The optimization of helical thoracic CT.
Our purpose was to determine the optimal helical thoracic CT scanning protocol. Three adult Suffolk sheep under general anesthesia were repeatedly scanned by a variety of variable thickness helical and conventional plus thin section high resolution (lung gold standard) CT sequences, reconstructed for mediastinal (standard interpolator and algorithm) and lung parenchymal (extrasharp interpolator, bone algorithm) detail. The images were evaluated in a random order by five separate blinded, experienced imagers utilizing a predetermined grading scale. At equivalent slice thicknesses, the mediastinal images showed no statistically significant differences between conventional and helical CT using pitches of 1.0, 1.5, and 2.0. However, the 5-mm-thick sections, regardless of technique, performed better than did either the 2- or the 10-mm-thick section images. For the lung interstitium, there was an obvious and marked advantage to reconstructing the lung images separately from the mediastinal images with edge-enhancing algorithms and interpolators. With 1-mm-high mA thin section, high resolution lung CT as the gold standard, 2 mm conventional and helical pitch 1.0, 1.5, and 2.0 images were all graded equivalent. Of the 5 mm images, the helical pitches of 1.0 and 1.5 were graded equivalent to the gold standard. All of the 10 mm lung sections using both conventional and helical CT were graded statistically worse than the gold standard (p < 0.05). The use of helical CT with a 5 mm beam collimation and a pitch of 1.0 or 1.5 reconstructed twice to maximize both the mediastinal and the lung parenchymal detail provides the optimal way to routinely evaluate the chest.


Proline precursors to sustain Mammalian collagen synthesis.
Biochemically, one-third of the collagen molecule is composed of glycine. The next largest amino acid component is formed by proline (PRO) and hydroxyproline, which together comprise approximately 23% of the collagen molecule. The best method to support wound collagen biosynthesis is to provide adequate host nutrition, assuring adequate provision of calories and protein. However, despite adequate nutrition, clinically, there is a need to enhance collagen synthesis and research has focused on methods to enhance collagen precursor availability. PRO biosynthesis is related to both the citric acid cycle and the urea cycle. During the early phases of wound healing, wound fluid PRO levels are at least 50% higher than plasma levels, suggesting active import of PRO into the wound. Providing additional PRO in the diet to enhance PRO bioavailability for collagen biosynthesis does not result in increased collagen accumulation. Provision of other citric cycle precursors such as glutamine also does not enhance wound collagen synthesis. In looking at other PRO biosynthetic pathways, the arginine (ARG) --> ornithine (ORN) --> glutamic semialdehyde --> PRO pathway looks the most promising. ARG administration in quantities above those required for growth and reproduction results in a marked enhancement in wound collagen deposition. This effect is also shared by ORN, which cannot replace ARG for growth requirement but shares many of its biological and pharmacological activities. Several mechanisms have been postulated to explain the positive effect of ARG on wound healing, although none have been firmly proven. In conclusion, ARG and ORN supplementation are most effective in increasing collagen deposition, but whether this is accomplished by conversion to PRO is uncertain.


Hypoglycemia in children with type 1 diabetes: current issues and controversies.
Hypoglycemia is a common complication of insulin therapy, particularly in the young. For children and adolescents with diabetes, the risk of hypoglycemia may not only prevent optimal glycemic control but can also add significantly to the psychosocial burden of the disease. Recently, surveys employing prospective monitoring techniques have allowed more precise information to be gained about rates of hypoglycemia, its clinical associations, and the impact of new therapies and technologies. A number of reports have estimated rates of hypoglycemic comas and convulsions to be approximately 20 events per 100 patient years in children on current conventional therapy. There is evidence that the introduction of new analog short- and longer-acting insulins and the more widespread use of continuous subcutaneous infusion therapies may allow improvements in glycemic control to occur without the usual increased rate of severe hypoglycemic episodes. The use of glucose sensor technology has brought into focus the widespread occurrence of asymptomatic hypoglycemia. Asymptomatic hypoglycemia has long been recognized, particularly at night, when the combination of excessive insulin action and suppressed counter-regulatory hormone responses put children at special risk of hypoglycemia. Hypoglycemia unawareness is common in the young and is associated with an increased risk of severe hypoglycemia. Whether episodes of severe hypoglycemia have long-term consequences is controversial. Early studies suggesting that the developing brain is sensitive to permanent neurological damage as a result of hypoglycemia have not been confirmed in more recent reports. Many studies have not found convincing evidence of neurological sequelae of the hypoglycemic events that are an inevitable complication of insulin therapy. The question, however, remains under active investigation. Continued prospective monitoring of hypoglycemia rates and consequences has become an essential component of diabetes management.


Total Upper Eyelid Reconstruction with Modified Cutler-Beard Procedure Using Autogenous Auricular Cartilage.
Malignant tumour in upper lid is a surgical challenge to oculoplastic surgeon. Full thickness defect created after removal of large tumour promptly treated with modified cutler beard procedure using autogenous auricular cartilage. Surgical procedure is two staged: In first stage, removal of the tumour followed by full thickness flap repaired; In second stage, opening the closed lid with lid margin repair. Post-operatively, there is good anatomical, functional and cosmetic restoration of the eyelid similar to the other eye. To evaluate the efficacy of the modified Cutler-Beard procedure using autogenous ear cartilage for tarsal plate reconstruction in the repair of 70-100% upper eyelid defects. This is a prospective, interventional case series of 16 patients over a period of three years. Patients with upper eyelid defects, secondary to removal of tumour, greater than or equal to 70% were included. Of these patients, those with lymph node involvement, distant metastasis, lower eyelid involvement, corneal infiltration or intra-orbital extension were excluded. FNAC was done in all the cases. Created defect was measured in mm (length and width) and later expressed in percentage. Pre and Post-operative measurement of Levator Palpebrae Superioris (LPS) was done. Pre and Post-operative measurement of Margin to Reflex Distance (MRD1) were also noted. Upper eyelid recreation was successful in all patients without complications. Pre-operative LPS action ranged from 0-4 mm, while post-operative LPS action was 12-14 mm. Pre-operative MRD1 ranged from -4 millimeters to -1 mm, while post-operative MRD1 was +3 to +4 millimeters. The follow-up period ranged from six months to two years. Every patient had a successful upper eyelid reconstruction. The modified Cutler-Beard procedure using an autogenous auricular cartilage graft is an effective procedure for repair of large upper eyelid defects, with acceptable functional and cosmetic results. Furthermore, it is particularly useful in resource-poor areas, due to lower cost than other available options.


Nonarticular Base and Shaft Fractures of Children's Fingers: Are Follow-up X-rays Needed? Retrospective Study of Conservatively Treated Proximal and Middle Phalangeal Fractures.
Phalangeal fractures of the hand are common in children, and most extra-articular fractures can be treated with nonoperative management. Minimally or nondisplaced fractures may simply be immobilized, whereas displaced fractures need closed reduction before immobilization. Although few of these fractures displace secondarily, most schemes currently recommend follow-up x-rays after initial diagnosis. Our primary objective was to identify subgroups of finger fractures that are stable, thus requiring no radiographic monitoring. This study was designed as a retrospective, single-center analysis of conservatively treated pediatric finger fractures of the proximal and middle phalanges. We included patients up to 16 years with base or shaft fractures of the index to little fingers who underwent nonoperative treatment and standardized follow-up controls in our pediatric hand surgery outpatients' clinic between 2010 and 2016. Fracture angular deformity in x-rays taken at diagnosis and after 1 and 3 weeks were reassessed blinded, and a statistical analysis was conducted to identify fracture types that are prone to secondary angular deformity. A total of 478 patients were eligible; 113 were lost due to missing final radiographic controls. Overall, 365 patients were analyzed; they had a mean age of 9.7 years (range, 1 to 16), and 33.4% required a primary closed reduction. A secondary angular deformity occurred in 2.2% (8/365) of all finger fractures. No secondary angulation occurred in primary minimally and nondisplaced fractures, but 6.6% (8/122) of the reduced fractures showed a subsequent loss of reduction. Minimally angulated (<10 degrees) and nondisplaced metaphyseal and diaphyseal fractures of proximal and middle phalanges of the index to little fingers are stable and therefore do not need radiographic follow-ups. However, initially angulated fractures requiring closed reduction bear a risk of subsequent loss of reduction. Level III-retrospective study.


Limited pollen dispersal and biparental inbreeding in Symphonia globulifera in French Guiana.
In this paper, we report a study of the mating system and gene flow of Symphonia globulifera, a hermaphroditic, mainly bird-pollinated tree species with a large geographic distribution in the tropical Americas and Africa. Using three microsatellites, we analysed 534 seeds of 28 open pollinated families and 164 adults at the experimental site 'Paracou' in French Guiana. We observed, compared to other tropical tree species, relatively high values for the effective number of alleles. Significant spatial genetic structure was detected, with trees at distances up to 150 m more genetically similar than expected at random. We estimated parameters of the mating system and gene flow by using the mixed mating model and the TwoGener approach. The estimated multilocus outcrossing rate, tm, was 0.920. A significant level of biparental inbreeding and a high proportion of full-sibs were estimated for the 28 seed arrays. We estimated mean pollen dispersal distances between 27 and 53 m according to the dispersal models used. Although the adult population density of S. globulifera in Paracou was relatively high, the joint estimation of pollen dispersal and density of reproductive trees gave effective density estimates of 1.6 and 1.3 trees/ha. The parameters of the mating system and gene flow are discussed in the context of spatial genetic and demographic structures, flowering phenology and pollinator composition and behaviour.


Unwarping of unidirectionally distorted EPI images.
Echo-planar imaging (EPI) is a fast nuclear magnetic resonance imaging (MRI) method. Unfortunately, local magnetic field inhomogeneities induced mainly by the subject's presence cause significant geometrical distortion, predominantly along the phase-encoding direction, which must be undone to allow for meaningful further processing. So far, this aspect has been too often neglected. In this paper, we suggest a new approach using an algorithm specifically developed for the automatic registration of distorted EPI images with corresponding anatomically correct MRI images. We model the deformation field with splines, which gives us a great deal of flexibility, while comprising the affine transform as a special case. The registration criterion is least squares. Interestingly, the complexity of its evaluation does not depend on the resolution of the control grid. The spline model gives us good accuracy thanks to its high approximation order. The short support of splines leads to a fast algorithm. A multiresolution approach yields robustness and additional speedup. The algorithm was tested on real as well as synthetic data, and the results were compared with a manual method. A wavelet-based Sobolev-type random deformation generator was developed for testing purposes. A blind test indicates that the proposed automatic method is faster, more reliable, and more precise than the manual one.


