Canadian Association of Gastroenterology policy on the application for, and implementation of, clinical practice guidelines.
An important mandate of the Canadian Association of Gastroenterology (CAG), as documented in the Association's governance policies, is to optimize the care of patients with digestive disorders. Clinical practice guidelines are one means of achieving this goal. The benefits of timely, high-quality and evidenced-based recommendations include: Enhancing the professional development of clinical members through education and dissemination of synthesized clinical research; Improving patient care provided by members by providing focus on quality and evidence; Creating legislative environments that favour effective clinical practice; Enhancing the clinical care provided to patients with digestive disease by nongastroenterologists; and Identifying areas that require further information or research to improve clinical care. The present document provides the foundation required to ensure that clinical practice guidelines produced by the CAG are necessary, appropriate, credible and applicable. These recommendations should be adhered to as closely as possible to obtain CAG endorsement.


Pharmacokinetics of marbofloxacin administered via intravenous regional limb perfusion in dairy cows: evaluation of two different tourniquets.
This study evaluated synovial and systemic plasma pharmacokinetic variables of marbofloxacin after a single intravenous regional limb perfusion (IVRLP) performed using two different tourniquets in clinically healthy, standing, non-sedated dairy cows. The authors hypothesised that the type of tourniquet used for IVRLP would influence the synovial fluid concentration of marbofloxacin in the perfused distal limb. The study had a randomised parallel-group design. Ten adult dairy cows were included. Unilateral hindlimb IVRLP through the dorsal common digital III vein was performed in two groups of five cows (group 1: wide rubber tourniquet; group 2: manual pneumatic tourniquet) using 0.67 mg/kg of marbofloxacin. The tourniquet was applied proximal to the tarsus and maintained for 30 minutes. Samples of jugular blood and synovial fluid from the tibiotarsal joints of the perfused limb were obtained before and at intervals after IVRLP. All samples were analysed for drug concentrations using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined to establish the influence of tourniquet types. Differences were considered significant at P≤0.05. No adverse effects from the procedure or marbofloxacin were observed in any animal. Significant differences in synovial concentrations and pharmacokinetic parameters were measured. The mean ± sd areas under the concentration versus time curve from time 0 to 24 hours were 178.98±58.08 µg hour/ml for group 2 and 21.11±9.93 µg hour/ml for group 1. The mean ± sd maximum marbofloxacin concentrations were 75.50±10.19 µg/ml for group 2 and 6.35±1.47 µg/ml for group 1. Performing IVRLP using the dorsal common digital III vein and a manual pneumatic tourniquet set at 300 mmHg above the tarsus in standing cows resulted in significantly higher marbofloxacin concentrations in the tibiotarsal joint compared with those with the wide rubber tourniquet. Local ethical committee (number 41/2012/CEISA).


Evaluation of the echolocation model for range estimation of multiple closely spaced objects.
Experimental evidence indicates that bats can use frequency-modulated echolocation to identify objects with an accuracy of less than 1 μs. However, when modeling this process, it is difficult to estimate the delay times of multiple closely spaced objects by analyzing the echo spectrum, because the sequence of delay separations cannot be determined without information on the temporal changes in the interference patterns of the echoes. To extract the temporal changes, Gaussian chirplets with a carrier frequency compatible with bat emission sweep rates are introduced. The delay time for object 1 (T(1)) is estimated from the echo spectrum around the onset time. The T(2) is obtained by adding the T(1) to the delay separation between objects 1 and 2. Further objects are located in sequence by this procedure. Here echoes were measured from single and multiple objects at a low signal-to-noise ratio. It was confirmed that the delay time for a single object could be estimated with an accuracy of about 1.3 μs. The range accuracy was less than 6 μs when the frequency bandwidth was less than 10 kHz. The delay time for multiple closely spaced objects could be estimated with a high range resolution by extracting the interference pattern.


Mechanically bonded macromolecules.
Mechanically bonded macromolecules constitute a class of challenging synthetic targets in polymer science. The controllable intramolecular motions of mechanical bonds, in combination with the processability and useful physical and mechanical properties of macromolecules, ultimately ensure their potential for applications in materials science, nanotechnology and medicine. This tutorial review describes the syntheses and properties of a library of diverse mechanically bonded macromolecules, which covers (i) main-chain, side-chain, bridged, and pendant oligo/polycatenanes, (ii) main-chain oligo/polyrotaxanes, (iii) poly[c2]daisy chains, and finally (iv) mechanically interlocked dendrimers. A variety of highly efficient synthetic protocols--including template-directed assembly, step-growth polymerisation, quantitative conjugation, etc.--were employed in the construction of these mechanically interlocked architectures. Some of these structures, i.e., side-chain polycatenanes and poly[c2]daisy chains, undergo controllable molecular switching in a manner similar to their small molecular counterparts. The challenges posed by the syntheses of polycatenanes and polyrotaxanes with high molecular weights are contemplated.


Midcarpal hemiarthroplasty for wrist arthritis: rationale and early results.
Midcarpal hemiarthroplasty is a novel motion-preserving treatment for radiocarpal arthritis and is an alternative to current procedures that provide pain relief at the expense of wrist biomechanics and natural motion. It is indicated primarily in active patients with a well-preserved distal row and debilitating arthritic symptoms. By resurfacing the proximal carpal row, midcarpal arthroplasty relieves pain while preserving the midcarpal articulation and the anatomic center of wrist rotation. This technique has theoretical advantages when compared with current treatment options (i.e., arthrodesis and total wrist arthroplasty) since it provides coupled wrist motion, preserves radial length, is technically simple, and avoids the inherent risks of nonunion and distal component failure. The KinematX midcarpal hemiarthroplasty has an anatomic design and does not disrupt the integrity of the wrist ligaments. We have implanted this prosthesis in nine patients with promising early results. The indications for surgery were as follows: scapholunate advanced collapse wrist (three), posttraumatic osteoarthritis (three), inflammatory arthritis (two), and Keinböck disease (one). Prospective data has been collected and the results are preliminary given the infancy of the procedure. The mean follow-up was 30.9 weeks (range: 16 to 56 weeks). The mean Mayo wrist score increased from 31.9 preoperatively to 58.8 (p < 0.05) and the mean DASH score improved significantly from 47.8 preoperatively to 28.7 (p < 0.05). There was a trend toward increased motion but statistical significance was not reached. Two patients required manipulation for wrist stiffness. There was no evidence of prosthetic loosening or capitolunate narrowing. The procedure is simple (average surgical time was 49 minutes) and maintains coupled wrist motion through preservation of the midcarpal articulation. The preliminary data show that it appears safe but considerably longer follow-up is required before conclusions can be drawn as to its durability, reliability, and overall success. The level of evidence for this study is therapeutic level IV (case series).


Moderation-Mediation Effects in Bilingualism and Cognitive Reserve.
We first provide a critical review of the existing findings on bilingualism as a contributor to cognitive reserve from moderator-mediator warranting cause-effect research conclusions. We next address the question of direct or indirect effects between bilingualism and neurocognitive protective factors influencing the associated age-related mental deficits. The existing findings support bilingualism as a predictor and as a moderator. Third, we propose cognitive reserve models of bilingualism describing analytical approaches that allow testing of these models and hypotheses related to path strength and causal relationships between predictors, moderators, and mediators. Lastly and most importantly, we suggest using large datasets available via open repositories. This can aid in the testing of theoretical models, clarifying the roles of moderators and mediators, and assessing the research viability of multi-causal paths that can influence cognitive reserve. Creating collaborative datasets to test these models would greatly advance our field and identify critical variables in the study of the bilingual aging brain.


Role of the anion-binding site in catalysis and regulation of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase.
D-3-Phosphoglycerate dehydrogenase from Mycobacterium tuberculosis displays substantial substrate inhibition in the direction of NADH oxidation by its physiological substrate, hydroxypyruvic acid phosphate (HPAP). Previous investigations showed that plots of substrate concentration versus activity derived from steady state assays could be fit with the equation for complete uncompetitive inhibition and that the mechanism may be allosteric. This investigation uses a simulation of transient kinetic data to demonstrate that the mechanism is consistent with the interaction of substrate at a second site called the anion-binding site. While addition of substrate at the active site is ordered, with HPAP binding before NADH, NADH can compete with the substrate for binding to the allosteric site and thereby eliminate the substrate inhibition. Fluorescence resonance energy transfer analysis of mutants with specific tryptophan residues converted to phenylalanine residues demonstrates that the main interaction of NADH with the enzyme, in the absence of substrate, is at the allosteric anion-binding site. This is further confirmed by mutations of basic residues at the anion-binding site which also demonstrates that these residues are necessary for inhibition by l-serine when it binds to the regulatory domain. This may indicate that a ligand must be bound to the anion-binding site for l-serine inhibition, providing a potential mechanism for low levels of activity in the presence of high levels of inhibitor.


Three-dimensional microorganization of the soil-root-microbe system.
Soils contain the greatest reservoir of biodiversity on Earth, and the functionality of the soil ecosystem sustains the rest of the terrestrial biosphere. This functionality results from complex interactions between biological and physical processes that are strongly modulated by the soil physical structure. Using a novel combination of biochemical and biophysical indicators and synchrotron microtomography, we have discovered that soil microbes and plant roots microengineer their habitats by changing the porosity and clustering properties (i.e., spatial correlation) of the soil pores. Our results indicate that biota act to significantly alter their habitat toward a more porous, ordered, and aggregated structure that has important consequences for functional properties, including transport processes. These observations support the hypothesis that the soil-plant-microbe complex is self-organized.


Outcome of penetrating keratoplasty after ocular trauma in children.
To characterize the outcome of penetrating keratoplasty in children for the visual rehabilitation of corneal injury. Multicenter retrospective study of the outcome of penetrating keratoplasty for ocular trauma in children. All children aged 12 years and younger who underwent penetrating keratoplasty between January 1975 and May 1993 for penetrating corneal (n = 18) or corneoscleral (n = 3) trauma and nonpenetrating corneal trauma (n = 1). Graft survival and postoperative visual acuity improvement. Twenty-two children underwent 25 penetrating keratoplasties during the study period. Graft survival was 84% at 1 year and 70% at 2 years after surgery. Visual acuity improved in 15 (83%) of the 18 children with measurable preoperative and postoperative vision. Children with posterior segment injury before keratoplasty were less likely to maintain a clear graft (P = .04) and less likely to have improved vision postoperatively (P = .06). Children who received amblyopia treatment and appropriate optical correction postoperatively were more likely to have visual improvement than those who did not (P = .02). Penetrating keratoplasty for corneal trauma is generally a successful operation in the pediatric age group, with visual improvement seen in more than four fifths of cases. Graft survival and visual outcome are best in patients with trauma limited to the anterior segment. Aggressive postoperative refractive correction and amblyopia management also appear to contribute to a better visual outcome in pediatric keratoplasty.


