Detection of macular function changes in early (AREDS 2) and intermediate (AREDS 3) age-related macular degeneration.
To evaluate if retinal sensitivity values obtained with a dedicated (screening) device can be used to functionally identify early and intermediate age-related macular degeneration (ARMD). A fully automatic fundus perimeter combined with an image-stabilized scanning laser ophthalmoscope was used in 200 ARMD patients (319 eyes) in 5 study sites. The age-matched control group consisted of 200 normals. Sensitivity point values (S values), mean retinal sensitivity, number of points below 24 dB (K value, cutoff for normal values) and fixation stability were recorded. Of 319 eyes, 164 were classified as early (AREDS 2) and 155 as intermediate (AREDS 3) ARMD. Mean retinal sensitivity was significantly reduced in ARMD patients versus normals (p < 0.001). K values were different between normals and ARMD patients (p < 0.001). Fixation stability did not differ between early and intermediate ARMD patients. Macular sensitivity is reduced in patients with early and intermediate ARMD when compared to age-matched normals. These changes may be detected with a screening device.


Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration.
To develop and characterize a heterozygous knock-in mouse model carrying the 5-bp deletion in Elovl4 (E_mut+/-) and to study the pathology underlying Stargardt-like macular degeneration (STGD3). E_mut+/- mice were generated by targeting a 5-bp deletion (AACTT) in the Elovl4 gene by homologous recombination. E_mut+/- mice of age 2 to 18 months and age-matched wild-type (Wt) littermate control animals were analyzed for the expression of Elovl4 transcript, ELOVL4 protein, photoreceptor-specific genes, and retinal fatty acid composition. Functional retinal changes were evaluated by electroretinography (ERG) and by morphologic and ultrastructural criteria. E_mut+/- mice retinas showed the presence of both Wt and mutant Elovl4 transcripts and proteins. Morphologic evaluation revealed cone photoreceptor ultrastructural abnormalities as early as 2 months of age, accumulation of lipofuscin in retinal pigment epithelium (RPE), and subretinal deposits at later ages. Shortening of rod outer segments (OS) was observed at approximately 10 months of age. Both cone and rod changes progressed with age. Unlike rod-specific genes, expression of selected cone specific genes was significantly reduced by 7 months of age. Mixed rod-cone and light-adapted b-waves were higher than normal at both 8 and 15 months. Levels of the fatty acids 20:5 (P = 0.027), 22:5 (P = 0.040) and 24:6 (P = 0.005) were found to be significantly lower in the retinas of E_mut+/- mice than in retinas of control subjects. E_mut+/- animals display characteristic features associated with Stargardt-like macular degeneration and serve as a model for the study of the mechanism underlying STGD3.


In situ intestinal absorption behaviors of tanshinone IIA from its inclusion complex with hydroxypropyl-beta-cyclodextrin.
In this paper, the intestinal permeability of the inclusion complex of tanshinone IIA (TS IIA) with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was investigated. The corresponding complexation of TS IIA-HP-beta-CD was obtained by coevaporation and characterized by differential scanning calorimetry and X-ray diffraction. The recirculation intestinal perfusion technique in rats was used to study the absorption behavior of free and complexed TS IIA. The change of concentration of TS IIA was separately calculated according to Michaelis-Menten and the Fick's equation to investigate its absorption rate-limiting step. Using the mathematical models above, it was concluded that the limit step to absorption of TS IIA was the dissolution process. Different concentrations of complexed TS IIA were administrated to three intestinal segments, with the intestinal permeability ranging from 3.16x10(-5) cm.s(-1) in the duodenum (50 microg.ml(-1)) to 4.11x10(-5) cm.s(-1) in the jejunum (100 microg.ml(-1)). With the increase of dosage of complex, TS IIA's absorption did not show saturated phenomenon, suggesting its transport mechanism in vivo might primary be passive transport. Besides, the permeability of TS IIA was not apparently influenced by the perfusion section studied, which indicated that there might not exist specific absorption site for TS IIA.


