%, respectively (p=0.012). The enlarged vestibular aqueduct (EVA) was the most common inner ear malformation and ∼79.10% of EVA cases were associated with the SLC26A4 mutations. More than one-fourth of children with severe or profound SNHL carried the common deafness mutations. The proportions of ethnic minorities and urban subjects could impact the frequency of the GJB2 and mtDNA mutations. The SLC26A4 hotspot mutations are prevalent and correlate strongly with EVA.


Middle-ear transmission in humans: wide-band, not frequency-tuned?
Postmortem and in vivo vibration responses to sound of the stapes and the umbo of human ears are surveyed. The magnitudes of umbo velocity responses recorded postmortem decay between 1 and 5 or 10 kHz at rates between 0 and -3 dB/octave. In contrast, the magnitudes of in vivo umbo vibration are relatively invariant over a wide frequency range, amply exceeding the bandwidth of the audiogram according to one report. Similarly, most studies of postmortem stapes vibration report velocities tuned to about 1 kHz, with magnitudes that decay at a rate of about -6 dB/octave at higher frequencies. In contrast, in vivo stapes responses are apparently only mildly tuned. We conjecture that the bandwidth of stapes vibration velocity in humans will eventually be shown to exceed the bandwidth of the audiogram, in line with findings in other amniotic vertebrates.


Varietal Response and Estimates of Heritability of Resistance to Meloidogyne javanica in Carrots.
With methods developed in this study, varietal responses to M. javanica were evaluated and heritability of resistance of two promising carrot cultivars was estimated. More egg masses were found on root systems inoculated with eggs added to the soil in three holes in 250 cm(3) cups than by mixing the inoculum with soil in the cups. A resistant breeding line, CNPH 1437, was discriminated from susceptible cultivar Nova Kuroda with inoculum levels higher than 2,000 eggs per cup. Greenhouse and field results suggested that cultivars Nantes Superior and Shin Kuroda were susceptible, Kuronan was somewhat tolerant, and Brasilia and Tropical were resistant to M. javanica. Nantes Superior or Shin Kuroda yielded less in carbofuran-treated soil (3 kg a.i./ha) than Kuronan, Brasilia, and Tropical did in nontreated soil. However, incorporation of the nematicide greatly increased yields of Kuronan (32%), Brasilia (62%), and Tropical (91%). Primary root galling at the seedling stage was an adequate parameter for resistance evaluation. Estimated heritability were 0.48 +/- 0.07 for primary root galling and 0.35 +/- 0.08 for egg mass production in Brasilia, and 0.16 +/- 0.11 for primary root galling and 0.31 +/- 0.09 for egg mass production in Kuronan.


Nonuniform Planning Target Volume Margins for Prostate Bed on the Basis of Surgical Clips on Daily Cone Beam Computed Tomography.
We hypothesized that the interfraction motions of the superior and inferior prostate beds differ and therefore require different margins. In this study, we used daily cone beam computed tomography (CBCT) to evaluate the motion of postprostatectomy surgical clips (separated to superior and inferior portions) within the planning target volume (PTV) to derive data-driven PTV margins. Our study cohort included consecutive patients with identifiable surgical clips undergoing prostate bed irradiation with daily CBCT image guidance. We identified and contoured the clips within the PTV on the planning computed tomography and CBCT scans. All CBCT scans were registered to the planning computed tomography scan on the basis of pelvic bony structures. The superior border of the pubic symphysis was used to mark the division between the superior and inferior portions. Eleven patients with 263 CBCT scans were included in the cohort. In the left-right direction, the global mean M, systematic error Σ, and residue error σ were 0.02, 0.03, and 0.16 cm, respectively, for superior clips, and 0.00, 0.03, and 0.03 cm, respectively, for inferior clips. In the anterior-posterior direction, the corresponding values were M = 0.01, Σ = 0.25, and σ= 0.37, respectively, for superior, and M = 0.08, Σ= 0.13, σ= 0.15, respectively, for inferior. In the superior-inferior direction, the values were M =-0.06, Σ= 0.23, and σ= 0.27, respectively, for superior, and M =-0.01, Σ= 0.21, σ= 0.20, respectively, for inferior. The results of the 2-tailed F tests showed that the anterior-posterior motion is statistically different between the superior and inferior portions in the anterior-posterior direction. There is no statistical difference in the superior-inferior and lateral directions. Therefore, we propose a set of nonuniform PTV margins (based on the formula 2.5 Σ+ 0.7σ) as 0.2 cm for all prostate beds in the left-right direction, 0.7 cm for all in superior-inferior, and 0.9 to 0.4 for superior-inferior in the anterior-posterior direction. The difference in motion between the superior and inferior portions of the prostate bed is statistically insignificant in the left-right and superior-inferior directions, but statistically significant in the anterior-posterior direction, which warrants a nonuniform PTV margin scheme.


Use of preclinical dog studies and absorption modeling to facilitate late stage formulation bridging for a BCS II drug candidate.
Formulation changes are common during drug development either due to clinical or manufacturing considerations. These changes especially at later stages of drug development oftentimes raise questions on the potential impact of a new formulation on bioavailability. In this work, the preclinical assessment of formulation bridging risk for a Biopharmaceutics Classification System II development compound is presented. Early clinical studies were conducted using a liquid-filled capsule (LFC). To assess the feasibility of a conventional solid dosage form, an initial analysis was conducted using absorption modeling which indicated conventional formulation of micronized active pharmaceutical ingredient (API) could be a viable option. Subsequently, test formulations were prepared and tested in vivo in dogs. The solid formulations were able to match exposures of the LFC capsule in the dog model; in addition, a sensitivity to API PSD was observed in line with the modeling predictions. When tested in the clinic, the conventional solid formulation resulted in exposures of approximately 25% lower compared to the LFC on an equivalent dose basis; however, bridging with a small dose adjustment would be feasible. The outcome of the clinical study was better predicted by the modeling approach while the dog model appeared to somewhat overestimate absorption. Through the use of preclinical tools and modeling and simulation, a risk assessment around formulation bridging can be conducted and inform formulation decisions or subsequent clinical study designs.


Implementation of a Defecation Posture Modification Device: Impact on Bowel Movement Patterns in Healthy Subjects.
The goal of this study was to evaluate the influence of defecation postural modification devices (DPMDs) on normal bowel patterns. The introduction of DPMDs has brought increased awareness to bowel habits in western populations. A prospective crossover study of volunteers was performed that included real-time collection of data regarding bowel movements (BMs) for 4 weeks (first 2 wk without DPMD and subsequent 2 wk with DPMD). Primary outcomes of interest included BM duration, straining, and bowel emptiness with and without DPMD use. In total, 52 participants (mean age, 29 y and 40.1% female) were recruited for this study. At baseline 15 subjects (28.8%) reported incomplete emptying, 23 subjects (44.2%) had increased straining, and 29 subjects (55.8%) noticed blood on their toilet paper in the past year. A total of 1119 BMs were recorded (735 without DPMD and 384 with DPMD). Utilizing the DPMD resulted in increased bowel emptiness (odds ratio, 3.64; 95% confidence interval (CI), 2.78-4.77) and reduced straining patterns (odds ratio, 0.23; 95% CI, 0.18-0.30). Moreover, without the DPMD, participants had an increase in BM duration (fold increase, 1.25; 95% CI, 1.17-1.33). DPMDs positively influenced BM duration, straining patterns, and complete evacuation of bowels in this study.


[Ultrasonography of biliopancreatoduodenal zone in patients with gastroduodenal ulcers].
Frequency of chronic gastroduodenal motility disorders and possibilities of ultrasound diagnostics of biliopancreatoduodenal zone in patients with gastroduodenal ulcers were studied. 95 patients, aged 20-78 years, were included in the study. Changes of echomorphology of the liver, gall bladder and pancreas reflected the severity of ulcer disease. Duodenal motility disorders defined the secondary nature of pathologic changes in involved biliopancreatic structures.


Stress as an endogenous adjuvant: augmentation of the immunization phase of cell-mediated immunity.
Stress is thought to be immunosuppressive but paradoxically exacerbates inflammatory and autoimmune diseases. We initially showed that acute stress enhances skin immunity. Such immunoenhancement could promote immunoprotection in case of wounding, infection or vaccination but could also exacerbate immunopathological diseases. Here we identify the molecular and cellular mediators of the immunoenhancing effects of acute stress. Compared with non-stressed mice, acutely stressed animals showed significantly greater pinna swelling and leukocyte infiltration, and up-regulated macrophage chemoattractant protein-1, macrophage inflammatory protein-3alpha, IL-1alpha, IL-1beta, IL-6, tumor necrosis factor-alpha and IFN-gamma, but not IL-4 gene expression at the site of primary antigen exposure. Stressed animals also showed enhanced maturation and trafficking of dendritic cells (DCs) from skin to lymph nodes (LNs), higher numbers of activated macrophages in skin and LNs, increased T cell activation in LNs, and enhanced recruitment of surveillance T cells to skin. These findings show that important interactive components of innate (DCs and macrophages) and adaptive (surveillance T cells) immunity are mediators of the stress-induced enhancement of a primary immune response. Such enhancement during primary immunization may induce a long-term increase in immunologic memory resulting in subsequent augmentation of the immune response during secondary antigen exposure. Thus, the evolutionarily adaptive fight-or-flight stress response may protectively prepare the immune system for impending danger (e.g. infection and wounding by a predator), but may also contribute to stress-induced exacerbation of inflammatory and autoimmune diseases.


