Lignin decomposition along an Alpine elevation gradient in relation to physicochemical and soil microbial parameters.
Lignin is an aromatic plant compound that decomposes more slowly than other organic matter compounds; however, it was recently shown that lignin could decompose as fast as litter bulk carbon in minerals soils. In alpine Histosols, where organic matter dynamics is largely unaffected by mineral constituents, lignin may be an important part of soil organic matter (SOM). These soils are expected to experience alterations in temperature and/or physicochemical parameters as a result of global climate change. The effect of these changes on lignin dynamics remains to be examined and the importance of lignin as SOM compound in these soils evaluated. Here, we investigated the decomposition of individual lignin phenols of maize litter incubated for 2 years in-situ in Histosols on an Alpine elevation gradient (900, 1300, and 1900 m above sea level); to this end, we used the cupric oxide oxidation method and determined the phenols' (13) C signature. Maize lignin decomposed faster than bulk maize carbon in the first year (86 vs. 78% decomposed); however, after the second year, lignin and bulk C decomposition did not differ significantly. Lignin mass loss did not correlate with soil temperature after the first year, and even correlated negatively at the end of the second year. Lignin mass loss also correlated negatively with the remaining maize N at the end of the second year, and we interpreted this result as a possible negative influence of nitrogen on lignin degradation, although other factors (notably the depletion of easily degradable carbon sources) may also have played a role at this stage of decomposition. Microbial community composition did not correlate with lignin mass loss, but it did so with the lignin degradation indicators (Ac/Al)s and S/V after 2 years of decomposition. Progressing substrate decomposition toward the final stages thus appears to be linked with microbial community differentiation.


MOF-GRU: A MOFid-Aided Deep Learning Model for Predicting the Gas Separation Performance of Metal-Organic Frameworks.
The remarkable versatility of metal-organic frameworks (MOFs) stems from their rich chemical information, leading to numerous successful applications. However, identifying optimal MOFs for specific tasks necessitates a thorough assessment of their chemical attributes. Conventional machine learning approaches for MOF prediction have relied on intricate chemical and structural details, hampering rapid evaluations. Drawing inspiration from recent advancements exemplified by Snurr et al., wherein a text string was used to represent a MOF (MOFid), we introduce a MOFid-aided deep learning model, named the MOF-GRU model. This model, founded on natural language processing principles and utilizing the gated recurrent unit architecture, leverages the serialized text string representation of metal-organic frameworks (MOFs) to forecast gas separation performance. Through a focused study on CH4/N2 separation, we substantiate the efficacy of this approach. Comparative assessments against traditional machine learning techniques underscore our model's superior predictive accuracy and its capacity to handle extensive data sets adeptly. The MOF-GRU model remarkably uncovers latent structure-performance relationships with only MOF sequences, obviating the necessity for intricate three-dimensional (3D) structural information. Overall, this model's judicious design empowers efficient data utilization, thereby hastening the discovery of high-performance materials tailored for gas separation applications.


Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes.
Brugada Syndrome (BrS) is a genetic heart condition linked to sudden cardiac death. Though the SCN5A gene is primarily associated with BrS, there is a lack of comprehensive studies exploring the connection between SCN5A mutation locations and the clinical presentations of the syndrome. This study aimed to address this gap and gain further understanding of the syndrome. The investigation classified 36 high-risk BrS patients based on SCN5A mutations within the transmembrane/structured (TD) and intra-domain loops (IDLs) lacking a 3D structure. We characterized the intrinsically disordered regions (IDRs) abundant in IDLs, using bioinformatics tools to predict IDRs and post-translational modifications (PTMs) in NaV1.5. Interestingly, it was found that current predictive tools often underestimate the impacts of mutations in IDLs and disordered regions. Moreover, patients with SCN5A mutations confined to IDL regions-previously deemed 'benign'-displayed clinical symptoms similar to those carrying 'damaging' variants. Our research illuminates the difficulty in stratifying patients based on SCN5A mutation locations, emphasizing the vital role of IDLs in the NaV1.5 channel's functioning and protein interactions. We advocate for caution when using predictive tools for mutation evaluation in these regions and call for the development of improved strategies in accurately assessing BrS risk.


Effect of serial brief ischemic episodes on extracellular K+, pH, and activation in the pig.
This study was performed to determine the reproducibility of the ionic and electrical changes associated with serial ischemic episodes. We used ion-selective and bipolar plunge electrodes to determine the changes in left ventricular extracellular potassium ([K+]e), extracellular pH (pHe), and local activation during sequential 10 min occlusions of the left anterior descending coronary artery separated by 50 min of reperfusion in open-chest anesthetized pigs. We found that uniformly during the initial occlusion, and in approximately 50% of animals during the second occlusion, [K+]e rose more rapidly but to a lower level than in subsequent occlusions. By the third occlusion the changes in [K+]e were reproducible. Extracellular acidosis was greatest in the first occlusion and decreased progressively with each subsequent occlusion. Local activation was characterized by a decrease in spontaneous improvement and increase in block with each successive occlusion. The occurrence of ventricular fibrillation could not be directly attributed to the magnitude of the change in [K+]e or pHe. Moreover, the occurrence of ventricular fibrillation in one occlusion did not necessarily predict its occurrence thereafter. Our results indicate that serial episodes of ischemia are associated with different but predictable changes in ionic and electrical events that may be clinically relevant and that must be appreciated before the results from similar protocols with serial ischemic episodes can be interpreted meaningfully.


[Vasopressin and its analogues in the therapy of shock].
Hemodynamic support during the circulatory failure with vasodilation, most frequently during the septic shock, is based on volume recovery and administration of inotropic drugs. If such therapy is not sufficient, vasoconstriction drugs are subsequently or parallel added to maintain the perfusion pressure. As a standard therapy, norepinephrine or other catecholamines with alpha-adrenergic effect are used in rising doses. Some patients do not respond to such therapy with desired hemodynamic changes--they develop catecholamine resistant shock. Because of serious side effects of high doses of catecholamines, alternative vasopressors are necessary. Vasopressin, antidiuretic hormone, has in physiological conditions only minimal effect of the vascular tone. During hypovolemia its concentration rises and it may significantly contribute to the maintenance of arterial pressure by vasoconstriction. Contrary to it, during septic shock the levels of vasopressine are very low and vasodilation clinically dominates. At the same time, the septic shock is accompanied by an increased sensitivity to vasopressin administration. In a critical shock a serious deficit of endogenous vasopressin is expected. At present several pilot studies with vasopressine administration in septic shock exist in literature describing beneficial effect of vasopressin on hemodynamic parameters. Such comparatively low doses have no side effects on perfusion and function of body organs. Terlipressin, which is available in Czech Republic, is a synthetic analogue of vasopressin with extended effect. Its intermittent administration is used for the treatment of portal hypertension complications. Terlipressin in animal model of septic shock has similarly beneficial effects as vasopressin. High doses of Terlipressin have, similarly to vasopressin, adverse effects on pulmonary circulation and other systems. Till present, only casuistic experience has been published with low doses of Terlipressin in the treatment of septic shock resistant to catecholamines, which has shown similar effects to vasopressin. In shock states with the deficit of endogenous vasopressin, which are resistant to high doses of catecholamines, administration of vasopressin analogues represents a new perspective therapy. The treatment should be studied from the point of morbidity and mortality. A careful approach has to be used in septic patients with pre-existing obliterative vassal disease.


Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs.
Generation of reactive oxygen metabolites, thromboxane increases, and vasoconstriction have been implicated in the pathogenesis of acute edematous lung injury, such as that seen in patients with the Adult Respiratory Distress Syndrome (ARDS), but their interactions are unknown. We hypothesized that reactive O2 products would stimulate arachidonic acid metabolism in lungs and that vasoactive products of arachidonate, such as the potent vasoconstrictor thromboxane A2, might then mediate O2-metabolite-induced pulmonary vasoconstriction. We found that O2 metabolites generated by injection of purine plus xanthine oxidase caused increases in mean pulmonary artery perfusion pressures (27 +/- 4 mmHg) in isolated perfused lungs. In addition, purine plus xanthine oxidase also caused 30-fold increases in perfusate levels of thromboxane B2 (the stable metabolite of thromboxane A2) compared with only twofold increases in 6-keto-PGF1a (the stable metabolite of prostacyclin). Moreover, prior addition of catalase inhibited both vasoconstriction and the thromboxane B2 production seen in isolated lungs following injection of purine plus xanthine oxidase. Similarly, pretreatment with cyclooxygenase inhibitors, either aspirin or indomethacin, also completely blocked thromboxane generation and markedly attenuated pressor responses usually seen after purine plus xanthine oxidase (increase in mean pulmonary artery perfusion pressures, 4.4 +/- 1.5 mmHg). Furthermore, imidazole, a thromboxane synthetase inhibitor, also decreased O2-metabolite-induced thromboxane generation and vasoconstriction. These results suggested that thromboxane generation might participate in O2-metabolite-induced vasoconstriction. However, since a significant correlation between thromboxane levels and the degree of vasoconstriction could not be demonstrated, and since addition of superoxide dismutase reduced thromboxane generation but did not affect the intensity of vasoconstriction, it is possible that thromboxane is not the only vasoactive mediator in this model. We conclude that exposing lungs to O2 metabolites results in thromboxane generation and that thromboxane is a major mediator of oxidant-induced vasoconstriction.


Estimating monthly PM2.5 concentrations from satellite remote sensing data, meteorological variables, and land use data using ensemble statistical modeling and a random forest approach.
Fine particulate matter (PM2.5) is associated with various adverse health outcomes and poses serious concerns for public health. However, ground monitoring stations for PM2.5 measurements are mostly installed in population-dense or urban areas. Thus, satellite retrieved aerosol optical depth (AOD) data, which provide spatial and temporal surrogates of exposure, have become an important tool for PM2.5 estimates in a study area. In this study, we used AOD estimates of surface PM2.5 together with meteorological and land use variables to estimate monthly PM2.5 concentrations at a spatial resolution of 3 km2 over Taiwan Island from 2015 to 2019. An ensemble two-stage estimation procedure was proposed, with a generalized additive model (GAM) for temporal-trend removal in the first stage and a random forest model used to assess residual spatiotemporal variations in the second stage. We obtained a model-fitting R2 of 0.98 with a root mean square error (RMSE) of 1.40 μg/m3. The leave-one-out cross-validation (LOOCV) R2 with seasonal stratification was 0.82, and the RMSE was 3.85 μg/m3, whereas the R2 and RMSE obtained by using the pure random forest approach produced R2 and RMSE values of 0.74 and 4.60 μg/m3, respectively. The results indicated that the ensemble modeling approach had a higher predictive ability than the pure machine learning method and could provide reliable PM2.5 estimates over the entire island, which has complex terrain in terms of land use and topography.