Photoaffinity labeling of the ATP transporter of rat liver microsomes.
A photoreactive azido derivative of ATP, 3 (2')-O-(p-azidobenzoyl)-ATP (AB-ATP), was synthesized by the reaction of ATP with N-hydroxysuccinimidyl-4-azidobenzoate (NHS-AB) to photolabel the ATP transporter of rat liver microsomes. AB-ATP specifically inhibited the transport of ATP into microsomes, which indicates that AB-ATP has a high affinity for the ATP transporter, so it can be utilized as a photoaffinity probe for the identification of the ATP transporter in rat liver microsomes. An SDS-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of microsomes photolabeled with [gamma-32P]AB-ATP indicates the presence of four major protein bands with apparent molecular sizes of 97, 56, 53, and 47 kDa. Among these labeled proteins, the 56 kDa protein was completely protected from the photoaffinity labeling by 30 microM ATP but not by the same amount of GTP, which is consistent with the specific labeling of the ATP binding site of the ATP transporter. The specific labeling of the only 56 kDa protein among them was sensitive to the anion transport inhibitor, 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS) but not sensitive to the mitochondrial ADP/ATP carrier inhibitor, atractyloside (ATR). Moreover, the 56 kDa protein was uniquely photolabeled with [gamma-32P]AB-ATP in the highly purified rough endoplasmic reticulum (RER) vesicles. These results strongly suggested that the 56 kDa protein represents the ATP transporter of rat liver endoplasmic reticulum (ER).


Testing the assumptions of an indicator of unmet need for obstetric surgery in Ghana: A cross-sectional study of linked hospital and population-based delivery data.
The Unmet Obstetric Need (UON) indicator has been widely used to estimate unmet need for life-saving surgery at birth; however, its assumptions have not been verified. The objective of this study was to test two UON assumptions: (a) Absolute maternal indications (AMIs) require surgery for survival and (b) 1%-2% of deliveries develop AMIs, implying that rates of surgeries for AMIs below this threshold indicate excess mortality from these complications. We used linked hospital and population-based data in central Ghana. Among hospital deliveries, we calculated the percentage of deliveries with AMIs who received surgery, and mortality among AMIs who did not. At the population level, we assessed whether the percentage of deliveries with surgeries for AMIs was inversely associated with mortality from these complications, stratified by education. A total of 380 of 387 (98%) hospital deliveries with recorded AMIs received surgery; an additional eight women with no AMI diagnosis died of AMI-related causes. Among the 50 148 deliveries in the population, surgeries for AMIs increased from 0.6% among women with no education to 1.9% among women with post-secondary education (P < .001). However, there was no association between AMI-related mortality and education (P = .546). Estimated AMI prevalence was 0.84% (95% CI: 0.76%-0.92%), below the assumed 1% minimum threshold. Obstetric providers consider AMIs absolute indications for surgery. However, low rates of surgeries for AMIs among less educated women were not associated with higher mortality. The UON indicator should be used with caution in estimating the unmet need for life-saving obstetric surgery; innovative approaches are needed to identify unmet need in the context of rising cesarean rates.


Effects of smokeless tobacco "Maras powder" use on respiratory functions.
In Turkey, "Maras Powder," which is a kind of powder yielded from the shields of tobacco, is widely used as smokeless tobacco through buccal mucosa or together with cigarette. Maras powder, composed of ash and a plant named Nicotiana Rustica Linn, is sometimes used to give up smoking. The present study was aimed to investigate the effects of Maras powder use on respiratory functions of healthy subjects who do not have any chronic disease. We found statistically significant differences in percentage of forced expiratory volume in the first second (FEV(1)%) (p = 0.001), the ratio of FEV(1) to forced vital capacity (FEV(1)/FVC) (p = 0.024), percent of maximum expiratory flow rate (FEF(25-75)%) (p = 0.002) and percent of peak expiratory flow (PEF%) (p = 0.037) between cigarette smokers with Maras powder use (n = 23) and control subjects (n = 24). Likewise, when cigarette smokers (n = 24) and control subjects were compared, the differences for all these parameters were significant (p = 0.022, p = 0.048, p = 0.011 and p = 0.047, respectively). Only FEV(1)% and FEF(25-75)% were significantly lower in cigarette smokers with Maras powder use than in Maras powder users (n = 28) (p = 0.011 and p = 0.022, respectively). There was a negative correlation between forced vital capacity and Maras powder use (r = -0.315, p = 0.03). The present study suggests that Maras powder does not cause serious bronchial obstruction. This may be due to usage of the smokeless tobacco through buccal mucosa but not through inhalation as in case of cigarette smoking.


Individual differences in infant visual attention: four-month-olds' discrimination and generalization of global and local stimulus properties.
Cognitive performance and development is negatively correlated with fixation duration patterns during infancy, and evidence suggests that long-looking infants may process visual information more slowly than short-looking infants. 3 experiments described here tested the possibility that these differences may be due to differential sensitivity to global and local visual information. Infants were administered discrimination and generalization tasks involving global and local information at varying levels of familiarization time. Results indicated that 4-month-olds process visual information in a global-to-local sequence. Both long- and short-looking infants were sensitive to both types of information, although long lookers required additional familiarization time to match the performance of short lookers. Finally, apparent "generalization" of global information at brief familiarization levels was traced to insensitivity to local stimulus properties. The results do not support the hypothesis that long- and short-looking infants are differentially sensitive to global versus local visual information at 4 months of age.


Effects of Boron Deficiency on Rubidium Uptake and Photosynthesis in the Diatom Cylindrotheca fusiformis.
Culturing the diatom Cylindrotheca fusiformis under boron-deficient conditions leads to changes in (86)Rb uptake and photosynthesis prior to any effect on the rate of cell division. The influx rate of (86)Rb into boron-deficient cells was 79% of the control rate after 5 to 5.5 hours culture. Despite lowered (86)Rb influx, however, boron-deficient diatoms accumulated more (86)Rb than did control cells; this was due to the deficient cells' lower efflux rate. After 24 hours culture, boron-deficient cells had accumulated 30% more (86)Rb than had control cells, while releasing (86)Rb at only one-half the control rate. Increased photosynthetic rates were another effect of boron deficiency during this early stage of culture. Prior to 20 hours boron-deficient culture, diatoms had photosynthetic rates 37% greater than those of control cells. Corresponding to the increase in photosynthesis, boron-deficient diatoms had 12% more carbohydrate than control cells after 16 hours culture.


Improving perinatal care services in Bangladesh and Nepal.
This article presents an overview of a three-year development project in Bangladesh and Nepal working in partnership with local non-governmental organisations (NGOs) to focus on improving services for mothers and their newborns.


Open Reduction and Tunneled Suspensory Device Fixation Compared with Nonoperative Treatment for Type-III and Type-IV Acromioclavicular Joint Dislocations: The ACORN Prospective, Randomized Controlled Trial.
Nonoperative management of complete acromioclavicular (AC) joint dislocation has yielded reasonable results, although patients may report dissatisfaction with the outcome. The purpose of this prospective, randomized, controlled trial was to compare patient outcome following nonoperative care versus operative treatment with open reduction and tunneled suspension device (ORTSD) fixation for acute, type-III or IV disruptions of the AC joint. Sixty patients aged 16 to 35 years with an acute type-III or IV disruption of the AC joint were randomized to receive ORTSD fixation or nonoperative treatment, following a power analysis to determine sample size. Functional outcomes were assessed with use of the Disabilities of the Arm, Shoulder and Hand (DASH) as the primary outcome measure and the Oxford Shoulder Scores (OSS) and Short Form (SF-12) as secondary outcome measures at 6 weeks, 3 months, 6 months, and 1 year after treatment. Reduction was evaluated with use of radiographs. Any complications were noted at each assessment. The economic implication of each treatment was evaluated. ORTSD and nonoperative groups were similar with regard to demographics at baseline. The mean degree of radiographic displacement was significantly less in patients following ORTSD fixation (1.75 mm) compared with patients who received nonoperative treatment (10.61 mm, p < 0.0001). At 1 year postoperatively, the mean DASH score was 4.67 in the nonoperative treatment group and 5.63 in the ORTSD group, and the mean OSS was 45.72 and 45.63, respectively. Patients managed with ORTSD fixation had inferior DASH scores at 6 weeks (p < 0.01). There were 5 patients who experienced failed nonoperative treatment and subsequently underwent a surgical procedure. ORTSD fixation (£3,359.73) was associated with significantly higher costs than nonoperative treatment (£796.22, p < 0.0001). ORTSD fixation confers no functional benefit over nonoperative treatment at 1 year following type-III or IV disruptions of the AC joint. Although patients managed nonoperatively generally recovered faster, a substantial group of patients remained dissatisfied following nonoperative treatment and required delayed surgical reconstruction. We were unable to identify any demographic or injury-related factors that predicted a poorer outcome in these patients. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.


Azole antifungal drugs in treatment of coccidioidomycosis.
For two decades amphotericin B has been the only antifungal drug with proven efficacy against Coccidioides immitis. The introduction of miconazole in the late 1970s ushered in a new era of antifungal therapy. Miconazole induced remissions in patients with disease refractory to amphotericin B and in patients who had relapsed after amphotericin B treatment. Almost as important, miconazole did not have the nephrotoxicity associated with amphotericin B. However, the necessity of intravenous administration and other toxicities limited the value of miconazole. The first child of miconazole was ketoconazole, which could be administered orally and had markedly less toxicity than amphotericin B or miconazole. Because coccidioidomycosis challenges any antifungal drug, doses were increased to as much as 2,000 mg/d. Ketoconazole can be used for long terms and at high doses, with many patients brought into remission. However relapses and failures still occurred; dose-related endocrine and gastrointestinal toxicities were uncovered. A third generation of azoles, the triazoles, was introduced to minimize these adverse effects, yet retain the efficacy of ketoconazole. Early clinical trials are promising for itraconazole. Other triazoles with advantageous pharmacokinetic properties are also coming into clinical trials. Shortly, we are likely to have available a whole range of antifungal agents for treatment of this most frustrating disease.