[Cataract and type 1 diabetes mellitus].
To evaluate the prevalence of cataract and associated risk factors in a diabetic type 1 population. 181 patients (362 eyes) were evaluated in a case-control study. Cases were classified when cataract was present at the time of the examination. The studied outcomes were the presence of diabetic retinopathy, retinal panphotocoagulation, high blood pressure, peripheral neuropathy, total cholesterol levels, triglyceride levels, HDL, LDL, body mass index, creatinine levels, albuminuria, glycosylated hemoglobin and glycemia levels. Cataract was present in 19.9% of the studied patients. The association of the presence of cataract and diabetic retinopathy, peripheral neuropathy, elevated levels of creatinine, panphotocoagulation and high blood pressure were statistically significant (univariate analysis). After the logistic regression analysis the presence of cataract was significantly associated with the presence of diabetic retinopathy. The prevalence of cataract was 19.9% and the presence and severity of the diabetic retinopathy were the main risk factors for its development.


Attention enhances category representations across the brain with strengthened residual correlations to ventral temporal cortex.
How does attention enhance neural representations of goal-relevant stimuli while suppressing representations of ignored stimuli across regions of the brain? While prior studies have shown that attention enhances visual responses, we lack a cohesive understanding of how selective attention modulates visual representations across the brain. Here, we used functional magnetic resonance imaging (fMRI) while participants performed a selective attention task on superimposed stimuli from multiple categories and used a data-driven approach to test how attention affects both decodability of category information and residual correlations (after regressing out stimulus-driven variance) with category-selective regions of ventral temporal cortex (VTC). Our data reveal three main findings. First, when two objects are simultaneously viewed, the category of the attended object can be decoded more readily than the category of the ignored object, with the greatest attentional enhancements observed in occipital and temporal lobes. Second, after accounting for the response to the stimulus, the correlation in the residual brain activity between a cortical region and a category-selective region of VTC was elevated when that region's preferred category was attended vs. ignored, and more so in the right occipital, parietal, and frontal cortices. Third, we found that the stronger the residual correlations between a given region of cortex and VTC, the better visual category information could be decoded from that region. These findings suggest that heightened residual correlations by selective attention may reflect the sharing of information between sensory regions and higher-order cortical regions to provide attentional enhancement of goal-relevant information.


HDAC Inhibitors as Novel Anti-Cancer Therapeutics.
Malignant growth of cells is a condition characterized by unchecked cellular proliferation, genetic instability and epigenetic dysregulation. Up-regulated HDAC (Histone Deacetylase) enzyme activity is associated with a closed chromatin assembly and subsequent gene repression, forming a characteristic feature of malignantly transformed cells. Novel therapeutics are now targeting the zinc containing HDAC enzymes for treating various types of cancers. Recently, a spate of drugs acting via HDAC inhibition have been undergoing clinical trials and several patents present exciting molecules like PCI-24781 (Abexinostat), ITF- 2357 (Givinostat); MS-275 (Entinostat), MGCD 0103 (Mocetinostat), LBH-589 (Panobinostat), FK228 (Romidepsin), PXD-101 (Belinostat) and Valproic Acid to be used as alternatives or adjuvants to traditional chemotherapeutics. However, only three HDAC inhibitors have acquired FDA approval till date. Recently, PXD-101 obtained FDA approval for the treatment of Refractory or Relapsed Peripheral T cell lymphoma. The current article reviews patents that have introduced novel molecules that are HDAC isoform specific, superior to first generation HDAC inhibitors like SAHA (Suberoylanilide Hydroxamic Acid) and TSA (Trichostatin A) and can be modified structurally to reduce toxic side effects and increase specificity. These molecules can combine the best characteristics of an ideal HDAC inhibiting drug either as monotherapy or in combinatorial therapy for cancer treatment thus, indicating promise to be included in the next generation of target specific HDAC inhibiting drugs.


Large deletions in the pAtC58 megaplasmid of Agrobacterium tumefaciens can confer reduced carriage cost and increased expression of virulence genes.
The accessory plasmid pAtC58 of the common laboratory strain of Agrobacterium tumefaciens confers numerous catabolic functions and has been proposed to play a role in virulence. Genomic sequencing of evolved laboratory strains of A. tumefaciens revealed the presence of multiple deletion events in the At plasmid, with reductions in plasmid size ranging from 25% to 30% (115-194 kb). Flanking both ends of the sites of these deletions is a short-nucleotide repeat sequence that is in a single copy in the deleted plasmids, characteristic of a phage- or transposon-mediated deletion event. This repeat sequence is widespread throughout the C58 genome, but concentrated on the At plasmid, suggesting its frequency to be nonrandom. In this study, we assess the prevalence of the larger of these deletions in multiple C58 derivatives and characterize its functional significance. We find that in addition to elevating virulence gene expression, this deletion is associated with a significantly reduced carriage cost to the cell. These observations are a clear demonstration of the dynamic nature of the bacterial genome and suggest a mechanism for genetic plasticity of these costly but otherwise stable plasmids. Additionally, this phenomenon could be the basis for some of the dramatic recombination events so ubiquitous within and among megaplasmids.


Solitary fibrous tumors of the soft tissues: review of the imaging and clinical features with histopathologic correlation.
Solitary fibrous tumors are rare soft-tissue tumors of submesothelial origin with variable malignant potential. Most of these tumors originate within the thoracic cavity, but they can occur in a variety of sites, including the abdomen, pelvis, and soft tissues and muscles. The purpose of this study was to review the imaging findings with clinicopathologic correlation in 34 cases. The finding of a large, solid, vascular tumor, particularly with prominent feeding vessels or a visible fatty component, should alert the radiologist to the possible diagnosis of solitary fibrous tumor. Percutaneous biopsy carries minimal risk and should be used for definitive diagnosis of these lesions, which in many cases are curable with surgery. The prognosis is good for patients with benign tumors but variable for those with malignant tumors.


Procera is a putative DELLA mutant in tomato (Solanum lycopersicum): effects on the seed and vegetative plant.
The procera (pro) mutant of tomato exhibits a well-characterized constitutive gibberellic acid (GA) response phenotype. The tomato DELLA gene LeGAI in the pro mutant background contains a point mutation that results in an amino acid change in the conserved VHVID putative DNA-binding domain in LeGAI to VHEID. This same point mutation is in four different genetic backgrounds exhibiting the pro phenotype, suggesting that this mutation co-segregates with the pro phenotype. Complementation of the mutant with a constitutively expressed wild-type LeGAI gene sequence was not conclusive due to the infertility of transgenic plants. The pro mutation alters tomato branching architecture through differential suppression of axillary bud development, indicating a role for DELLA proteins in the regulation of plant structure. Isolated gib-1 pro double mutant embryo axes, which are unable to synthesize GA, germinate faster than their wild-type counterparts, and exert greater embryo growth potential. The pro mutation is therefore regulating GA responses within the tomato embryo. Transient expression of a LeGAI-GFP (green fluorescent protein) fusion protein in onion epidermis results in its location to the nucleus, and this protein is rapidly degraded by the proteasome in the presence of GA.


Single session educational programme for caregivers of psychogeriatric in-patients--results from a randomised controlled pilot study.
Family caregivers of patients with psychiatric or medical disorders are at risk of developing psychological distress. Studies including family caregivers of patients with dementia have shown that psychoeducative programmes reduce distress and postpone institutionalisation. Little is known about the effect of psychoeducation of relatives of psychogeriatric patients. The aim of this study was to investigate the effect of a single-session educational intervention of relatives of psychogeriatric in-patients. A randomised controlled intervention study was carried out with 16 relatives in the intervention group and 14 in the control group. The intervention was carried out as a single session programme. Primary outcome measures were psychological well-being and depression as measured by means of General Health Questionnaire (GHQ-30), Impact of Event Scale (IES) and Geriatric Depression Scale (GDS). Outcome measures were performed at baseline, at discharge and at 3-month follow-up. Psychological distress was high. Daughters were more depressed and distressed than spouses. Patients' diagnoses did not seem to exert influence on the relatives' well-being. There was a significant worsening of psychological distress in the intervention group as measured by GHQ-30. The study is small and results must be interpreted with caution. Distress among relatives was high regardless of patient's diagnosis. The results of the intervention might lead us to conclude that single-session interventions towards this specific group of relatives do not improve psychological stress and might, in some aspects, even worsen it.


Resistive switching memory performance in oxide hetero-nanocrystals with well-controlled interfaces.
For realization of new informative systems, the memristor working like synapse has drawn much attention. We developed isolated high-density Fe3O4 nanocrystals on Ge nuclei/Si with uniform and high resistive switching performance using low-temperature growth. The Fe3O4 nanocrystals on Ge nuclei had a well-controlled interface (Fe3O4/GeOx/Ge) composed of high-crystallinity Fe3O4 and high-quality GeOx layers. The nanocrystals showed uniform resistive switching characteristics (high switching probability of ~90%) and relatively high Off/On resistance ratio (~58). The high-quality interface enables electric field application to Fe3O4 and GeOx near the interface, which leads to effective positively charged oxygen vacancy movement, resulting in high-performance resistive switching. Furthermore, we successfully observed memory effect in nanocrystals with well-controlled interface. The experimental confirmation of the memory effect existence even in ultrasmall nanocrystals is significant for realizing non-volatile nanocrystal memory leading to neuromorphic devices.


Effects of nimodipine and isradipine on endothelin-1-induced contraction of pregnant rat myometrium.
The purpose of this study was to investigate the effect of nimodipine and isradipine on endothelin-1-induced contractions of isolated pregnant rat myometrium. Endothelin-1 at 10(-10)-10(-8) M dose-dependently increased the amplitude and frequency of contractions and decreased the duration of contractions. Basal tone of myometrium was increased with the higher endothelin-1 concentrations (10(-9) and 10(-8) M). After pretreatment for 30 min with 10(-6) M nimodipine or 10(-5) M isradipine, amplitude and duration of endothelin-1-induced contractions were significantly decreased, but frequency of myometrial contractions increased markedly. However, neither agent abolished the stimulating effect of higher endothelin-1 concentrations (10(-9) and 10(-8) M) on the basal tone. Our study showed that phasic activity is inhibited by nimodipine and isradipine, whereas tonic activity is not inhibited. The contraction of myometrial strips isolated from the pregnant rat may be modulated by endothelin-1, and this effect is only partly modulated by dihydropyridine-type Ca2+ channels. The remaining resistance to nimodipine- and isradipine-induced inhibition may be explained by pregnancy-associated changes in the other electrophysiological and biochemical factors.