Interleukin 27 Protects From Gastric Atrophy and Metaplasia During Chronic Autoimmune Gastritis.
The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis. We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3-/- mice, which develop gastritis but do not express IL27. In some experiments, mice were given high-dose tamoxifen to induce parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM). Recombinant IL27 was administered to mice with mini osmotic pumps. Stomachs were collected and analyzed by histopathology and immunofluorescence; we used flow cytometry to measure IL27 and identify immune cells that secrete IL27 in the gastric mucosa. Single-cell RNA sequencing was performed on immune cells that infiltrated stomach tissues. We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes. In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell-mediated inflammation in the gastric mucosa.


Cellular responses to enteropathogenic Escherichia coli infection.
Enteropathogenic Escherichia coli (EPEC), first described in the 1940's and 1950's, remain an important cause of severe infantile diarrhoea in many parts of the developing world. EPEC do not produce enterotoxins and are not invasive; instead their virulence depends upon exploitation of host cell signalling pathways and the host cell cytoskeleton both as a means of colonizing mucosal surfaces of the small intestine and causing diarrhoea. Following initial mucosal attachment, EPEC secrete 'signalling' proteins and express a surface adhesin, intimin, to produce 'attaching & effacing' lesions in the enterocyte brush border membrane characterised by localised destruction of brush border microvilli, intimate bacterial adhesion and cytoskeletal reorganisation and accretion beneath attached bacteria. The pathophysiology of EPEC diarrhoea is also complex and probably results from a combination of epithelial cell responses including both electrolyte secretion and structural damage.


A comparison of survey method efficiencies for estimating densities of zebra mussels (Dreissena polymorpha).
Abundance surveys are commonly used to estimate plant or animal densities and frequently require estimating detection probabilities to account for imperfect detection. The estimation of detection probabilities requires additional measurements that take time, potentially reducing the efficiency of the survey when applied to high-density populations. We conducted quadrat, removal, and distance surveys of zebra mussels (Dreissena polymorpha) in three central Minnesota lakes and determined how much survey effort would be required to achieve a pre-specified level of precision for each abundance estimator, allowing us to directly compare survey design efficiencies across a range of conditions. We found that the required sampling effort needed to achieve our precision goal depended on both the survey design and population density. At low densities, survey designs that could cover large areas but with lower detection probabilities, such as distance surveys, were more efficient (i.e., required less sampling effort to achieve the same level of precision). However, at high densities, quadrat surveys, which tend to cover less area but with high detection rates, were more efficient. These results demonstrate that the best survey design is likely to be context-specific, requiring some prior knowledge of the underlying population density and the cost/time needed to collect additional information for estimating detection probabilities.


The care needs and experiences with the use of services of people with young-onset dementia and their caregivers: a systematic review.
In this review, the care needs and experiences with the use of available services of individuals with young-onset dementia (YOD) and their caregivers were investigated. This knowledge is an important prerequisite for the development of appropriate interventions and personalized care to address their specific needs and problems. A systematic literature search was performed in PubMed, Psycinfo and Cinahl. A quality checklist for observational and qualitative studies was used to appraise the methodological quality of the studies. Twenty-seven studies were included, and a synthesis of the literature revealed six themes. The first theme concerned problems in the diagnostic period. Early recognition and referral was reported as an essential area that required improvement in order to obtain appropriate help in time. The second theme discussed the need for information about YOD and the availability of care throughout the caregiving trajectory. The third theme described barriers in access to care that hindered caregivers in finding the right services. The fourth theme showed the availability of appropriate services and specific unmet needs. The fifth theme illustrated that behavioural and personality changes pose a significant challenge for caregivers and other family members. The last theme showed the profound impact of YOD on caregivers. The literature indicates that people with YOD and their caregivers face a wide range of difficulties during the disease process. The reviewed studies provide an important foundation for knowledge and awareness about the specific care needs and experiences of people with YOD and their caregivers. Copyright © 2016 John Wiley & Sons, Ltd.