Intestinal absorption of protein hydrolysis products: a review.
Many experimental techniques have allowed researchers to probe the fate of hydrolysis products from proteins in the small intestine. An overview of amino acid and peptide absorption from the small intestine is presented with attention given to historical perspectives that have led to current concepts. Speculation about nutritional significance of these processes is offered. Species differences exist in site of amino acid absorption. Numerous mechanisms are available for the transport of amino acids, including Na(+)-dependent carriers (energy-requiring), Na(+)-independent carriers and diffusion. The relative contribution each transport system makes to absorption is dependent on substrate concentration. Individual amino acids are not absorbed with equal efficiency; methionine usually is absorbed in the greatest proportion. There are interactions among amino acids for transports by specific transport systems. Small peptides (mostly di- and tripeptides) are absorbed from the small intestine more rapidly than are free amino acids; peptides are transported by systems independent of those responsible for transporting free amino acids. Evidence exists that the active transport of these peptides is via a proton gradient. Although the concept that peptides are absorbed intact into the circulation is not universally accepted, evidence supporting the possibility of tissue utilization of these small peptides is accumulating.


Concomitant asthma medication use in patients receiving omalizumab: results from three large insurance claims databases.
Omalizumab (Xolair®) is a monoclonal antibody indicated for moderate to severe persistent allergic asthma patients with symptoms that are inadequately controlled with inhaled corticosteroids (ICS). This study describes concomitant asthma medication use in patients treated with omalizumab. An analysis of health insurance claims from MarketScan (2002-2009), Medicaid (2002-2009), and the HealthCore Integrated Research Database (HIRD™) (2002-2010) was conducted. Medical charts were also extracted for a subset of HIRD patients. Patients aged ≥12 years and newly initiated on omalizumab with 12 months of continuous insurance coverage prior to the first omalizumab dispensing (baseline period) and ≥2 asthma claims were included. Concomitant asthma medication use was summarized in eight medication classes. A total of 6038 patients were identified (Medicaid: 731; MarketScan: 3521; HIRD: 1786). A high proportion of new omalizumab users had an asthma-related emergency room visit (Medicaid: 34%; MarketScan: 17%; HIRD: 16%) or hospitalization (Medicaid: 36%; MarketScan: 14%; HIRD: 21%) within 12 months prior to initiating omalizumab. Most patients (Medicaid: 96%; MarketScan: 89%; HIRD: 86%) received three concomitant asthma medication classes or more during the baseline period. Concomitant ICS use was observed in 95%, 89%, and 86% of Medicaid, MarketScan, and HIRD patients, respectively. In HIRD patients without evidence of receiving other asthma medication prior to omalizumab, 17 out of 20 patients had a documented baseline history of asthma-related medication use in their medical charts. This large observational study using health insurance claims from three databases and confirming results from medical charts provides evidence that nearly all omalizumab users had received other asthma medications prior to initiating omalizumab.


Cuproptosis-related lncRNA predict prognosis and immune response of lung adenocarcinoma.
Lung adenocarcinoma (LUAD) accounts for 50% of lung cancers, with high mortality and poor prognosis. Long non-coding RNA (lncRNA) plays a vital role in the progression of tumors. Cuproptosis is a newly discovered form of cell death that is highly investigated. Therefore, in the present study, we aimed to investigate the role of cuproptosis-related lncRNA signature in clinical prognosis prediction and immunotherapy and the relationship with drug sensitivity. Genomic and clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and cuproptosis-related genes were obtained from cuproptosis-related studies. The prognostic signature was constructed by co-expression analysis and Cox regression analysis. Patients were divided into high and low risk groups, and then, a further series of model validations were carried out to assess the prognostic value of the signature. Subsequently, lncRNAs were analyzed for gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes Enrichment (KEGG), immune-related functions, and tumor mutation burden (TMB). Finally, we used tumor immune dysfunction and exclusion (TIDE) algorithms on immune escape and immunotherapy of cuproptosis-related lncRNAs, thereby identifying its sensitivity toward potential drugs for LUAD. A total of 16 cuproptosis-related lncRNAs were obtained, and a prognostic signature was developed. We found that high-risk patients had worse overall survival (OS) and progression-free survival (PFS) and higher mortality. Independent prognostic analyses, ROC, C-index, and nomogram showed that the cuproptosis-related lncRNAs can accurately predict the prognosis of patients. The nomogram and heatmap showed a distinct distribution of the high- and low-risk cuproptosis-related lncRNAs. Enrichment analysis showed that the biological functions of lncRNAs are associated with tumor development. We also found that immune-related functions, such as antiviral activity, were suppressed in high-risk patients who had mutations in oncogenes. OS was poorer in patients with high TMB. TIDE algorithms showed that high-risk patients have a greater potential for immune escape and less effective immunotherapy. To conclude, the 16 cuproptosis-related lncRNAs can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.


Calcitonin gene-related peptide: release by capsaicin and prolongation of the action potential in the guinea-pig heart.
The mechanisms underlying the stimulatory effects of capsaicin on the contractility of the guinea-pig heart were studied in vitro. Capsaicin (10(-7) to 10(-5) M) caused an increased overflow of immunoreactive material, suggesting release of calcitonin gene-related peptide (CGRP)-and neurokinin A (NKA)-like immunoreactivity (-LI), but not of neuropeptide Y (NPY)-LI from the isolated Langendorff-perfused whole heart. The capsaicin-induced release was calcium-dependent. During exposure to capsaicin, the heart rate was increased, while the contractile force was reduced. In addition to releasing CGRP and NKA-LI, potassium (60 mM) also increased the overflow of NPY-LI. The potassium-induced release of peptides was less calcium-dependent than the response to capsaicin. Considerably higher tissue levels of CGRP-LI were found in the atria (about 30 pmol g-1) than in the ventricles (about 10 pmol g-1). In experiments on the right atria using transmembrane action-potential recordings of myocytes, CGRP induced a prolongation of the action potential concomitantly with an increase in rate and contractile force, which was similar to the effect of noradrenaline. Furthermore, CGRP increased the contractile force and relaxation velocity of the electrically stimulated atria. Capsaicin (10(-7) M) also increased the duration of the atrial action potential. In conclusion, CGRP-like material is released by capsaicin from the isolated guinea-pig heart. Both CGRP and capsaicin prolong the plateau phase of the action potential of atrial myocytes. Therefore, the present data give further evidence that CGRP release from sensory nerves within the heart underlies the cardiostimulatory actions of capsaicin.


Proliferative activity in oral carcinomas studied with Ag-NOR and electron microscopy.
This study was conducted on 61 patients (27 males and 34 females). The age ranged from 27 to 81 years (mean 54 years). All suffered from oral squamous cell carcinoma and were treated by surgery and deep X-ray therapy (DXT). The UICC and TNM classification and staging recommendations were used for evaluation of the patients. All sections were stained with Ag-NORs stain for examination of the proliferative activity of the squamous cell carcinomas. Biopsies were also taken from another 6 cases--3 cases with normal striated muscle and 3 cases from normal oral mucosa--and served as controls. Statistical studies of Ag-NOR scores were classified into 3 scores: the p values of score I (ANOVA test) were .0001, score II (ANOVA test) was .0001, and score III (ANOVA test) was 06. Both scores I and II were highly significant and score III was significant. Electron microscopy (EM) showed tumor cells with irregular shape and size and with remarkable division of nuclei and chromatin clumps emarginated toward nuclear membrane, and some cases showed chromatin condensed at one pole of the nucleus. Few mitochondria with dilated cristae (?) and abundant rough endoplasmic reticulum (RER) were observed. Few apoptotic changes were noted. This study showed a high proliferation in poorly differentiated squamous cell carcinomas. The amount of Ag-NOR in poorly differentiated squamous cell carcinomas was a prognostic factor and represented an unfavorable prognostic feature in squamous cell carcinoma of the oral mucosa.


Non-obsessive-compulsive anxiety disorders in child and adolescent mental health services--Are they underdiagnosed, and how accurate is referral information?
Previous studies have reported low prevalence of non-obsessive-compulsive (OCD) anxiety disorders in child and adolescent mental health services (CAMHSs), suggesting that these disorders may go unrecognized. Possible reasons may be lack of routinely used standardized diagnostic instruments, and/or an under-reporting of anxiety symptoms in the referral information. To examine the frequency of non-OCD anxiety disorders in referred children based on a standardized diagnostic interview, to compare the results with data from the Norwegian Patient Register (NPR), and to explore the correspondence between anxiety as a referral symptom and anxiety as a diagnosis, and the influence of heterotypic co-morbidity on this correspondence. Parents of 407 consecutive referrals to CAMHS aged 7-13 years were interviewed with the semi-structured diagnostic interview Kiddie-SADS-PL at the time of admittance. Referral symptoms were collected from national referral forms. A total of 133 referred children (32.7%) met the criteria for a non-OCD anxiety disorder compared with about 5% in the NPR. Half of those who met diagnostic criteria for an anxiety disorder did not have anxiety as a referral symptom. Co-morbid ADHD or disruptive disorder was significantly associated with a lower probability of having anxiety as a referral symptom. The use of a standardized diagnostic interview in consecutively referred children yielded significantly higher rates of anxiety disorders than the NPR prevalence rates. Co-morbid ADHD or disruptive disorder may contribute to the underdiagnosing of anxiety disorders. Diagnostic instruments covering the whole range of child psychiatric symptoms should be implemented routinely in CAMHS.


Pathological fractures of the proximal femur with impending shaft fractures treated by THR and cemented intramedullary nailing: a report of nine cases.
We have used total hip replacement combined with cemented intramedullary nailing to treat a selected group of nine patients with pathological fractures of the proximal femur and impending fractures of the shaft due to metastases. One patient died from cardiopulmonary failure on the third postoperative day, but the others were able to walk within the first week after operation. Complications included one recurrent dislocation of the THR and one fracture of an osteolytic lesion of the femoral shaft during nail insertion. Both were managed successfully. The hybrid osteosynthesis which we describe is an alternative to the use of tumour or long-stem prostheses; it has the advantage of preserving bone stock and muscle attachments.