Transmittance analysis of diffraction phase grating.
In order to accurately analyze and design the transmittance characteristic of a diffraction phase grating, the validity of both the scalar diffraction theory and the effective medium theory is quantitatively evaluated by the comparison of diffraction efficiencies predicted from both simplified theories to exact results calculated by the rigorous vector electromagnetic theory. The effect of surface profile parameters, including the normalized period, the normalized depth, and the fill factor for the precision of the simplified methods is determined at normal incidence. It is found that, in general, when the normalized period is more than four wavelengths of the incident light, the scalar diffraction theory is useful to estimate the transmittance of the phase grating. When the fill factor approaches 0.5, the error of the scalar method is minimized, and the scalar theory is accurate even at the grating period of two wavelengths. The transmittance characteristic as a function of the normalized period is strongly influenced by the grating duty cycle, but the diffraction performance on the normalized depth is independent of the fill factor of the grating. Additionally, the effective medium theory is accurate for evaluating the diffraction efficiency within an error of less than around 1% when no higher-order diffraction waves appear and only the zero-order waves exist. The precision of the effective medium theory for calculating transmittance properties as a function of the normalized period, the normalized groove depth, and the polarization state of incident light is insensitive to the fill factor of the phase grating.


Oro-facial impairment in stroke patients.
Stroke is considered one of the leading causes of death and acquired disability with a peak prevalence over the age of 80 years. Stroke may cause debilitating neurological deficiencies that frequently result in sensory deficits, motor impairment, muscular atrophy, cognitive deficits and psychosocial impairment. Oro-facial impairment may occur due to the frequent involvement of the cranial nerves' cortical representation areas, central nervous system pathways or motoneuron pools. The aim of this narrative, non-systematic review was to discuss the implications of stroke on oro-facial functions and oral health-related quality of life (OHRQoL). Stroke patients demonstrate an impaired masticatory performance, possibly due to reduced tongue forces and disturbed oral sensitivity. Furthermore, facial asymmetry is common, but mostly discrete and lip restraining forces are reduced. Bite force is not different between the ipsi- and contra-lesional side. In contrast, the contra-lesional handgrip strength and tongue-palate contact during swallowing are significantly impaired. OHRQoL is significantly reduced mainly because of the functional impairment. It can be concluded that impaired chewing efficiency, dysphagia, facial asymmetry, reduced lip force and OHRQoL are quantifiable symptoms of oro-facial impairment following a stroke. In the absence of functional rehabilitation, these symptoms seem not to improve. Furthermore, stroke affects the upper limb and the masseter muscle differently, both, at a functional and a morphological level. The rehabilitation of stroke survivors should, therefore, also seek to improve the strength and co-ordination of the oro-facial musculature. This would in turn help improve OHRQoL and the masticatory function, subsequently preventing weight loss and malnutrition.


High-SNR multiple T2 (*)-contrast magnetic resonance imaging using a robust denoising method based on tissue characteristics.
To develop an effective method that can suppress noise in successive multiecho T2 (*)-weighted magnetic resonance (MR) brain images while preventing filtering artifacts. For the simulation experiments, we used multiple T2 -weighted images of an anatomical brain phantom. For in vivo experiments, successive multiecho MR brain images were acquired from five healthy subjects using a multiecho gradient-recalled-echo (MGRE) sequence with a 3T MRI system. Our denoising method is a nonlinear filter whose filtering weights are determined by tissue characteristics among pixels. The similarity of the tissue characteristics is measured based on the l2 -difference between two temporal decay signals. Both numerical and subjective evaluations were performed in order to compare the effectiveness of our denoising method with those of conventional filters, including Gaussian low-pass filter (LPF), anisotropic diffusion filter (ADF), and bilateral filter. Root-mean-square error (RMSE), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were used in the numerical evaluation. Five observers, including one radiologist, assessed the image quality and rated subjective scores in the subjective evaluation. Our denoising method significantly improves RMSE, SNR, and CNR of numerical phantom images, and CNR of in vivo brain images in comparison with conventional filters (P < 0.005). It also receives the highest scores for structure conspicuity (8.2 to 9.4 out of 10) and naturalness (9.2 to 9.8 out of 10) among the conventional filters in the subjective evaluation. This study demonstrates that high-SNR multiple T2 (*)-contrast MR images can be obtained using our denoising method based on tissue characteristics without noticeable artifacts. Evidence level: 2 J. MAGN. RESON. IMAGING 2017;45:1835-1845.


Effects of platelet-activating factor on lipid metabolism in rats in vivo. Origin of the hypertriglyceridaemia.
Administration of platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine; PAF) did not alter the rate of triacylglycerol entry into the plasma. The gastrointestinal absorption of [1-14C]triolein was, however, inhibited by PAF, yet there was increased accumulation of [14C]lipid in the plasma and hypertriglyceridaemia. The half-life of injected [9,10(n)-3H]triolein in the plasma increased by 47%, and there was decreased accumulation of [3H]lipid in brown adipose tissue. This was accompanied by a decrease in lipoprotein lipase activity. The hypertriglyceridaemia induced by PAF appears to be mainly due to decreased peripheral removal, one important site affected being brown adipose tissue.


Frequencies of hprt(-) mutations and bcl-2 translocations in circulating human lymphocytes are correlated with United Kingdom sunlight records.
Between 1983 and 1995 we have monitored human populations for evidence of exposure to environmental mutagens, taking blood samples to measure hprt(-) mutant frequency in T cells and more recently bcl-2 t(14:18) translocation frequency in B cells. We have now analysed data from 785 assays on 448 blood samples from 308 normal subjects and find that there is a highly significant statistical correlation between hprt(-) mutant frequency and the sunlight record for the 3 weeks prior to taking the blood sample. We discuss the weaknesses in retrospective studies of this nature and the possibility of spurious epidemiological correlations that may result. More controlled experiments can be envisaged that would give a firmer basis to the statistical associations observed. hprt(-) mutations in T cells show little evidence of a UV fingerprint, so that the correlation may be due to immunomodulation rather than mutation. We also find a correlation between the sunlight record and bcl-2 translocation. This translocation is found at a low frequency in the B cells of many normal subjects and is the commonest translocation observed in non-Hodgkin's lymphoma. Our results strengthen the case for a link between sunlight and this increasingly common cancer.


Microbial and Viral Communities and Their Antibiotic Resistance Genes Throughout a Hospital Wastewater Treatment System.
Antibiotic resistance poses a serious threat to global public health, and antibiotic resistance determinants can enter natural aquatic systems through discharge of wastewater effluents. Hospital wastewater in particular is expected to contain high abundances of antibiotic resistance genes (ARGs) compared to municipal wastewater because it contains human enteric bacteria that may include antibiotic-resistant organisms originating from hospital patients, and can also have high concentrations of antibiotics and antimicrobials relative to municipal wastewater. Viruses also play an important role in wastewater treatment systems since they can influence the bacterial community composition through killing bacteria, facilitating transduction of genetic material between organisms, and modifying the chromosomal content of bacteria as prophages. However, little is known about the fate and connections between ARGs, viruses, and their associated bacteria in hospital wastewater systems. To address this knowledge gap, we characterized the composition and persistence of ARGs, dsDNA viruses, and bacteria from influent to effluent in a pilot-scale hospital wastewater treatment system in Israel using shotgun metagenomics. Results showed that ARGs, including genes conferring resistance to antibiotics of high clinical relevance, were detected in all sampling locations throughout the pilot-scale system, with only 16% overall depletion of ARGs per genome equivalent between influent and effluent. The most common classes of ARGs detected throughout the system conferred resistance to aminoglycoside, cephalosporin, macrolide, penam, and tetracycline antibiotics. A greater proportion of total ARGs were associated with plasmid-associated genes in effluent compared to in influent. No strong associations between viral sequences and ARGs were identified in viral metagenomes from the system, suggesting that phage may not be a significant vector for ARG transfer in this system. The majority of viruses in the pilot-scale system belonged to the families Myoviridae, Podoviridae, and Siphoviridae. Gammaproteobacteria was the dominant class of bacteria harboring ARGs and the most common putative viral host in all samples, followed by Bacilli and Betaproteobacteria. In the total bacterial community, the dominant class was Betaproteobacteria for each sample. Overall, we found that a variety of different types of ARGs and viruses were persistent throughout this hospital wastewater treatment system, which can be released to the environment through effluent discharge.


Amino acid identity at one position within the alpha1 helix of both the histidine kinase and the response regulator of the WalRK and PhoPR two-component systems plays a crucial role in the specificity of phosphotransfer.
Two-component systems usually function as cognate pairs, thereby ensuring an appropriate response to the detected signal. The ability to exclusively phosphorylate a partner protein, often in the presence of many competing homologous substrates, demonstrates a high level of specificity that must derive from the interacting surfaces of the two-component system. Here, we identify positions within the histidine kinases and response regulators of the WalRK and PhoPR two-component systems of Bacillus subtilis that make a major contribution to the specificity of phosphotransfer. Changing the identity of the amino acid at position 11 within the alpha1 helix of WalK and at position 17 within the alpha1 helix of PhoP altered discrimination and allowed phosphotransfer to occur with the non-cognate partner. Changing amino acids at additional positions of the WalK kinase increased phosphotransfer, while changes at additional positions in PhoP only had an effect in the presence of the change at position 17. The importance of amino acid identity at these two positions is supported by the fact that the amino acid combinations of Ile and Ser in WalRK, and Leu and Gly in PhoPR, are very highly conserved among orthologues, while modelling indicates that these amino acid pairs are juxtaposed in the WalRK and PhoPR complexes.