Islet amyloid polypeptide regulates multiple steps in stimulus-secretion coupling of beta cells in rat pancreatic islets.
Islet amyloid polypeptide (IAPP) is produced in pancreatic beta cells. Intraislet function of IAPP is still uncertain. In the present study, we investigated effects of IAPP and somatostatin on stimulus-secretion coupling of beta cells in isolated rat pancreatic islets. Insulin secretion induced by 22.2 mM glucose was increased by an IAPP antiserum (0.1%) or an IAPP antagonist (IAPP8-37, 10 microM). Pretreatment of islets with pertussis toxin (PTX) abolished the stimulating effect of IAPP8-37 on glucose-induced insulin secretion. In contrast, IAPP antiserum and IAPP8-37 did not change insulin secretion induced by 30 mM KCl. Somatostatin (1 nM) inhibited insulin secretion induced by 22.2 mM glucose, 10 mM L-arginine, 25 microM forskolin, and 200 microM carbachol. IAPP (10 microM) enhanced the inhibitory effect of somatostatin on insulin secretion induced by L-arginine or forskolin. PTX pretreatment abolished the effects of somatostatin and IAPP on arginine-induced insulin secretion. In conclusion, IAPP regulates multiple steps in signal transductions of beta cells. The effects of IAPP on beta cells are mediated by PTX-sensitive regulatory G proteins.


Effect of chewing gums containing the probiotic bacterium Lactobacillus reuteri on oral malodour.
To evaluate the effect of chewing gums containing probiotic bacteria on oral malodour. The null hypothesis was that no difference would be displayed compared with placebo gums. Twenty-five healthy young adults with self-reported malodorous morning breath completed this randomized double-blind placebo-controlled cross-over trial. The design included run-in and wash-out periods interspersed by two intervention periods of 14 days each. The subjects were instructed to chew one gum in the morning and one in the evening containing either two strains of probiotic lactobacilli (L. reuteri DSM 17938 and L. reuteri ATCC PTA 5289) or placebo. The outcome measures were (i) organoleptic scores (0-5) by a certified test panel, (ii) concentration of volatile sulphur compounds (VSC) measured with a Halimeter and (iii) concentration of VSC after a cysteine rinse. Registrations were made at baseline and after each intervention period. Differences between the groups were assessed by non-parametric paired statistics and chi-square test. The median organoleptic score was similar (score 2) in both groups at baseline. After 14 days of treatment, the organoleptic scores were significantly lower in the probiotic group compared with the placebo group (p < 0.05). Assessments of the VSC levels displayed no significant differences between the groups, either before or after rinsing with L-cysteine. No adverse effects were registered. The results demonstrated that probiotic chewing gums may have some beneficial effect on oral malodour assessed by organoleptic scores. The results indicate that the probiotic gum may affect bacteria that produce malodourous compounds other than VSCs.


Pseudomonas aeruginosa AlgZ, a ribbon-helix-helix DNA-binding protein, is essential for alginate synthesis and algD transcriptional activation.
The Pseudomonas aeruginosa algD gene is the first gene of an operon encoding most of the enzymes necessary for biosynthesis of the exopolysaccharide alginate. Transcriptional activation of algD results in the high-level synthesis of alginate, an important P. aeruginosa virulence factor with antiphagocytic and adherence properties. Previously, we have identified a protein(s), AlgZ, expressed in mucoid P. aeruginosa CF isolates that specifically bound to sequences located 280 bp upstream of the algD promoter. Mutagenesis of the AlgZ DNA binding site and transcription assays were used to show that AlgZ was an activator of algD transcription. In the current study, the monomeric size of AlgZ was estimated to be between 6 kDa and 15 kDa by electroelution of a protein preparation from an SDS-PAGE gel and analysis of the fractions via protein staining and electrophoretic mobility shift assays. A biochemical enrichment procedure, resulting in a 130-fold enrichment for AlgZ, was devised, the protein identified and a partial amino-terminal sequence obtained. Using the P. aeruginosa Genome Project database, a complete sequence was obtained, and algZ was cloned and expressed in Escherichia coli. Expression of algZ was sufficient for the observed AlgZ DNA binding previously observed from extracts of P. aeruginosa. A protein database search revealed that AlgZ is homologous to the Mnt and Arc repressors of the ribbon-helix-helix family of DNA-binding proteins. An algZ deletion mutant was constructed in the mucoid CF isolate FRD1. The resulting strain was non-mucoid and exhibited no detectable algD transcription. As an indirect role in transcription would probably result in some residual algD transcription, these data suggest that AlgZ is an integral activator of algD and support the hypothesis that both AlgZ and the response regulator AlgR are involved in direct contact with RNA polymerase containing the alternative sigma factor, AlgT. The cloning of algZ is a crucial step in determining the mechanism of algD activation.


Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum.
Myhre syndrome is a rare multisystem connective tissue disorder, characterized by short stature, facial dysmorphology, variable intellectual disability, skeletal abnormalities, arthropathy, cardiopathy, laryngotracheal anomalies, and stiff skin. So far, all molecularly confirmed cases harbored a de novo heterozygous gain-of-function mutation in SMAD4, encoding the SMAD4 transducer protein required for both transforming growth factor-beta and bone morphogenic proteins signaling. We report on four novel patients (one female proband and her two affected children, and one male proband) with Myhre syndrome harboring the recurrent c.1486C>T (p.Arg496Cys) mutation in SMAD4. The female proband presented with a congenital heart defect, vertebral anomalies, and facial dysmorphic features. She developed severe tracheal stenosis requiring a total laryngectomy. With assisted reproductive treatment, she gave birth to two affected children. The second proband presented with visual impairment following lensectomy in childhood, short stature, brachydactyly, stiff skin, and decreased peripheral sensitivity. Transmission electron microscopy (TEM) of the dermis shows irregular elastin cores with globular deposits and almost absent surrounding microfibrils and suggests age-related increased collagen deposition. We report on the first familial case of Myhre syndrome and illustrate the variable clinical spectrum of the disorder. Despite the primarily fibrotic nature of the disease, TEM analysis mainly indicates elastic fiber anomalies.


The kinetochores of Caenorhabditis elegans.
Light microscopy of the mitotic chromosomes of Caenorhabditis elegans suggests that non-localized kinetochores are present, since the chromosomes appear as stiff rods 1 to 2 micrometers in length and lack any visible constriction. The holokinetic structure was confirmed by reconstructions of electron micrographs of dividing nuclei in serially sectioned embryos. In prophase the kinetochore appears as an amorphous projection approximately 0.18-0.2 micrometer in diameter in cross section and in longitudinal section it appears to be continuous along the chromatin. At prometaphase and metaphase the kinetochore is a convex plaque covering the poleward face of the chromosome and extending the length of the chromosome. In longitudinal section the kinetochore is a trilaminar structure with electron dense inner and outer layers of 0.02 micrometer, and an electron lucent middle layer of 0.03 micrometer. The inner layer is adjacent to a more electron dense region of chromatin. The kinetochore was also seen as a band extending the length of the chromosome in whole mount preparations of chromosomes stained with ethanolic phosphotungstic acid. Most gamma ray induced chromosome fragments segregate normally in embryonic mitoses, but some fragments display aberrant behavior. Similar behavior was seen in embryos carrying a genetically characterized free duplication. It is suggested that mitotic segregation of small fragments may be inefficient because the probability of attachment of microtubules to the kinetochore is proportional to kinetochore length.


In vivo human comparison of intravascular ultrasonography and angiography.
This study evaluates the in vivo correlation of intravascular ultrasonography and uniplanar angiography in determining the luminal dimensions of normal and moderately atherosclerotic human arteries. Five French and 8F rotating A scan intravascular ultrasound catheters were used to obtain 48 images in four superficial femoral arteries, five iliac arteries, and one aorta in eight patients undergoing vascular surgery. Cross-sectional areas measured by intravascular ultrasonography were compared to cross-sectional areas calculated by uniplanar angiography of the same location in the vessel. Maximum and minimum luminal diameters were also measured from intravascular ultrasound images. An ellipticity index was defined as the maximum/minimum diameter ratio (max/min) and ranged from 1.0 to 1.8 (mean, 1.2). Comparison of the cross-sectional areas measured from intravascular ultrasound images and those calculated from uniplanar angiography showed no significant difference at any level of ellipticity studied. However, when the values of cross-sectional areas were analyzed in groups corresponding to the diameter of the vessel, that is, aortic, iliac, and femoral, the values for the iliac arteries calculated from uniplanar angiography were significantly greater by 9.8% +/- 0.7% (n = 29, p = 0.03) when compared to those measured by intravascular ultrasonography. In addition to providing accurate luminal determinations, intravascular ultrasound images displayed transmural morphology, the location and character of the atherosclerotic lesions, and the thickness of the vessel wall. We conclude that intravascular ultrasound imaging provides accurate, novel information regarding human vessels and that this technology may play a significant role in future diagnostic and interventional therapies.


Alcohol Use Patterns During and After the COVID-19 Pandemic Among Veterans in the United States.
Veterans may be especially susceptible to increased alcohol consumption following the COVID-19 pandemic. We aim to evaluate trends in alcohol use among U.S. Veterans before, during, and following the onset of the COVID-19 pandemic. All U.S. Veterans utilizing Veterans Affairs healthcare facilities in the U.S. from March 1, 2018 to February 28, 2023 with ≥1 AUDIT-C score were categorized into 1) No alcohol use (AUDIT-C = 0), 2) Low-risk alcohol use (AUDIT-C 1-2 for women, 1-3 for men), and 3) High-risk alcohol use (AUDIT-C ≥ 3 for women, ≥ 4 for men). Trends in the proportion of Veterans reporting high-risk alcohol use, stratified by sex, age, race/ethnicity, and urbanicity were evaluated. Among a cohort of 2.15 to 2.60 million Veterans, 15.5% reported high-risk alcohol use during March 2018-February 2019, which declined to 14.6% during the first year of the pandemic, increased to 15.2% in the second year, and then decreased to 14.9% from March 2022-February 2023. Among non-Hispanic whites, African Americans, Asians, and Hispanics, the proportion of women reporting high-risk alcohol use surpassed that of men during the onset of the pandemic and beyond. The greatest proportion of high-risk alcohol use was observed among young Veterans aged 18-39 years (17-27%), which was consistent across all race/ethnic groups. High-risk alcohol use among U.S. Veterans has increased since the COVID-19 pandemic onset, and in the third year following pandemic onset, 15% of Veterans overall and over 20% of young Veterans aged 18-39 years reported high -risk alcohol use.