Suppression of the epidermal growth factor receptor inhibits epithelial-mesenchymal transition in human pancreatic cancer PANC-1 cells.
Aberrant expression of epidermal growth factor receptor (EGFR) has been detected in pancreatic cancer; however, the mechanisms of EGFR in inducing pancreatic cancer development have not been adequately elucidated. The objective of this study was to determine the role of EGFR in mediating epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. Pancreatic cancer cell line PANC-1 was transfected with small interfering RNA of EGFR by use of a lentiviral expression vector to establish an EGFR-knockdown cell line (si-PANC-1). PANC-1 cells transfected with lentiviral vector expressing negative control sequence were used as negative control (NC-PANC-1). Scratch assay and transwell study were used to analyze cell migration and invasion. Real-time PCR and Western blotting were used to detect the expression of EMT markers E-cadherin, N-cadherin, vimentin, and fibronectin and transcription factors snail, slug, twist1, and sip1 in PANC-1, NC-PANC-1, and si-PANC-1 cells. Immunofluorescent staining with these antibodies and confocal microscopy were used to observe their cellular location and morphologic changes. After RNA interference of EGFR, the migration and invasion ability of si-PANC-1 cells decreased significantly. The expression of epithelial phenotype marker E-cadherin increased and the expression of mesenchymal phenotype markers N-cadherin, vimentin, and fibronectin decreased, indicating reversion of EMT. We also observed intracellular translocation of E-cadherin. Expression of transcription factors snail and slug in si-PANC-1 cells decreased significantly. Suppression of EGFR expression can significantly inhibit EMT of pancreatic cancer PANC-1 cells. The mechanism may be related with the down-regulation of the expression of transcription factors snail and slug.


[Notch signaling in chondrogenesis].
Notch is a signaling molecule which plays a critical role in the determination of multiple cellular differentiation pathways and morphogenesis in various biological systems, such as neurogenesis, immune system, and hematopoiesis. However, roles of Notch signaling in osteo/chondrogenesis have not been well studied. We will present our recent progress in investigating roles of Notch signaling in chondrogenesis using in vitro chondrogenic system. We will also discuss about the recent reports which used conditional knockout mice to investigate roles of Notch signaling molecules in vivo .


Emergency presentations to Northern Territory public hospitals: demand and access analysis.
This study aims to quantify trends in emergency presentations to Northern Territory (NT) public hospitals over the past five years with respect to demand and access. Retrospective analysis was undertaken on data extracted from the NT Module of Caresys and the Hospital Morbidity Data System. There has been a 4.6% decrease in presentations to the five public hospitals between 1996 and 2001 compared to a 9.4% growth in the population. Despite the apparent decline in total presentations, the acuity of patients has increased dramatically over the same period. Access analysis of presentations seen within the recommended triage time revealed considerable variability, especially for triage categories 2, 3 and 4. The access block problem, discrepancies in recorded waiting time and irregularities among the regional hospitals within the triage system have also been identified. Recommendations including improved access to inpatient beds and admission to wards were developed in response to the changing role of the emergency department.


Trophoblast apoptosis in placentas from pregnancies complicated by preeclampsia.
To assess trophoblast apoptosis separately in the cytotrophoblast, syncytiotrophoblast, total villous trophoblast, syncytial knots and syncytial knot formation, and to investigate the expression of apoptotic factors Fas ligand (FasL), Bcl-2 and proliferation marker Ki-67 in the trophoblast of placentas from preeclamptic patients. The study included placental samples from 25 preeclamptic and 25 normal pregnancies. For the detection of apoptosis and proliferation, antibody M30 and antibody against Ki-67 antigen were used. Expression of FasL and Bcl-2 was assessed using semi-quantitative HSCORE method. Syncytial knots were expressed as the number of syncytial knots per individual villus and as the total number of syncytial knots in each placental sample. Trophoblast apoptosis, number of syncytial knots per individual villus and the total number of syncytial knots in each placental sample were significantly higher in preeclamptic placentas than in control group placentas. FasL expression was significantly less, and Bcl-2 expression significantly greater in the villus trophoblast among the study subjects compared with controls. There was no difference in the trophoblast proliferation between groups. Our findings might suggest that increased apoptosis and syncytial knot formation combined with reduced FasL expression could be involved in pathophysiological mechanisms of preeclampsia.


Problem of living liver donation in the absence of deceased liver transplantation program: Mansoura experience.
We report our experience with potential donors for living donor liver transplantation (LDLT), which is the first report from an area where there is no legalized deceased donation program. This is a single center retrospective analysis of potential living donors (n = 1004) between May 2004 and December 2012. This report focuses on the analysis of causes, duration, cost, and various implications of donor exclusion (n = 792). Most of the transplant candidates (82.3%) had an experience with more than one excluded donor (median = 3). Some recipients travelled abroad for a deceased donor transplant (n = 12) and some died before finding a suitable donor (n = 14). The evaluation of an excluded donor is a time-consuming process (median = 3 d, range 1 d to 47 d). It is also a costly process with a median cost of approximately 70 USD (range 35 USD to 885 USD). From these results, living donor exclusion has negative implications on the patients and transplant program with ethical dilemmas and an economic impact. Many strategies are adopted by other centers to expand the donor pool; however, they are not all applicable in our locality. We conclude that an active legalized deceased donor transplantation program is necessary to overcome the shortage of available liver grafts in Egypt.


Biocompatibility, antioxidant activity and collagen photoprotection properties of C60 fullerene adduct with L-methionine.
Functionalization of the fullerene core with amino acids has become a new and promising direction in the field of nanochemistry. The biologic activity of water-soluble fullerene derivatives is based on such properties as lipophilicity, electron deficiency and photosensitivity. The complex of above-mentioned properties can be used to develop protection of biomolecules (in particular, proteins) from external physical and chemical influences. Thus, development and up-scaling of synthesis procedures, as well as investigation of the biological properties of these derivatives, are extremely important. This paper presents new data on the biocompatibility studies of C60 fullerene adduct with L-methionine (C60[C5H11NO2S]3; C60-Met). Antiradical activity, binding to human serum albumin (HSA), collagen and deoxyribonucleic acid (DNA), hemocompatibility, photodynamic properties, genotoxicity and cytotoxicity were studied. In addition, it was found that C60-Met increases the photostability of the collagen molecule, and this effect is dose-dependent.


Behavioral responses of longtailed macaques to different cage sizes and common laboratory experiences.
The authors tested the effects of varying cage size on the behavior of 10 female and 10 male Macaca fascicularis by singly caging them for 2 weeks in each of 5 cage sizes, ranging from approximately 20% to 148% of regulation size. Behavior in the regulation cage size, a size 23% smaller, and a size 48% larger did not differ in any analysis. Locomotion was significantly less in the 2 smallest cage sizes. Abnormal behavior occurred only 5% of the time, did not increase as cage size decreased, and did not change significantly over nearly 3 years. Disruption of the normal activity budget in the laboratory environment proved to be a useful indicator of psychological well-being. Moving to a new room and, to a lesser extent, moving into a new, clean cage, regardless of size, was associated with disrupted sleep the 1st night and suppressed activity, especially self-grooming, the next day.


Sustainability of agricultural and wild cereals to aerotechnogenic exposure.
In recent decades, the problem of the constantly increasin level of anthropogenic load on the environment is becoming more and more acute. Some of the most dangerous pollutants entering the environment from industrial emissions are heavy metals. These pollutants are not susceptible to biodegradation over time, which leads to their accumulation in the environment in dangerous concentrations. The purpose of this work is to study the sustainability of cultivated and wild plants of the Poaceae family to aerotechnogenic pollution in the soil. The content of heavy metals in couch grass (Elytrigia repens (L.) Nevski), meadow bluegrass (Poa pratensis L.) and soft wheat (Triticum aestivum) plants grown in the impact zone of Novocherkassk Power Station has been analyzed. Contamination of cultivated and wild cereals with Pb, Zn, Ni and Cd has been established. It has been shown that the accumulation of heavy metals is individual for each plant species. An average and close correlation have been established between the total HM content and the content of their mobile forms in the soil and their content in plants. For the plants studied, the translocation factor (TF) and the distribution coefficient (DC) of HM have been calculated. The TF is formed by the ratio of the concentration of an element in the root plant dry weight to the content of its mobile compounds in the soil. The DC value makes it possible to estimate the capacity of the aboveground parts of plants to absorb and accumulate elements under soil pollution conditions and is determined as the ratio of the metal content in the aboveground biomass to its concentration in the roots. TF and DC values have shown a significant accumulation of elements by plants from the soil, as well as their translocation from the root system to the aboveground part. It has been revealed that even within the same Poaceae family, cultural species are more sensitive to man-made pollution than wild-growing ones.


Comparison of Continuous Wave and Rapid Scan X-band Electron Paramagnetic Resonance of Irradiated Clipped Fingernails.
X-band rapid scan electron paramagnetic resonance (EPR) measures the free radicals in irradiated clipped fingernails with higher signal-to-noise (S/N) and lower standard deviation of the signal amplitude for replicate measurements than does conventional continuous wave (CW) EPR in the same measurement time. For a clipped fingernail sample irradiated to 10 Gy and data acquisition time of 30 s with B1 = 8.5 μT, the S/N for rapid scan is >2000 for the absorption spectrum and 1200 for the corresponding first derivative. The standard deviation for replicate measurements of signal amplitude is ~1%. For CW spectra, the S/N depends on the modulation amplitude. The CW signal has a first derivative peak-to-peak linewidth of 0.95 mT. For 30 s of CW acquisition time, the S/N was 30 for a conservative modulation amplitude of 0.2 mT and B1 of 2.3 μT or 90 for a modulation amplitude of 0.4 mT and B1 of 3.2 μT, which resulted in standard deviations of replicate measurements of 5% or 2%, respectively.