Indices of changes in adiposity in American Indian children.
Pathways, a randomized trial, evaluated the effectiveness of a school-based obesity prevention program on body composition changes in American Indian children. Several body composition methods were compared in intervention and control schools for assessing body composition changes. Body composition methods, including skinfolds, bioelectric impedance analysis (BIA), body mass index (BMI), and using a combination of body composition methods were selected to assess 3-year changes in PBF in 705 children within 21 intervention schools and 663 children within 20 control schools. The study equation using skinfolds, BIA, and BMI was developed on a previous sample of American Indian children using deuterium oxide dilution as the criterion method. Body fat changes among methods for the intervention sample ranged from 5.4% (BMI method) to 7.1% (combination of methods) and for the control sample, from 5.8% (BMI method) to 7.3% (combination of methods). The study equation estimates were significantly higher than the other methods and the BMI equation estimates were significantly lower than the other methods except by BIA. The BIA equation showed a significantly larger standard deviation of the difference over the 3-year intervention than each of the other methods indicating less reliability for detecting body composition changes. Within the Pathways large scale intervention trial with American Indian children, we found comparable yet significantly different mean PBF changes among methods. However, BIA was not as reliable as skinfolds and the combination of BIA, skinfolds, and body weight in assessing PBF changes.


Anemias beyond B12 and iron deficiency: the buzz about other B's, elementary, and nonelementary problems.
The term "unexplained anemia" appears frequently in a request for a hematology consultation. Although most anemia consultations are fairly routine, they occasionally represent challenging problems that require an amalgam of experience, insight, and a modicum of "out-of-the-box" thinking. Problem anemia cases and pitfalls in their recognition can arise for one of several reasons that are discussed in the cases presented herein. "Anemias beyond B12 and iron deficiency" covers a vast domain of everything that lies beyond the commonly encountered anemias caused by simple deficiencies of 2 currently major hematologically relevant micronutrients. However, even these deficiencies may be obscured when they coexist or are not considered because of misleading distractions. They may also be mistakenly identified when other less common nutrient deficiencies occur. I present herein case examples of such situations: a young patient with pancytopenia and schistocytes who was responsive to plasmapheresis, but in whom pernicious anemia was not suspected because of ethnicity and age; a bicytopenic patient with anemia and myelodysplastic features caused by copper deficiency after gastric reduction surgery; and a patient with BM hypoplasia and a dimorphic blood smear who was found to have paroxysmal nocturnal hemoglobinuria. These "pearls" represent but 3 examples of the many varieties of problems in anemia diagnosis and are used to illustrate potential pitfalls and how to avoid them.


Ecology of helminth parasitism in bobwhites from northern Florida.
Examination of 700 northern bobwhites (Colinus virginianus), 50 each February from 1971 through 1984, from Tall Timbers Research Station, Leon County, Florida, disclosed 15 species of helminth parasites. Nine species (Raillietina cesticillus, R. colinia, Aproctella stoddardi, Cheilospirura spinosa, Cyrnea colini, Dispharynx nasuta, Heterakis isolonche, Tetrameres pattersoni, and Trichostrongylus tenuis) generally were found on an annual basis and were considered characteristic components of the helminth fauna. Infrequently found species were Brachylecithum nanum, Rhabdometra odiosa, Capillaria sp., Gongylonema ingluvicola, H. gallinarum, and Oxyspirura matogrosensis. Intensities of C. colini and H. isolonche differed among host sex and age classes, and prevalences and/or intensities of A. stoddardi, C. spinosa, T. pattersoni, and T. tenuis differed between host age classes. Prevalences and/or abundances of seven species (R. cesticillus, R. colinia, C. spinosa, C. colini, H. isolonche, T. pattersoni, and T. tenuis) varied with bobwhite density, apparently because bobwhites were either the primary or only definitive host on the area. Two species (A. stoddardi and D. nasuta) did not vary with bobwhite density, apparently due to the buffering effect of a broad range of definitive hosts on the area. Prevalences and/or intensities of R. colinia, C. spinosa, and T. tenuis differed with agricultural fields status (cultivated versus fallow) suggesting that land use and its attendant habitat changes influenced transmission of these species. The occurrence of C. spinosa and T. pattersoni in individual bobwhites was not independent and was attributed to utilization of the same species of grasshoppers as intermediate hosts. Localized tissue damage and inflammation were associated with A. stoddardi, D. nasuta, C. spinosa, C. colini and T. pattersoni. Decreases in body weight in juvenile bobwhites were associated with increasing intensities of H. isolonche and T. tenuis. The observed relationships to bobwhite density and other variables are discussed with regard to known aspects of life histories of the nine most common species.


Anionic iodotyrosine residues are required for iodothyronine synthesis.
Biosynthesis of iodothyronines in thyroglobulin occurs by oxidative coupling of two iodotyrosine residues catalyzed by thyroperoxidase. To study the mechanism of iodothyronine formation, iodine-free thyroglobulin was non-enzymatically iodinated and after removal of non-incorporated iodide, incubated with lactoperoxidase and glucose oxidase between pH 4 and 9. The amount of thyroxine (T4). 3,5,3'-tri-iodothyronine (T3), 3,3',5'-tri-iodothyronine (rT3) and 3,3'-di-iodothyronine (T2) formed was measured by radioimmunoassays after hydrolysis of thyroglobulin. T4 is synthesized out of two di-iodotyrosine (DIT) residues in thyroglobulin. The pH dependence of T4 formation fits the dissociation curve of the DIT phenoxy group (pKa 6.5). The formation of T2, synthesized out of two mono-iodotyrosine (MIT) residues, shows a quite different pH dependence. Below pH 6, T2 synthesis could not be observed, while above pH 7.4 a relatively large increase occurred. The values up to pH 8 fitted the dissociation curve of the MIT-phenoxy group with a pKa of 8.7. The gradual loss in enzymatic activity of peroxidase and oxidase in the reaction made the values obtained above pH 8 unreliable. The importance of the ionization of the phenoxy group for the coupling reaction was further consolidated by showing that the pH-dependent oxidation of 2-methoxy-phenol (guaiacol) had 50% maximal product formation at pH 7, a value concordant with pKa 7.0 for the ionization of the phenoxy group of this agent. T3 and rT3 synthesis followed mainly the ionization curve of the inner-ring hydroxyl group, indicating that this ring has the greatest influence on hormonogenesis. Since anion formation facilitates the removal of an electron under oxidative conditions, the pH dependence agrees with the involvement of phenoxy radicals in iodothyronine synthesis, a process that most likely also occurs in vivo since it is mainly T4 that is formed in thyroglobulin.


[Medical supervision of sports events and the role of the team physician].
Medical supervision of sports events and the role of the team physician are the cornerstones of sports medicine. These activities demand precise professional preparation and organization. This paper discusses the specifics of medical organization in sport, criteria to accept such responsibility, composition of the medical staff, professional code of ethics, materiel and medications necessary for a successful mission, problems related to insurance, and communication and relations with the media. We propose that this will help physicians who commit themselves to the medical supervision of sports events, teams, and national federations.


[Sensitization to common airborne allergens in school children with bronchial asthma].
The main purpose of the paper was to assess the prevalence of atopy in the population of preadolescent children in Krakow on the basis of allergic skin testing to airborne allergens and to look into the relationship between atopy and chronic asthma-like respiratory symptoms. The field study was carried out in 1998 among 311 children being the subgroup of the cohort of 1044 children included in the 3-year follow-up in Krakow. The health assessment accounted for the standardised interviews and skin prick testing to 11 common airborne allergens. In the total, the positive allergic reaction at least to only one allergen was found in 32.5% children, and it was more prevalent in boys than in girls (40.4% vs 28.1%). Allergy only to indoor allergens was present in 9.7% children, allergy only to outdoor allergens in 9.7%, and allergy both to outdoor and indoor allergens was confirmed in 13% persons. Most frequently, allergy was established to house mites: Dermatophagoides pter. (16.2%), Dermatophagoides farinae (12.0%) and to cat dander (11.4%). Asthma-like symptoms occurred in 11.0% of children and asthma diagnosed by physician in 7.8% of the sample under the study. The results of this study proved that the prevalence of asthma was about twice so high in boys than in girls. The risk of asthma-like symptoms and/or asthma diagnosed by physician increased significantly with the number of positive allergic tests to airborne allergens (OR = 1.30; 95% CI: 1.11-1.52) and atopy in mother (OR = 1.84; 95% CI: 1.03-3.37).


Prosthodontic decision making among general dentists in Sweden. II: The choice between fixed and removable partial dentures.
The purpose of this study was to describe how dentists evaluated various items related to a treatment choice between fixed partial dentures (FPD) and removable partial dentures (RPD), and to determine if the differences could be explained by dentist-related variables ("social and demographic attributes," "job situation," and "attitudes"). Questionnaires were sent to a random sample of 2,059 Swedish general dentists, with a response rate of 76%. In the questionnaire, the choice between FPDs and RPDs in a clinical situation was presented. The dentists were asked to mark on 14-item visual analogue scales the relative importance he or she gave the different items. The items were analyzed through principal components analysis, where a 3-factor solution was obtained; the factors were labeled as "time," "health," and "comfort." The factors were run as dependent variables in multiple regression analyses. Great individual variations were seen, but the differences between groups of dentists were small. The items evaluated as most important were "patient's wish," "condition of possible abutment teeth," and "prognosis for delivered treatment." Male dentists gave significantly greater importance to the "health" factor compared to female dentists. The attitudinal variable "patient information" showed significant associations with all 3 factors in the multivariate models. Great individual differences were seen regarding the importance of the various items. In multiple regression models, several independent variables showed significant associations, most interestingly the attitudinal variable "patient information." Low explanatory (R2) values indicate that it is necessary to capture more variables of importance for the prosthodontic decision-making process.


Magnetic resonance imaging contrast enhancement of extra-ocular muscles in dogs with no clinical evidence of orbital disease.
Enhancement of extra-ocular muscles has been reported in cases of orbital pathology in both veterinary and medical magnetic resonance imaging. We have also observed this finding in the absence of orbital disease. The purpose of this retrospective study was to describe extra-ocular muscle contrast enhancement characteristics in a group of dogs with no known orbital disease. Magnetic resonance images (MRI) from dogs with no clinical evidence of orbital disease and a reportedly normal MRI study were retrieved and reviewed. Contrast enhancement percentages of the medial, lateral, ventral, and dorsal rectus muscles were calculated based on signal-to-noise ratios that were in turn determined from hand-traced regions of interest in precontrast, immediate postcontrast and 10-min postcontrast scans. Comparison measurements were made in the pterygoid muscle. Contrast enhancement of the extra-ocular muscles was observed in all patients (median contrast enhancement percentage 45.0%) and was greater than that of pterygoid muscle (median contrast enhancement percentage 22.7%). Enhancement of the extra-ocular muscles persisted 10 min after contrast administration (median contrast enhancement percentage 43.4%). Findings indicated that MRI contrast enhancement of extra-ocular muscles is likely normal in dogs.