Stathmin gene family: phylogenetic conservation and developmental regulation in Xenopus.
The ubiquitous cytoplasmic phosphoprotein stathmin was proposed to play a general role as an intracellular relay integrating diverse signals regulating the proliferation, differentiation, and functions of cells (Sobel, A. (1991) Trends Biol. Sci. 16, 301-305). It was originally identified in mammalian cells and tissues, but antibodies directed against the mammalian protein also recognized a stathmin-like 19-kDa protein in all vertebrate classes. The immunoreactive protein in Xenopus laevis displayed, like mammalian stathmin, several nonphosphorylated and phosphorylated heat-soluble forms with distinct migration on two-dimensional polyacrylamide gel electrophoresis. Screening of Xenopus oocyte and brain cDNA libraries with a rat stathmin cDNA probe allowed us to isolate several stathmin-related cDNA clones, among which clone XO35 encodes the Xenopus homologue of stathmin whose deduced amino acid sequence is 79% identical to and displays most of the characteristic structural features of the mammalian protein. In particular, one of the cAMP-dependent protein kinase and the two "proline-directed" kinase-specific sites known to be phosphorylated in rat stathmin are also present in the Xenopus protein. Furthermore, two other sets of clones coding for related proteins belonging to the stathmin gene family were also isolated; clone SC15 encodes the Xenopus homologue of SCG10, a rat protein specifically related to neuronal differentiation; clone XB3 encodes a protein which, as SCG10 or SC15, possesses a stathmin-like domain and an additional N-terminal extension but is more distant from SCG10 than SC15. Interestingly, the mRNA transcripts of Xenopus stathmin (XO35) appear ubiquitous, like stathmin in mammals, whereas the SC15 and XB3 mRNAs appeared as markers of the nervous tissue in Xenopus. During Xenopus oogenesis, stathmin accumulates and remains stable as a maternal product throughout early development. Concurrently, its phosphorylation is regulated from essentially unphosphorylated forms to highly phosphorylated ones in the mature egg, which are then progressively dephosphorylated again from the midblastula to the tailbud stage. Altogether, our results demonstrate the high evolutionary conservation of stathmin together with the members of its related gene family, not only at the level of their molecular structures, but also of their biochemical and biological regulation. These observations are thus further in favor of a very general and likely essential role of stathmin in the normal control of cells throughout development and in the adult.


Definitive treatment of combat casualties at military medical centers.
More than 9,000 casualties have been evacuated during the current conflict, and more than 40,000 orthopaedic surgical procedures have been performed. The most severely injured patients are treated in the United States at military medical centers. Individualized reconstructive plans are developed, and patients are treated with state-of-the-art techniques. Rehabilitation includes the assistance of the physical medicine and rehabilitation, physical therapy, and occupational therapy services, as well as, when necessary, psychiatric or other services. The extreme challenges of treating war-related soft-tissue defects include neurovascular injuries, burns, heterotopic ossification, infection, prolonged recovery, and persistent pain. Such injuries do not allow full restoration of function. Because of such devastating injuries, and despite use of up-to-date methods, outcomes can be less than optimal.


Risk of Postoperative Complications Among Inflammatory Bowel Disease Patients Treated Preoperatively With Vedolizumab.
Vedolizumab is increasingly used to treat patients with ulcerative colitis (UC) and Crohn's disease (CD), however, its safety during the perioperative period remains unclear. We compared the 30-day postoperative complications among patients treated preoperatively with vedolizumab, anti-tumor necrosis factor (TNF)-α agents or non-biological therapy. The retrospective study cohort was comprised of patients receiving vedolizumab, anti-TNF-α agents or non-biological therapy within 4 weeks of surgery. The rates of 30-day postoperative complications were compared between groups using univariate and multivariate analysis. Propensity score-matched analysis was performed to compare the outcome between groups. Among 443 patients (64 vedolizumab, 129 anti-TNF-α agents, and 250 non-biological therapy), a total of 144 patients experienced postoperative complications (32%). In multivariate analysis, age >65 (odds ratio (OR) 3.56, 95% confidence interval (CI) 1.30-9.76) and low-albumin (OR 2.26, 95% CI 1.28-4.00) were associated with increased risk of 30-day postoperative complications. For infectious complications, steroid use (OR 3.67, 95% CI 1.57-8.57, P=0.003) and low hemoglobin (OR 3.03, 95% CI 1.32-6.96, P=0.009) were associated with increased risk in multivariate analysis. Propensity score matched analysis demonstrated that the risks of postoperative complications were not different among patients preoperatively receiving vedolizumab, anti-TNF-α agents or non-biological therapy (UC, P=0.40; CD, P=0.35). In the present study, preoperative vedolizumab exposure did not affect the risk of 30-day postoperative complications in UC and CD. Further, larger studies are required to confirm our findings.