The SEIQoL and functional status: how do they relate?
Over recent years, an emphasis has emerged in the UK and international policy documents, over the involvement of people in the delivery of health care. However, evaluations of health services still largely rest on outcome measures that reflect professional concerns. As new health services are being developed, new patient-centred outcome measures are needed to evaluate them. This paper aims at exploring the possibility of individual quality of life as an outcome measure for health services. As a first step, it aims to elucidate the relationship of functional outcome measures to the Schedule for the Evaluation of Individual Quality of Life (SEIQoL) in groups of people whose age or medical diagnosis serve as the basis for health service design. Its objectives are to study the relation of SEIQoL scores and life areas to functional status in an older population and in a group of people with chronic obstructive pulmonary disease (COPD). Older people selected their health most frequently as one of the most important areas in their life (9.9%, vs. 8.6% for people with COPD) and were more satisfied with it (U = 2,512, p = 0.007). People's health status did not impact on the way they defined their quality of life, but on their level of satisfaction with discrete life areas. The weights attributed to health were significantly negatively correlated to people's overall quality of life score in the overall sample (rho = -0.34, p < 0.001). In the light of recent national and international policy documents advocating for the development of new, more person-centred health services, our results support the proposition of the authors of SEIQoL, that individual quality of life measures have the potential to bring a significant contribution to the evaluation of health services.


Cervical muscle response to whiplash-type right lateral impacts.
Nine healthy volunteers were subjected to right lateral impacts of 4.9, 8.8, 10.8, and 13.7 m/sec acceleration at two levels of expectation: expected and unexpected. To determine the response of the cervical muscles to increasing low-velocity right lateral impacts and compare the quantitative effects of expected and unexpected impact. The literature contains little information on the etiology of whiplash injuries. In particular, in vivo studies of the cervical muscular response and head-neck kinematics to lateral impacts are rare. A previous study of left lateral impacts suggests that the burden of impact is borne primarily by the muscles contralateral to the side of impact. Bilateral electromyograms of the sternocleidomastoids, trapezii, and splenii capitis were recorded. Triaxial accelerometers recorded the acceleration of the chair, torso at the shoulder level, and head of the participant. At an acceleration of 13.7 m/sec2, both sternocleidomastoids, both trapezii, and the right splenius capitis generated on average around 40% or less of their maximal voluntary contraction electromyogram in both the expected and unexpected impact conditions. The left splenius capitis (i.e., contralateral to the right lateral impact), however, generated 84% of its maximal voluntary contraction electromyogram (double the response of other muscles). Electromyographic variables were affected significantly by the levels of acceleration (P < 0.01). The time to onset and time to peak electromyogram time for all muscles decreased progressively with increasing levels of acceleration. The kinetic variables and the electromyographic variables regressed significantly on the acceleration (P < 0.01), and the head acceleration was affected significantly by expectation (P < 0.01). In response to right lateral impacts, muscle responses were generally greater, with higher levels of acceleration, and greatest for the splenius capitis muscle contralateral to the side of impact (P < 0.01). Because the muscular component of the head-neck complex likely plays a central role in the abatement of higher acceleration levels, it may be a primary site of injury in the whiplash phenomenon in lateral collisions, and specifically, the splenius capitis muscle contralateral to the side of impact is most likely to be injured. Being aware of an impact may reduce the degree of head perturbation.


Towards calixarene-based prodrugs: Drug release and antibacterial behaviour of a water-soluble nalidixic acid/calix[4]arene ester adduct.
A water-soluble calixarene-based heterocyclic podand incorporating a quinolone antibiotic subunit, the nalidixic acid, was synthesised and fully characterised. Its prodrug behaviour was assessed in vitro by HPLC, demonstrating the release of the tethered quinolone in model biological conditions. Microbiological studies performed on various Gram-positive and Gram-negative reference strains showed very interesting antibacterial activities.


Reversibility of long-standing urinary tract obstruction requiring long-term dialysis.
Urinary tract obstruction of longer than 4 to 6 weeks' duration is usually said to be irreversible. Older reports of unilateral obstruction have documented return of kidney function after longer periods of obstruction. The duration of bilateral obstruction compatible with return of life-sustaining renal function is poorly defined. We report herein three cases of long-standing urinary tract obstruction leading to apparent dialysis-dependent end-stage renal disease, where relief of obstruction eventually led to discontinuation of dialysis.


Versatile and efficient genome editing in human cells by combining zinc-finger nucleases with adeno-associated viral vectors.
Zinc-finger nucleases (ZFNs) have become a valuable tool for targeted genome engineering. Based on the enzyme's ability to create a site-specific DNA double-strand break, ZFNs promote genome editing by activating the cellular DNA damage response, including homology-directed repair (HDR) and nonhomologous end-joining. The goal of this study was (i) to demonstrate the versatility of combining the ZFN technology with a vector platform based on adeno-associated virus (AAV), and (ii) to assess the toxicity evoked by this platform. To this end, human cell lines that harbor enhanced green fluorescence protein (EGFP) reporters were generated to easily quantify the frequencies of gene deletion, gene disruption, and gene correction. We demonstrated that ZFN-encoding AAV expression vectors can be employed to induce large chromosomal deletions or to disrupt genes in up to 32% of transduced cells. In combination with AAV vectors that served as HDR donors, the AAV-ZFN platform was utilized to correct a mutation in EGFP in up to 6% of cells. Genome editing on the DNA level was confirmed by genotyping. Although cell cycle profiling revealed a modest G2/M arrest at high AAV-ZFN vector doses, platform-induced apoptosis could not be detected. In conclusion, the combined AAV-ZFN vector technology is a useful tool to edit the human genome with high efficiency. Because AAV vectors can transduce many cell types relevant for gene therapy, the ex vivo and in vivo delivery of ZFNs via AAV vectors will be of great interest for the treatment of inherited disorders.


Validation of intravascular ultrasound-derived parameters with fractional flow reserve for assessment of coronary stenosis severity.
We assessed optimal intravascular ultrasound (IVUS) criteria for predicting functional significance of intermediate coronary lesions. Overall, 201 patients with 236 coronary lesions underwent IVUS and invasive physiological assessment before intervention. Fractional flow reserve (FFR) was measured at maximal hyperemia induced by intravenous adenosine infusion. FFR <0.80 at maximum hyperemia was seen in 49 (21%) of the overall 236 lesions. The independent determinants of FFR were minimal lumen area (MLA; β=0.020; 95% confidence interval [CI], 0.008 to 0.031; P=0.032), plaque burden (β=-0.002; 95% CI, -0.003 to 0.001; P=0.001), lesion length with a lumen area <3.0 mm(2) (β=-0.003; 95% CI, -0.005 to -0.001; P=0.005), and left anterior descending artery location (β=-0.035; 95% CI, -0.055 to -0.016; P=0.001). The best cutoff value (with a maximal accuracy) of the MLA to predict FFR <0.80 was <2.4 mm(2), with a diagnostic accuracy of 68% (90% sensitivity, 60% specificity, and area under the curve=0.800; 95% CI, 0.742 to 0.848; P<0.001). The cutoff value of plaque burden to predict FFR <0.80 was ≥79% (69% sensitivity, 72% specificity, and area under the curve=0.756; 95% CI, 0.696 to 0.810; P<0.001). The cutoff value of lesion length with a lumen area <3.0 mm(2) was 3.1 mm (84%sensitivity, 63%specificity, and area under the curve=0.765; 95% CI, 0.706 to 0.818; P<0.001). Among 117 lesions with an MLA ≥2.4 mm(2), 112 (96%) had an FFR ≥0.80,; and all but 1 showed FFR ≥0.75. Conversely, 44 (37%) lesions with an MLA <2.4 mm(2) had an FFR <0.80. IVUS-derived MLA ≥2.4 mm(2) may be useful to exclude FFR <0.80, but poor specificity limits its value for physiological assessment of lesions with MLA <2.4 mm(2). Thus, FFR or stress tests may be necessary to accurately identify ischemia-inducible intermediate stenoses.


Vaccine-associated paralytic poliomyelitis: a review of the epidemiology and estimation of the global burden.
Vaccine-associated paralytic poliomyelitis (VAPP) is a rare adverse event associated with oral poliovirus vaccine (OPV). This review summarizes the epidemiology and provides a global burden estimate. A literature review was conducted to abstract the epidemiology and calculate the risk of VAPP. A bootstrap method was applied to calculate global VAPP burden estimates. Trends in VAPP epidemiology varied by country income level. In the low-income country, the majority of cases occurred in individuals who had received >3 doses of OPV (63%), whereas in middle and high-income countries, most cases occurred in recipients after their first OPV dose or unvaccinated contacts (81%). Using all risk estimates, VAPP risk was 4.7 cases per million births (range, 2.4-9.7), leading to a global annual burden estimate of 498 cases (range, 255-1018). If the analysis is limited to estimates from countries that currently use OPV, the VAPP risk is 3.8 cases per million births (range, 2.9-4.7) and a burden of 399 cases (range, 306-490). Because many high-income countries have replaced OPV with inactivated poliovirus vaccine, the VAPP burden is concentrated in lower-income countries. The planned universal introduction of inactivated poliovirus vaccine is likely to substantially decrease the global VAPP burden by 80%-90%.


[Kallmann's syndrome in families].
The authors present the incidence of Kallmann's syndrome in two families in four persons. In one family the syndrome was present in a boy and the brother of his mother. In the second family in siblings -- a boy and a girl. The two boys at preschool age underwent a surgery because of bilateral cryptorchism. In the first patient and his uncle additional hearing dysfunction and agenesis of the left kidney were diagnosed. In all the patients anosmia was diagnosed. All the patients receive a pharmacological treatment which improved significantly their clinical state, caused the development of tertiary sexual feature and an improvement of the psychological condition. 1. In patients with an abnormal development of the urethro-sexual organs a diagnosis for other disturbances or developmental defects is necessary. 2. In patients with an abnormal urethro-sexual development a permanent care of a psychologist is necessary.


Resources and transgenesis techniques for functional genomics in Xenopus.
Recent developments in genomic resources and high-throughput transgenesis techniques have allowed Xenopus to 'metamorphose' from a classic model for embryology to a leading-edge experimental system for functional genomics. This process has incorporated the fast-breeding diploid frog, Xenopus tropicalis, as a new model-system for vertebrate genomics and genetics. Sequencing of the X. tropicalis genome is nearly complete, and its comparison with mammalian sequences offers a reliable guide for the genome-wide prediction of cis-regulatory elements. Unique cDNA sets have been generated for both X. tropicalis and X. laevis, which have facilitated non-redundant, systematic gene expression screening and comprehensive gene expression analysis. A variety of transgenesis techniques are available for both X. laevis and X. tropicalis, and the appropriate procedure may be chosen depending on the purpose for which it is required. Effective use of these resources and techniques will help to reveal the overall picture of the complex wiring of gene regulatory networks that control vertebrate development.