Proportions of B-cell subsets are altered in incomplete systemic lupus erythematosus and correlate with interferon score and IgG levels.
Incomplete SLE (iSLE) patients display symptoms typical for SLE but have insufficient criteria to fulfil the diagnosis. Biomarkers are needed to identify iSLE patients that will progress to SLE. IFN type I activation, B-cell-activating factor (BAFF) and B-cell subset distortions play an important role in the pathogenesis of SLE. The aim of this cross-sectional study was to investigate whether B-cell subsets are altered in iSLE patients, and whether these alterations correlate with IFN scores and BAFF levels. iSLE patients (n = 34), SLE patients (n = 41) with quiescent disease (SLEDAI ≤4) and healthy controls (n = 22) were included. Proportions of B-cell subsets were measured with flow cytometry, IFN scores with RT-PCR and BAFF levels with ELISA. Proportions of age-associated B-cells were elevated in iSLE patients compared with healthy controls and correlated with IgG levels. In iSLE patients, IFN scores and BAFF levels were significantly increased compared with healthy controls. Also, IFN scores correlated with proportions of switched memory B-cells, plasma cells and IgG levels, and correlated negatively with complement levels in iSLE patients. In this cross-sectional study, distortions in B-cell subsets were observed in iSLE patients and were correlated with IFN scores and IgG levels. Since these factors play an important role in the pathogenesis of SLE, iSLE patients with these distortions, high IFN scores, and high levels of IgG and BAFF may be at risk for progression to SLE.


The diacylated lipopeptide FSL-1 enhances phagocytosis of bacteria by macrophages through a Toll-like receptor 2-mediated signalling pathway.
A significant amount of evidence has been accumulated to show that Toll-like receptors (TLRs) function as sensors for microbial invasion. However, little is known about how signalling triggered by TLRs leads to the phagocytosis of pathogens. This study was designed to determine whether stimulation of TLR2 mainly with the lipopeptide FSL-1 plays a role in the phagocytosis of pathogens by macrophages. FSL-1 enhanced the phagocytosis of Escherichia coli to a markedly greater extent than it did that of Staphylococcus aureus, but did not enhance the phagocytosis of latex beads. FSL-1 stimulation resulted in enhanced phagocytosis of bacteria by macrophages from TLR2(+/+) mice but not by those from TLR2(-/-) mice. Chinese hamster ovary cells stably expressing TLR2 failed to phagocytose these bacteria, but the cells expressing CD14 did. FSL-1 induced upregulation of the expression of phagocytic receptors, including MSR1, CD36, DC-SIGN and Dectin-1 in THP-1 cells. Human embryonic kidney 293 cells transfected with DC-SIGN and MSR1 phagocytosed these bacteria. These results suggest that the FSL-1-induced enhancement of phagocytosis of bacteria by macrophages may be explained partly by the upregulation of scavenger receptors and the C-type lectins through TLR2-mediated signalling pathways, and that TLR2 by itself does not function as a phagocytic receptor.


Height and weight in cystic fibrosis: a cross sectional study. UK Cystic Fibrosis Survey Management Committee.
Cross sectional data reporting the height, weight, and body mass index of UK patients with cystic fibrosis are presented. During the first decade of life height and weight in patients with cystic fibrosis are maintained at about 0.5 SD below those of the general population, which reflects an improvement over earlier published observations. Postpubertal stature and weight maintenance in the cystic fibrosis population still show substantial deficits which may be related to treatment.


Overexpression of the SK3 channel alters vascular remodeling during pregnancy, leading to fetal demise.
The maternal cardiovascular system undergoes hemodynamic changes during pregnancy via angiogenesis and vasodilation to ensure adequate perfusion of the placenta. Improper vascularization at the maternal-fetal interface can cause pregnancy complications and poor fetal outcomes. Recent evidence indicates that small conductance Ca(2+)-activated K(+) channel subtype 3 (SK3) contributes to vascular remodeling during pregnancy, and we hypothesized that abnormal SK3 channel expression would alter the ability of the maternal cardiovascular system to adapt to pregnancy demands and lead to poor fetal outcomes. We investigated this hypothesis using transgenic Kcnn3(tm1Jpad)/Kcnn3(tm1Jpad) (SK3(T/T)) mice that overexpress the channel. Isolated pressurized uterine arteries from nonpregnant transgenic SK3(T/T) mice had larger basal diameters and decreased agonist-induced constriction than those from their wild-type counterparts; however, non-receptor-mediated depolarization remained intact. In addition to vascular changes, heart rates and ejection fraction were increased, whereas end systolic volume was reduced in SK3(T/T) mice compared with their wild-type littermates. Uterine sonography of the fetuses on pregnancy day 14 showed a significant decrease in fetal size in SK3(T/T) compared with wild-type mice; thus, SK3(T/T) mice displayed an intrauterine growth-restricted phenotype. The SK3(T/T) mice showed decreased placental thicknesses and higher incidence of fetal loss, losing over half of their complement of pups by midgestation. These results establish that the SK3 channel contributes to both maternal and fetal outcomes during pregnancy and point to the importance of SK3 channel regulation in maintaining a healthy pregnancy.


Development of a clinical definition for acute respiratory distress syndrome using the Delphi technique.
The objective of this study is to describe the implementation of formal consensus techniques in the development of a clinical definition for acute respiratory distress syndrome. A Delphi consensus process was conducted using e-mail. Sixteen panelists who were both researchers and opinion leaders were systematically recruited. The Delphi technique was performed over 4 rounds on the background of an explicit definition framework. Item generation was performed in round 1, item reduction in rounds 2 and 3, and definition evaluation in round 4. Explicit consensus thresholds were used throughout. Of the 16 panelists, 11 actually participated in developing a definition that met a priori consensus rules on the third iteration. New incorporations in the Delphi definition include the use of a standardized oxygenation assessment and the documentation of either a predisposing factor or decreased thoracic compliance. The panelists rated the Delphi definition as acceptable to highly acceptable (median score, 6; range, 5-7 on a 7-point Likert scale). We conclude that it is feasible to consider using formal consensus in the development of future definitions of acute respiratory distress syndrome. Testing of sensibility, reliability, and validity are needed for this preliminary definition; these test results should be incorporated into future iterations of this definition.


FUNGIpath: a tool to assess fungal metabolic pathways predicted by orthology.
More and more completely sequenced fungal genomes are becoming available and many more sequencing projects are in progress. This deluge of data should improve our knowledge of the various primary and secondary metabolisms of Fungi, including their synthesis of useful compounds such as antibiotics or toxic molecules such as mycotoxins. Functional annotation of many fungal genomes is imperfect, especially of genes encoding enzymes, so we need dedicated tools to analyze their metabolic pathways in depth. FUNGIpath is a new tool built using a two-stage approach. Groups of orthologous proteins predicted using complementary methods of detection were collected in a relational database. Each group was further mapped on to steps in the metabolic pathways published in the public databases KEGG and MetaCyc. As a result, FUNGIpath allows the primary and secondary metabolisms of the different fungal species represented in the database to be compared easily, making it possible to assess the level of specificity of various pathways at different taxonomic distances. It is freely accessible at http://www.fungipath.u-psud.fr. As more and more fungal genomes are expected to be sequenced during the coming years, FUNGIpath should help progressively to reconstruct the ancestral primary and secondary metabolisms of the main branches of the fungal tree of life and to elucidate the evolution of these ancestral fungal metabolisms to various specific derived metabolisms.


Early detection, reactivation of cytomegalovirus DNA & immediate early (IE)-mRNA expression in a hemetopoitic stem cell-transplant patient.
Human cytomegalovirus (HCMV) reactivation is a major cause of morbidity and mortality among stem cell transplant recipients post-transplantation. HCMV immediate-early messenger RNA (IE-mRNA) was evaluated as marker of post-transplant HCMV reactivation in bone marrow transplant recipients. ology: An in-house real-time reverse transcriptase PCR targeting IE-mRNA was developed to estimate HCMV mRNA levels post-transplantation. Blood samples collected in K2-EDTA tubes from patients (n = 162) admitted with Department of Clinical Hematology were transported in cold condition for routine HCMV DNA screening. For HCMV IE-mRNA quantification, peripheral blood mononuclear cells (PBMCs) were separated from whole blood and stored in RNA later at -70 °C until testing. Samples were collected weekly once for first 3 weeks post-transplantation and thereafter from week 4-12, samples were collected twice weekly. A total of 2467 samples were collected from 162 study participants. Thirty five patients (21.6 %) had post-transplant HCMV reactivation. Twenty five patients with complete follow-up were selected for monitoring HCMV DNA. HCMV IE-mRNA PCR was performed for 15 patients and 7(46.6 %) patients had detectable mRNA levels. HCMV IE-mRNA was detected in all patients with increasing HCMV DNA levels except for one patient in whom IE-mRNA appeared 3 days before HCMV DNA was detected. One patient had detectable HCMV IE-mRNA during declining HCMV DNA level. However the patient showed an increased HCMV DNA one week later, indicating the importance of HCMV mRNA in predicting HCMV replication. Quantification of HCMV IE-mRNA may be a valuable tool to predict progression of HCMV infection post-transplantation, with further prospective studies needed for validation.