Intimacy and the life cycle in the marital relationships of the Scottish elite during the long eighteenth century.
Traditionally marriage has been treated as one step in the life cycle, between youth and old age, singleness and widowhood. Yet an approach to the life cycle that treats marriage as a single step in a person's life is overly simplistic. During the eighteenth century many marriages were of considerable longevity during which time couples aged together and power dynamics within the home were frequently renegotiated to reflect changing circumstances. This study explores how intimacy developed and changed over the life cycle of marriage and what this meant for power, through a study of the correspondence of two elite Scottish couples.


Analysis of expression and structure of the TSG101 gene in cervical cancer cells.
Human papillomavirus (HPV)-mediated transformation of human epithelial cells has been recognized as a multi-step process in which additional unknown factors and (epi)genetic events are required. The tumor susceptibility gene 101 (TSG101) was discovered in mouse NIH3T3 fibroblast cells as a gene whose functional knockout leads to transformation. TSG101 protein is involved in a variety of important biological functions, such as ubiquitination, transcriptional regulation, endosomal trafficking, virus budding, proliferation and cell survival. It is suggested that TSG101 is an important factor for maintaining cellular homeostasis and that perturbation of TSG101 functions leads to cell transformation. Interestingly, a recent report showed up- or down-regulation of TSG101 in several human malignancies. At present, the role of TSG101 in cervical tumorigenesis is unexplained. TSG101 expression in tumors, where carcinogenesis is connected with viral infection, and a mechanism of TSG101 expression regulation in cancer cells are also unknown. The aim of our study was to estimate the TSG101 mRNA and protein level in cervical cancer and non-tumor epithelial cells. We also analyzed the TSG101 coding and promoter sequence using the PCR-SSCP technique and methylation pattern of the TSG101 promoter. Our real-time PCR and Western blot analysis showed decreased TSG101 mRNA and protein level in cervical cancer tissue in comparison to normal (non-tumor) HPV(-) and HPV16(+) epithelial cells. Our results suggest that TSG101 down-regulation in cervical cancer cells is not regulated by genetic or epigenetic events. However, we detected novel single nucleotide polymorphisms in the promoter of this gene.


Glyoxylate cycle in toad urinary bladder: possible stimulation by aldosterone.
A homogenate of the toad urinary bladder epithelial cell layer has the two enzymatic activities unique to the glyoxylate cycle--isocitrate lyase (threo-Ds-isocitrate glyoxylate-lyase, EC 184.108.40.206) and malate synthase [L-malate glyoxylate-lyase (CA-acetylating), EC 184.108.40.206]--as well as the capacity to carry out CN-insensitive palmitoyl-CoA oxidation. When tissue is incubated in the presence of a fatty acid substrate, tissue glycogen levels increase. Additionally, in the presence of aldosterone, glycogen levels are higher. These data demonstrate the presence of glyoxylate cycle enzymes in tissue of a higher animal and raise the possibility that such tissue can convert lipid to carbohydrate.


Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling.
Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174.


[Application prospects of structure-function studies of gonadotropins].
The study of the respective roles of the polypeptide and oligosaccharide parts of gonadotropins in their biological activities has been undertaken for many years through chemical and enzymatic modifications of natural hormones, expression of wild-type and mutated recombinant hormones and synthesis of active peptides. The present paper proposes a short summary of the future application prospects of these studies as undertaken in our laboratory.