Identifying Individuals at High Risk of Psychosis: Predictive Utility of Support Vector Machine using Structural and Functional MRI Data.
The identification of individuals at high risk of developing psychosis is entirely based on clinical assessment, associated with limited predictive potential. There is, therefore, increasing interest in the development of biological markers that could be used in clinical practice for this purpose. We studied 25 individuals with an at-risk mental state for psychosis and 25 healthy controls using structural MRI, and functional MRI in conjunction with a verbal memory task. Data were analyzed using a standard univariate analysis, and with support vector machine (SVM), a multivariate pattern recognition technique that enables statistical inferences to be made at the level of the individual, yielding results with high translational potential. The application of SVM to structural MRI data permitted the identification of individuals at high risk of psychosis with a sensitivity of 68% and a specificity of 76%, resulting in an accuracy of 72% (p < 0.001). Univariate volumetric between-group differences did not reach statistical significance. By contrast, the univariate fMRI analysis identified between-group differences (p < 0.05 corrected), while the application of SVM to the same data did not. Since SVM is well suited at identifying the pattern of abnormality that distinguishes two groups, whereas univariate methods are more likely to identify regions that individually are most different between two groups, our results suggest the presence of focal functional abnormalities in the context of a diffuse pattern of structural abnormalities in individuals at high clinical risk of psychosis.


Oxygen-limited metabolism in the methanotroph Methylomicrobium buryatense 5GB1C.
The bacteria that grow on methane aerobically (methanotrophs) support populations of non-methanotrophs in the natural environment by excreting methane-derived carbon. One group of excreted compounds are short-chain organic acids, generated in highest abundance when cultures are grown under O2-starvation. We examined this O2-starvation condition in the methanotroph Methylomicrobium buryatense 5GB1. The M. buryatense 5GB1 genome contains homologs for all enzymes necessary for a fermentative metabolism, and we hypothesize that a metabolic switch to fermentation can be induced by low-O2 conditions. Under prolonged O2-starvation in a closed vial, this methanotroph increases the amount of acetate excreted about 10-fold, but the formate, lactate, and succinate excreted do not respond to this culture condition. In bioreactor cultures, the amount of each excreted product is similar across a range of growth rates and limiting substrates, including O2-limitation. A set of mutants were generated in genes predicted to be involved in generating or regulating excretion of these compounds and tested for growth defects, and changes in excretion products. The phenotypes and associated metabolic flux modeling suggested that in M. buryatense 5GB1, formate and acetate are excreted in response to redox imbalance. Our results indicate that even under O2-starvation conditions, M. buryatense 5GB1 maintains a metabolic state representing a combination of fermentation and respiration metabolism.


Origin and differentiation of hepatic natural killer cells (pit cells).
Liver sinusoids contain a population of large granular lymphocytes or natural killer cells, originally termed pit cells. After isolation and purification, these cells were separated into a low-density and a high-density fraction. The liver low-density fraction differs significantly in morphology and function from cells of the blood, whereas the liver high-density fraction shows intermediate properties. In this study we demonstrate that this morphological and functional heterogeneity is based on subsequent steps of differentiation of the large granular lymphocytes within the liver. When cell proliferation was suppressed by sublethal total body irradiation, the life span of the hepatic large granular lymphocytes could be determined: high-density and low-density populations were totally depleted within 1 and 2 wk after irradiation, respectively. By using intravenous asialo-GM1 anti-serum to deplete animals of asialo-GM1-positive cells, we found that the depletion of the asialo-GM1-positive cells preceded the depletion of asialo-GM1-negative hepatic low-density large granular lymphocytes by approximately 1 wk. Direct evidence that the asialo-GM1-positive high-density large granular lymphocytes are precursors of the low-density large granular lymphocytes was given by adoptive transfer experiments with fluorescent-labeled high-density cells. Three days after their injection, labeled large granular lymphocytes were found in the hepatic low-density fraction of the recipient rat, and these cells had developed morphological characteristics of low-density large granular lymphocytes. It is concluded therefore that marginating blood large granular lymphocytes differentiate through high-density large granular lymphocytes into the typical liver specific low-density large granular lymphocytes or pit cells.


Origins of binding specificity of the A1 heterogeneous nuclear ribonucleoprotein.
The A1 heterogeneous nuclear ribonucleoprotein (hnRNP) is the best studied of the "core" hnRNP proteins that are tightly associated with heterogeneous nuclear RNA (hnRNA) within eukaryotic nuclei. Previous studies suggested that hnRNP A1 preferentially binds (under nonequilibrium conditions) to the pyrimidine-rich span of sequence at the 3'splice site of most introns [Swanson, M.S., & Dreyfuss, G. (1988) EMBO J. 11, 3519-3529; Buvoli et al. (1990) Nucleic Acids Res. 18, 6595-6600; Ishikawa et al. (1993) Mol. Cell. Biol. 13, 4301-4310]. Recently, Burd and Dreyfuss [(1994) EMBO J. 13, 1197-1204] used selection/amplification from pools of random sequence RNA to uncover an even higher-affinity A1 oligo that contained two copies of a high-affinity consensus sequence, UAGGGU/A. We have extended these studies by using a fluorescence assay to characterize the equilibrium binding properties of A1 to each of these oligonucleotides. By also characterizing the binding of A1 to sequence-randomized control oligonucleotides, we have been able to better evaluate the inherent "sequence-specific" binding properties of A1. Although these studies indicate that under equilibrium conditions A1 cannot specifically recognize the beta-globin, 3'-splice site DNA oligo analogue studied by Buvoli et al. (1990), they confirmed the high-affinity binding to the "winner" 20-mer RNA that was uncovered via selection/amplification and that has the sequence UAUGAUAGGGACUUAGGGUG (Burd & Dreyfuss, 1994). In 0.1 M NaCl, we found that A1 has approximately 100-fold higher affinity for this winner sequence sequence than it does for either a randomized version of this sequence or a 20-mer oligo corresponding to an unrelated beta-globin intron sequence. This winner RNA oligo aggregates in solution to form an apparent dimer that may represent a G-quartet resulting from dimerization of two Hoogsteen base-paired hairpins. On the basis of salt sensitivity studies carried out with various fragments of A1, the ability of A1 to discriminate the winner sequence from its randomized control results primarily from increased ionic interactions with the glycine-rich, COOH terminal domain of A1 that extends from residue 196 to 319. Nonetheless, most of the overall energy of binding for the A1 winner complex results from determinants that are resident within the first 195 residues of A1. The unique ability of the winner sequence (but not its sequence-randomized control) to form a higher-order aggregate, which may correspond to a G-tetrad, appears to facilitate the additional ionic interactions with the COOH terminal domain. Taken together, these data suggest the need to reevaluate possible and probable functions of A1 in vivo.


Role of fixed parenchyma cells in blastema formation of the planarian Dugesia japonica.
Observations of fixed parenchyma cells using electron microscopy were carried out in an attempt to understand the morphogenetic process of blastema formation in regenerating planarians. Fixed parenchyma cells could be found throughout one-day blastemata. In the mid-blastema region where migrating regenerative cells build up a compact cell aggregate, long and slender cytoplasmic processes of the fixed parenchyma cells were seen occupying spaces among regenerative cells. A characteristic feature of such processes was orderly arranged microtubules. Ruthenium red staining revealed thickened portions of cell coats on these processes and occasional formation of gap junctions between the cytoplasmic process of the fixed parenchyma cell and the regenerative cell undergoing migration. Colchicine treatment (M/1,000) caused detachment of the cytoplasmic processes from the regenerative cells. Microtubules within such processes became depolymerized. As a result, directional migration of regenerative cells was inhibited by colchicine treatment. To determine the extracellular site of fibronectin, immunoelectron microscopy was performed in one-day blastema. Immunogold labeling was detected at the surface area of fixed parenchyma cells and regenerative cells. In particular the reactivity was conspicuous at the cytoplasmic process of the fixed parenchyma cells. These observations suggest that the cytoplasmic processes of fixed parenchyma cell are related to directional movement of regenerative cells by providing a contact guidance system. The biological implications of this system are discussed in relation to the extracellular matrix components.


Aesthetic Augmentation Phalloplasty: A Systematic Review of Techniques and Outcomes.
Aesthetic augmentation phalloplasty is a set of procedures aimed at increasing penile length and/or girth; many of these procedures are investigational. This systematic review set out to summarize available literature on these procedures in patients with normal penile anatomy. A systematic review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The MEDLINE/PubMed, Scopus, and Cochrane Databases were used to identify articles on aesthetic augmentation phalloplasty in cis-gender men without penile deformity from 1990 to 2018. Data on outcomes, complications, and patient-reported satisfaction were collected. Sixteen articles, involving 1192 patients, met our inclusion criteria. Mean age ranged from 23 to 44 years, and follow-up time ranged from 6 to 48 months. The quality of the studies was poor regarding methodology for patient selection and outcomes reporting. Surgical interventions included suspensory ligament incision, grafting, flaps, and penile disassembly. Augmentation was performed for length only in 16 percent of patients, girth only in 70.6 percent, and combined in 13.4 percent. Length gain ranged from 8 to 83 percent in the flaccid state and 12 to 53 percent in the erect state. Girth gain ranged from 16 to 56 percent in the flaccid state and 19 to 30 percent in the erect state. The pooled complication rate was 14.6 percent, with those undergoing combined augmentation having the highest complication rate. Patients were generally satisfied; reported satisfaction rates ranged from 50 to 100 percent. Enhancement procedures are controversial and investigational. Data point to inconsistent methodology when reporting penile dimensions, outcomes, and patient satisfaction. Despite the reportedly high satisfaction rates, patients should be counseled regarding high complication rates. Best-practice guidelines will be critical to achieve safe and reliable outcomes.


Hydrogen-Deuterium Exchange Desorption Electrospray Ionization Mass Spectrometry Visualizes an Acidic Tumor Microenvironment.
We report that microdroplet hydrogen-deuterium exchange (HDX) detected by desorption electrospray ionization mass spectrometry imaging (DESI-MSI) allows the measurement of the acidity of a tissue sample. The integration of HDX and DESI-MSI has been applied to visualize the acidic tumor microenvironment (TME). HDX-DESI-MSI enables the simultaneous collection of regional pH variation and its corresponding in-depth metabolomic changes. This technique is a cost-effective tool for providing insight into the pH-dependent tumor metabolism heterogeneity.