Chondroclasts in fusarium-induced tibial dyschondroplasia. A histomorphometric study.
The role of chondroclasts in the pathogenesis of Fusarium roseum-induced tibial dyschondroplasia (TD) was examined in a histomorphometric study. TD developed rapidly in broiler chickens placed at 1 day of age on rations containing either 3% (Experiment 1) or 2% (Experiment 2) F roseum cultures. In Experiment 1 the frequency of TD in birds killed at 4 weeks of age was 90%. In Experiment 2, birds were killed at intervals from 4 days until 4 weeks of age. By 1 week of age, 70% of birds examined had characteristic accumulations of prehypertrophic cartilage at the proximal tibial physis, and the frequency of TD in 4-week-old birds was 80%. Sections of hypertrophic cartilage from F roseum-fed and control birds from both experiments were examined for determination of the volume density of chondroclasts along the vascular channel boundary. Chondroclast density was consistently lower in F roseum-fed than in control birds, but the difference was significant only at 4 weeks of age. The fact that gross lesions were evident before a significant decrease in chondroclast density occurred indicates that a decrease in the density of chondroclasts was not an essential factor in the accumulation of cartilage characteristic of TD.


Removable orthodontic appliances: new perspectives on capabilities and efficiency.
Removable appliances are a dependable choice for many patients but like all orthodontic appliances, they have some limitations in use. Patient selection and appropriate appliance design are two key factors for success. Many patients, especially adults, prefer intra-oral appliances to extra-oral devices. Sometimes a removable intra-oral appliance can solve a dental problem in a shorter period of time compared to fixed treatment, and this has also been repeatedly seen in molar distalisation. From the interceptive perspective, the appliance can prevent or alleviate an impending crowding for erupting permanent incisors. This article describes 5 patients with different orthodontic problems: impending crowding for erupting upper canine with 2 approaches, provision of space for upper cuspids, resolution of chronic attrition of anterior teeth, relief of space shortage for upper canines eruption, and reduction of excess overjet. All subjects were treated with removable appliances of various designs.


Two-Dimensional Folding of Polypeptides into Molecular Nanostructures at Surfaces.
Herein we report the fabrication of molecular nanostructures on surfaces via two-dimensional (2D) folding of the nine amino acid peptide bradykinin. Soft-landing electrospray ion beam deposition in conjunction with high-resolution imaging by scanning tunneling microscopy is used to fabricate and investigate the molecular nanostructures. Subnanometer resolved images evidence the large conformational freedom of the molecules if thermal motion is inhibited and the formation of stable uniform dimers of only one specific conformation when diffusion can take place. Molecular dynamics modeling supported by density functional theory calculations give atomically precise insight into the induced-fit binding scheme when the folded dimer is formed. In the absence of solvent, we find a hierarchy of binding strength from polar to nonpolar, manifested in an inverted polar-nonpolar segregation which suppresses unspecific interactions at the rim of the nanostructure. The demonstrated 2D-folding scheme resembles many key properties of its native 3D counterpart and shows that functional, molecular nanostructures on surfaces fabricated by folding could be just as versatile and specific.


Patient selection for lung volume reduction surgery: An objective model based on prior clinical decisions and quantitative CT analysis.
We used whole-lung quantitative CT analysis (QCT)-an objective method of evaluating emphysema severity and distribution based on measurement of lung density-to determine whether subjective selection criteria for lung volume reduction surgery are applied consistently and to model the patient selection process, and assessed the relationship of the model to postoperative outcome. Logistic regression analysis using QCT indexes of emphysema and preoperative physiologic test results as the independent variables, and the decision to operate as the dependent variable. University hospital. Seventy patients selected for bilateral lung volume reduction surgery and 32 otherwise operable patients excluded from surgery based on subjective assessment of emphysema morphology on chest radiography, CT, and perfusion scintigraphy. Bilateral lung volume reduction surgery in the selected group. Emphysema in patients selected for surgery was more severe overall and in the upper lungs by multiple QCT indexes (p < 0.01, unpaired two-tailed t test). Physiologic abnormalities were slightly more severe in selected patients (p < 0.05, unpaired two-tailed t test). The range of many QCT and physiologic values overlapped considerably between the selected and excluded groups. The percent severe emphysema (<- 960 Hounsfield units [HU]), upper/lower lung emphysema ratio (- 900 HU threshold), and residual volume were the key variables in the model predicting selection decisions (model r(2) = 0.48; p < 0.0001). The model correctly predicted selection decisions in 87% of all cases, 91% of the selected group, and 78% of the excluded group. Surgical patients with a higher model-derived probability of selection had greater postoperative improvement in FEV(1) and 6-min walk distance. Radiologic selection criteria are applied consistently to the majority of patients. QCT features are strongly associated with selection decisions, are related to outcome, and may help improve consistency and confidence in patient selection.


Effect of recombinant human erythropoietin on lymphocyte phenotyping and phagocyte activity in hemodialysis patients.
The effect of recombinant human erythropoietin (rHmEPO) on lymphocytic phenotyping as well as on the phagocyte activity of polymorphonuclear cells and monocytes was evaluated in 16 patients on maintenance hemodialysis. The mean age of the patients was 38.2 +/- 16.2 years. There were seven men and nine women. All patients were started on 50 U/kg of rHmEPO intravenously three times per week, and the dosage was increased gradually to achieve target haemoglobin of 12 g/dL. Predialysis blood samples were taken monthly for 3 months, and phagocyte respiratory burst as well as lymphocyte subsets were studied. Healthy blood donors were taken as controls. By 3 months of rHmEPO treatment, there was no significant increase in total T and B cells, but there was a significant increase in both CD4 (P < 0.001) and CD8 (P < 0.005): however, there was no significant change in the CD4/CD8 ratio. There was significant reduction in the natural killer cells (P < 0.005). The phagocyte activity studies showed a significant increase in the respiratory burst in whole blood (P < 0.001) and opsonized zymosan (P < 0.001) as well as improvement in the suppressed polymorphonuclear cell and monocyte activity by uremia. Phagocytosis studied by yeast uptake showed significant improvement from the pretreatment suppressed phagocytes to normal activity posttreatment. In conclusion, treatment with rHmEPO increases CD4 and CD8 cell counts without affecting the CD4/CD8 ratio, decreases the natural killer cells, and improves the impaired phagocyte activity in hemodialysis patients.


Catabolism of coffee chlorogenic acids by human colonic microbiota.
Several studies have indicated potential health benefits associated with coffee consumption. These benefits might be ascribed in part to the chlorogenic acids (CGAs), the main (poly)phenols in coffee. The impact of these dietary (poly)phenols on health depends on their bioavailability. As they pass along the gastrointestinal tract, CGAs are metabolized extensively and it is their metabolites rather than the parent compounds that predominate in the circulatory system. This article reports on a study in which after incubation of espresso coffee with human fecal samples, high-performance liquid chromatography-mass spectrometry (HPLC-MS) and gas chromatography-mass spectrometry (GC-MS) were used to monitor CGA breakdown and identify and quantify the catabolites produced by the colonic microflora. The CGAs were rapidly degraded by the colonic microflora and over the 6-h incubation period, 11 catabolites were identified and quantified. The appearance of the initial degradation products, caffeic and ferulic acids, was transient, with maximum quantities at 1 h. Dihydrocaffeic acid, dihydroferulic acid, and 3-(3'-hydroxyphenyl)propionic acid were the major end products, comprising 75-83% of the total catabolites, whereas the remaining 17-25% consisted of six minor catabolites. The rate and extent of the degradation showed a clear influence of the composition of the gut microbiota of individual volunteers. Pathways involved in colonic catabolism of CGAs are proposed and comparison with studies on the bioavailability of coffee CGAs ingested by humans helped distinguish between colonic catabolites and phase II metabolites of CGAs.


Treatment of obese children with and without their mothers: changes in weight and blood pressure.
Weight and blood pressure changes were evaluated in a 16-month controlled trial comparing three methods of involving mothers in the treatment of their obese adolescents (aged 12 to 16 years). The treatments were: (1) Mother-Child Separately--children and mothers attended separate groups; (2) Mother-Child Together--the children and mothers met together in the same group; and (3) Child Alone--the children met in groups and mothers were not involved. The program consisted of behavior modification, social support, nutrition, and exercise. The Mother-Child Separately group lost more weight (8.4 kg) during treatment than did the other two groups (5.3 and 3.3 kg). Differences between the groups increased at the 1-year follow-up: compared to pretreatment weight, the Mother-Child Separately group lost 7.7 kg compared with gains of approximately 3 kg in the other two groups. Blood pressures of children with the highest initial pressures decreased by 16/9 mm Hg at the end of treatment and by 16/5 mm Hg at the 1-year follow-up. These results suggest that a program of behavior modification and parent involvement can lead to significant weight losses in obese children, and that the nature of parent involvement may be important.


Assessment and management of pain in the paediatric patient.
A combination of pharmacological and non-pharmacological interventions can ensure the highest standard of care in the management of pain in children. Nurses are in a prime position to care for children and educate them and their parents on effective pain management strategies.


From the Clinical Mycology Laboratory: New Species and Changes in Fungal Taxonomy and Nomenclature.
Fungal taxonomy is the branch of mycology by which we classify and group fungi based on similarities or differences. Historically, this was done by morphologic characteristics and other phenotypic traits. However, with the advent of the molecular age in mycology, phylogenetic analysis based on DNA sequences has replaced these classic means for grouping related species. This, along with the abandonment of the dual nomenclature system, has led to a marked increase in the number of new species and reclassification of known species. Although these evaluations and changes are necessary to move the field forward, there is concern among medical mycologists that the rapidity by which fungal nomenclature is changing could cause confusion in the clinical literature. Thus, there is a proposal to allow medical mycologists to adopt changes in taxonomy and nomenclature at a slower pace. In this review, changes in the taxonomy and nomenclature of medically relevant fungi will be discussed along with the impact this may have on clinicians and patient care. Specific examples of changes and current controversies will also be given.