Multi-task deep learning for glaucoma detection from color fundus images.
Glaucoma is an eye condition that leads to loss of vision and blindness if not diagnosed in time. Diagnosis requires human experts to estimate in a limited time subtle changes in the shape of the optic disc from retinal fundus images. Deep learning methods have been satisfactory in classifying and segmenting diseases in retinal fundus images, assisting in analyzing the increasing amount of images. Model training requires extensive annotations to achieve successful generalization, which can be highly problematic given the costly expert annotations. This work aims at designing and training a novel multi-task deep learning model that leverages the similarities of related eye-fundus tasks and measurements used in glaucoma diagnosis. The model simultaneously learns different segmentation and classification tasks, thus benefiting from their similarity. The evaluation of the method in a retinal fundus glaucoma challenge dataset, including 1200 retinal fundus images from different cameras and medical centers, obtained a [Formula: see text] AUC performance compared to an [Formula: see text] obtained by the same backbone network trained to detect glaucoma. Our approach outperforms other multi-task learning models, and its performance pairs with trained experts using [Formula: see text] times fewer parameters than training each task separately. The data and the code for reproducing our results are publicly available.


Evolutionary and mechanistic insights from the reconstruction of α-humulene synthases from a modern (+)-germacrene A synthase.
Germacrene A synthase (GAS) from Solidago canadensis catalyzes the conversion of farnesyl diphosphate (FDP) to the plant sesquiterpene (+)-germacrene A. After diphosphate expulsion, farnesyl cation reacts with the distal 10,11-double bond to afford germacrene A (>96%) and <2% α-humulene, which arises from 1,11-cyclization of FDP. The origin of the 1,11-activity of GAS was investigated by amino acid sequence alignments of 1,10- and 1,11-synthases and comparisons of X-ray crystal structures with the homology model of GAS; a triad [Thr 401-Gly 402-Gly 403] that might be responsible for the predominant 1,10-cyclization activity of GAS was identified. Replacement of Gly 402 with residues of increasing size led to a progressive increase of 1,11-cyclization. The catalytic robustness of these 1,10- /1,11-GAS variants point to Gly 402 as a functional switch of evolutionary significance and suggests that enzymes with strict functionalities have evolved from less specific ancestors through a small number of substitutions. Similar results were obtained with germacrene D synthase (GDS) upon replacement of the homologous active-site residue Gly 404: GDS-G404V generated approximately 20% bicyclogermacrene, a hydrocarbon with a cyclopropane ring that underlines the dual 1,10-/1,11-cyclization activity of this mutant. This suggests that the reaction pathways to germacrenes and humulenes might be connected through a bridged 1,10,11-carbocation intermediate or transition state that resembles bicyclogermacrene. Mechanistic studies using [1-(3)H1]-10-fluorofarnesyl diphosphate and deuterium-labeling experiments with [12,13-(2)H6]-FDP support a germacrene-humulene rearrangement linking 1,10- and 1,11-pathways. These results support the bioinformatics proposal that modern 1,10-synthases could have evolved from promiscuous 1,11-sesquiterpene synthases.


Sputter growth and characterization of metamagnetic B2-ordered FeRh epilayers.
Chemically ordered alloys are useful in a variety of magnetic nanotechnologies. They are most conveniently prepared at an industrial scale using sputtering techniques. Here we describe a method for preparing epitaxial thin films of B2-ordered FeRh by sputter deposition onto single crystal MgO substrates. Deposition at a slow rate onto a heated substrate allows time for the adatoms to both settle into a lattice with a well-defined epitaxial relationship with the substrate and also to find their proper places in the Fe and Rh sublattices of the B2 structure. The structure is conveniently characterized with X-ray reflectometry and diffraction and can be visualised directly using transmission electron micrograph cross-sections. B2-ordered FeRh exhibits an unusual metamagnetic phase transition: the ground state is antiferromagnetic but the alloy transforms into a ferromagnet on heating with a typical transition temperature of about 380 K. This is accompanied by a 1% volume expansion of the unit cell: isotropic in bulk, but laterally clamped in an epilayer. The presence of the antiferromagnetic ground state and the associated first order phase transition is very sensitive to the correct equiatomic stoichiometry and proper B2 ordering, and so is a convenient means to demonstrate the quality of the layers that can be deposited with this approach. We also give some examples of the various techniques by which the change in phase can be detected.


MBD4 interacts with and recruits USP7 to heterochromatic foci.
MBD4 is the only methyl-CpG binding protein that possesses a C-terminal glycosylase domain. It has been associated with a number of nuclear pathways including DNA repair, DNA damage response, the initiation of apoptosis, transcriptional repression, and DNA demethylation. However, the precise contribution of MBD4 to these processes in development and relevant diseases remains elusive. We identified UHRF1 and USP7 as two new interaction partners for MBD4. Both UHRF1, a E3 ubiquitin ligase, and USP7, a de-ubiquinating enzyme, regulate the stability of the DNA maintenance methyltransferase, Dnmt1. The ability of MBD4 to directly interact with and recruit USP7 to chromocenters implicates it as an additional factor that can potentially regulate Dnmt1 activity during cell proliferation.


[Examination of body concept of female patients with borderline personality disorder].
The operationalized diagnosis of borderline personality disorder (BPD) by DSM-IV and ICD-10 (research criteria) is meanwhile considered as valid and reliable. A disturbed or inappropriate body image within the group of borderline patients is not assessed by these instruments. Using the "Frankfurter Körperkonzeptskalen" [6], we compared the body concept of 47 female patients with BPD with a group of patients with the diagnosis of Bulimia nervosa and with a representative sample of healthy subjects. We found highly significant differences between patients with BPD and the clinical controls as well as to the norm group. Neither dissociative symptoms nor sexual child abuse correlate with the extent of the negative body concept. Correlations between self-concept (Giessen-Test) and body concept as well as clinical implications of these findings are discussed.


New contribution to scattering of weakly interacting massive particles on nuclei.
A weakly interacting massive particle (WIMP) is perhaps the most promising candidate for the dark matter in the Galactic halo. The WIMP detection rate in laboratory searches is fixed by the cross section for elastic WIMP-nucleus scattering. Here we calculate the contribution to this cross section from two-nucleon currents from pion exchange in the nucleus and show that it may, in some cases, be comparable to the one-nucleon current that has been considered in prior work and perhaps help resolve the discrepancies between the various direct dark-matter search experiments. We provide simple expressions that allow these new contributions to be included in current calculations.


Willingness to pay for personalised nutrition across Europe.
Personalised nutrition (PN) may promote public health. PN involves dietary advice based on individual characteristics of end users and can for example be based on lifestyle, blood and/or DNA profiling. Currently, PN is not refunded by most health insurance or health care plans. Improved public health is contingent on individual consumers being willing to pay for the service. A survey with a representative sample from the general population was conducted in eight European countries (N = 8233). Participants reported their willingness to pay (WTP) for PN based on lifestyle information, lifestyle and blood information, and lifestyle and DNA information. WTP was elicited by contingent valuation with the price of a standard, non-PN advice used as reference. About 30% of participants reported being willing to pay more for PN than for non-PN advice. They were on average prepared to pay about 150% of the reference price of a standard, non-personalised advice, with some differences related to socio-demographic factors. There is a potential market for PN compared to non-PN advice, particularly among men on higher incomes. These findings raise questions to what extent personalized nutrition can be left to the market or should be incorporated into public health programs.


Surgical management of acute epidural hematomas.
An epidural hematoma (EDH) greater than 30 cm3 should be surgically evacuated regardless of the patient's Glasgow Coma Scale (GCS) score. An EDH less than 30 cm3 and with less than a 15-mm thickness and with less than a 5-mm midline shift (MLS) in patients with a GCS score greater than 8 without focal deficit can be managed nonoperatively with serial computed tomographic (CT) scanning and close neurological observation in a neurosurgical center. It is strongly recommended that patients with an acute EDH in coma (GCS score < 9) with anisocoria undergo surgical evacuation as soon as possible. There are insufficient data to support one surgical treatment method. However, craniotomy provides a more complete evacuation of the hematoma.


Differential regulation of polarized synaptic vesicle trafficking and synapse stability in neural circuit rewiring in Caenorhabditis elegans.
Neural circuits are dynamic, with activity-dependent changes in synapse density and connectivity peaking during different phases of animal development. In C. elegans, young larvae form mature motor circuits through a dramatic switch in GABAergic neuron connectivity, by concomitant elimination of existing synapses and formation of new synapses that are maintained throughout adulthood. We have previously shown that an increase in microtubule dynamics during motor circuit rewiring facilitates new synapse formation. Here, we further investigate cellular control of circuit rewiring through the analysis of mutants obtained in a forward genetic screen. Using live imaging, we characterize novel mutations that alter cargo binding in the dynein motor complex and enhance anterograde synaptic vesicle movement during remodeling, providing in vivo evidence for the tug-of-war between kinesin and dynein in fast axonal transport. We also find that a casein kinase homolog, TTBK-3, inhibits stabilization of nascent synapses in their new locations, a previously unexplored facet of structural plasticity of synapses. Our study delineates temporally distinct signaling pathways that are required for effective neural circuit refinement.


Genetic, morphological, and spectral characterization of relictual Niobrara River hybrid aspens (Populus × smithii).
Aspen groves along the Niobrara River in Nebraska have long been a biogeographic curiosity due to morphological differences from nearby remnant Populus tremuloides populations. Pleistocene hybridization between P. tremuloides and P. grandidentata has been proposed, but the nearest P. grandidentata populations are currently several hundred kilometers east. We tested the hybrid-origin hypothesis using genetic data and characterized putative hybrids phenotypically. We compared nuclear microsatellite loci and chloroplast sequences of Niobrara River aspens to their putative parental species. Parental species and putative hybrids were also grown in a common garden for phenotypic comparison. On the common garden plants, we measured leaf morphological traits and leaf-level spectral reflectance profiles, from which chemical traits were derived. The genetic composition of the three unique Niobrara aspen genotypes is consistent with the hybridization hypothesis and with maternal chloroplast inheritance from P. grandidentata. Leaf margin dentition and abaxial pubescence differentiated taxa, with the hybrids showing intermediate values. Spectral profiles allowed statistical separation of taxa in short-wave infrared wavelengths, with hybrids showing intermediate values, indicating that traits associated with internal structure of leaves and water absorption may vary among taxa. However, reflectance values in the visible region did not differentiate taxa, indicating that traits related to pigments are not differentiated. Both genetic and phenotypic results support the hypothesis of a hybrid origin for these genetically unique aspens. However, low genetic diversity and ongoing ecological and climatic threats to the hybrid taxon present a challenge for conservation of these relictual boreal communities.