[Study on C21 steroidal glycosides of Cynanchum atratum by LC-MS].
High performance liquid chromatography coupled with on-line electrospray tandem mass spectrometry (HPLC/ESI-MS/MS) was used to identify C21 steroidal glycosides in the roots of Cynanchum atratum. The structures of C21 steroidal glycosides were deduced from mass fragments features in positive and negative mode. The constituents of C. atratum were separated and detected. 7 compounds were identified by comparing their ESI-MS/MS data with the reference compounds and 2 compounds were inferred solely by the ESI-MS/MS data. The method is sensitive, and provides good separation and rapid qualitative characterization of C21 steroidal glycosides in the roots of C. atratum.


Antiproliferative effects of AAV-delivered CRISPR/Cas9-based degradation of the HPV18-E6 gene in HeLa cells.
Human papillomavirus infections are associated with most cervical cancers, which are the fourth most common cancer in women. HPV-E6 protein binds to protein p53 and inhibits its function, leading to the switching of normal cells toward cancer cells. Here, we disrupted the HPV-E6 gene and investigated its effects on the proliferation and apoptosis of HeLa cells. The HPV18-E6 gene was targeted with two designed sgRNAs cloned into an AAV-CRISPR-based plasmid. The AAV-E6-CRISPR/Cas9 virions were prepared and titrated in HEK293t cells. The cleavage created in the HPV-E6 gene was detected using the T7E1 assay. Cell cycle profiling, MTT assay, and annexin V/PI staining were performed. Also, the p53 protein level was measured by Western blotting. Our data showed that disruption of the HPV-E6 gene led to increased cell apoptosis and decreased cell proliferation. A significant accumulation of infected cells in sub-G1 phase was observed in the cell profiling assay. Also, HPV-E6 gene disruption resulted in a significant increase in the level of P53 protein. Our findings indicated that AAV-mediated delivery of CRISPR/Cas9 can effectively target the HPV-E6 gene in HeLa cells, and its antiproliferative effects may provide therapeutic benefits of local administration of this gene-editing system for HPV-related cervical cancers.


Effect of Intense Pulsed Light Therapy in Dry Eye Disease Caused by Meibomian Gland Dysfunction: A Systematic Review and Meta-Analysis.
This study aimed to systematically evaluate the effect of intense pulsed light (IPL) therapy in patients harboring dry eye disease caused by meibomian gland dysfunction (MGD) based on qualified studies. The electronic databases, including PubMed, Cochrane, and Embase, were searched using keywords to identify available publications updated to November 2021. Relative risk or weighted mean difference combined with 95% confidence interval was used to synthesize the outcomes of included studies. The meta-analysis included 15 randomized controlled trials with 1,142 patients (2,284 eyes). The results revealed that IPL could significantly decrease the ocular surface disease index (OSDI), standard patient evaluation of eye dryness (SPEED), artificial tear usage, tear film lipid layer, meibomian gland quality (MGQ), meibomian gland expression (MGX), and corneal fluorescein staining (CFS) while increase tear break-up time (TBUT) and noninvasive tear break-up time (NIBUT) compared with sham. Compared with MGX, IPL+MGX markedly decreased the SPEED, CFS, and tear meniscus height (TMH), but with increased TBUT. Compared with MGX, IPL showed significant effect in increasing the OSDI and TBUT, but decreasing the TMH and NIBUT. However, no significant differences were seen between IP+MGX and MGX in OSDI, MGQ, and MGX, nor between IPL and MGX in OSDI, SPEED, and TBUT. We identified that the application of IPL alone or IPL combined with MGX elicited superior clinical effect for improving the eye function and symptoms in the treatment of MGD-related dry eye disease, which is considered available for wide clinical application.


Quantitative assessment of myocardial infarction prognosis to 1 and 6 mth--from clinical data.
Survival of 312 patients with acute myocardial infarction was studied from data collected during the first 48 h in the coronary care unit. Only patients with recent onset of symptoms (48 h), with a 48-h survival, and with evidence of myocardial infarction, were selected. Mortality rate at 1 mth was 15.3% and 24.6% at 6. The following factors were significant for poor survival: increasing age, female sex, diabetes, previous angina, low blood pressure on admission and at the 48th h low average value and the lowest observed value of blood pressure, clinical and radiological left ventricular failure, high level of LDH, increased urea and leukocytosis. Among ECG data, the presence of signs related to extent of infarction, anterior as compared to inferior location, antero-lateral as compared to anterior, QRS frontal axis deviation, absence of sinus rhythm, sinus tachycardia, tachyarrhythmias with wide QRS complex, right bundle branch block, 3rd-degree AV block with wide QRS complex, was associated with significantly worse survival than the absence of these signs. A multivariate analysis of the 42 most significant data, assuming linear regression, was used to establish a discriminant prognostic index. Using this index, survival was predicted correctly in 90.2% of patients at 1 mth and 85.7% at 6 mth. Thus prognosis can be established in nonclear-cut groups of patients with myocardial infarction (severe and benign forms being excluded by criteria) from simple clinical data.


Contrast agents for hepatic magnetic resonance imaging.
The current availability of liver-specific contrast media (LSCM) allows the possibility to obtain an accurate diagnosis when studying focal liver lesions (FLL). It is necessary to have an in-depth knowledge of the biologic and histologic characteristics of FLL and the enhancement mechanism of LSCM to gain significant accuracy in the differential diagnosis of FLL. It is possible to subdivide FLL into three main groups according to the kinetics of contrast enhancement: hypervascular FLL, hypovascular FLL, and FLL with delayed enhancement. Dynamic contrast-enhanced magnetic resonance imaging is an important tool in the identification and characterization of FLL. LSCM with a first phase of extracellular distribution give both dynamic (morphologic) and late phase (functional) information useful for lesion characterization. With LSCM it is possible to differentiate with high accuracy benign from malignant lesions and hepatocellular from nonhepatocellular lesions. To understand contrast behavior after injection of LSCM, it is necessary to correlate contrast enhancement with the biologic and histologic findings of FLL.


Perception of goal proximity, latency and duration of action plans, and worry in relation to goal distance in time and personality characteristics.
128 male high school students were tested for achievement motives, future-time orientation and perceived intrinsic instrumentality, and answered several questions related to future goals or tests at different distances in time. Success-oriented individuals and individuals with high future-time orientation perceived the goals as closer, planned to initiate preparations for the goals earlier, and planned to devote more time in the preparation than failure-oriented individuals and those with low future-time orientation. Interactions of motives and future-time orientation on the perception of goal proximity and planned time of initiating goal preparations did also emerge. Motives and future-time orientation affected the dependent variables most when the goals were at some distance in time (i.e., 1 yr. and 3 mo.), and the effects were minimized for the goal relatively close in time (i.e., 1 wk.). Individuals with high instrumentality report that they would start preparations earlier, devote more time to all goal preparations, and perceive more worry for the goal closest in time than individuals with low instrumentality. In addition, interactions of motives and instrumentality and of future-time orientation and instrumentality are presented. The results are interpreted and discussed in relation to the dynamics of action theory of Atkinson and Birch and other theories of achievement motivation.


The TSH, T4, T3 and prolactin responses to consecutive infusions of a potent and stabilized thyrotrophin releasing hormone analogue, RX77368, in man.
The endocrine manifestations of a stabilized thyrotrophin releasing hormone (TRH) analogue, RX77368, have been investigated in six male volunteers. Infusions were given on two occasions, with a 5-day interval between infusions. On the second exposure to RX77368, there was a significant reduction in the TSH response, despite normal basal T3 and T4 levels, while the response of prolactin to RX77368 was unaltered. Domperidone administered during the infusion of RX77368 caused a further elevation of prolactin levels, whilst TSH levels were unchanged. This study shows the differential regulation of thyrotrophs and lactotrophs in response to stimulation by a TRH analogue, and shows, for the first time, down-regulation of the TSH response in vivo, in the presence of normal peripheral thyroid hormone levels. The T3 response to infusions of RX77368 was less than to a bolus injection of TRH, despite a greater TSH response to the analogue, suggesting impaired biological activity of TSH released in response to an infusion of the analogue.


Lidocaine in the treatment of decompression illness: a review of the literature.
While recompression and hyperbaric oxygen administration remain the mainstays of treatment for decompression illness (DCI), drugs that might improve outcomes or prove beneficial in first aid management have been sought. There has been much interest in lidocaine, a sodium channel-blocking agent used clinically as an antiarrhythmic and local anesthetic. The relevant literature is reviewed. Lidocaine is neuro-protective in cerebral arterial gas embolism (CAGE) in vivo, and in a variety of in vivo and in vitro models of ischemic brain injury. There has been limited in vivo investigation of efficacy in DCI where bubbles have formed from dissolved nitrogen. Mechanisms of neuro-protection by lidocaine include deceleration of ischemic ion fluxes across the neuronal cell membrane and prevention of the consequent neurotoxic events. In addition, lidocaine lowers neuronal metabolism, exerts advantageous effects on cerebral hemodynamics, and is a potent anti-inflammatory. There is one randomized double blind study that demonstrates improved neuropsychological outcomes in cardiac surgery patients receiving lidocaine. Clinical evidence of efficacy in DCI is limited to anecdotal reports. Expeditious administration of lidocaine is justified in cases of unequivocal CAGE. Speculative use may be justified in severe neurologic DCI after patient counseling and consent.


Why Should the "Alternative" Method of Estimating Local Interfacial Shear Strength in a Pull-Out Test Be Preferred to Other Methods?
One of the most popular micromechanical techniques of determining the local interfacial shear strength (local IFSS, τd) between a fiber and a matrix is the single fiber pull-out test. The τd values are calculated from the characteristic forces determined from the experimental force⁻displacement curves using a model which relates their values to local interfacial strength parameters. Traditionally, the local IFSS is estimated from the debond force, Fd, which corresponds to the crack initiation and manifests itself by a "kink" in the force⁻displacement curve. However, for some specimens the kink point is hardly discernible, and the "alternative" method based on the post-debonding force, Fb, and the maximum force reached in the test, Fmax, has been proposed. Since the experimental force⁻displacement curve includes three characteristic points in which the relationship between the current values of the applied load and the crack length is reliably established, and, at the same time, it is fully determined by only two interfacial parameters, τd and the interfacial frictional stress, τf, several methods for the determination of τd and τf can be proposed. In this paper, we analyzed several theoretical and experimental force⁻displacement curves for different fiber-reinforced materials (thermoset, thermoplastic and concrete) and compared all seven possible methods of τd and τf calculation. It was shown that the "alternative" method was the most accurate and reliable one, while the traditional approach often yielded the worst results. Therefore, we proposed that the "alternative" method should be preferred for the experimental force⁻displacement curves analysis.