Screening for selective inhibitors of xanthine oxidase from Flos Chrysanthemum using ultrafiltration LC-MS combined with enzyme channel blocking.
In this study, a new method based on ultrafiltration liquid chromatography-mass spectrometry (UF-LC-MS) combined with enzyme channel blocking (ECB) was developed to discover bioactive components from herbal medicines. Xanthine oxidase (XOD), a critical enzyme for treating gout, was employed as the target protein for screening. By comparing chromatographic profiles of the compounds binding to XOD before and after the ECB experiment, the selective ligands could be distinguished from the non-selective binders. In this experiment, febuxostat bound to the channel entering into the active site of the enzyme and prevented potential ligands from binding. Finally, four compounds, namely, luteolin-7-O-glucoside, apigenin-7-O-glucoside, luteolin and apigenin were screened and identified as the candidate XOD inhibitors based on the ultrafiltration chromatogram of Flos Chrysanthemum, a famous traditional Chinese medicine used in many prescriptions for gout treatment. To verify the compounds screened further, a microplate method was applied to evaluate their enzyme inhibitory activities. The IC50 values of the above 4 compounds were 23.61, 38.80, 1.54 and 1.96μM, respectively. The structure-function relationship was also estimated according to the in vitro assay. The results were in favor of the hypothesis that the Flos Chrysanthemum extract might be used for gout treatment by inhibiting XOD.


Mechanical induction of interleukin-11 regulates osteoblastic/cementoblastic differentiation of human periodontal ligament stem/progenitor cells.
The periodontal ligament (PDL) is continually exposed to mechanical loading caused by mastication or occlusion. Physiological loading is thus considered a key regulator of PDL tissue homeostasis; however, it remains unclear how this occurs. We recently reported that an appropriate magnitude of mechanical stretch can maintain PDL tissue homeostasis via the renin-angiotensin system. In the present study, we investigated the expression of interleukin-11 (IL-11) in human primary PDL cells (HPDLCs) exposed to stretch loading, the contribution of angiotensin II (Ang II) to this event and the effects of IL-11 on osteoblastic/cementoblastic differentiation of human PDL progenitor cells (cell line 1-17). Human primary PDL cells, derived from human tissues, with or without antagonists against the Ang II receptors AT1 or AT2, were subjected to cyclical stretch loading with 8% elongation for 1 h. Expression of IL-11 was measured by ELISA in these cultures and by immunohistochemistry in the sectioned maxillae of rats. The osteoblastic/cementoblastic potential of cell line 1-17 was determined using cell proliferation, gene expression and Alizarin Red staining. Positive staining for IL-11 was observed in the PDL of rat maxillae and in cultures of HPDLCs. In HPDLCs exposed to stretch, expression of the IL11 gene and the IL-11 protein were up-regulated, concomitant with an increase in Ang II and via AT2. Recombinant human IL-11 (rhIL-11) stimulated an increase in expression of mRNA for the cementoblast-specific marker, CP-23, and for the osteoblastic markers, osteopontin and bone sialoprotein, and promoted proliferation in cell line 1-17. In addition, rhIL-11 also increased the degree of mineralized nodule formation in cell line 1-17 cultures treated with CaCl2 . Mechanical loading appears to control proliferation and osteoblastic/cementoblastic differentiation of human PDL stem/progenitor cells through the regulation of Ang II and AT2 by IL-11.


Nicotine modulates cytokine production by Chlamydia pneumoniae infected human peripheral blood cells.
Nicotine, the addictive component of cigarette smoke, has been shown to have immunomodulatory effects. This drug alters proinflammatory cytokine production by immune cells, including lymphocytes, monocytes, and macrophages. The present study focuses on the effects of nicotine on infection by Chlamydia pneumoniae (Cpn), a ubiquitous intracellular pathogen which causes acute and chronic inflammatory diseases such as pulmonary infections, and may be associated with arthritis and atherosclerosis. Previous studies in our laboratory showed that lymphocytes and macrophages are susceptible to Cpn infection. The present study aimed at investigating the effect of nicotine on TGF-beta1, IL-10, IL-12, and TNF-alpha production in Cpn-infected human peripheral blood mononuclear cells (PBMCs). Cytokine levels in the supernatant were assessed by ELISA. The results showed that Cpn infection alters the expression levels of IL-10, IL-12, and TNF-alpha in a time-dependent fashion. Nicotine treatment of the Cpn-infected cells up-regulated IL-10, but not TNF-alpha and IL-12, and also resulted in significant down-regulation of TGF-beta1 production which was marked in the Cpn-infected control cells. The combined action of nicotine and Cpn on cytokine production may have an impact in chronic inflammatory diseases.


Genetic engineering for xenotransplantation.
Xenotransplantation is being pursued vigorously to solve the shortage of allogeneic donor organs. Experimental studies of the major xenoantigen (Gal) and of complement regulation enable model xenografts to survive hyperacute rejection. When the Gal antigen is removed or reduced and complement activation is controlled, the major barriers to xenograft survival include unregulated coagulation within the graft and cellular reactions involving macrophages, neutrophils, natural killer (NK) cells, and T lymphocytes. Unlike allografts, where specific immune responses are the sole barrier to graft survival, molecular differences between xenograft and recipient that affect normal receptor-ligand interactions (largely active at the cell surface and which may not be immunogenic), are also involved in xenograft failure. Transgenic strategies provide the best options to control antigen expression, complement activation, and coagulation. Although the Gal antigen can be eliminated by gene knockout in mice, that outcome has only become a possibility in pigs due to the recent cloning of pigs after nuclear transfer. Instead, the use of transgenic glycosyl transferase enzymes and glycosidases, which generate alternative terminal carbohydrates on glycolipids and glycoproteins, has reduced antigen in experimental models. As a result, novel strategies are being tested to seek the most effective solution. Transgenic pigs expressing human complement-regulating proteins (DAF/CD55, MCP/CD46, or CD59) have revealed that disordered regulation of the coagulation system requires attention. There will undoubtedly be other molecular incompatibilities that need addressing. Xenotransplantation, however, offers hope as a therapeutic solution and provides much information about homeostatic mechanisms.


Evaluating the combinative effects on human lymphocyte DNA damage induced by ultraviolet ray C plus 1.8 GHz microwaves using comet assay in vitro.
The objective of this study was to observe whether 1.8 GHz microwaves (MW) (SAR, 3 W/kg) exposure can influence human lymphocyte DNA damage induced by ultraviolet ray C (UVC). The lymphocytes, which were from three young healthy donors, were exposed to 254 nm UVC at the doses of 0.25, 0.5, 0.75, 1.0, 1.5 and 2.0 J m(-2), respectively. The lymphocytes were irradiated by 1.8 GHz MW (SAR, 3 W/kg) for 0, 1.5 and 4 h. The combinative exposure of UVC plus MW was conducted. The treated cells were incubated for 0, 1.5 and 4 h. Finally, comet assay was used to measure DNA damage of above treated lymphocytes. The results indicated that the difference of DNA damage induced between MW group and control group was not significant (P>0.05). The MTLs induced by UVC were 1.71+/-0.09, 2.02+/-0.08, 2.27+/-0.17, 2.27+/-0.06, 2.25+/-0.12, 2.24+/-0.11 microm, respectively, which were significantly higher than that (0.96+/-0.05 microm) of control (P<0.01). MTLs of some sub-groups in combinative exposure groups at 1.5-h incubation were significantly lower that those of corresponding UVC sub-groups (P<0.01 or P<0.05). However, MTLs of some sub-groups in combinative exposure groups at 4-h incubation were significantly higher that those of corresponding UVC sub-groups (P<0.01 or P<0.05). In this experiment it was found that 1.8 GHz (SAR, 3 W/kg) MW exposure for 1.5 and 4 h did not enhance significantly human lymphocyte DNA damage, but could reduce and increase DNA damage of human lymphocytes induced by UVC at 1.5-h and 4-h incubation, respectively.


Effect of pictorial depth cues, binocular disparity cues and motion parallax depth cues on lightness perception in three-dimensional virtual scenes.
Surface lightness perception is affected by scene interpretation. There is some experimental evidence that perceived lightness under bi-ocular viewing conditions is different from perceived lightness in actual scenes but there are also reports that viewing conditions have little or no effect on perceived color. We investigated how mixes of depth cues affect perception of lightness in three-dimensional rendered scenes containing strong gradients of illumination in depth. Observers viewed a virtual room (4 m width x 5 m height x 17.5 m depth) with checkerboard walls and floor. In four conditions, the room was presented with or without binocular disparity (BD) depth cues and with or without motion parallax (MP) depth cues. In all conditions, observers were asked to adjust the luminance of a comparison surface to match the lightness of test surfaces placed at seven different depths (8.5-17.5 m) in the scene. We estimated lightness versus depth profiles in all four depth cue conditions. Even when observers had only pictorial depth cues (no MP, no BD), they partially but significantly discounted the illumination gradient in judging lightness. Adding either MP or BD led to significantly greater discounting and both cues together produced the greatest discounting. The effects of MP and BD were approximately additive. BD had greater influence at near distances than far. These results suggest the surface lightness perception is modulated by three-dimensional perception/interpretation using pictorial, binocular-disparity, and motion-parallax cues additively. We propose a two-stage (2D and 3D) processing model for lightness perception.


Pisum sativum Defensin 1 Eradicates Mouse Metastatic Lung Nodules from B16F10 Melanoma Cells.
Psd1 is a pea plant defensin which can be actively expressed in Pichia pastoris and shows broad antifungal activity. This activity is dependent on fungal membrane glucosylceramide (GlcCer), which is also important for its internalization, nuclear localization, and endoreduplication. Certain cancer cells present a lipid metabolism imbalance resulting in the overexpression of GlcCer in their membrane. In this work, in vitroassays using B16F10 cells showed that labeled fluorescein isothiocyanate FITC-Psd1 internalized into live cultured cells and targeted the nucleus, which underwent fragmentation, exhibiting approximately 60% of cells in the sub-G0/G1 stage. This phenomenon was dependent on GlcCer, and the participation of cyclin-F was suggested. In a murine lung metastatic melanoma model, intravenous injection of Psd1 together with B16F10 cells drastically reduced the number of nodules at concentrations above 0.5 mg/kg. Additionally, the administration of 1 mg/kg Psd1 decreased the number of lung inflammatory cells to near zero without weight loss, unlike animals that received melanoma cells only. It is worth noting that 1 mg/kg Psd1 alone did not provoke inflammation in lung tissue or weight or vital signal losses over 21 days, inferring no whole animal cytotoxicity. These results suggest that Psd1 could be a promising prototype for human lung anti-metastatic melanoma therapy.