An in vivo study of the corneal surface in keratoconjunctivitis sicca.
Thirteen normal subjects and thirteen subjects with bona fide keratoconjunctivitis sicca were examined employing wide-field colour specular microscopy of the corneal epithelium. The prevalence of small, medium and large cells is different in these two groups with a shift to small cells in patients with keratoconjunctivitis. Increased rose bengal dye uptake filaments, coarse mucus plaques and pre-exfoliative sheets are also seen in keratoconjunctivitis sicca. These findings suggest an accelerated epithelial cell loss from the surface of the eye in keratoconjunctivitis sicca.


Effect of plant growth-promoting bacteria on the growth and fructan production of Agave americana L.
The effect of plant growth-promoting bacteria inoculation on plant growth and the sugar content in Agave americana was assessed. The bacterial strains ACO-34A, ACO-40, and ACO-140, isolated from the A. americana rhizosphere, were selected for this study to evaluate their phenotypic and genotypic characteristics. The three bacterial strains were evaluated via plant inoculation assays, and Azospirillum brasilense Cd served as a control strain. Phylogenetic analysis based on the 16S rRNA gene showed that strains ACO-34A, ACO-40 and ACO-140 were Rhizobium daejeonense, Acinetobacter calcoaceticus and Pseudomonas mosselii, respectively. All of the strains were able to synthesize indole-3-acetic acid (IAA), solubilize phosphate, and had nitrogenase activity. Inoculation using the plant growth-promoting bacteria strains had a significant effect (p<0.05) on plant growth and the sugar content of A. americana, showing that these native plant growth-promoting bacteria are a practical, simple, and efficient alternative to promote the growth of agave plants with proper biological characteristics for agroindustrial and biotechnological use and to increase the sugar content in this agave species.


Neuromuscular adaptations and serum hormones in women during short-term intensive strength training.
The effects were investigated in ten women of intensive heavy resistance strength training lasting for 3 weeks on electromyographic (EMG) activity, muscle cross-sectional area (CSA) and voluntary force production characteristics of leg extensor muscles. Blood samples for the determinations of serum hormones were taken from five of the subjects. Significant increases occurred in the higher force portions of the isometric force-time curve with an increase of 9.7 (SD 8.4)% (P less than 0.01) in maximal peak force. An increase of 15.8 (SD 20.9)% (P less than 0.05) took place also in the maximal neural activation (integrated EMG) of the trained muscles, while an enlargement of 4.6 (SD 7.4)% (P less than 0.05) occurred in the CSA of the quadriceps femoris muscle. Maximal force per muscle CSA increased significantly (P less than 0.05). No statistically significant changes were observed during the training in the mean concentrations of serum testosterone, free testosterone, cortisol and sex hormone binding globulin (SHBG). The individual concentrations of serum testosterone:SHBG ratio correlated with the individual changes obtained during the training in the muscle CSA (r = 0.99; P less than 0.01). The present findings in women indicated that the increases in maximal strength during short-term but intensive strength training were primarily due to the increased voluntary activation of the trained muscles, while muscle hypertrophy remained limited in magnitude. Large interindividual differences in women in serum testosterone concentrations could indicate corresponding differences in muscle hypertrophy and strength development even during a short-term but intensive strength training period.


Medical need and health need.
I introduce a distinction between health need and medical need, and raise several questions about their interaction. Health needs are needs that relate directly to our health condition. Medical needs are needs which bear some relation to medical institutions or processes. I suggest that the question of whether medical insurance or public care should cover medical needs, health needs, or only needs which fit both categories is a political question that cannot be resolved definitionally. I also argue against an overly strict definition of medical need on the grounds that this presupposes, wrongly, that medical intervention should always be a last resort.


Medicinal Cannabis Prescribing in Australia: An Analysis of Trends Over the First Five Years.
A regulatory framework allowing legal access to medicinal cannabis (MC) products has operated in Australia since November 2016. MC prescribing by healthcare practitioners (HCPs) is primarily conducted through the Special Access Scheme - Category B (SAS-B) pathway, through which prescribers apply to the Therapeutic Goods Administration (TGA-the federal regulator) for approval to prescribe a category of product to an individual patient suffering from a specific indication. The dataset collected by the TGA provides a unique opportunity to examine MC prescribing trends over time in the Australian population. Here we analysed this TGA SAS-B dataset since inception with respect to age, gender, product type (e.g., oil, flower, etc.), CBD content, indication treated, and prescriber location. Results are presented descriptively as well as being analysed using non-linear regression models. Relationship between variables were explored via correspondence analyses. Indications were classified with reference to the International Statistical Classification of Diseases and Related Health Problems (10th Revision). As of 31 August 2021, a total of 159,665 SAS-B approvals had been issued for MC products, 82.4% of were since January 2020. Leading indications for approvals were for pain, anxiety, and sleep disorders. Oil products were the most popular product type, while CBD-dominant products (≥98% CBD) accounted for 25.1% of total approvals. Approvals for flower products increased markedly during 2020-2021, as did approvals involving younger age groups (18-31 years old), male patients, and non-CBD dominant products. A disproportionate number of SAS-B MC applications (around 50%) came from HCPs in the state of Queensland. Associations between patient gender and age and/or indication with product type were found. For example, approvals for oil products were commonly associated with approvals for pain. While, overall prescribing increased dramatically over the last 2 years of analysis, stabilization of approval numbers is evident for some indications, such as pain. Current prescribing practices do not always reflect provided TGA guidance documents for MC prescribing. While acknowledging some limitations around the SAS-B dataset, it provides a unique and valuable resource with which to better understand current prescribing practices and utilisation of MC products within Australia.


Hyponatremia during arginine vasopressin therapy in children following cardiac surgery.
To describe the incidence and severity of hyponatremia after initiation of arginine vasopressin therapy in children recovering from cardiothoracic surgery, and to compare these patients with a control group with similar disease complexity and severity who did not receive arginine vasopressin. Retrospective chart review. PICU at a tertiary care university hospital. Twenty-nine patients who received arginine vasopressin for at least 6 hours during the first 48 postoperative hours following cardiothoracic surgery were compared with 47 patients who did not receive arginine vasopressin. After surgery, all patients received intravenous fluids consisting of dextrose and 0.22% saline for daily fluid requirements as well as isotonic colloid and blood products as needed for additional resuscitation. Mean initial postoperative serum sodium did not differ between groups, 144.6 ± 3.4 in those patients who received arginine vasopressin and 144.5 ± 3.7 in those who did not, p = 0.969. Mean lowest sodium in the first 72 hours, however, was 134.7 ± 3.8 in those who received arginine vasopressin as compared with 137.1 ± 4.3 in the control group, p = 0.019. Hyponatremia occurred in 14 of the patients (48%) who received arginine vasopressin but only in 8 of the patients (17%) in the control group, p = 0.004. Mean age, weight, sex, Aristotle score, and duration of cardiopulmonary bypass were not statistically different between groups. Mean volumes of hypotonic fluids administered and cumulative diuretic dosing during the first 72 hours post-surgery were also not statistically different between groups. Hyponatremia occurred in nearly half of the infants and children receiving arginine vasopressin therapy in this study. Clinicians should be aware of this association, monitor serum sodium values closely, and consider providing less free water to these patients before hyponatremia occurs.


[Mitral valve insufficiency in acute myocardial infarction. Assessment with pulsed and coded Doppler color].
We studied 108 patients who sustained an acute myocardial infarction (AMI) by means of echocardiography, pulsed doppler (PD) and Doppler color flow imaging (CD). We evaluate the presence of mitral regurgitation (MR) and it relationship to the site of the AMI and also to the ventricular function. The incidence of MR was 50.92%, (55/108), it was detected in higher percentage when the AMI was inferior (61.8%) than when anterior (39.6%). The correlation with the ejection fraction (EF) was only significative when the AMI was anterior. The incidence of MR was 57.1% when the EF was below 25%. CD had better diagnostic capabilities independently of the site of the AMI, (48% vs 32.1% when the AMI was anterior and 76.1% vs 52.6% when it was inferior).


The non-benzodiazepine anxiolytic etifoxine limits mechanical allodynia and anxiety-like symptoms in a mouse model of streptozotocin-induced diabetic neuropathy.
More than 450 million people worldwide suffer from diabetes, or 1 in 11 people. Chronic hyperglycemia degrades patients' quality of life and the development of neuropathic pain contributes to the burden of this disease. In this study, we used the mouse model of streptozocin-induced diabetic type 1 neuropathy to assess the analgesic potential of etifoxine. Etifoxine is a prescribed anxiolytic that increases GABAAA receptor function through a direct positive allosteric modulation effect and, indirectly, by stimulating the production of endogenous GABAA receptor positive modulators such as allopregnanolone-type neurosteroids. We show that a post-symptomatic or preventive treatment strongly and durably reduces mechanical hyperalgesia and anxiety in diabetic neuropathic mice. This analgesic and neuroprotective effect on painful symptoms and emotional comorbidities is promising and should now be clinically evaluated.