Cost analysis of brachial plexus injuries: variability of compensation by insurance companies before and after surgery.
Traumatic paralysis of the brachial plexus is an extremely disabling pathology. The type of trauma most frequently suffered by this group of patients is due to motorcycle injuries. It therefore affects a population of young patients. In the majority of cases, these patients receive compensation for permanent damage from insurance companies. Surgery of the brachial plexus enables various forms of functional recovery, depending on the number of roots of the brachial plexus involved in the injury. The aim of this study is to compare the functional deficit and the extent of the related compensation before and after surgical intervention, and to evaluate the saving in economic terms (understood as the cost of compensation paid by insurance companies) obtainable through surgical intervention. The authors analysed the functional recovery obtained through surgery in 134 patients divided into 4 groups on the basis of the number of injured roots. The levels of compensation payable to the patient before surgical intervention, and 3 years after, were then compared. The results showed that the saving obtainable through surgical treatment of brachial plexus injuries may exceed 65% of the economic value of the compensation that would have been attributable to the same patients if they had not undergone surgical treatment.


Surrogate markers of antitumor responses: in vitro activation of T cells by autologous tumor peptides.
The increasing ability to augment antitumor immunity in model systems has led to increased numbers of clinical trials. However, progress in detecting immune responses by patients against autologous tumors has been slow. Although a considerable number of tumor antigens, as well as peptides derived from them, and the MHC determinants together with which they are presented have been identified for melanoma, this is not so for the majority of solid tumors. Furthermore, tumor cells themselves are poor stimulators of immunity. Thus, approaches that do not depend upon defined antigens or using tumor cells as stimulators would be desirable. To attempt to measure immune responses in these situations, we tested whether total peptides, prepared from autologous tumor tissue, stimulated cytokine release by T cells. Peripheral blood mononuclear cells (PBMCs) were mixed with antigen-presenting cells (APCs), pulsed with tumor peptides, and tested in the ELISPOT assay for IFN-gamma secretion. Few spots were obtained when PBMCs were cultured with unpulsed APCs or in wells with peptide-pulsed APC alone. In contrast, a strong response was seen when PBMCs were cultured with APCs that had been pulsed with autologous total tumor peptides. This system should help to identify those immunotherapeutic approaches that induce responses against tumor cells in vivo. Because different cytokine profiles are associated with distinct arms of the immune response, testing in the ELISPOT assay may also help us understand the mechanisms responsible.


[Options for correction of endothelial dysfunction and oxidative stress in patients with primary open-angle glaucoma].
To evaluate the efficacy of Tanakan in patients with primary open-angle glaucoma (POAG) with respect to its influence on vascular endothelial function and oxidative stress. Oxidative stress severity and antioxidant status were investigated in 52 patients with POAG divided into two groups. The effect of different treatment schemes on flow-dependent vasodilation and dynamic level of endotelin-1 (ET-1), which is a marker of endothelial dysfunction, was studied. In the main group glaucomatous optic neuropathy progressed significantly as compared to the baseline (p<0.05). A trend for a decrease in malondialdehyde-modified low-density lipoproteins (MDA-LDL) and plasma malondialdehyde (MDA) levels (p<0.1) was also found, which indicates the activation of antioxidant response and resolution of oxidative stress. Due to endothelial dysfunction, plasma ET-1 levels in glaucoma patients are on average 5 times higher than the corresponding median physiological concentration. After the treatment started plasma ET-1 levels reduced and 3 months later approached the normal range. Reactive hyperemia testing and assessment of flow-dependent vasodilation revealed a poor initial endothelial response in 64.6% of patients. During the treatment paradoxical vasoconstriction was noted in 12.4% of patients. After the treatment patients from the main group demonstrated a statistically significant increase in brachial artery diameter. Tanakan is showed to produce a positive effect on vascular remodeling in patients with POAG, which indicates its high antioxidant and antihypoxic activity. A significantly increased flow-dependent vasodilation found in the main group (especially 1-3 months after the beginning of the therapy) is thought to be due to an improved vasodilating ability of the vascular endothelium as the result of Tanakan use.


Influenza and other respiratory virus infections in outpatients with medically attended acute respiratory infection during the 2011-12 influenza season.
Respiratory tract infections are a major cause of outpatient visits, yet only a portion is tested to determine the etiologic organism. Multiplex reverse transcriptase polymerase chain reaction (MRT-PCR) assays for detection of multiple viruses are being used increasingly in clinical settings. During January-April 2012, outpatients with acute respiratory illness (≤ 7 days) were tested for influenza using singleplex RT-PCR (SRT-PCR). A subset was assayed for 18 viruses using MRT-PCR to compare detection of influenza and examine the distribution of viruses and characteristics of patients using multinomial logistic regression. Among 662 participants (6 months-82 years), detection of influenza was similar between the MRT-PCR and SRT-PCR (κ = 0.83). No virus was identified in 267 (40.3%) samples. Commonly detected viruses were human rhinovirus (HRV, 15.4%), coronavirus (CoV, 10.4%), respiratory syncytial virus (RSV, 8.4%), human metapneumovirus (hMPV, 8.3%), and influenza (6%). Co-detections were infrequent (6.9%) and most commonly occurred among those <18 years old. In regression analyses, compared with non-viral illnesses, RSV and hMPV were significantly more frequent in children and less frequent in 18- to 49-year-olds than in those ≥ 50 years (P = 0.01), fever was more common in hMPV and influenza infections (P = 0.008), nasal congestion was more frequent in CoV, HRV, hMPV, influenza and RSV infections (P = 0.001), and body mass index was higher among those with influenza (P = 0.036). Using MRT-PCR, a viral etiology was found in three-fifths of patients with medically attended outpatient visits for acute respiratory illness during the influenza season; co-detected viruses were infrequent. Symptoms varied by viral etiology.


Graphene Oxide-Carbon Nanotube (GO-CNT) Hybrid Mixed Matrix Membrane for Pervaporative Dehydration of Ethanol.
The pervaporation process is an energy-conservative and environmentally sustainable way for dehydration studies. It efficiently separates close boiling point and azeotrope mixtures unlike the distillation process. The separation of ethanol and water is challenging as ethanol and water form an azeotrope at 95.6 wt.% of ethanol. In the last few decades, various polymers have been used as candidates in membrane preparation for pervaporation (PV) application, which are currently used in the preparation of mixed matrix membranes (MMMs) for ethanol recovery and ethanol dehydration but have not been able to achieve an enhanced performance both in terms of flux and selectivity. Composite membranes comprising of poly (vinyl alcohol) (PVA) incorporated with carboxylated carbon nanotubes (CNT-COOH), graphene oxide (GO) and GO-CNT-COOH mixtures were fabricated for the dehydration of ethanol by pervaporation (PV). The membranes were characterized with Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), Raman spectroscopy, Raman imaging, contact angle measurement, and water sorption to determine the effects of various nanocarbons on the intermolecular interactions, surface hydrophilicity, and degrees of swelling. The effects of feed water concentration and temperature on the dehydration performance were investigated. The incorporation of nanocarbons led to an increase in the permeation flux and separation factor. At a feed water concentration of 10 wt.%, a permeation flux of 0.87 kg/m2.h and a separation factor of 523 were achieved at 23 °C using a PVA-GO-CNT-COOH hybrid membrane.


A generalized transducing phage for the murine pathogen Citrobacter rodentium.
A virulent phage (phiCR1) capable of generalized transduction in Citrobacter rodentium was isolated from the environment and characterized. C. rodentium is a natural pathogen of mice, causing transmissible murine colonic hyperplasia. Sequencing of its genome has recently been completed and will soon be fully annotated and published. C. rodentium is an important model organism for infections caused by the human pathogens enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC). phiCR1 uses a lipopolysaccharide receptor, has a genome size of approximately 300 kb, and is able to transduce a variety of markers. phiCR1 is the first reported transducing phage for C. rodentium and will be a useful tool for functional genomic analysis of this important natural murine pathogen.


[Proteus peritonitis-bacteremia in mice--a model for studying postvaccinal Proteus immunity].
The dynamics of the formation of postvaccinal immunity after immunization with preparations obtained with the use of hydroxylamine (HA) preparations from Proteus strains of different O serogroups, Salmonella minnesota Re-mutant and the common antimicrobial antigen isolated from Escherichia coli 14 has been studied on mice with Proteus peritonitis-bacteremia used as a model. The study has revealed that intraperitoneal immunization with Proteus HA preparations stimulates the phagocytic activity of peritoneal mononuclear cells in mice and induces an increase in the titers of specific O antibodies. Proteus antigens ensure the formation of anti-Proteus immunity, preventing the death of the animals from peritonitis-bacteremia. The protection of mice from such infection resulting from the injection of the common antigens of gram-negative bacteria is considerably less. These data are indicative of the possibility of using Proteus peritonitis-bacteremia as a model for the study of the protective potency of Proteus vaccines.


Critical success factors for thriving under PPS.
Home care agencies must work hard in the months ahead to successfully implement PPS. The new system is a fair and equitable one. Home care agencies will have to co-manage cost and quality. PPS, if implemented and administered appropriately, will benefit both the provider and the patient. Proper planning and hard work throughout the transition process will drive success. The prospective system is a reality and will become effective October 1, 2000. Agencies must start now to not only accomplish and meet the basic compliance issues, but also to develop the change in processes needed to become efficient and cost effective.