Acrosome reaction induced by recombinant human zona pellucida 3 peptides rhuZP3a22 approximately 176 and rhuZP3b177 approximately 348 and their mechanism.
To explore the biological characteristics of the recombinant zona pellucida 3 (ZP3) peptides of rhuZP3a22 approximately 176 and rhuZP3b177 approximately 348, we examined whether rhuZP3a22 approximately 176 or rhuZP3b177 approximately 348 trigger the acrosome reaction (AR) of human spermatozoa and we investigated the underlying mechanism. The assessment of AR was performed using chlortetracycline staining. The intracellular free calcium concentration ([Ca2+]i) in Fura-2/AM-loaded human sperm was monitored with a spectrofluorophotometer. We found that rhuZP3a22 approximately 176 and rhuZP3b177 approximately 348 were capable of eliciting AR at different concentrations. With the addition of either peptide, the [Ca2+]i level was raised to a peak with or without a plateau. The AR could be inhibited by pertussis toxin (PTX), EGTA, and pimozide (a T-type calcium channel blocker), whereas verapamil was less effective in this regard. The results of the present study suggest that peptides rhuZP3a22 approximately 176 and rhuZP3b177 approximately 348 have a role similar to human ZP3, and that the mechanism of the response to the peptides involves influx of calcium, the G protein pathway, and a T-type calcium channel.


Predicting and forecasting the impact of local outbreaks of COVID-19: use of SEIR-D quantitative epidemiological modelling for healthcare demand and capacity.
The world is experiencing local/regional hotspots and spikes in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19 disease. We aimed to formulate an applicable epidemiological model to accurately predict and forecast the impact of local outbreaks of COVID-19 to guide the local healthcare demand and capacity, policy-making and public health decisions. The model utilized the aggregated daily COVID-19 situation reports (including counts of daily admissions, discharges and bed occupancy) from the local National Health Service (NHS) hospitals and COVID-19-related weekly deaths in hospitals and other settings in Sussex (population 1.7 million), Southeast England. These data sets corresponded to the first wave of COVID-19 infections from 24 March to 15 June 2020. A novel epidemiological predictive and forecasting model was then derived based on the local/regional surveillance data. Through a rigorous inverse parameter inference approach, the model parameters were estimated by fitting the model to the data in an optimal sense and then subsequent validation. The inferred parameters were physically reasonable and matched up to the widely used parameter values derived from the national data sets by Biggerstaff M, Cowling BJ, Cucunubá ZM et al. (Early insights from statistical and mathematical modeling of key epidemiologic parameters of COVID-19, Emerging infectious diseases. 2020;26(11)). We validate the predictive power of our model by using a subset of the available data and comparing the model predictions for the next 10, 20 and 30 days. The model exhibits a high accuracy in the prediction, even when using only as few as 20 data points for the fitting. We have demonstrated that by using local/regional data, our predictive and forecasting model can be utilized to guide the local healthcare demand and capacity, policy-making and public health decisions to mitigate the impact of COVID-19 on the local population. Understanding how future COVID-19 spikes/waves could possibly affect the regional populations empowers us to ensure the timely commissioning and organization of services. The flexibility of timings in the model, in combination with other early-warning systems, produces a time frame for these services to prepare and isolate capacity for likely and potential demand within regional hospitals. The model also allows local authorities to plan potential mortuary capacity and understand the burden on crematoria and burial services. The model algorithms have been integrated into a web-based multi-institutional toolkit, which can be used by NHS hospitals, local authorities and public health departments in other regions of the UK and elsewhere. The parameters, which are locally informed, form the basis of predicting and forecasting exercises accounting for different scenarios and impacts of COVID-19 transmission.


Evidence for pyroglutamyl peptidase I and prolyl endopeptidase activities in the rat insulinoma cell line RINm 5F: lack of relationship with TRH metabolism.
Thyrotropin-Releasing hormone (TRH)-degrading pyroglutamyl peptidase I (PGP I) and prolylendopeptidase (PE) activities have been demonstrated in rat insulinoma RINm 5F cell line. These two enzymes catalyze the conversion of TRH to Histydyl-Proline-Diketopiperazine and to acid TRH respectively. After cell fractionation, we found all the PGP I and PE activities in the cytosolic fraction. The membrane-bound PGP II activity is not detectable in the RINm 5F cells. Further investigations on these two cytosolic enzymes show that pyroglutamyl- and proline-containing peptides are inhibitors of each TRH-degrading enzyme. Gel filtration chromatography on Sephadex G100 shows that PGP I and PE activity have an apparent molecular mass of about 18 kDa and 57 kDa, respectively. Kinetic analysis with TRH as substrate, gives a Km of 44 microM and 235 microM, and a Vmax of 1.49 and 8.80 pmol/min/micrograms protein for PGP I and PE, respectively. Immunoreactive TRH, His-Pro-Diketopiperazine and acid TRH levels in the cell line extracts are 2.2 +/- 0.9, 22.5 +/- 11.1 and 28.7 +/- 14.6 pg/1O6 cells, respectively. When cells have been incubated for 2 to 72 hours with a P.E. inhibitor (Z-Gly-Pro-CHN2) at 5 x 10(-7) M, both cell PGP I and PE activities are inhibited. No change in the cellular content of immunoreactive TRH, His-Pro-Diketopiperazine and acid TRH have been observed in treated cells.(ABSTRACT TRUNCATED AT 250 WORDS)