Parametric image reconstruction using the discrete cosine transform for optical tomography.
It is well known that the inverse problem in optical tomography is highly ill-posed. The image reconstruction process is often unstable and nonunique, because the number of the boundary measurements data is far fewer than the number of the unknown parameters to be reconstructed. To overcome this problem, one can either increase the number of measurement data (e.g., multispectral or multifrequency methods), or reduce the number of unknowns (e.g., using prior structural information from other imaging modalities). We introduce a novel approach for reducing the unknown parameters in the reconstruction process. The discrete cosine transform (DCT), which has long been used in image compression, is here employed to parameterize the reconstructed image. In general, only a few DCT coefficients are needed to describe the main features in an optical tomographic image. Thus, the number of unknowns in the image reconstruction process can be drastically reduced. We show numerical and experimental examples that illustrate the performance of the new algorithm as compared to a standard model-based iterative image reconstructions scheme. We especially focus on the influence of initial guesses and noise levels on the reconstruction results.


A Multi-disciplinary and Comparative Approach to Evaluating Pre-trial Detention Decisions: Towards Evidence-Based Reform.
The decision to remand a defendant into custody pre-trial is one of the most controversial criminal justice decisions because it deprives individuals of their liberty while they are presumed to be innocent of a crime. Indeed, pre-trial detention decisions can have significant consequences for defendants, which need to be balanced against the potential implications of bail for public safety and the course of criminal proceedings. Despite this, court-based bail and remand decision-making remains relatively underexplored. In this paper, we compare court-based bail/remand decision-making in England and Wales and The Netherlands. We focus on (i) the procedure and structure of decision-making, (ii) the substantive relevant legal frameworks, (iii) the courts in which the decisions are made and the decision-makers in those courts, (iv) the conditions characterizing the decision task, and (v) the court's reasoning of bail and remand in custody decisions. Using a comparative and multi-disciplinary approach, relying on Law, Criminology, and Psychology, we make predictions about bail and remand in custody rates in the two jurisdictions as well as the decision performance of court-based decision-makers. These predictions are then evaluated using available (official) statistics and past research. We identify the need to collect more nuanced statistical data on bail and remand in custody rates and point to potentially fruitful avenues for future research. A comparative, multi-disciplinary, evidence-based approach can underpin remand reform in England and Wales, The Netherlands, and beyond.


Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients.
Drug interactions constitute a major problem in the treatment of epilepsy because drug combinations are so common. Valproic acid is a widely used anticonvulsant drug with a broad therapeutic spectrum. Case reports suggest interaction between valproic acid and other drugs metabolized mainly by cytochrome P450 isoforms. The aim of this study was to evaluate the inhibitory effect of valproic acid on cytochrome P450 2C9 (CYP2C9) activity by using losartan oxidation as a probe in epilepsy patients. Patients were prescribed sodium valproate (mean 200 mg/day for the first week and 400 mg/day in the following period) according to their clinical need. A single oral dose of 25 mg losartan was given to patients before and after the first dose, first week and 4 weeks of valproic acid treatment. Losartan and E3174, the CYP2C9-derived carboxylic acid metabolite of losartan in 8 hr urine were assayed by using high pressure liquid chromatography. Urinary losartan/E3174 ratio did not change significantly on the first day (0.9, 0.3-3.5; median, range), and first week (0.6, 0.2-3.8; median, range), while a significant increase was observed after 4 weeks of valproic acid treatment (1.1, 0.3-5.7; median, range) as compared to that of measured before valproic acid administration (0.6, 0.1-2.1; median, range) (P = 0.039). The degree of inhibition was correlated with the steady-state plasma concentrations of valproic acid (r(2) = 0.70, P = 0.04). The results suggest an inhibitory effect of valproic acid on CYP2C9 enzyme activity in epilepsy patients at steady state. The risk of pharmacokinetic drug-drug interactions should be taken into account during concomitant use of valproic acid and CYP2C9 substrates.


Reframing strategic, managed retreat for transformative climate adaptation.
Human societies will transform to address climate change and other stressors. How they choose to transform will depend on what societal values they prioritize. Managed retreat can play a powerful role in expanding the range of possible futures that transformation could achieve and in articulating the values that shape those futures. Consideration of retreat raises tensions about what losses are unacceptable and what aspects of societies are maintained, purposefully altered, or allowed to change unaided. Here we integrate research on retreat, transformational adaptation, climate damages and losses, and design and decision support to chart a roadmap for strategic, managed retreat. At its core, this roadmap requires a fundamental reconceptualization of what it means for retreat to be strategic and managed. The questions raised are relevant to adaptation science and societies far beyond the remit of retreat.


Association of depression phenotypes and antidepressant treatment with mortality due to cancer and other causes: a community-based cohort study.
This study aimed to assess the association of somatic depressive symptoms (SDS), cognitive/emotional depressive symptoms (C-EDS), and antidepressant treatment on mortality due to cancer and other causes in a community cohort. A community-based sample recruited in 1995, 2000, and 2005 aged between 35 and 75 years was examined in two waves and followed for a median of 6.7 years. SDS and C-EDS phenotypes were assessed using the Patient Health Questionnaire-9. Medication used by participants was collected. Deaths and their causes were registered during follow-up. Cox proportional hazard models stratified by sex were performed to determine the association between depressive phenotypes and mortality. The cohort consisted of 5,646 individuals (53.9% women) with a mean age of 64 years (SD = 11.89). During the follow-up, 392 deaths were recorded, of which 27.8% were due to cancer. C-EDS phenotype was associated with an increased risk of cancer mortality in both men (HR = 2.23; 95% CI = 1.11-4.44) and women (HR = 3.69; 95% CI = 1.69-8.09), and SDS was significantly associated with non-cancer mortality in men (HR = 2.16; 95 CI % = 1.46-3.18). Selective serotonin reuptake inhibitors (SSRIs) were significantly associated with both cancer (HR = 2.78; 95% CI = 1.10-6.98) and non-cancer mortality (HR = 2.94; 95% CI = 1.76-4.90) only in the male population. C-EDS phenotype was related to an increased risk of cancer mortality at 6 years. In addition, the use of SSRIs in the male population was associated with cancer and all-cause mortality.


Vitamin A deficiency inhibits intestinal adaptation by modulating apoptosis, proliferation, and enterocyte migration.
In a prior study, vitamin A-deficient rats subjected to submassive small bowel resections did not mount a normal intestinal adaptive response by 10 days postoperatively, although adaptive increases in crypt cell proliferation were not attenuated and there were no differences in apoptotic indexes. The present study was designed to address the mechanisms by which vitamin A status effects adaptation by analyzing proliferation, apoptosis, and enterocyte migration in the early postoperative period (16 and 48 h) in vitamin A-sufficient, -deficient, and partially replenished sham-resected and resected rats. At 16 h postresection, apoptosis was significantly greater in the remnant ileum of resected vitamin A-deficient rats compared with the sufficient controls. Crypt cell proliferation was increased by resection in all dietary groups at both timepoints. However, at 48 h postresection, proliferation was significantly decreased in the vitamin A-deficient and partially replenished rats. By 48 h after resection, vitamin A deficiency also reduced enterocyte migration rates by 44%. This occurred in conjunction with decreased immunoreactive collagen IV at 48 h and 10 days postoperation. Laminin expression was also reduced by deficiency at 10 days postresection, whereas fibronectin and pancadherin were unchanged at 48 h and 10 days. These studies indicate that vitamin A deficiency inhibits intestinal adaptation following partial small bowel resection by reducing crypt cell proliferation, by enhancing early crypt cell apoptosis, and by markedly reducing enterocyte migration rates, which may be related to changes in the expression of collagen IV and other extracellular matrix components.


Knockdown of subunit 3 of the COP9 signalosome inhibits C2C12 myoblast differentiation via NF-KappaB signaling pathway.
The COP9 signalosome (CSN) is a conserved protein complex composed of 8 subunits designated CSN1-CSN8. CSN3 represents the third subunit of the CSN and maintains the integrity of the complex. CSN3 binds to the striated muscle-specific β1D integrin tail, and its subcellular localization is altered in differentiated skeletal muscle cells. However, the role of CSN3 in skeletal muscle differentiation is unknown. The main goal of this study was to identify whether CSN3 participates in myoblast differentiation and the signalling mechanisms involved using C2C12 cells as a skeletal muscle cell model. Small-hairpin (shRNA) was used to knockdown CSN3 in C2C12 cells. Differentiation was evaluated by immunostaining and confocal microscopy. Markers of differentiation, NF-κB signaling and CSN subunits expression, were assessed by immunoblotting and/or immunostaining. Cell proliferation was analysed by cell counting, flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Data were analyzed by one or two-way analysis of variance (ANOVA) followed by post-hoc testing. Transduction of C2C12 cells with two distinct CSN3 shRNAs led to the production of two cells lines expressing 7% of CSN3 protein (shCSN3-Low) and 43% of CSN3 protein (CSN3-Med) compared to controls. Knockdown of CSN3 was accompanied by destabilization of several CSN subunits and increased nuclear NF-κB localization. shCSN3-Med cells expressed less myogenin and formed shorter and thinner myotubes. In contrast, the shCSN3-Low cells expressed higher levels of myogenin prior and during the differentiation and remained mononucleated throughout the differentiation period. Both CSN3 knockdown cell lines failed to express sarcomeric myosin heavy chain (MHC) protein during differentiation. The fusion index was significantly higher in control cells than in shCSN3-Med cells, whereas shCSN3-Low cells showed no cell fusion. Interestingly, CSN3 knockdown cells exhibited a significantly slower growth rate relative to the control cells. Cell cycle analysis revealed that CSN3 knockdowns delayed in S phase and had increased levels of nuclear p21/Cip1 and p27/Kip1. This study clarifies the first step toward unrevealing the CSN3/CSN-mediated pathways that controls C2C12 differentiation and proliferation. Further in vivo characterization of CSN/CSN3 may lead to the discovery of novel therapeutic target of skeletal muscle diseases such as muscular dystrophies.