Characterization of vaginal microbiota in Chinese women with cervical squamous intra-epithelial neoplasia.
Although persistent human papillomavirus (HPV) infection is a major cause of cervical squamous intra-epithelial neoplasia, the relationship between vaginal microbiota and different grades of squamous intra-epithelial neoplasia is not well established. We explored the possible relationship between the vaginal microbiota and the progression of cervical squamous intra-epithelial neoplasia. We evaluated 69 women who attended the Obstetrics and Gynecology Hospital of Fudan University. The vaginal bacterial composition of three groups of women was characterized by deep sequencing of bar-coded 16S rRNA gene fragments (V3-4) using Illumina MiSeq. Exclusion criteria were any previous hysterectomy, history of cervical or other lower genital cancer, and/or destructive therapy of the cervix. Women who had autoimmune disorders, who were HIV positive, who received antibiotics within 15 days of sampling, or who had engaged in sexual intercourse or douching within 48 hours prior to sampling were also excluded. P values for age and proportions of organisms were calculated using one-way ANOVA and p values for HPV status and community state types (CSTs) were calculated using a χ2 test. The vaginal bacterial composition of three groups of women, those without an intra-epithelial lesion or malignancy (n=31), those with a low-grade squamous intra-epithelial lesion (LSIL) (n=22), and those with a high-grade squamous intra-epithelial lesion (HSIL) (n=16) were analyzed. Lactobacillus was the most dominant genus overall. Prevotella and Streptococcus were increased in the HSIL group. Cervical disease progression was associated with the prevalence of high-risk HPV infection. Squamous intra-epithelial neoplasia converted the vaginal bacterial community structure from CSTs IV to II. Microbiota diversity was more pronounced in CST types II and IV (p<0.001), especially in type II. We found a significant enrichment in the Peptostreptococcaceae family, Pseudomonadales order, and other types of bacteria in the group of women without intra-epithelial lesions or malignancy compared with women with squamous intra-epithelial neoplasia. We found enrichment in Delftia in the LSIL and HSIL groups compared with the group without an intra-epithelial lesion or malignancy. Our results show that the vaginal microbiota is directly or indirectly related to the progression of squamous intra-epithelial neoplasia, and Delftia might be a microbiological hallmark of cervical pre-cancerous lesions.


Role of pulmonary artery reactivity and nitric oxide in injury and inflammation following lung contusion.
The mechanisms contributing to hypoxia in lung contusion (LC) remain unclear and not temporally associated with the peak onset of acute inflammation. We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. In addition, the role of antioxidants in reversing this process was examined. PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a nitric oxide synthase (NOS) inhibitor, L-nitro arginine (10(-3) M), or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT), or both (L-nitro arginine + SOD/CAT). Rings were constricted with norepinephrine and relaxed with an NOS agonist (A23187) or NO donor (SNAP [S-nitrosyl amino penicillamine]). Immunochemical and mass spectrometric quantification for nitrotyrosine was performed. Rats were hypoxemic at 4 h after contusion compared with controls, but recovered by 24 h (PaO(2)/FIO(2) ratio: baseline, 443 ± 28; 4 h, 288 ± 46; and 24 h, 417 ± 23). Pulmonary arterial constriction to NOS inhibition and relaxation to A23187 were impaired 4 h after LC. Pulmonary arterial relaxation to SNAP was decreased at 4 and 24 h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA were upregulated, and soluble guanylyl cyclase mRNA was downregulated 24 h after LC. Immunohistochemistry and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4 h following LC consistent with superoxide generation and formation of peroxynitrite. Collectively, these data suggest that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC.


Dynamic arrest of colloids in porous environments: disentangling crowding and confinement.
Using numerical simulations we study the slow dynamics of a colloidal hard-sphere fluid adsorbed in a matrix of disordered hard-sphere obstacles. We calculate separately the contributions to the single-particle dynamic correlation functions due to free and trapped particles. The separation is based on a Delaunay tessellation to partition the space accessible to the centres of fluid particles into percolating and disconnected voids. We find that the trapping of particles into disconnected voids of the matrix is responsible for the appearance of a nonzero long-time plateau in the single-particle intermediate scattering functions of the full fluid. The subdiffusive exponent z, obtained from the logarithmic derivative of the mean squared displacement, is essentially unaffected by the motion of trapped particles: close to the percolation transition, we determined z approximately = 0.5 for both the full fluid and the particles moving in the percolating void. Notably, the same value of z is found in single-file diffusion and is also predicted by mode-coupling theory along the diffusion-localization line. We also reveal subtle effects of dynamic heterogeneity in both the free and the trapped component of the fluid particles, and discuss microscopic mechanisms that contribute to this phenomenon.


Long-term follow-up after open-window corpectomy in patients with advanced cervical spondylosis and/or ossification of the posterior longitudinal ligament.
Prospective study was performed in case with cervical spondylosis and ossification of the posterior longitudinal ligament (OPLL). A novel anterior approach was defined and some patients were operated in this study. The late results of open-window corpectomy (OWC) were documented in a group of patients. The aim of this study was to assess long-term clinical and radiologic outcomes after OWC in patients with advanced cervical spondylosis and/or OPLL. Data were collected from 15 patients at 3 time points: preoperatively and at 15 months and 92 months postoperatively. The clinical parameters were pain (assessed by visual analog scale) and upper extremity function (assessed by Japanese Orthopedics Association) score. The radiologic parameters recorded from magnetic resonance imaging and computed tomography were lordosis angles (cervical and segmental) and cervical spinal canal diameter. Group means were calculated and findings at the 3 time points were statistically compared. Adjacent-segment degeneration was also evaluated at 92 months. Concerning visual analog scale and Japanese Orthopedics Association results, the 2 postoperative mean scores were both significantly better than the preoperative mean but were not statistically different. The postoperative mean results for cervical and segmental lordosis angles and spinal canal diameter were all significantly better than the respective preoperative means for these parameters. Comparisons of postoperative means revealed no significant change in cervical lordosis, segmental lordosis, or cervical spinal canal diameter from short-term to long-term follow-ups. Five patients showed mild degeneration at adjacent segments in long-term follow-up. Long-term follow-up indicates that OWC yields satisfactory clinical and radiologic outcomes in patients with anterior compressive cervical spondylosis and/or OPLL. OWC technique creates a more stable construct with 3-point fixation and offers better load sharing among implants and healthy vertebrae. Our observations suggest that OWC is a good surgical option for this patient group.


The relationship between wall shear stress distributions and intimal thickening in the human abdominal aorta.
The goal of this work was to determine wall shear stress (WSS) patterns in the human abdominal aorta and to compare these patterns to measurements of intimal thickness (IT) from autopsy samples. The WSS was experimentally measured using the laser photochromic dye tracer technique in an anatomically faithful in vitro model based on CT scans of the abdominal aorta in a healthy 35-year-old subject. IT was quantified as a function of circumferential and axial position using light microscopy in ten human autopsy specimens. The histomorphometric analysis suggests that IT increases with age and that the distribution of intimal thickening changes with age. The lowest WSS in the flow model was found on the posterior wall inferior to the inferior mesenteric artery, and coincided with the region of most prominent IT in the autopsy samples. Local geometrical features in the flow model, such as the expansion at the inferior mesenteric artery (common in younger individuals), strongly influenced WSS patterns. The WSS was found to correlate negatively with IT (r2 = 0.3099; P = 0.0047). Low WSS in the abdominal aorta is co-localized with IT and may be related to atherogenesis. Also, rates of IT in the abdominal aorta are possibly influenced by age-related geometrical changes.


Initial cell type choice in Dictyostelium.
Much remains to be understood about how a group of cells break symmetry and differentiate into distinct cell types. The simple eukaryote Dictyostelium discoideum is an excellent model system for studying questions such as cell type differentiation. Dictyostelium cells grow as single cells. When the cells starve, they aggregate to develop into a multicellular structure with only two main cell types: spore and stalk. There has been a longstanding controversy as to how a cell makes the initial choice of becoming a spore or stalk cell. In this review, we describe how the controversy arose and how a consensus developed around a model in which initial cell type choice in Dictyostelium is dependent on the cell cycle phase that a cell happens to be in at the time that it starves.


Iron and brain functions.
The purpose of this study is to highlight recent research findings that advance our understanding of the relation between iron status and neural functioning. Recent findings have helped to answer questions pertaining to the interrelationship of iron and neural functioning in three primary areas: reversibility of changes occurring with early-life iron deficiency, association of severity of deficiency with negative outcomes and underlying mechanisms responsible for the cognitive and behavioural changes seen with iron deficiency. Results of recent studies indicate long-term negative consequences of early-life iron deficiency that may be irreversible and these negative consequences may be encountered by those with iron deficiency that has not yet reached the point of anaemia, indicating the likelihood that iron deficiency and not simply hypoxia from iron deficiency anaemia is causing the observed cognitive and behavioural alterations. Finally, recent studies have advanced our understanding of the underlying mechanisms by using animal models that isolate the deficiency to the hippocampus in addition to models that generate a whole-body iron deficiency. These advances should help to inform policy, particularly with respect to preventing and treating iron deficiency and, thereby, improve the health status of millions of individuals worldwide.


Characterization of colon cancer cells: a functional approach characterizing CD133 as a potential stem cell marker.
Isolation and characterization of tumourigenic colon cancer initiating cells may help to develop novel diagnostic and therapeutic procedures. We characterized a panel of fourteen human colon carcinoma cell lines and their corresponding xenografts for the surface expression of potential stem cell markers CD133, CD24, CD44, CDCP1 and CXCR4. In five cell lines and nine xenografts, mRNA expression of these markers was determined. Tumour growth behaviour of CD133+, CD133- and unsorted SW620 cells was evaluated in vivo. All five putative stem cell markers showed distinct expression patterns in the tumours examined. Two patient-derived cell lines highly expressed CD133 (> 85% of positive cells) and three other cell lines had an expression level of about 50% whereas in long-term culture based models CD133 expression ranged only from 0 to 20%. In 8/14 cell lines, more than 80% of the cells were positive for CD24 and 11/14 were over 70% positive for CD44. 10/14 cell lines expressed CDCP1 on ≥ 83% of cells. CXCR4 expression was determined solely on 94 L and SW480.Analyses of the corresponding xenografts revealed a significant reduction of cell numbers expressing the investigated surface markers and showed single cell fractions expressing up to three markers simultaneously.Statistical analysis revealed that the CXCR4 mRNA level correlates negatively with the protein expression of CD133, CD44, CD24 and CDCP1 in cell lines and xenografts.A lower differentiation grade of donor material correlated with a higher CDCP1 mRNA expression level in the respective tumour model.In vivo growth behaviour studies of SW620 revealed significantly higher take rates and shorter doubling times in the tumour growth of CD133 positive subclones in comparison to the unsorted cell line or CD133 negative subclones. Our data revealed correlations in the expression of surface markers CD44 and CD24 as well as CD44 and CDCP1 and strongly suggest that CD133 is a stem cell marker within our colon carcinoma panel. Further studies will elucidate its role as a potential therapeutic target.