Long-term control of ambulatory hypertension in children: improving with time but still not achieving new blood pressure goals.
Short-term therapy can decrease blood pressure (BP) to less than the 95th percentile in only about 50% of children. The aim of our study was to investigate the long-term control of hypertension (HT) in children using ambulatory BP monitoring (ABPM). We analyzed data from all children who started ramipril monotherapy in our center. Controlled HT was defined according to the most current guidelines as systolic and diastolic BP at daytime and nighttime <90th percentile in primary HT and <75th percentile in renoparenchymal HT. Thirty-eight children who were on therapy ≥1 year were included. Thirty-two children had renoparenchymal, and 6 had primary HT. The median age at the beginning of therapy was 13.6 years (range = 4.1-18.0 years), and the median time of antihypertensive therapy was 2.6 years (range = 1.0-11.8 years). Thirty-four percent of children received combination therapy; the median number of antihypertensive drugs was 1.5 drugs/patient (range = 1-4). Sixty-eight percent of children had BP <95th percentile, but only 34% of the children had controlled HT. Children with uncontrolled HT had a tendency to have a higher daytime diastolic BP index before the start of therapy than children with controlled HT (0.99±0.11 vs. 0.94±0.11; P = 0.09). There was a significant decrease in prevalence of nondipping (from 47% to 16%; P = 0.006) with therapy. This first pediatric study focusing on long-term control of HT using ABPM showed that long-term control of HT is better than short-term control, but still only one-third of children achieve the new BP goals. The low control of HT might be improved by more intensive therapy.


Alzheimer's disease pathogenesis: The role of disturbed sleep in attenuated brain plasticity and neurodegenerative processes.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairments. The classical symptoms of the disease include gradual deterioration of memory and language. Epidemiological studies indicate that around 25-40% of AD patients have sleep-wake cycle disturbances. Importantly, a series of studies suggested that the relationship between AD and sleep disturbance may be complex and bidirectional. Indeed, accumulation of the extracellular neuronal protein amyloid-beta (Aβ) leads to altered sleep-wake behavior in both mice and humans. At the same time, disturbances of the normal sleep-wake cycle may facilitate AD pathogenesis. This paper will review the mechanisms underlying this potential interrelated connection including locus coeruleus damage, reductions in orexin neurotransmission, alterations in melatonin levels, and elevated cytokine levels. In addition, we will also highlight how both the development of AD and sleep disturbances lead to changes in intracellular signaling pathways involved in regulating neuronal plasticity and connectivity, particularly extremes in cofilin phosphorylation. Finally, current pharmacological and nonpharmacological therapeutic approaches will be discussed.


Behavioral and emotional manifestations in a child with Prader-Willi syndrome.
Prader-Willi syndrome is a neurodevelopmental disorder characterized by mental retardation and distinct physical, behavioral, and psychiatric features. Maladaptive behaviours, cognitive impairment, and impediments in speech and language seriously affect the early development and long-term functioning of individuals affected by the illness. We present a case of a 9-year-old child with Prader-Willi syndrome whose behavioural symptoms were treated with low-dose antipsychotic medications.


Patients' and caregivers' expectations and experiences of remote monitoring for peritoneal dialysis: A qualitative interview study.
Peritoneal dialysis (PD) can offer more flexibility and independence compared with hemodialysis, yet uptake of PD remains low. Barriers to PD include the fear of dialyzing without medical assistance and uncertainty about recognizing and managing complications. There is increasing use of remote monitoring in automated peritoneal dialysis (APD), but little is known about its acceptability by patients and caregivers. We aimed to describe patients' and caregivers' expectations and experiences of remote monitoring for APD. Qualitative study design, using semi-structured face-to-face interviews of patients who either receiving PD or were considered eligible for PD, and their caregivers. Transcripts were analyzed using thematic analysis. Of the 34 participants, 27 were patients and the remainder caregivers. Four themes (with subthemes) were identified reducing patient burden (seeking reassurance and shared responsibility, convenience and accuracy); strengthening partnerships in care (empowering knowledge and understanding, increased accountability to dialysis team); improving access to treatment (saving time and money, providing timely care and avoiding hospital); and preserving quality patient-provider interactions (enhancing face-to-face contact, clarifying expectations of access and use of data). Remote monitoring may increase patient knowledge about their kidney disease and its treatment, encourage accountability to the clinical team, enhance partnerships with clinicians, and improve access to treatment and timely care. It is also important to ensure that remote monitoring does not replace face-to-face clinical contact with clinicians.


Neuroprotection of GluR5-containing kainate receptor activation against ischemic brain injury through decreasing tyrosine phosphorylation of N-methyl-D-aspartate receptors mediated by Src kinase.
Previous studies indicate that cerebral ischemia breaks the dynamic balance between excitatory and inhibitory inputs. The neural excitotoxicity induced by ionotropic glutamate receptors gain the upper hand during ischemia-reperfusion. In this paper, we investigate whether GluR5 (glutamate receptor 5)-containing kainate receptor activation could lead to a neuroprotective effect against ischemic brain injury and the related mechanism. The results showed that (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), a selective GluR5 agonist, could suppress Src tyrosine phosphorylation and interactions among N-methyl-D-aspartate (NMDA) receptor subunit 2A (NR2A), postsynaptic density protein 95 (PSD-95), and Src and then decrease NMDA receptor activation through attenuating tyrosine phosphorylation of NR2A and NR2B. More importantly, ATPA had a neuroprotective effect against ischemia-reperfusion-induced neuronal cell death in vivo. However, four separate drugs were found to abolish the effects of ATPA. These were selective GluR5 antagonist NS3763; GluR5 antisense oligodeoxynucleotides; CdCl(2), a broad spectrum blocker of voltage-gated calcium channels; and bicuculline, an antagonist of gamma-aminobutyric acid A (GABA(A)) receptor. GABA(A) receptor agonist muscimol could attenuate Src activation and interactions among NR2A, PSD-95 and Src, resulting the suppression of NMDA receptor tyrosine phosphorylation. Moreover, patch clamp recording proved that the activated GABA(A) receptor could inhibit NMDA receptor-mediated whole-cell currents. Taken together, the results suggest that during ischemia-reperfusion, activated GluR5 may facilitate Ca(2+)-dependent GABA release from interneurons. The released GABA can activate postsynaptic GABA(A) receptors, which then attenuates NMDA receptor tyrosine phosphorylation through inhibiting Src activation and disassembling the signaling module NR2A-PSD-95-Src. The final result of this process is that the pyramidal neurons are rescued from hyperexcitability.


[Formation of bacterial biofilm on deep vein catheters in burn patients and its significance].
To observe the biofilm (BF) formation of Staphylococcus aureus (SA), Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) on the surface of deep vein catheters in burn patients after infection. The bacteria from deep vein catheters in 20 patients hospitalized from November 2008 to August 2009 were isolated, and were compared with their respective standard stains. Catheters tips were examined with scanning electron microscope (SEM). The semi-quantitative adhesion assay of bacterial BF was performed with modified microtiter-plate test, and the thickness of BF was scanned and measured by confocal laser scanning microscopy (CLSM) after double fluorescence staining, after being cultured in vitro for 12, 24, 48, 72 hours and 5 days, respectively. Data were processed with grouped t test. Six strains of SA, 8 strains of AB, and 6 strains of PA, all drug resistant, were isolated from the deep vein catheters. SEM showed that the BF structures on the inner surfaces of catheters were in diverse in their shape and degree, characterized by adherence and flake formation, and embedded in polysaccharide matrix. BF gathered in clusters, forming three-dimensional structure, in which small amount of red blood cells were found. A small number of bacteria were incompletely embedded, with some bacteria adhered to them. The absorbance values for SA after 24, 48 and 72 hours of culture (PCH) were above the cut-off value, the same for AB at PCH 12, 24, 48 and 72, and PA after PCH 48. Except for PA standard strain, CLSM showed scattered green fluorescence, mainly close to the bottom of plate, while the red fluorescence was observed in full scope at PCH 24 for each strain. At PCH 48 green fluorescence increased obviously and extended upward from the bottom, overlapping partly with red fluorescence, forming yellow fluorescence, and among the bacteria it was most obvious in AB culture, with SA the next. Compared with those of the standard stains, the intensity and quantity of fluorescence from the clinical strains were stronger; at PCH 72 the green fluorescence increased obviously especially for PA and its standard strain, while the yellow fluorescence was full of the scope for other strains. On in vitro culture day 5, the green fluorescence was dispersed and was obvious on the bottom of the plate. BF mature time for AB and SA was PCH 48, and for PA was PCH 72. The BF thickness of AB was (18.2 +/- 3.6) microm at PCH 72, which was thicker than that [(9.4 +/- 2.6) microm] of its standard strain (t = 5.42, P < 0.05), and was also the thickest among the three clinically found strains. SA, AB and PA, which are commonly found bacteria in burn patients, can form BF in deep vein catheters. Their ability to form BF seems to be stronger than other usually pathogenic strains, especially AB, which is the important pathogen leading to catheter related infection.


[Analysis of NPM1 gene mutations in acute myeloid leukemia].
The aim of this study was to evaluate the nucleophosmin (NPM1) gene exon 12 mutation in patients with acute myelogenous leukemia (AML) and its clinical characteristics. Genomic DNAs from 33 AML patients were amplified by PCR and sequencing for NPM1 mutations. The results showed that the NPM1 exon 12 mutations were found is 8 patients from 33 AML patients (24.2%) including 1 of M(1), 3 of M(2), 1 of M(4) and 3 of M(5). The NPM1 gene mutations were found in 7 out of 19 patients with normal karyotype and their incidence was significantly higher than that in patients with karyotype abnormalities (1/14, 7.1%, p < 0.005). The proportion of bone marrow blast cells and the count of peripheral white blood cells in patients with NPMI exon 12 mutation were higher than that in patients with wild type NPMI gene. It is concluded that the occurrence of NPM1 exon 12 mutations is observed more in AML patients with normal karyotype. NPM1 mutant cases are associated with more high amount of boon marrow blast cells and peripheral white blood cell count.