Generation of ultrasound by repetitively Q-switching a pulsed Nd:YAG laser.
Repetitively Q-switching a Nd:YAG laser during a single flashlamp pulse has been used successfully to generate a train of acoustic pulses with a repetition rate as high as 53 kHz. The spectral content of this multiple-pulse ultrasonic signal is significantly narrower in bandwidth than that of a single pulse. A corresponding reduction in the detection system bandwidth results in a marked improvement in detection sensitivity.


Current status of lung cancer screening.
Recent results have demonstrated a major reduction in lung cancer mortality through computed tomography screening and no benefit from chest radiograph (CXR) screening. This presents a huge potential for benefit but also poses challenges regarding management of details to minimize harm. Many unresolved questions remain that must be addressed to implement computed tomography screening for lung cancer in a thoughtful and responsible way.


Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors.
Preclinical data suggest multiple roles for the IGF1 receptor (IGF1R) in neuroendocrine tumors (NETs), including mediating resistance to mammalian target of rapamycin (mTOR) inhibitors. Everolimus, an oral mTOR inhibitor, and octreotide long-acting repeatable (LAR) are approved for subgroups of well-differentiated NET. The primary objective of the present study was to establish the safety and recommended phase II dose (RP2D) of cixutumumab, a monoclonal antibody (MAB) against IGF1R, with everolimus and octreotide LAR. Patients with well-differentiated NET were treated with 10 mg everolimus p.o. daily, 20 mg octreotide LAR i.m. every 21 days, and escalating doses of cixutumumab. An expansion cohort was enrolled at RP2D. Correlative studies included the evaluation of mTOR pathway inhibition in paired tumor biopsies and the effects of this combination on metabolism via indirect calorimetry. Nineteen patients with progressive disease were enrolled, including nine to the expansion portion. Two patients had dose-limiting toxicities of grade 3 mucositis at 15 mg/kg cixutumumab. Long-term tolerance at RP2D was problematic, and the most common ≥grade 3 adverse event was fatigue. One patient with metastatic insulinoma had a confirmed partial response, whereas 17 had stable disease. The median progression-free survival was 43.6 weeks, and the median overall survival was 25.5 months. The RP2D of this combination per the predefined study protocol of 10 mg/kg cixutumumab i.v., 20 mg octreotide LAR i.m. every 21 days plus 10 mg everolimus p.o. daily is associated with non-dose-limiting toxicities that limit long-term tolerance. Although a signal of activity was noted in the present study, this will need to be reconciled with limited tolerance of the combination and data from larger studies of anti-IGF1R MABs in NET that have been disappointing.


Hospitalizations and deaths caused by diarrhea in children five years old and younger at four hospitals in Haiti, 2010-2012.
Worldwide, diarrhea is a major contributor to morbidity and mortality in children; however, there are few data on the burden of diarrheal disease in Haiti. We conducted a retrospective review of hospital discharge registries from 2010 to 2012 in the pediatric wards of four Haitian hospitals and recorded the number of all-cause hospitalizations and deaths as well as diarrheal hospitalizations and deaths by age (≤ 2 and 3-5 years) and epidemiological week. Diarrhea was associated with 3,582 (33.7%) of 10,621 hospitalizations and 62 (11.5%) of 540 in-hospital deaths in children ≤ 5 years old. Of these children, 88.5% and 96.8%, respectively, were among children ≤ 2 years old. The highest proportions of diarrhea-associated hospitalizations occurred from January to April. At four Haitian hospitals over a 3-year period, during which time a major epidemic of cholera occurred, diarrheal disease in children ≤ 5 years was a major contributor to pediatric hospitalizations and mortality.


Understanding the origins of the basic equations of statistical fibrillatory dynamics.
The mechanisms governing cardiac fibrillation remain unclear; however, it most likely represents a form of spatiotemporal chaos with conservative system dynamics. Renewal theory has recently been suggested as a statistical formulation with governing equations to quantify the formation and destruction of wavelets and rotors in fibrillatory dynamics. In this perspective Review, we aim to explain the origin of the renewal theory paradigm in spatiotemporal chaos. The ergodic nature of pattern formation in spatiotemporal chaos is demonstrated through the use of three chaotic systems: two classical systems and a simulation of cardiac fibrillation. The logistic map and the baker's transformation are used to demonstrate how the apparently random appearance of patterns in classical chaotic systems has macroscopic parameters that are predictable in a statistical sense. We demonstrate that the renewal theory approach developed for cardiac fibrillation statistically predicts pattern formation in these classical chaotic systems. Renewal theory provides governing equations to describe the apparently random formation and destruction of wavelets and rotors in atrial fibrillation (AF) and ventricular fibrillation (VF). This statistical framework for fibrillatory dynamics provides a holistic understanding of observed rotor and wavelet dynamics and is of conceptual significance in informing the clinical and mechanistic research of the rotor and multiple-wavelet mechanisms of AF and VF.


Detection of simulated lesions on data-compressed digital mammograms.
To evaluate retrospectively the effect of a wavelet-based compression method on the detection of simulated masses of various sizes and clustered microcalcifications on data-compressed digital mammograms. The images used in this study were acquired with institutional review board approval and patient informed consent, both of which allowed subsequent image data analysis. Patient identification was removed from images, and the study complied with requirements of the Health Insurance Portability and Accountability Act. Masses 3, 6, and 8 mm in diameter were analytically simulated and added to clinical mammographic backgrounds. In addition, microcalcifications were extracted from a clinical mammogram and hybridized with simulated microcalcifications for use in this study. Image compression conditions of 1:1, 15:1, and 30:1 were investigated. Observer responses were recorded with a six-point rating scale, and receiver operating characteristic (ROC) analysis was performed. In addition, two well-established numeric observer models were used to study the effect of image compression under the same compression conditions as were used with human observers. Analysis of variance was performed after observer adjustment to compare the mean values for area under the ROC curve (A(z)) across the three compression levels for the masses and microcalcification clusters. The results of the study indicated no significant differences in the A(z) values for masses with the compression conditions investigated. For images of microcalcifications, there were significant differences in A(z) values between compression ratios of 1:1 and 30:1 (P = .0005) and of 15:1 and 30:1 (P = .004); the difference between compression ratios of 1:1 and 15:1 was nonsignificant (P = .053). The observer models and human observers exhibited similar trends in detection of the masses investigated in this study. Detection of simulated masses was not affected by the compression method with the conditions used in this study, while the detection of microcalcifications was significantly reduced with a compression ratio of more than 15:1.


Prognostic Power of a Tumor Differentiation Gene Signature for Bladder Urothelial Carcinomas.
Muscle-invasive bladder cancers (MIBCs) cause approximately 150 000 deaths per year worldwide. Survival for MIBC patients is heterogeneous, with no clinically validated molecular markers that predict clinical outcome. Non-MIBCs (NMIBCs) generally have favorable outcome; however, a portion progress to MIBC. Hence, development of a prognostic tool that can guide decision-making is crucial for improving clinical management of bladder urothelial carcinomas. Tumor grade is defined by pathologic evaluation of tumor cell differentiation, and it often associates with clinical outcome. The current study extrapolates this conventional wisdom and combines it with molecular profiling. We developed an 18-gene signature that molecularly defines urothelial cellular differentiation, thus classifying MIBCs and NMIBCs into two subgroups: basal and differentiated. We evaluated the prognostic capability of this "tumor differentiation signature" and three other existing gene signatures including the The Cancer Genome Atlas (TCGA; 2707 genes), MD Anderson Cancer Center (MDA; 2252 genes/2697 probes), and University of North Carolina at Chapel Hill (UNC; 47 genes) using five gene expression data sets derived from MIBC and NMIBC patients. All statistical tests were two-sided. The tumor differentiation signature demonstrated consistency and statistical robustness toward stratifying MIBC patients into different overall survival outcomes (TCGA cohort 1, P = .03; MDA discovery, P = .009; MDA validation, P = .01), while the other signatures were not as consistent. In addition, we analyzed the progression (Ta/T1 progressing to ≥T2) probability of NMIBCs. NMIBC patients with a basal tumor differentiation signature associated with worse progression outcome (P = .008). Gene functional term enrichment and gene set enrichment analyses revealed that genes involved in the biologic process of immune response and inflammatory response are among the most elevated within basal bladder cancers, implicating them as candidates for immune checkpoint therapies. These results provide definitive evidence that a biology-prioritizing clustering methodology generates meaningful insights into patient stratification and reveals targetable molecular pathways to impact future therapeutic approach.


Legius syndrome: case report and review of literature.
A 8-month-old child was referred to our Dermatologic Unit for suspected Neurofibromatosis type 1 (NF 1), because of the appearance, since few days after birth, of numerous café-au-lait spots (seven larger than 5 mm); no other sign evocative of NF 1 was found. Her family history was remarkable for the presence of multiple café-au-lait spots in the mother, the grandfather and two aunts. The family had been already examined for NF 1, but no sign evocative of the disease was found. We then suspected Legius syndrome, a dominant disease characterized by a mild neurofibromatosis 1 phenotype. The diagnosis was confirmed by the finding of a mutation in SPRED1 gene, a feedback regulator of RAS/MAPK signaling. Here, we discuss the differential diagnosis of cafè-au-lait spots and we briefly review the existing literature about Legius syndrome.