Effect of calcium on phospholipid interaction with pulmonary surfactant protein C.
Porcine pulmonary surfactant-associated protein SP-C was incorporated into bilayers of chain-perdeuterated dipalmitoylphosphatidylglycerol (DPPG-d62) and chain-perdeuterated dipalmitoyl-phosphatidylcholine (DPPC-d62) and into bilayers containing 70 mol% dipalmitoyl-phosphatidylcholine (DPPC) and 30 mol% DPPG-d62 or 70 mol% DPPC-d62 and 30 mol% dipalmitoylphosphatidylglycerol (DPPG). The effect of SP-C on the phase behavior, lipid chain order, and dynamics in these bilayers was examined by using deuterium nuclear magnetic resonance. SP-C was found to have a similar effect on the chain order and phase behavior of DPPC-d62 and DPPG-d62 in bilayers with a single lipid component. In gel phase DPPC/DPPG (7:3) bilayers with one or the other lipid component chain-perdeuterated, SP-C was found to affect first spectral moment more strongly for DPPG-d62 than for DPPC-d62. This may indicate that SP-C induced a nonrandom lateral distribution in the mixed lipid bilayer. SP-C was also found to influence motions responsible for deuteron transverse relaxation in both the gel and liquid crystalline phases. The presence of 5 mM Ca2+ in the aqueous phase substantially altered the effect of SP-C on transverse relaxation in the bilayer.


Protein binding: what does it mean?
Protein binding can enhance or detract from a drug's performance. As a general rule, agents that are minimally protein bound penetrate tissue better than those that are highly bound, but they are excreted much faster. Among drugs that are less than 80-85 percent protein bound, differences appear to be of slight clinical importance. Agents that are highly protein bound may, however, differ markedly from those that are minimally bound in terms of tissue penetration and half-life. Drugs may bind to a wide variety of plasma proteins, including albumin. If the percentage of protein-bound drug is greater when measured in human blood than in a simple albumin solution, the clinician should suspect that the agent may be bound in vivo to one of these "minority" plasma proteins. The concentration of several plasma proteins can be altered by many factors, including stress, surgery, liver or kidney dysfunction, and pregnancy. In such circumstances, free drug concentrations are a more accurate index of clinical effect than are total concentrations. Formulary committees must grasp the clinical significance of qualitative and quantitative differences in protein binding when evaluating competing agents.


Remdesivir plus Dexamethasone in COVID-19: A cohort study of severe patients requiring high flow oxygen therapy or non-invasive ventilation.
Remdesivir and Dexamethasone represent the cornerstone of therapy for critically ill patients with acute hypoxemic respiratory failure caused by Coronavirus Disease 2019 (COVID-19). However, clinical efficacy and safety of concomitant administration of Remdesivir and Dexamethasone (Rem-Dexa) in severe COVID-19 patients on high flow oxygen therapy (HFOT) or non-invasive ventilation (NIV) remains unknown. Prospective cohort study that was performed in two medical Intensive Care Units (ICUs) of a tertiary university hospital. The clinical impact of Rem-Dexa administration in hypoxemic patients with COVID-19, who required NIV or HFOT and selected on the simplified acute physiology score II, the sequential organ failure assessment score and the Charlson Comorbidity Index score, was investigated. The primary outcome was 28-day intubation rate; secondary outcomes were end-of-treatment clinical improvement and PaO2/FiO2 ratio, laboratory abnormalities and clinical complications, ICU and hospital length of stay, 28-day and 90-day mortality. We included 132 patients and found that 28-day intubation rate was significantly lower among Rem-Dexa group (19.7% vs 48.5%, p<0.01). Although the end-of-treatment clinical improvement was larger among Rem-Dexa group (69.7% vs 51.5%, p = 0.05), the 28-day and 90-day mortalities were similar (4.5% and 10.6% vs. 15.2% and 16.7%; p = 0.08 and p = 0.45, respectively). The logistic regression and Cox-regression models showed that concomitant Rem-Dexa therapy was associated with a reduction of 28-day intubation rate (OR 0.22, CI95% 0.05-0.94, p = 0.04), in absence of laboratory abnormalities and clinical complications (p = ns). In COVID-19 critically ill patients receiving HFO or NIV, 28-day intubation rate was lower in patients who received Rem-Dexa and this finding corresponded to lower end-of-treatment clinical improvement. The individual contribution of either Remdesevir or Dexamethasone to the observed clinical effect should be further investigated.


Atopy and bronchial reactivity in older patients with cystic fibrosis.
We studied 25 adolescent and adult patients with cystic fibrosis (CF) and 25 control subjects to determine if the prevalence of atopy and bronchial hyperreactivity was increased in this disease. Results showed that atopic symptoms, as defined by history, were more frequently present in the CF patients. Prick testing of the skin produced positive reactions in 88% of the CF group and 36% of the control subjects (p less than 0.001), and the mean number of reactions per subject was significantly higher in the former group (p less than 0.001); reactions to fungal antigens were strikingly positive in the CF group. The CF patients had a significantly higher mean serum IgG4 (p less than 0.001), IgE (p less than 0.01), and higher mean eosinophil count (p less than 0.05). Clear-cut bronchial hyperreactivity was demonstrated in the CF group compared with control subjects. Bronchial provocation with 400 micrograms of histamine led to a greater than 15% fall in the preinhalation FEV1 in 35% of the CF subjects compared with 4% of the control group, with a mean percentage fall of 15% and 3% respectively (p less than 0.001). In the CF group a greater than 15% rise in PEFR occurred in 32% after inhalation of the parasympatholytic, ipratropium bromide (54 micrograms), and in 27% after inhalation of the sympathomimetic, fenoterol (400 micrograms). No correlation was found between bronchial reactivity and atopic status, HLA phenotype pattern, or disease severity. The cause of the increased prevalence of atopy and bronchial reactivity in CF patients remains unknown. However, it is clear that a trial of bronchodilator therapy is warranted in adolescents and young adults with CF.


Influencing Factors for Abdominal Aortic Aneurysm Sac Shrinkage and Enlargement after EVAR: Clinical Reviews before Introduction of Preoperative Coil Embolization.
We previously reported effectiveness of coil embolization (CE) to aortic branched vessels before endovascular aortic repair (EVAR) for abdominal aortic aneurysm (AAA) because of significant shrinkage of aneurysmal sac. In this study, we investigated EVAR cases to clarify influential factors of aneurysmal shrinkage and enlargement. 148 consecutive cases before the introduction of CE were retrospectively reviewed based on the presence of PT2EL (persistent type 2 endoleak) and change in sac diameter after EVAR by multivariate analysis. (A) PT2EL risk factors were patent inferior mesenteric artery (IMA) and thinner mural thrombus inside aneurysmal sac. (B) Sac enlargement risk factors were antiplatelet intake, PT2EL, and female gender. (C) Sac shrinkage predictive factors were the absences of thoracic aortic aneurysm, antiplatelet intake, PT2EL, and coronary artery disease. CE to IMA was considered to be effective because patent IMA and antiplatelet intake were significant risk factors for sac enlargement. So, more meticulous therapeutic strategy, including treatment priority (AAA first or CAD first) and choice of treatment (EVAR vs. AAA) based on anatomical features of AAA was required to improve late outcomes.


Validation of a new procedure to determine plasma fatty acid concentration and isotopic enrichment.
Assessment of free fatty acid (FFA) concentration and isotopic enrichment is useful for studies of FFA kinetics in vivo. A new procedure to recover the major FFA from plasma for concentration and isotopic enrichment measurements is described and validated. The procedure involves extraction of plasma lipids with hexane, methylation with iodomethane (CH(3)I) to form fatty acid methyl esters (FAME), and subsequent purification of FAME by solid phase extraction (SPE) chromatography. The new method was compared with a traditional method using thin-layer chromatography (TLC) to recover plasma FFA, with subsequent methylation by BF(3)/methanol. The TLC method was found to be less reliable than the new CH(3)I method because of contamination with extraneous fatty acids, chemical fractionation of FFA species, and incomplete recovery of FFA associated with TLC. In contrast, the CH(3)I/SPE method was free of contamination, did not exhibit chemical fractionation, and had higher recovery. The iodomethane reaction was specific for free fatty acids; no FAME were formed when esterified fatty acids (triglycerides, cholesteryl esters, phospholipids) were subjected to the methylation reaction. We conclude that the CH(3)I/SPE method provides rapid and convenient recovery of plasma fatty acids for quantification or GC/MS analysis as methyl esters, and is not subject to the problems of contamination, reduced recovery, and chemical fractionation associated with recovery of FFA by TLC.


Rebound of clinical disease activity after fingolimod discontinuation? A nationwide cohort study of patients in Denmark.
We investigated whether clinical rebound occurred after fingolimod discontinuation in a complete population of patients with relapsing-remitting multiple sclerosis (RRMS) in Denmark. We further identified clinical and demographical factors associated with disease reactivation after fingolimod discontinuation. The population comprised 992 RRMS patients treated with fingolimod for 6 months or more. We estimated annualised relapse rates (ARR) before, during and after treatment. We estimated overall ARRs and ARRs stratified by disease activity before discontinuation. We calculated the proportion of patients with a higher clinical disease activity after discontinuation than before treatment start. Finally, we analysed the association between variables at discontinuation and time to first relapse after discontinuation. The ARR 3 months after discontinuation (ARR=0.56; 95% CI=0.47 to 0.66) was statistically significantly lower (p<0.01) than the ARR 1 year before treatment (ARR=0.74; 95% CI=0.69 to 0.80). Results were similar when repeating analyses in patients with and without disease activity before discontinuation. In total, 124 patients (12.5%) had clinical rebound. Of those, 36 had no disease breakthrough before discontinuation (3.6% of total population). On treatment disease activity (HR=1.98, p<0.01), lower age (HR=0.98, p=0.01) and female sex (HR=1.68, p=0.02) were associated with a higher relapse risk after discontinuation. Based on average ARR levels, there was no evidence of clinical rebound after fingolimod discontinuation. In total, 12.5% of patients had clinical rebound. Only 3.6%, however, had clinical rebound without disease activity before discontinuation. Disease activity before discontinuation, female sex and younger age were statistically significantly associated with a higher relapse risk after discontinuation.