[Population pharmacokinetics of vancomycin from severe in patients with lower respiratory tract infection].
Objective: To develop a population pharmacokinetic (PPK) model of vancomycin in Chinese inpatients with severe lower respiratory tract infection. Methods: We gathered serum concentrations of vancomycin from inpatients who received vancomycin during Nov 2011 to Nov 2012.Vancomycin serum concentrations was measured by high performance liquid chromatography. Vancomycin PPK analysis was performed using nonlinear mixed effects model (NONMEM) program. Results: We gathered the data of 70 inpatients with lower respiratory tract infection at respiratory ward or respiratory intensive care unit(RICU) between Nov 2011 to Nov 2012 [58 males, 12 females; 78(23-91) years old; the mean of APACHⅡ score was 16.4±4.8]. A total of 267 concentrations of vancomycin were gathered from 70 patients. A 2-compartment model fit the concentration data best. The final vancomycin PPK model was: CL(i)=1.67×e(η1), V(1i)=33.04×[1-0.199×(60/Scr)] ×e(η2), Q(i)=7.08×2.053(AI)×e(η3), V(2i)=19.29×e(η4).(CL: vancomycin clearance; V(1): distribution volume of the central compartment; Q: intercompartment clearance; V(2): distribution volume of the intercompartment). The population mean values were 1.67 L/h, 33.04 L; 7.08 L/h and 19.29 L respectively. Serum creatinine was the covariate to affect vancomycin apparent distribution volume of the central compartment. Intercompartment clearance was 2.053 times larger in patients with albumin infusion than that in patients without. Conclusions: We found that a 2-compartment model fit the concentration data best in Chinese patients with severe lower respiratory tract infection. Serum creatinine and albumin infusion were the most significant covariates to affect vancomycin PK.


Performance and microbial diversity of a membrane bioreactor treating real textile dyeing wastewater.
The textile industry is one of the major industries of Taiwan but unfortunately it produces toxic and low biodegradable wastewater. To remedy this problem, this study compared the performance of the membrane bioreactor (MBR) and sequencing batch reactor (SBR) processes for treating real textile dyeing wastewater. The microbial diversity of the MBR process was also identified by a combination of culturing methods and molecular biotechnology. The removal efficiencies of the MBR process for color, COD, BOD, and SS were 54, 79, 99, and 100%, respectively, all higher than the corresponding parameters for the SBR process: i.e., 51, 70, 96, and 60%. All the above four parameters for the MBR effluent meet the criteria of the Taiwan EPA, while on the other hand, for the SBR process, only color and COD meet the Taiwan EPA effluent criteria. Furthermore, the genus Microbacterium, in particular Microbacterium aurum, was the most predominant population, accounting for 70.6% of the total isolates, and might be responsible for the degradation of the dyeing wastewater. Another two textile dyeing degradation bacteria, Paenibacillus azoreducens and Bacillus sp., were also observed as predominant bacteria in MBR sludge.


Refined Calibration Model for Improving the Orientation Precision of Electron Backscatter Diffraction Maps.
For the precise determination of orientations in polycrystalline materials, electron backscatter diffraction (EBSD) requires a consistent calibration of the diffraction geometry in the scanning electron microscope (SEM). In the present paper, the variation of the projection center for the Kikuchi diffraction patterns which are measured by EBSD is calibrated using a projective transformation model for the SEM beam scan positions on the sample. Based on a full pattern matching approach between simulated and experimental Kikuchi patterns, individual projection center estimates are determined on a subgrid of the EBSD map, from which least-square fits to affine and projective transformations can be obtained. Reference measurements on single-crystalline silicon are used to quantify the orientation errors which result from different calibration models for the variation of the projection center.