Species composition and risk of transmission of some Aedes-borne arboviruses in some sites in Northern Ghana.
Aedes-borne viral diseases mainly Yellow Fever (YF), Dengue (DEN), Zika (ZIK) and Chikungunya (CHK) have contributed to many deaths' in the world especially in Africa. There have been major outbreaks of these diseases in West Africa. Although, YF outbreaks have occurred in Ghana over the years, no outbreak of DEN, ZIK and CHK has been recorded. However, the risk of outbreak is high due to its proximity to West African countries where outbreaks have been recently been recorded. This study surveyed the mosquito fauna to assess the risk of transmission of Yellow fever (YFV), Dengue (DENV), Chikungunya (CHKV) and Zika (ZIKV) viruses in Larabanga and Mole Game Reserve areas in Northern Ghana. The immature and adult stages of Aedes mosquitoes were collected from Larabanga and Mole Game Reserve area. There was a significant (P>0.001) number of mosquitoes collected during the rainy season than the dry season. A total of 1,930 Aedes mosquitoes were collected during the rainy season and morphologically identified. Of these, 1,915 (99.22%) were Aedes aegypti and 15 (0.22%) were Aedes vittatus. During the dry season, 27 Ae. aegypti mosquitoes were collected. A total of 415 Ae. aegypti mosquitoes were molecularly identified to subspecies level of which Ae. (Ae) aegypti aegypti was the predominant subspecies. Both Ae. aegypti aegypti and Ae aegypti formosus exist in sympatry in the area. All Aedes pools (75) were negative for DENV, ZIKV and CHKV when examined by RT- PCR. Three Larval indices namely House Index, HI (percentage of houses positive for Aedes larvae or pupae), Container Index, CI (the percentage of containers positive for Aedes larvae or pupae) and Breteau Index, BI (number of positive containers per 100 houses inspected) were assessed as a measure for risk of transmission in the study area. The HI, CI and BI for both sites were as follows; Mole Game Reserve (HI, 42.1%, CI, 23.5% and BI, 100 for rainy season and 0 for all indices for dry season) and Larabanga (39%, 15.5% and 61 for rainy season and 2.3%, 1.3% and 2.3 for dry season). The spatial distribution of Aedes breeding sites in both areas indicated that Aedes larvae were breeding in areas with close proximity to humans. Lorry tires were the main source of Aedes larvae in all the study areas. Information about the species composition and the potential role of Aedes mosquitoes in future outbreaks of the diseases that they transmit is needed to design efficient surveillance and vector control tools.


Ten-year follow-up of a rotating-platform, posterior-stabilized total knee arthroplasty.
The rotating-platform, posterior-stabilized knee was designed to decrease polyethylene wear and to address challenges associated with Low Contact Stress mobile-bearing knees. The purpose of the present prospective study was to investigate the long-term clinical and radiographic results and the survival rate for this implant. From January 2000 to October 2001, 117 consecutive patients (138 knees) underwent rotating-platform posterior-stabilized total knee arthroplasty with cement. All patients were followed prospectively. At a mean of 10 ± 0.4 years (range, 9.5 to eleven years) of follow-up, twenty patients had died and eight had been lost to follow-up, leaving eighty-nine patients (106 knees) for analysis. A good to excellent result according to the Knee Society pain score, which improved from an average of 44 to 94 points, was achieved in 96% (eighty-five) of the eighty-nine patients in the final cohort. The mean knee motion improved from 111° to 119°. The prevalence of postoperative pain was 14%. The prevalence of asymptomatic crepitation was 9.4%, and the prevalence of painful crepitation requiring scar excision was 3.8%. Radiographic analysis revealed no malalignment, aseptic loosening, or osteolysis. There were three revisions: one for the treatment of infection and two for the treatment of traumatic supracondylar fractures. Kaplan-Meier analysis revealed that the ten-year survival rate was 100% with revision due to mechanical failure as the end point, 97.7% with revision for any reason as the end point, and 95% with any reoperation as the end point. The ten-year follow-up of the rotating-platform, posterior-stabilized total knee arthroplasty demonstrated excellent clinical results and survival rates with no failures due to osteolysis or loosening.


Near-Field Manipulation in a Scanning Tunneling Microscope Junction with Plasmonic Fabry-Pérot Tips.
Near-field manipulation in plasmonic nanocavities can provide various applications in nanoscale science and technology. In particular, a gap plasmon in a scanning tunneling microscope (STM) junction is of key interest to nanoscale imaging and spectroscopy. Here we show that spectral features of a plasmonic STM junction can be manipulated by nanofabrication of Au tips using focused ion beam. An exemplary Fabry-Pérot type resonator of surface plasmons is demonstrated by producing the tip with a single groove on its shaft. Scanning tunneling luminescence spectra of the Fabry-Pérot tips exhibit spectral modulation resulting from interference between localized and propagating surface plasmon modes. In addition, the quality factor of the plasmonic Fabry-Pérot interference can be improved by optimizing the overall tip shape. Our approach paves the way for near-field imaging and spectroscopy with a high degree of accuracy.


Multivariate analysis of dermatoglyphics of severe mental retardates: an application of the constellation graphical method for discriminant analysis.
We studied the dermatoglyphics of 353 severe mental retardates (excluding those with chromosomal abnormalities and major limb malformations), using multivariate analysis, to determine how early intrauterine factors are related to the etiology of mental retardation. First, dermatoglyphics were compared between 140 individuals with undefined prenatal factors and 700 normal controls. After 6 and 9 dermatoglyphic traits were chosen as discriminative variables for males and females, respectively, the data were subjected separately for each sex to the constellation graphical method for discriminant analysis. The same formula as obtained in the idiopathic group was subsequently applied to data from cases in other etiological categories. When the misclassification rate was 0.03, the rates of correct classification of the male patients into the etiological categories of undefined prenatal, defined prenatal, perinatal, postnatal and unknown (no anamnestic data available) categories were 19.7% (13/66), 20.0% (3/15), 8.8% (5/57), 5.0% (1/20) and 7.7% (2/26), while the correct classification rates of females were 24.3% (18/74), 42.1% (8/19), 18.9% (7/37), 5.1% (1/16) and 13.0% (3/23), respectively. The results suggest that early intrauterine factors such as those producing dermatoglyphic deviations may contribute to the pathogenesis of severe mental retardation not only in patients with undefined prenatal etiological factors but also in those with perinatal factors, especially those of the female sex.


First report of highly pathogenic Echinococcus granulosus genotype G1 in dogs in a European urban environment.
Echinococcus granulosus and E. multilocularis are tapeworm parasites of major medical and veterinary importance, causing cystic and alveolar echinococcosis, respectively. Both diseases are listed among the most severe parasitic diseases in humans, representing 2 of the 17 neglected diseases prioritised by the World Health Organisation. However, little is known about the role of urban animals in transmission of both parasite species. A sensitive non-invasive genetic method was used to monitor E. granulosus and E. multilocularis infection among dog faecal samples collected from an urban area in Estonia in 2012-13. Out of 181 dog faecal samples analysed, 2.2% tested positive for E. granulosus, determined by sequencing as genotype G1. None of the samples tested positive for E. multilocularis. We report contamination of an urban environment with highly pathogenic E. granulosus G1 disseminated by dogs, and a potential risk to human health.


Facilitating transdisciplinary research: the experience of the transdisciplinary tobacco use research centers.
Cigarette smoking is the largest preventable cause of death and morbidity in the United States. Heightened recognition of this public health concern has led researchers from multiple and varied disciplines to address this complex and multidimensional behavior. The need for an alternative research paradigm, focusing on a transdisciplinary approach that integrates work across disciplines in order to advance the field most quickly, has been identified. This recognized need led to the development of the Transdisciplinary Tobacco Use Research Centers (TTURC) initiative, funded jointly by the National Cancer Institute, the National Institute on Drug Abuse, and The Robert Wood Johnson Foundation. This paper discusses the formation and early implementation stages of the initiative, including meetings that led to the development of the TTURCs, funders' and research centers' perspectives on implementation, and early observations about the products of the initiative.


Elevation of intraluminal pressure and cyclooxygenase inhibitors increases duodenal alkaline secretion.
Our aim was to study the effects of intraluminal hydrostatic pressure on duodenal mucosal alkaline secretion (DMAS) and permeability in anesthetized rats. A segment of proximal duodenum was perfused with saline and the rate of DMAS determined by backtitration. Mucosal permeability was assessed by measuring the clearance of 51Cr-EDTA (ED-C1) from blood to lumen. Raising the intraluminal hydrostatic pressure 6 mmHg above basal for 40 min induced a 75% increase in DMAS and a transient increase in ED-C1. This stimulation of DMAS was not affected by pretreatment with the muscarinergic receptor antagonist atropine (0.5 mg/kg i.v.), or the opioid receptor antagonist naloxone (15 micrograms/kg i.v.) but was strongly reduced by stripping the nerves around the carotid arteries and abolished by the ganglion blocker hexamethonium (10 mg/kg i.v.). When the distension was prolonged to 90 min, the net increase in DMAS decreased with time, indicating an adaptive mechanism. The cyclooxygenase inhibitors indomethacin (5 mg/kg i.v.) and meclofenamate (5 mg/kg i.v.) induced intermittent elevations of intraluminal pressure and increased DMAS by > 100%. This was associated with a transient increase in ED-C1. Indomethacin increased DMAS in a dose-related fashion, and the rise in both intraluminal pressure and DMAS was abolished by hexamethonium but not affected by stripping the nerves around the carotid arteries. Elevation of intraluminal pressure did not augment the rise in DMAS induced by indomethacin. It is concluded that luminal distension and cyclooxygenase inhibition increase DMAS by a similar, but not identical, neural mechanism involving nicotinergic receptors. It is speculated that the indomethacin-induced rise in DMAS is mediated via induction of duodenal motility.