Retinal blood flow changes in patients with insulin-dependent diabetes mellitus and no diabetic retinopathy.
The authors investigated retinal blood flow changes in patients with insulin-dependent diabetes mellitus (IDDM) and no diabetic retinopathy compared to age-matched subjects without diabetes. They also investigated whether blood glucose levels could modulate retinal blood flow in these patients with diabetes and whether this modulation would impact retinal blood flow data used in cross-sectional studies assessing changes in retinal blood flow. Retinal blood flow was measured using video fluorescein angiography, and blood glucose levels were manipulated using glucose clamp methodologies with continuous basal insulin replacement. Blood glucose levels were clamped at 100, 200, and 300 mg/dl. Retinal blood flow measurements were performed at each blood glucose level after subjects had been stabilized for an hour at each of the different blood glucose levels. Retinal blood flow was found to be significantly decreased (P< 0.01) in the group of patients with no diabetic retinopathy (19.4 +/- 4.6 arbitrary units [AU]) compared to retinal blood flow in subjects without diabetes (28.7 +/- 6.4 AU). During glucose clamp adjustment of blood glucose levels, it was found that as blood glucose levels were increased from euglycemia (100 mg/dl) to 200 mg/dl and to 300 mg/dl, retinal blood flow was significantly increased at the 200 mg/dl level (21.5 +/- 4.7 AU, P < 0.05) and at the 300 mg/dl level (25.9 +/- 8.8 AU, P <0.01) compared to the 100 mg/dl level (16.3 +/- 3.8 AU). In addition, the retinal blood flow at the 100 and 200 mg/dl levels was significantly reduced (P < 0.01) compared to nondiabetic retinal blood flow (28.7 +/- 6.4 AU). Retinal blood flow was found to be decreased in patients with IDDM with no diabetic retinopathy, and acute elevations in blood glucose levels resulted in increased retinal blood flow in these patients. The acute modulation of retinal blood flow by blood glucose levels should be considered in cross-sectional studies investigating retinal blood flow changes in patients with diabetes. The results from this study indicate that if blood glucose levels are not accounted for in the analyses, larger populations would have to be studied to demonstrate statistically significant differences between groups with and without diabetes.


Information system powers innovative research project aimed at managing the care of senior citizens.
HealthAmerica Pennsylvania, Inc., in Pittsburgh, is aiming to increase access to health care for senior citizens in its Advantra health plan in Pittsburgh. Under its Senior Life Management program, Coventry Health Care, parent company of HealthAmerica, hired nine personal service representatives (PSRs) and is asking them to provide outreach to 5,000 senior citizens. The PSRs and other staff members will get to know each senior citizen in the program, evaluate and recognize their health needs, and develop methods to ensure that their needs are met before any patient's condition becomes unnecessarily costly. The goal of this innovative program is to improve access to health care for these 5,000 members and thus improve their satisfaction with care and help to reduce health care costs.


Blood utilization in revision versus first-time cardiac surgery: an update in the era of patient blood management.
Relative to first-time (primary) cardiac surgery, revision cardiac surgery is associated with increased transfusion requirements, but studies comparing these cohorts were performed before patient blood management (PBM) and blood conservation measures were commonplace. The current study was performed as an update to determine if this finding is still evident in the PBM era. Primary and revision cardiac surgery cases were compared in a retrospective database analysis at a single tertiary care referral center. Two groups of patients were assessed: 1) those having isolated coronary artery bypass (CAB) or valve surgery and 2) all other cardiac surgeries. Intraoperative and whole hospital transfusion requirements were assessed for the four major blood components. Compared to the primary cardiac surgery patients, the revision surgery patients required approximately twofold more transfused units intraoperatively (p < 0.0001) and approximately two- to threefold more transfused units for the whole hospital stay (p < 0.0001). Intraoperative massive transfusion (>10 red blood cell [RBC] units) was substantially more frequent with revision versus primary cardiac surgery (2.6% vs. 0.1% [p < 0.0001] for isolated CAB or valve and 6.1% vs. 1.9% [p < 0.0001] for all other cardiac surgeries). Revision surgery was an independent risk factor for both moderate (6-10 RBC units) and massive intraoperative transfusion. In the era of PBM, with restrictive transfusion strategies and a variety of methods for blood conservation, revision cardiac surgery patients continue to have substantially greater transfusion requirements relative to primary cardiac surgery patients. This difference in transfusion requirement was greater than what has been previously reported in the pre-PBM era.


mRuby, a bright monomeric red fluorescent protein for labeling of subcellular structures.
A monomeric variant of the red fluorescent protein eqFP611, mRuby, is described. With excitation and emission maxima at 558 nm and 605 nm, respectively, and a large Stokes shift of 47 nm, mRuby appears particularly useful for imaging applications. The protein shows an exceptional resistance to denaturation at pH extremes. Moreover, mRuby is about ten-fold brighter compared to EGFP when being targeted to the endoplasmic reticulum. The engineering process of eqFP611 revealed that the C-terminal tail of the protein acts as a natural peroxisomal targeting signal (PTS). Using an mRuby variant carrying the eqFP611-PTS, we discovered that ordered inheritance of peroxisomes is widespread during mitosis of different mammalian cell types. The ordered partitioning is realized by the formation of peroxisome clusters around the poles of the mitotic spindle and ensures that equal numbers of the organelle are inherited by the daughter cells. The unique spectral properties make mRuby the marker of choice for a multitude of cell biological applications. Moreover, the use of mRuby has allowed novel insights in the biology of organelles responsible for severe human diseases.


Gastric acid secretion in patients with duodenal ulcer and benign gastric outlet obstruction.
With the standard dose of histamine acid phosphate 40 microgram/kg body weight, the peak and maximal acid outputs were calculated in 102 patients with uncomplicated duodenal ulcer disease, forty-seven controls and forty-seven patients with benign gastric outlet obstruction. The results obtained for maximal acid output showed significant differences between the control group and the other two groups separately. These figures are much lower than values from Western countries, but similar to those reported from studies in non-Caucasians.


Ligand.Info small-molecule Meta-Database.
Ligand.Info is a compilation of various publicly available databases of small molecules. The total size of the Meta-Database is over 1 million entries. The compound records contain calculated three-dimensional coordinates and sometimes information about biological activity. Some molecules have information about FDA drug approving status or about anti-HIV activity. Meta-Database can be downloaded from the http://Ligand.Info web page. The database can also be screened using a Java-based tool. The tool can interactively cluster sets of molecules on the user side and automatically download similar molecules from the server. The application requires the Java Runtime Environment 1.4 or higher, which can be automatically downloaded from Sun Microsystems or Apple Computer and installed during the first use of Ligand.Info on desktop systems, which support Java (Ms Windows, Mac OS, Solaris, and Linux). The Ligand.Info Meta-Database can be used for virtual high-throughput screening of new potential drugs. Presented examples showed that using a known antiviral drug as query the system was able to find others antiviral drugs and inhibitors.


Undersizing the Exeter stem in hip hemiarthroplasty increases the risk of periprosthetic fracture.
Whether under- or oversizing of the femoral component of cemented hip hemiarthroplasties impacts the risk of periprosthetic fractures (PPF) has only been examined experimentally. This study was carried out to add more knowledge about the risks of PPF in cemented polished tapered hemiarthroplasties. 20 patients with PPF following hip hemiarthroplasty with cemented Exeter V40 stems were compared to 50 controls who never suffered PPF having received the same type of Exeter hemiprosthesis for the same indication. The difference between stem size and post-hoc radiographic ideal templated size was investigated as a predictor of PPF. Cases had a median size difference to post-hoc templating of -2, while controls had a median size difference of -1 (p = 0.09). An ROC curve constructed to find an optimal cutoff point in size difference between cases and controls arrived at an area under curve of 63%, with -1.5 as the cutoff. Patients with size differences exceeding -1.5 had a statistically significant increased PPF risk (odds ratio = 3.8, 95% confidence interval, 1.1-13.3, p < 0.05). This group covered 55% of all cases. An implanted femoral component that is 2 or more sizes smaller than the template that is shown to be appropriate will increase the risk of PPF in Exeter hip hemiarthroplasties.


An evaluation of epidural analgesia following circumferential belt lipectomy.
Belt lipectomy combines traditional abdominoplasty with a circumferential excision of skin and fat, with resultant buttock and lateral thigh lifts. Because of the extensive nature of the procedure, postoperative pain management can be difficult. Epidural analgesia has been shown to be efficacious in treating postoperative pain. This study compares the postoperative use of epidural analgesia with more traditional pain management regimens in a large series of belt lipectomy patients. Charts of 62 belt lipectomy patients were examined retrospectively. Postoperative pain control regimen, pain scores, total amount of opioids administered, and side effects encountered were recorded. Twenty-seven patients had traditional pain control regimens, opioids on demand, and pain control pumps. Thirty-five patients received epidural analgesia as their primary mode of postoperative pain control. Pain scores and total nonepidural opioids used were lower in the epidural analgesia group on postoperative days 0 and 1 compared with the nonepidural group. The two groups converged on postoperative days 2 through 5, sharing similar pain scores and opioid use after discontinuation of epidural analgesia. The incidence of side effects was similar in the two groups, with the exception of pruritus, which was much more prominent in the epidural group. Eight of the 35 epidural patients (23 percent) experienced transient and minor complications associated with epidural therapy; several resolved spontaneously, whereas the balance resolved with cessation or modification of the epidural infusion. Epidural analgesia is more effective than traditional pain control methods in reducing immediate postoperative pain in belt lipectomy patients. On the basis of these findings, epidural analgesia should also be considered for postoperative pain management in other truncal procedures.


Visceral protein increase associated with interrupt versus continuous enteral hyperalimentation.
Periodic parenteral hyperalimentation, the interruption of feeding for a period of time each day, parallels the fasted vs fed state in the meal eater. The fasted state appears to be more physiologic and seems to be associated with an increase of visceral proteins. Intravenous hyperalimentation data that have been published seem to confirm this fact. The purpose of this study was to compare the effect of continuous enteral hyperalimentation and interrupt enteral hyperalimentation on the visceral protein compartment. Two groups of 10 afebrile matched control patients (group 1) were on continuous enteral hyperalimentation for 19 +/- 6 days with no improvement in serum albumin or serum transferrin levels. No changes were made in the feeding schedules of 10 of the patients. Feeding schedules of the other 10 patients were changed to an 8-hr interrupt enteral hyperalimentation with calories, protein, and volume being provided remaining the same. Repeat serum albumin and transferrin levels were obtained after 10 days. There was a significant increase in albumin and transferrin levels (p less than 0.005) in those patients changed to an interrupt feeding schedule.