Low-dose carbenicillin prophylaxis for vaginal and abdominal hysterectomy.
A double-blind prospective study of 99 patients undergoing vaginal and abdominal hysterectomy was performed at North Carolina Baptist Hospital of the Bowman Gray School of Medicine at Wake Forest University. The study indicated that low-dose intravenous carbenicillin begun preoperatively and continued for 24 hours resulted in decreased febrile morbidity, postoperative infection rate, and shortened hospital stay in patients undergoing both vaginal and abdominal hysterectomy. The indications for operation, clinical characteristics of patients, and operative and postoperative management were similar for the control and study groups. For the vaginal hysterectomy group, febrile morbidity was reduced from 34.6% in the control group to 7.7% in the group receiving carbenicillin. For patients undergoing abdominal hysterectomy, febrile morbidity was reduced from 54.1% in the control group to 4.0% in the group receiving prophylactic carbenicillin. Similar reductions for the carbenicillin study group in fever index and average total hospital stay were also noted. Urinary tract infections were determined to be present more commonly in the group of patients with febrile morbidity receiving no prophylactic antibiotics. The incidence of pelvic infections were reduced in both carbenicillin-treated groups. This investigation suggests that low-dose carbenicillin prophylaxis is beneficial in reduction of morbidity following both vaginal and abdominal hysterectomy.


Multivariable analysis of the relationship between pain referral patterns and the source of chronic low back pain.
Discogenic, facet joint, and sacroiliac joint mediated axial low back pain may be associated with overlapping pain referral patterns into the lower limb. Differences between pain referral patterns for these three structures have not been systematically investigated. To examine the individual and combined relationship of age, hip/girdle pain, leg pain, and thigh pain and the source of internal disc disruption (IDD), facet joint pain (FJP), or sacroiliac joint pain (SIJP) in consecutive chronic low back pain (CLBP) patients. Retrospective chart review. Community based interventional spine practice. 378 cases from 358 consecutive patients were reviewed and 157 independent cases from 153 patients who underwent definitive diagnostic injections were analyzed. Charts of consecutive low back pain patients who underwent definitive diagnostic spinal procedures were retrospectively reviewed. Patients underwent provocation lumbar discography, dual diagnostic medial branch blocks, or intra-articular diagnostic sacroiliac joint injections based on clinical presentation. Some subjects underwent multiple diagnostic injections until the source of their chronic low back pain (CLBP) was identified. Based on the results of diagnostic injections, subjects were classified as having IDD, FJP, SIJP, or other. The mean age/standard deviation and the count/percentage of patients reporting hip girdle pain, leg pain, or thigh pain were estimated for each diagnostic group and compared statistically among the IDD, FJP, SIJP, and other source groups. Next, the 4 predictor variables were simultaneously modeled with a single multinomial logistic regression model to explore the adjusted relationship between the predictors and the source of CLBP. The mean age was significantly different among the source groups. IDD cases were significantly younger than FJP, SIJP, and other source groups and FJP cases were significantly younger than other sources. The age by thigh pain interaction effect was statistically significant (P = 0.021), indicating that the effect of age on the source of CLBP depends on thigh pain, and similarly, that the effect of thigh pain on the source of CLBP depends on age. Retrospective study design. The presence or absence of thigh pain possesses a significant correlation on the source of CLBP for varying ages, whereas the presence of hip/girdle pain or leg pain did not significantly discriminate among IDD, FJP, or SIJP as the etiology of CLBP. Younger age was predictive of IDD regardless of the presence or absence of thigh pain.


Open MoA: revealing the mechanism of action (MoA) based on network topology and hierarchy.
Many approaches in systems biology have been applied in drug repositioning due to the increased availability of the omics data and computational biology tools. Using a multi-omics integrated network, which contains information of various biological interactions, could offer a more comprehensive inspective and interpretation for the drug mechanism of action (MoA). We developed a computational pipeline for dissecting the hidden MoAs of drugs (Open MoA). Our pipeline computes confidence scores to edges that represent connections between genes/proteins in the integrated network. The interactions showing the highest confidence score could indicate potential drug targets and infer the underlying molecular MoAs. Open MoA was also validated by testing some well-established targets. Additionally, we applied Open MoA to reveal the MoA of a repositioned drug (JNK-IN-5A) that modulates the PKLR expression in HepG2 cells and found STAT1 is the key transcription factor. Overall, Open MoA represents a first-generation tool that could be utilized for predicting the potential MoA of repurposed drugs and dissecting de novo targets for developing effective treatments. Source code is available at https://github.com/XinmengLiao/Open_MoA.


Practical clinical tool to monitor dementia symptoms: the HABC-Monitor.
Dementia care providers need a clinical assessment tool similar to the blood pressure cuff (sphygmomanometer) used by clinicians and patients for managing hypertension. A "blood pressure cuff " for dementia would be an inexpensive, simple, user-friendly, easily standardized, sensitive to change, and widely available multidomain instrument for providers and informal caregivers to measure severity of dementia symptoms. The purpose of this study was to assess the reliability and validity of the Healthy Aging Brain Care Monitor (HABC-Monitor) for measuring and monitoring the severity of dementia symptoms through caregiver reports. The first prototype of the HABC-Monitor was developed in collaboration with the Indianapolis Discovery Network for Dementia, which includes 200 members representing 20 disciplines from 20 local organizations, and an expert panel of 22 experts in dementia care and research. The HABC-Monitor has three patient symptom domains (cognitive, functional, behavioral/psychological) and a caregiver quality of life domain. Patients (n = 171) and their informal caregivers (n = 171) were consecutively approached and consented during, or by phone shortly following, a patient's routine visit to their memory care provider. The HABC-Monitor demonstrated good internal consistency (0.73-0.92); construct validity indicated by correlations with the caregiver-reported Neuropsychiatric Inventory (NPI) total score and NPI caregiver distress score; sensitivity to three-month change compared with NPI "reliable change" groups; and known-groups validity, indicated by significant separation of Mini-Mental Status Examination severity groups and clinical diagnostic groups. Although not designed as a screening study, there was evidence for good operating characteristics, according to area under the receiver-operator curve with respect to gold standard clinical diagnoses, relative to Mini-Mental Status Examination or NPI. The HABC-Monitor demonstrates good reliability and validity as a clinically practical multidimensional tool for monitoring symptoms of dementia through the informal caregiver.


Wound healing in db/db mice with type 2 diabetes using non-contact exposure with an argon non-thermal atmospheric pressure plasma jet device.
A non-thermal atmospheric pressure plasma jet (APPJ) may stimulate cells and tissues or result in cell death depending on the intensity of plasma at the target; therefore, we herein investigated the effects of non-thermal plasma under non-contact conditions on the healing of full-thickness wounds in diabetic mice (DM+ group) and normal mice (DM- group). A hydrogen peroxide colorimetric method and high performance liquid chromatography showed that APPJ produced low amounts of reactive oxygen and nitrogen species. Ten-week-old male C57BL/6j mice with normal blood glucose levels (DM- group) and 10-week-old male C57BLKS/J Iar-+Leprdb/+Leprdb mice (DM+ group) received two full-thickness cutaneous wounds (4 mm in diameter) on both sides of the dorsum. Wounds were treated with or without the plasma jet or argon gas for 1 minute and were then covered with a hydrocolloid dressing (Hydrocolloid), according to which mice were divided into the following groups: DM+Plasma, DM+Argon, DM+Hydrocolloid, DM-Plasma, DM-Argon, and DM-Hydrocolloid. Exudate weights, wound areas, and wound area ratios were recorded every day. Hematoxylin and eosin staining was performed to assess re-epithelialization and α-SMA immunohistological staining to evaluate the formation of new blood vessels. Non-thermal plasma under non-contact conditions reduced the production of exudate. Exudate weights were smaller in the DM+Plasma group than in the DM+Hydrocolloid and DM+Argon groups. The wound area ratio was smaller for plasma-treated wounds, and was also smaller in the DM+Plasma group than in the DM+Hydrocolloid and DM+Argon groups on days 1-21 (p<0.01). Wound areas were smaller in the DM-Plasma group than in the DM-Argon group until day 14 and differences were significant on days 1-5 (p<0.01). The percentage of re-epithelialization was significantly higher in the DM+Plasma group than in the DM+Argon and DM+Hydrocolloid groups (p<0.01). The number of new blood vessels that had formed by day 7 was significantly higher in the DM+Plasma group than in the DM+Hydrocolloid and DM+Argon groups (p<0.05). These results indicate that treatment with the current non-thermal plasma APPJ device under non-contact conditions accelerated wound healing in diabetic mice.


[The effects of alcohol on the developing brain].
In the review the literature data on the effect of alcohol on the developing brain of human and animals are summarized. The information is presented on the neuroimaging, histological, cellular and molecular-genetic disturbances in the brain in fetal alcohol syndrome and following exposure to alcohol during the early postnatal period. The structural developmental abnormalities of the different parts of the brain, disorders of neurogenesis and neuronal apoptosis, changes in metabolism, receptors and secondary signals system of neurons are described. Prenatal alcohol exposure causes significant, various long-term disturbances of the brain structures at the organ, tissue, cellular and subcellular level, which may lay in the basis of the observed neurological, behavioral and metal disorders.


[Detailed model of semi-conservative DNA replication. Possible role of DNA-polymerase errors in fragmented copying of both matrix strands].
A model of semiconservative DNA synthesis is considered. The model is based on a suggestion that the synthesis proceeds in the course of one-directional stretching of both matrix strands through the replicase complex (replisome), or of one-directional movement of the replisome along the chromosome. Each nucleotide link of the matrix strand find itself successively in the section of RNA primer synthesis, in the section of DNA polymerase and in the control section of a proofreading 3' leads to 5' exonuclease. Deoxynucleoside incorrectly joined by DNA polymerase of the replisome to the 3'-OH end of growing chain are, as a rule, removed when transferred in the control section. Since the reverse movement is prohibited, the DNA polymerase loses the 3'-OH end of new DNA chain and proves to be incapable to continue the synthesis. It can be renewed only after a new RNA primer formation. For continuation of the DNA synthesis after an incorrect deoxynucleotide addition, replicase must take two more mistakes in succession: to retain the incorrect nucleotide and to join the next one to this unproperly arranged primer. Only in that case the non-complementary nucleotide in a new DNA chain can escape the action of proofreading exonucleases. Hence, according to the model under discussion, the frequency of mutations should be many times lower than that of incorrect nucleotide joinings. The latter results, as a rule, in DNA chain synthesis cessation and in fragments formation. Taking into consideration the frequency of spontaneous mutations in bacteria (about 10(-9) per base-pair), the frequency of non-complementary joinings during semiconservative synthesis can be suggested of the order 10(-3) in accordance with the average Okazaki fragments size of 1000 nucleotides. Another possible reason for periodical interruptions of semiconservative DNA synthesis and for fragments formation is a distortion of replisome structure, accompanying the release of the matrix strand being copied in the direction of already replicated chromosome region. Both mechanisms can participate concurrently in DNA fragments formation. If replisomes are attached to a cell membrane, the sites of chromosome that are also fastened in the membrane, in particular, the site of "origin", are to be replicated using some mobile replicase complex.