Gene and protein expression and metabolic flux analysis reveals metabolic scaling in liver ex vivo and in vivo.
Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have largely been restricted to mathematical modeling of caloric intake and oxygen consumption, and mostly rely on computational modeling. The possibility that other metabolic processes scale with body size has not been comprehensively studied. To address this gap in knowledge, we employed a systems approach including transcriptomics, proteomics, and measurement of in vitro and in vivo metabolic fluxes. Gene expression in livers of five species spanning a 30,000-fold range in mass revealed differential expression according to body mass of genes related to cytosolic and mitochondrial metabolic processes, and to detoxication of oxidative damage. To determine whether flux through key metabolic pathways is ordered inversely to body size, we applied stable isotope tracer methodology to study multiple cellular compartments, tissues, and species. Comparing C57BL/6 J mice with Sprague-Dawley rats, we demonstrate that while ordering of metabolic fluxes is not observed in in vitro cell-autonomous settings, it is present in liver slices and in vivo. Together, these data reveal that metabolic scaling extends beyond oxygen consumption to other aspects of metabolism, and is regulated at the level of gene and protein expression, enzyme activity, and substrate supply.


Mother-to-Child Transmission of Arboviruses during Breastfeeding: From Epidemiology to Cellular Mechanisms.
Most viruses use several entry sites and modes of transmission to infect their host (parenteral, sexual, respiratory, oro-fecal, transplacental, transcutaneous, etc.). Some of them are known to be essentially transmitted via arthropod bites (mosquitoes, ticks, phlebotomes, sandflies, etc.), and are thus named arthropod-borne viruses, or arboviruses. During the last decades, several arboviruses have emerged or re-emerged in different countries in the form of notable outbreaks, resulting in a growing interest from scientific and medical communities as well as an increase in epidemiological studies. These studies have highlighted the existence of other modes of transmission. Among them, mother-to-child transmission (MTCT) during breastfeeding was highlighted for the vaccine strain of yellow fever virus (YFV) and Zika virus (ZIKV), and suggested for other arboviruses such as Chikungunya virus (CHIKV), dengue virus (DENV), and West Nile virus (WNV). In this review, we summarize all epidemiological and clinical clues that suggest the existence of breastfeeding as a neglected route for MTCT of arboviruses and we decipher some of the mechanisms that chronologically occur during MTCT via breastfeeding by focusing on ZIKV transmission process.


Treatments of premature ejaculation and psychogenic impotence: a critical review of the literature.
Research on the treatments of premature ejaculation and psychogenic impotence is reviewed. Problems with the existing definitions of these disorders are discussed. The studies are reviewed under seven major headings: depth therapies, behavior therapies, hypnosis, drug therapy, mechanotherapy, reeducative and supportive therapies, and extensive retraining programs. Most of the studies were case reports. Considerable methodological weaknesses were found, most notably the failure to specify subject and treatment variables, the confounding of treatment methods, inadequate or nonexistent control groups, limited, if any, follow-up assessments of treatment effects, and a failure to obtain partner validation of subjects' progress. The studies which used systematic desensitization and the studies which assessed the extensive retraining programs reported the most consistently positive results, although better-controlled replications are needed. Among other issues, it was suggested that future investigators examine the impact of treatment of homogeneous samples and conduct controlled comparisons of different treatment methods.


Transcriptional up-regulation of host-specific terpene metabolism in aphid-induced galls of Pistacia palaestina.
Galling insects gain food and shelter by inducing specialized anatomical structures in their plant hosts. Such galls often accumulate plant defensive metabolites protecting the inhabiting insects from predation. We previously found that, despite a marked natural chemopolymorphism in natural populations of Pistacia palaestina, the monoterpene content in Baizongia pistaciae-induced galls is substantially higher than in leaves of their hosts. Here we show a general up-regulation of key structural genes in both the plastidial and cytosolic terpene biosynthetic pathways in galls as compared with non-colonized leaves. Novel prenyltransferases and terpene synthases were functionally expressed in Escherichia coli to reveal their biochemical function. Individual Pistacia trees exhibiting chemopolymorphism in terpene compositions displayed differential up-regulation of selected terpene synthase genes, and the metabolites generated by their gene products in vitro corresponded to the monoterpenes accumulated by each tree. Our results delineate molecular mechanisms responsible for the formation of enhanced monoterpene in galls and the observed intraspecific monoterpene chemodiversity displayed in P. palaestina. We demonstrate that gall-inhabiting aphids transcriptionally reprogram their host terpene pathways by up-regulating tree-specific genes, boosting the accumulation of plant defensive compounds for the protection of colonizing insects.


Directed disruption of the tobacco ndhB gene impairs cyclic electron flow around photosystem I.
To evaluate the physiological significance of cyclic electron flow around photosystem (PS) I, we used a reverse genetic approach to focus on 11 chloroplast genes that encode homologs of mitochondrial complex I subunits (ndhA-K). Since their discovery, the exact function of the respiratory components in plant chloroplasts has been a matter of discussion. We disrupted one of these genes (ndhB) in tobacco by chloroplast transformation. Analysis of the transient increase in chlorophyll fluorescence after actinic light illumination and the redox kinetics of P700 (reaction center chlorophylls of PS I) suggest that the cyclic electron flow around PS I is impaired in the ndhB-deficient transformants. Transformants grew normally in a greenhouse, suggesting that the cyclic electron flow around PS I mediated by ndh gene products is dispensable in tobacco under mild environmental conditions.


Appropriate Air Medical Services Utilization and Recommendations for Integration of Air Medical Services Resources into the EMS System of Care: A Joint Position Statement and Resource Document of NAEMSP, ACEP, and AMPA.
This update to the 2013 joint position statement, Appropriate and Safe Utilization of Helicopter Emergency Medical Services, provides guidance for air medical services utilization based on currently available evidence. Air medical services utilization considerations fall into three major categories: clinical considerations, safety considerations, and system integration and quality assurance.Clinically, air medical services should accomplish one or more of three primary patient-centered goals: initiation or continuation of locally unavailable advanced or specialty care; expedited delivery to definitive care for time-sensitive interventions; and/or extraction from physically remote or otherwise inaccessible locations that limit timely access to necessary care. Ground-EMS (GEMS) transport is preferred when it is able to provide the necessary level of care and timely transport to definitive care.Risk identification and safety of both the patient and crew must be uniformly balanced against the anticipated degree of patient medical benefit. While auto-ready and auto-launch practices may increase access to air medical services, they also risk over-use, and so must be rigorously reviewed. Safety is enhanced during multi-agency emergency responses by coordinated interagency communication, ideally through centralized communication centers. Helicopter shopping and reverse helicopter shopping both create significant safety risks and their use is discouraged.Regional EMS systems must integrate air medical services to facilitate appropriate utilization in alignment with the primary patient goals while being cognizant of local indications, resources, and needs. To maximize consistent, informed air medical services utilization decisions, specific indications for and limitations to air medical services utilization that align with local and regional system and patient needs should be identified, and requests routed through centralized coordinating centers supported by EMS physicians.To limit risk and promote appropriate utilization of air medical services, GEMS clinicians should be encouraged to cancel an air medical services response if it is not aligned with at least one of the three primary patient-centered goals. Similarly, air medical services clinicians should be empowered to redirect patient transport to GEMS. Air medical services should not routinely be used solely to allow GEMS to remain in their primary service area.


Clinical, radiological, and pathological findings of primary nasal osteosarcoma in a Libyan cat.
Although bone tumors are common pathologies in companion animals, limited reports describe nasal osteosarcoma (OSA) in cats. A case of nasal OSA in a local Libyan cat was admitted to the Veterinary Teaching Hospital at the Faculty of Veterinary Medicine, University of Tripoli-Libya, with nasal swelling and discharges and facial deformity. The radiological findings revealed nasal osteolysis with the absence of evidence of lung metastasis. In addition, fungal growth was not identified in microbiological culture. Furthermore, the pathological examination has grossly revealed a destructed nasal bone due to the presence of a tumor mass, with a mucohemorrhagic nasal discharge and absence of metastasis. OSA was confirmed histopathologically. This report presents the clinical, radiological, and pathological findings of a primary nasal OSA in a Libyan cat with no tumor metastasis to other body organs.


Gustilo IIIC fractures in the lower limb: our 15-year experience.
Controversy continues to surround the management of patients with an open fracture of the lower limb and an associated vascular injury (Gustilo type IIIC). This study reports our 15-year experience with these fractures and their outcome in 18 patients (15 male and three female). Their mean age was 30.7 years (8 to 54) and mean Mangled Extremity Severity Score (MESS) at presentation was 6.9 (3 to 10). A total of 15 lower limbs were salvaged and three underwent amputation (two immediate and one delayed). Four patients underwent stabilisation of the fracture by external fixation and 12 with an internal device. A total of 11 patients had damage to multiple arteries and eight had a vein graft. Wound cover was achieved with a pedicled flap in three and a free flap in six. Seven patients developed a wound infection and four developed nonunion requiring further surgery. At a mean follow-up of five years (4.1 to 6.6) the mean visual analogue scale for pain was 64 (10 to 90). Depression and anxiety were common. Activities were limited mainly because of pain, and the MESS was a valid predictor of the functional outcome. Distal tibial fractures had an increased rate of nonunion when associated with posterior tibial artery damage, and seven patients (39%) were not able to return to their previous occupation.