Furosemide promotes patent ductus arteriosus in premature infants with the respiratory-distress syndrome.
Furosemide stimulates the renal synthesis of prostaglandin E2, a potent dilator of the ductus arteriosus. We administered this drug to 33 premature infants with the respiratory-distress syndrome, to determine whether it increased the incidence of patent ductus arteriosus. Chlorothiazide, a diuretic that does not stimulate prostaglandin E synthesis, was used as the control drug in 33 other infants. During the study, the incidence of patent ductus arteriosus was significantly higher (P less than 0.02) in the furosemide group (18 of 33 infants) than in the chlorothiazide group (8 of 33). Eleven infants in the furosemide group and seven in the chlorothiazide group required ductal ligation (P greater than 0.2). An additional six infants (all from the furosemide group) who did not have evidence of a patent ductus during the study were later found to have one. Overall survival was 76 and 61 per cent in the furosemide and chlorothiazide groups, respectively (P greater than 0.2). Small (less than twofold) increases in the urinary excretion of prostaglandin E were seen after the initial dose of both drugs. When the analysis was repeated after the fifth day of life, prostaglandin E excretion tripled after furosemide administration, whereas no increase occurred with chlorothiazide. We conclude that furosemide increases the incidence of patent ductus arteriosus in premature infants with the respiratory-distress syndrome, probably through a prostaglandin-mediated process.


Tandem duplication of the NF1 gene detected by high-resolution FISH in the 17q11.2 region.
The gene for neurofibromatosis type 1 (NF1), mapping to 17q11.2, has one of the highest observed mutation rates, partially because of its large size and gene conversion primed by NF1 pseudogenes. We have previously shown by means of high resolution fluorescence in situ hybridization (FISH) that a number of the loci flanking the NF1 gene are duplicated, in agreement with the reported presence of NF1 repetitive sequences (REPs). We report a direct tandem duplication of the NF1 gene identified in 17q11.2 by high-resolution FISH. FISH on stretched chromosomes with locus-specific probes revealed the duplication of the NF1 gene from the promoter to 3'UTR, but with at least the absence of exon 22. Fiber FISH with P1 artificial and bacterial artifical chromosomes, including the NF1 5'UTR and 3'UTR and flanking regions, visualized the direct tandem duplication with a similar, but not identical, genomic organization of the NF1 duplicon copies. Duplication was probably present in the human-chimpanzee-gorilla common ancestor, as demonstrated here by the finding of the duplicated NF1 gene at orthologous chromosome loci. The NF1 intrachromosomal duplication may contribute to the high whole-gene mutation rate by gene conversion, although the functional activity of the NF1 copy remains to be investigated. Detection of the NF1 duplicon by high-resolution FISH may pave the way to filling the gaps in the human genomic sequence of the pericentromeric 17q11.2 region.


Political identities of Chinese international students: Patterns and change in transnational space.
Amid the ongoing international tensions surrounding China, Chinese international students (CISs) in Western countries have become targets of political suspicion. Against discriminatory voices that make sweeping generalisations about CISs, this research argues that their political identities are in fact diverse and malleable. Using theories of postmodernism and transnationalism, this study applies thematic analysis and discourse analysis to interviews with 28 CISs, yielding four major findings. First, it identifies three distinct patterns of political identity: Chinese nationalists who endorse conservative politics in the West; advocates of liberal democracy; and transnational neoliberals who avoid political participation. Second, it argues that CISs undergo identity changes depending on a range of individual and social characteristics. Among these characteristics, third, it highlights the role of socioeconomic status in shaping the political identities of CISs, and in so doing, reflects on the inadequacy of race and nationality as identity markers. Fourth, it suggests that the political identities of CISs are transnationally hinged on both China and the host countries. On the practical front, the study may inform professions working with CISs such as education and policymaking. Theoretically, it suggests that the political identities of CISs are heterogenous, impressionable and transnationally contingent.


Olfactory testing does not predict β-amyloid, MRI measures of neurodegeneration or vascular pathology in the British 1946 birth cohort.
To explore the value of olfactory identification deficits as a predictor of cerebral β-amyloid status and other markers of brain health in cognitively normal adults aged ~ 70 years. Cross-sectional observational cohort study. 389 largely healthy and cognitively normal older adults were recruited from the MRC National Survey of Health and Development (1946 British Birth cohort) and investigated for olfactory identification deficits, as measured by the University of Pennsylvania Smell Identification Test. Outcome measures were imaging markers of brain health derived from 3 T MRI scanning (cortical thickness, entorhinal cortex thickness, white matter hyperintensity volumes); 18F florbetapir amyloid-PET scanning; and cognitive testing results. Participants were assessed at a single centre between March 2015 and January 2018. Mean (± SD) age was 70.6 (± 0.7) years, 50.8% were female. 64.5% had hyposmia and 2.6% anosmia. Olfaction showed no association with β-amyloid status, hippocampal volume, entorhinal cortex thickness, AD signature cortical thickness, white matter hyperintensity volume, or cognition. In the early 70s, olfactory function is not a reliable predictor of a range of imaging and cognitive measures of preclinical AD. Olfactory identification deficits are not likely to be a useful means of identifying asymptomatic amyloidosis. Further studies are required to assess if change in olfaction may be a proximity marker for the development of cognitive impairment.


Helicobacter pylori infection and dyspepsia.
Dyspepsia is defined as a persistent or recurrent pain or discomfort, localised in the upper abdomen, which may or may not be related to meals. Its prevalence in the general population is extraordinarily high (20-40%). Several pathological conditions can provoke dyspepsia, although non ulcer dyspepsia is the main cause. The relationships between Helicobacter pylori and non ulcer dyspepsia are discussed, namely the prevalence of Helicobacter pylori infection and the efficacy of its eradication in non ulcer dyspepsia. The management of dyspeptic patients in the community is analysed according to the Maastricht Consensus of 1996. Our opinion is that, in Helicobacter pylori-positive dyspeptic patients, after a careful investigation with exclusion of other organic diseases, the bacterium should be eradicated.


Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis.
Molecular antagonists of the inhibitor of apoptosis protein survivin have shown promise as novel anticancer strategies for triggering tumor cell apoptosis, dysregulating mitotic progression, and inhibiting tumor growth in preclinical models. However, how survivin couples to the cell death machinery has remained elusive, and the relevant cellular targets of survivin antagonists have not been completely elucidated. Human umbilical vein and dermal microvascular endothelial cells were infected with replication-deficient adenoviruses encoding survivin (pAd-Survivin), green fluorescent protein (pAd-GFP), or a phosphorylation-defective survivin Thr(34)-->Ala (pAd-T34A) dominant negative mutant. The effect of wild-type or mutant survivin was investigated on capillary network stability, endothelial cell viability, and caspase activation in vitro and on kinetics of tumor growth and development of angiogenesis in a breast cancer xenograft model in vivo. The cell death pathway initiated by survivin targeting was mapped with respect to cytochrome c release, changes in mitochondrial transmembrane potential, and apoptosome requirements using mouse embryonic fibroblasts deficient in Apaf-1 or caspase-9. Adenoviral transduction of endothelial cells with pAd-Survivin inhibited growth factor deprivation- or ceramide-induced apoptosis, reduced caspase-3 and -7 generation, and stabilized three-dimensional capillary networks in vitro. Conversely, expression of pAd-T34A caused apoptosis in umbilical vein and dermal microvascular endothelial cells and resulted in caspase-3 activity. Cell death induced by survivin targeting exhibited the hallmarks of mitochondrial-dependent apoptosis with release of cytochrome c and loss of mitochondrial transmembrane potential and was suppressed in Apaf-1 or caspase-9 knockout mouse embryonic fibroblasts. When injected in human breast cancer xenografts, pAd-T34A inhibited growth of established tumors and triggered tumor cell apoptosis in vivo. This was associated with a approximately 60% reduction in tumor-derived blood vessels by quantitative morphometry of CD31-stained tumor areas, and appearance of endothelial cell apoptosis by internucleosomal DNA fragmentation in vivo. Survivin functions as a novel upstream regulator of mitochondrial-dependent apoptosis, and molecular targeting of this pathway results in anticancer activity via a dual mechanism of induction of tumor cell apoptosis and suppression of angiogenesis.


Intraoral condylomata acuminata. A case report.
Condylomata acuminata occurred intraorally in a 6 year old Nigerian girl. Since she had no skin or genital lesions and no history of sexual contact, the virus was probably acquired from environmental sources. Non-sexual modes of transmission should, therefore, be considered, particularly when the lesions are extragenital.


Gestational and early postnatal hypothyroidism alters VGluT1 and VGAT bouton distribution in the neocortex and hippocampus, and behavior in rats.
Thyroid hormones are fundamental for the expression of genes involved in the development of the CNS and their deficiency is associated with a wide spectrum of neurological diseases including mental retardation, attention deficit-hyperactivity disorder and autism spectrum disorders. We examined in rat whether developmental and early postnatal hypothyroidism affects the distribution of vesicular glutamate transporter-1 (VGluT1; glutamatergic) and vesicular inhibitory amino acid transporter (VGAT; GABAergic) immunoreactive (ir) boutons in the hippocampus and somatosensory cortex, and the behavior of the pups. Hypothyroidism was induced by adding 0.02% methimazole (MMI) and 1% KClO4 to the drinking water starting at embryonic day 10 (E10; developmental hypothyroidism) and E21 (early postnatal hypothyroidism) until day of sacrifice at postnatal day 50. Behavior was studied using the acoustic prepulse inhibition (somatosensory attention) and the elevated plus-maze (anxiety-like assessment) tests. The distribution, density and size of VGluT1-ir and VGAT-ir boutons in the hippocampus and somatosensory cortex was abnormal in MMI pups and these changes correlate with behavioral changes, as prepulse inhibition of the startle response amplitude was reduced, and the percentage of time spent in open arms increased. In conclusion, both developmental and early postnatal hypothyroidism significantly decreases the ratio of GABAergic to glutamatergic boutons in dentate gyrus leading to an abnormal flow of information to the hippocampus and infragranular layers of the somatosensory cortex, and alter behavior in rats. Our data show cytoarchitectonic alterations in the basic excitatory hippocampal loop, and in local inhibitory circuits of the somatosensory cortex and hippocampus that might contribute to the delayed neurocognitive outcome observed in thyroid hormone deficient children born in iodine deficient areas, or suffering from congenital hypothyroidism.