Non isocentric film-based intracavitary brachytherapy planning in cervical cancer: a retrospective dosimetric analysis with CT planning.
To compare intracavitary brachytherapy dose estimation for organs at risk (bladder and rectum) based on semi-orthogonal reconstruction of radiographs on non-isocentric X-ray unit and Computed Tomography (CT) - based volumetric planning in cervical cancer. Bladder and rectal points as per International Commission on Radiation Units and Measurements (ICRU) report 38, were retrospectively evaluated on 15 high dose rate intracavitary brachytherapy applications for cervical cancer cases. With the same source configuration as obtained during planning on radiographs performed on a non-isocentric X-ray unit, the mean doses to 2cc of most irradiated part of bladder and rectum were computed by CT planning and these estimates were compared with the doses at ICRU bladder and rectal points. The mean ICRU point dose for bladder was 3.08 Gy (1.9-5.9 Gy) and mean dose to 2 cc (D2cc) bladder was 6.91 Gy (2.9-12.2 Gy). ICRU rectal dose was 3.8 Gy (2.4-4.45 Gy) and was comparable with D2cc rectum dose 4.2 Gy (2.8-5.9 Gy). Comparison of mean total dose (ICRU point vs. D2cc) for each patient was found to be significantly different for bladder (p = 0.000), but not for rectum (p = 0.08). On comparison of ICRU point based planning with volumetric planning on CT, it was found that bladder doses were underestimated by the film based method. However, the rectal doses were found to be similar to the D2cc doses. The results with non isocentric film based treatment planning were similar to the existing literature on orthogonal film based simulator planning.


Study of Antiglycation, Hypoglycemic, and Nephroprotective Activities of the Green Dwarf Variety Coconut Water (Cocos nucifera L.) in Alloxan-Induced Diabetic Rats.
Coconut water (CW) is a natural nutritious beverage, which contains several biologically active compounds that are traditionally used in the treatment of diarrhea and rehydration. Several works with CW have been related with antioxidant activity, which is very important in the diabetic state. To evaluate the hypoglycemic and nephroprotective activities of CW, alloxan-induced diabetic rats were pre- and post-treated by gavage with CW (3 mL/kg), caffeic acid (CA) (10 and 15 mg/kg), and acarbose (Acb) (714 μg/kg) during a period of 16 days. Body weight, blood glucose, glycated hemoglobin (HbA1c), and Amadori products in plasma and kidney homogenates were evaluated in all groups and used as parameters for the monitoring of the diabetic state. The results showed that rats of the CW+diabetic group had maintenance in blood glucose compared with the control group (P<.05) in addition to a decrease of HbA1c levels and increase of body weight when compared with the diabetic group rats (P<.05). The animals of the CA and CA+diabetic groups did not have significant variation of body weight (P<.05) during the experiment; however, they showed decrease in their HbA1c and urea levels in plasma as well as Amadori products in kidney homogenates when compared with the diabetic group (P<.05). Our results indicate that CW has multiple beneficial effects in diabetic rats for preventing hyperglycemia and oxidative stress caused by alloxan.


Novel chemoembolization using calcium-phosphate ceramic microsphere incorporating TNP-470, an anti-angiogenic agent.
The purpose of the present study was to develop a new method of chemoembolization to improve the therapeutic effectiveness and safety profile of cancer treatment. A chemoembolization approach was designed for human solid tumors using resorbable calcium-phosphate ceramic microspheres loaded with an agent anti-angiogenic to tumor vasculature in vivo. The human uterine sarcoma cell line FU-MMT-3 was used in this study because this tumor is aggressive and also exhibits a poor response to radiotherapy or any chemotherapy currently used. The calcium-phosphate ceramic microspheres loaded with TNP-470, an anti-angiogenic agent, were injected into FU-MMT-3 xenografts in nude mice three times per week for 8 weeks. The treatment using TNP-470-loaded microspheres suppressed tumor growth, compared to treatment with TNP-470 alone, microspheres alone, and the control. The mean tumor weight after treatment using TNP-470-loaded microspheres was significantly lower than that after treatment with microspheres alone. These ceramic microspheres were remarkably embolized in tumor microvessels as well as in the feeding arteries and a significant reduction of intratumoral vascularity was also demonstrated following treatment with TNP-470-loaded microspheres. Severe loss of body weight was not observed in any mice treated with the TNP-470-loaded microspheres, compared to treatment with TNP-470 alone. These results suggest that targeting tumor vasculature in human uterine sarcoma using calcium-phosphate microspheres might be more effective and safer than the treatment that employs anti-angiogenic agent alone. This new chemoembolization method incorporating an anti-angiogenic agent may contribute to the effective treatment of locally advanced or recurrent solid tumors.


Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety study of celecoxib versus traditional non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis: protocol of the standard care versus celecoxib outcome trial (SCOT).
Cyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects. Data from randomised and observational studies suggest that celecoxib has similar cardiovascular toxicity to traditional NSAIDs. The overall safety balance of a strategy of celecoxib therapy versus traditional NSAID therapy is unknown. The European Medicines Agency requested studies of the cardiovascular safety of celecoxib within Europe. The Standard care versus Celecoxib Outcome Trial (SCOT) compares the cardiovascular safety of celecoxib with traditional NSAID therapy in the setting of the European Union healthcare system. SCOT is a large streamlined safety study conducted in Scotland, England, Denmark and the Netherlands using the Prospective Randomised Open Blinded Endpoint design. Patients aged over 60 years with osteoarthritis or rheumatoid arthritis, free from established cardiovascular disease and requiring chronic NSAID therapy, are randomised to celecoxib or their previous traditional NSAID. They are then followed up for events by record-linkage within their normal healthcare setting. The hypothesis is non-inferiority with a confidence limit of 1.4. The primary endpoint is the first occurrence of hospitalisation or death for the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are (1) first hospitalisation or death for upper gastrointestinal ulcer complications (bleeding, perforation or obstruction); (2) first occurrence of hospitalised upper gastrointestinal ulcer complications or APTC endpoint; (3) first hospitalisation for heart failure; (4) first hospitalisation for APTC endpoint plus heart failure; (5) all-cause mortality and (6) first hospitalisation for new or worsening renal failure. SCOT has been approved by the relevant ethics committees. The trial results will be published in a peer-reviewed scientific journal. Clinicaltrials.gov (NCT00447759).


Effects of counseling for late stage cancer patients.
Much has been written about working with the dying. Few, if any, controlled studies have examined the application of principles set forth. The authors evaluate the effectiveness of working with dying cancer patients by assessing changes in quality of life, physical functioning, and survival. One-hundred twenty men with end-stage cancer were randomly assigned to experimental or control groups; the 62 experimental group patients were seen regularly by a counselor. Patients were assessed before random assignment and at one, three, six, nine, and 12 months on quality of live and functional status. Experimental group patients improved significantly more than the control group on quality of life within three months. Functional status and survival did not differ between groups. A subsample of lung cancer patients provided cross-validation of findings. Although survival was not expected to differ, it was predicted that functioning would be enhanced if quality of life improved. One interpretation is that little can be done to alter physical function and survival when intervention occurs late in the progression of a fatal disease. This in no way reduces the value of improving overall quality of life, since enhancing the quality of survival for end-stage cancer patients is a high priority medical goal.


Designing Methuselah: an ethical argument against germline genetic modification to prolong human longevity.
Precise editing of the human germline has been considered an unlikely and an unethical proposition. Recently, tools to edit the human germline have been developed and it is now a realistic prospect. Consequently, the ethical arguments around prohibiting human genome editing need to be re-evaluated. It is anticipatable that using it to eradicate disease-causing mutations will be acceptable if clinical risks can be shown to be sufficiently low. Some go further and advocate that genetically 'enhancing' humans will also be permissible. Here I argue that there are instances where human germline editing should be prohibited because harms can be anticipated from the results of studies of aspects of human psychology. The example I have chosen to illustrate this argument is prolongation of the human lifespan. Cohort and longitudinal studies demonstrate that a vital ingredient of human contentment and health is being integrated into a cohort of similarly aged people and experiencing life's trials and tribulations contemporaneously. A person genetically engineered to live longer than their peers will experience the loss of their cohort and many from the generation following them-an established risk factor for discontentment and ill health. Since germline genome editing precludes obtaining the consent of the individual in question, and that such a predictable harm will be commonly encountered, it is questionable that human germline editing to extend lifespan can ever be considered an ethical practice.


A molecular recombination map of Antirrhinum majus.
Genetic recombination maps provide important frameworks for comparative genomics, identifying gene functions, assembling genome sequences and for breeding. The molecular recombination map currently available for the model eudicot Antirrhinum majus is the result of a cross with Antirrhinum molle, limiting its usefulness within A. majus. We created a molecular linkage map of A. majus based on segregation of markers in the F2 population of two inbred lab strains of A. majus. The resulting map consisted of over 300 markers in eight linkage groups, which could be aligned with a classical recombination map and the A. majus karyotype. The distribution of recombination frequencies and distorted transmission of parental alleles differed from those of a previous inter-species hybrid. The differences varied in magnitude and direction between chromosomes, suggesting that they had multiple causes. The map, which covered an estimated of 95% of the genome with an average interval of 2 cM, was used to analyze the distribution of a newly discovered family of MITE transposons and tested for its utility in positioning seven mutations that affect aspects of plant size. The current map has an estimated interval of 1.28 Mb between markers. It shows a lower level of transmission ratio distortion and a longer length than the previous inter-species map, making it potentially more useful. The molecular recombination map further indicates that the IDLE MITE transposons are distributed throughout the genome and are relatively stable. The map proved effective in mapping classical morphological mutations of A. majus.