Cytotoxic and inflammatory effects of contact lens solutions on human corneal epithelial cells in vitro.
To ascertain the effect that four contact lens (CL) multipurpose solutions (MPS) have on the viability and release of pro-inflammatory cytokines from human corneal epithelial cells (HCEC). HCEC were exposed to four different MPS at various concentrations for 18 hours. The cells were also exposed to phosphate buffer, borate buffer, and PHMB. The cell viability was evaluated using the alamarBlue assay. The release of pro-inflammatory cytokines was measured using a Multiplex electrochemiluminescent assay. MPS-A, MPS-B and MPS-C all reduced cell metabolic activity p < 0.05 from control with MPS-A showing the greatest cytotoxic effect (maximum reduction, 90.6%). In contrast, MPS-D showed no significant reductions in cytotoxicity except at the highest concentration tested (19% reduction at 20% MPS concentration). Of the four cytokines evaluated MPS-C showed a substantial increase in the release of IL-1β, IL-6, IL-8, and TNF-α at higher concentrations when compared to control p < 0.05. At the 20% concentration of MPS-A and MPS-B the release of IL-1 β increased p < 0.05 but the release of IL-6, IL-8, and TNF-α decreased. MPS-D did not cause a change in the release of cytokines IL-1β, IL-6, IL-8 and TNF-α p > 0.05. Exposing the cells to borate buffer and PHMB caused an increase in the release of TNF-α p < 0.05. This investigation demonstrates that at different concentration levels, several of the MPS tested showed a decrease in viability and an increase in the release of inflammatory cytokines from HCEC. The borate buffer component as well as PHMB appears to contribute to this pro-inflammatory reaction.


A rare case of cellulitis after tetanus toxoid (TT) vaccination.
Cellulitis is a bacterial infection of the deeper layers of the skin, namely, the dermis and the subcutaneous tissue. The most common organisms involved in causing cellulitis are group A β-hemolytic streptococci and Staphylococcus organisms. Rare causes include Pseudomonas aeruginosa in case of puncture wounds, anaerobes, Eikenella, Viridans streptococci in human bites. Cellulitis is mainly a clinical diagnosis but blood counts and ESR can be done to confirm its occurrence. Risk factors for cellulitis include breaks in the skin which allows an entry point for the bacteria, other risk factors include immune deficient states such as HIV/leukemia, conditions that affect the vascular system, and skin conditions such as eczema and psoriasis. Vaccination is an extremely rare cause of cellulitis with no cases of cellulitis reported since 1998 due to complication of vaccination. In our case, patients presented signs and symptoms of cellulitis 2 days after receiving the tetanus prophylaxis vaccine. He was treated with broad-spectrum antibiotics after admission and discharged once the condition settled.


Influence of material alterations and machine impairment on throughput related sensor-based sorting performance.
Experiments with sensor-based sorting (SBS) machinery provide insight into the effect of throughput rate and input composition on the sorting performance. For this purpose, material mixtures with certain compositions and particle size distributions were created from waste fractions and sorted at various throughput rates. To evaluate the sorting performance of the SBS unit (using near infrared technology) in dependence of the applied load, four assessment factors concerning the output fractions were studied: yield, product purity, recovery/product quantity and incorrectly discharged share of reject particles. The influences on the assessment parameters of light twodimensional (2D) particles in the input of a sorting stage and failing air valves in an SBS unit were evaluated for various input compositions at different throughput rates. It was found that a share of approximately 5 wt% 2D particles in the input had a similar negative effect on the yield as the malfunction of 20% of all air valves in an SBS machine at high throughput rates. Additionally, the failure of the air valves reduced the product purity of the sorting stage at increased throughput rates. Furthermore, qualitative observations concerning systematic effects of prior studies could be confirmed. Resulting graphs for a specific input composition of an SBS unit at varying throughput rates could be used to adjust the throughput rate to meet the exact demands for a sorting stage.


The prevalence of TMD in orthodontic patients prior to treatment at NCKUH in southern Taiwan. National Cheng Kung University Hospital.
Orthodontic treatment is considered one of the risk factors for temporomandibular disorders (TMD). However, TMD may occur before orthodontic treatment. The purpose of this study was to investigate the prevalence of TMD in orthodontic patients prior to treatment. The samples consisted of 508 patients (214 males and 294 females) at the National Cheng Kung University Hospital (NCKUH) in southern Taiwan. Ages ranged from 6 to 56 years. TMD signs were recorded by clinical examination prior to treatment. The overall prevalence of TMD was 26.6%. The prevalence was slightly higher in females (27.2%) than males (24.8%). However, the difference was not statistically significant. The prevalence of TMD in children (ages 6-17) and adults (ages 18-56) was 16.5% and 43.6%, respectively. The difference was statistically significant. Distribution of TMD signs was joint sounds (32.3%), muscle or joint pains (32.3%), muscle or joint pains (32.3%), mouth opening less than 35 mm (18%), combination of two signs (16.5%) and combination of three signs (0.8%).


Internucleosomal DNA cleavage and neuronal cell survival/death.
Serum-free PC12 cell cultures have been used to study the mechanisms of neuronal death after neurotrophic factor deprivation. We previously reported that PC12 cells undergo "apoptotic" internucleosomal DNA cleavage after withdrawal of trophic support. Here, we have used a sensitive method to detect PC12 cell DNA fragmentation within three hrs of serum removal and have exploited this assay to examine several aspects regarding the mechanisms of neuronal survival/death. Major advantages of this assay are that it permits acute experiments to be performed well before other manifest signs of cell death and under conditions that cannot be applied chronically. We find that this apopotic DNA fragmentation is distinct from the random DNA degradation that occurs during necrotic death. Major observations include the following: (a) There is a good correlation between the ability of trophic substances to promote PC12 cell survival and to inhibit early DNA fragmentation. (b) Phorbol ester, an activator of PKC, acutely suppresses DNA fragmentation, but does not promote long-term survival or inhibition of endonuclease activity when applied chronically due to its downregulation of PKC. (c) Cells undergoing apoptosis within 3 h of serum withdrawal have a "commitment point" of only 1.0-1.5 h beyond which they can no longer be rescued by NGF. (d) Aurin, a non-carboxylic analog of the endonuclease inhibitor ATA, also inhibits DNA fragmentation and promotes short-term survival of PC12 cells. (e) Macromolecular synthesis is not required for DNA fragmentation or for NGF to prevent this event. (f) Extracellular Ca2+ is not required for internucleosomal DNA cleavage caused by serum withdrawal or for suppression of this by NGF. (g) DNA fragmentation can also be detected in cultures of rat sympathetic neurons as early as 10 h after removal of NGF. As in PC12 cell cultures, this precedes morphological signs of cell death.


[Orbitotomy by means of ultrasound-instruments (author's transl)].
A surgical ultrasound-instrument was tested experimentally as well as clinically in the operative treatment of 48 patients with various orbital tumours. The transducer was shaped either as a scalpel or as a saw. The device worked on a frequency of 44,000 cps, the transducer-amplitude was 15 to 30 microns. This tool facilitates cutting of bony tissue and the incision of soft parts, it stops also bleeding of smaller and middle-sized vessels.


Observation and Calculation of the Quasibound Rovibrational Levels of the Electronic Ground State of H2+.
Although the existence of quasibound rotational levels of the X^{+} ^{2}Σ_{g}^{+} ground state of H_{2}^{+} was predicted a long time ago, these states have never been observed. Calculated positions and widths of quasibound rotational levels located close to the top of the centrifugal barriers have not been reported either. Given the role that such states play in the recombination of H(1s) and H^{+} to form H_{2}^{+}, this lack of data may be regarded as one of the largest unknown aspects of this otherwise accurately known fundamental molecular cation. We present measurements of the positions and widths of the lowest-lying quasibound rotational levels of H_{2}^{+} and compare the experimental results with the positions and widths we calculate using a potential model for the X^{+} state of H_{2}^{+} which includes adiabatic, nonadiabatic, relativistic, and radiative corrections to the Born-Oppenheimer approximation.


Circulating levels of HER-2/neu oncoprotein in breast cancer.
HER-2/neu, also known as c-erbB-2/neu, is an oncogene located in chromosome 17 which encodes HER-2/neu, a transmembrane protein belonging to the EGFR family. The external domain of this protein is released by the cell and can be studied in serum by immunoassay. HER-2/neu in serum is a specific tumor marker and only slight elevations may be found in the absence of malignancy, mainly in association with liver diseases. Likewise, the highest concentrations of this oncoprotein are found in patients with breast cancer, but lower concentrations may be found in other malignancies, particularly ovarian, prostate and lung cancer (mainly adenocarcinomas). HER-2/neu assay sensitivity in patients with untreated primary loco-regional breast cancer is <10% and seems to be related to overexpression in tissue as well as to the most important prognostic factors: tumor size and nodal involvement. Serial HER-2/neu determinations after surgery seem to be useful in the early diagnosis of recurrence, mainly in patients with HER-2/neu overexpression in tissue, but additional studies are necessary to confirm these results. HER-2/neu sensitivity (proportion of patients with abnormal values) in patients with metastasis is around 40%-45%, with a clear relationship to tissue overexpression and to site (higher in visceral metastases) and number of metastases. The clinical utility of HER-2/neu in patients with advanced disease is mainly for therapeutic monitoring. Likewise, in most of the studies published, a relationship has been found between serum HER-2/neu levels (either pretreatment or at follow-up) with tumor response.


Virtual reality in neurorehabilitation: a review of its effects on multiple cognitive domains.
Neurological diseases frequently cause adult-onset disability and have increased the demand for rehabilitative interventions. Neurorehabilitation has been progressively relying on computer-assisted programs and, more recently, on virtual reality (VR). Current reviews explore VR-based neurorehabilitation for assessing and treating the most common neurological pathologies. However, none of them explored specifically the impact of VR on multiple cognitive domains. The present work is a review of 6 years of literature (2015-2020) on VR in neurorehabilitation with the purpose of analyzing its effects on memory, attention, executive functions, language, and visuospatial ability. Our review suggests that VR-based neurorehabilitation showed encouraging results for executive functions and visuospatial abilities particularly for both acute and neurodegenerative conditions. Conversely, memory, and attention outcomes are conflicting, and language did not show significant improvements following VR-based rehabilitation. Within five years, it is plausible that VR-based intervention would be provided in standalone and mobile-based platforms that won't need a PC to work, with reduced latency and improved user interaction.