Halting in Single Word Production: A Test of the Perceptual Loop Theory of Speech Monitoring.
The perceptual loop theory of speech monitoring (Levelt, 1983) claims that inner and overt speech are monitored by the comprehension system, which detects errors by comparing the comprehension of formulated utterances to originally intended utterances. To test the perceptual loop monitor, speakers named pictures and sometimes attempted to halt speech in response to auditory (Experiments 1 and 3) or visual (Experiments 2, 4, and 5) words that differed from the picture name. These stop-signal words were varied in terms of their semantic or phonological similarity to the intended word. The ability to halt word production was sensitive to phonological similarity and, in Experiment 5, to emotional valence, but not to semantic similarity. These results suggest that the perceptual loop detects errors by making comparisons at a level where phonological knowledge is represented. These data also imply that dialogue, back channeling, and other areas where speech production is affected by simultaneous comprehension may operate based on phonological comparisons.


[Arrhythmia-induced dilated cardiomyopathies].
Arrhythmic cardiomyopathies are due to ventricular dysfunction following prolonged or chronic tachycardia; the clinical pictures one of congestive heart failure, which is totally reversible after the treatment of tachycardia and the restoration of sinus rhythm. Since Whipple's first description of this model of heart failure, several teams have shown that ventricular or atrial pacing at rates exceeding 220 beats per minute produces a profound and largely reversible depression of ventricular function, and a constellation of neuroendocrine abnormalities and metabolic, electrophysiological and anatomic alterations of the myocardium. The associated heart failure generally starts to improve within days of achieving ventricular rhythm control, but clinical recovery may take several weeks or months. All forms of chronic tachycardia may induce heart failure, but the onset of cardiomyopathy depends more on the heart rate and the duration of the arrhythmia than on its type. The pathophysiological mechanisms are multiple and complex, and include abnormalities in the structure and function of cardiomyocytes and disturbances in excitation-contraction coupling. Treatment consists of restoring and maintaining sinus rhythm, or at least of controlling the ventricular rate. Because of its curative effect, selective radiofrequency ablation is the treatment of choice when the arrhythmogenic substrate is localized. Control of the ventricular rate by radiofrequency modification of atrioventricular conduction is the treatment of choice for chronic atrial fibrillation.


Selective Inhibition of ADAM17 Efficiently Mediates Glycoprotein Ibα Retention During Ex Vivo Generation of Human Induced Pluripotent Stem Cell-Derived Platelets.
Donor-independent platelet concentrates for transfusion can be produced in vitro from induced pluripotent stem cells (iPSCs). However, culture at 37°C induces ectodomain shedding on platelets of glycoprotein Ibα (GPIbα), the von Willebrand factor receptor critical for adhesive function and platelet lifetime in vivo, through temperature-dependent activation of a disintegrin and metalloproteinase 17 (ADAM17). The shedding can be suppressed by using inhibitors of panmetalloproteinases and possibly of the upstream regulator p38 mitogen-activated protein kinase (p38 MAPK), but residues of these inhibitors in the final platelet products may be accompanied by harmful risks that prevent clinical application. Here, we optimized the culture conditions for generating human iPSC-derived GPIbα+ platelets, focusing on culture temperature and additives, by comparing a new and safe selective ADAM17 inhibitor, KP-457, with previous inhibitors. Because cultivation at 24°C (at which conventional platelet concentrates are stored) markedly diminished the yield of platelets with high expression of platelet receptors, 37°C was requisite for normal platelet production from iPSCs. KP-457 blocked GPIbα shedding from iPSC platelets at a lower half-maximal inhibitory concentration than panmetalloproteinase inhibitor GM-6001, whereas p38 MAPK inhibitors did not. iPSC platelets generated in the presence of KP-457 exhibited improved GPIbα-dependent aggregation not inferior to human fresh platelets. A thrombus formation model using immunodeficient mice after platelet transfusion revealed that iPSC platelets generated with KP-457 exerted better hemostatic function in vivo. Our findings suggest that KP-457, unlike GM-6001 or p38 MAPK inhibitors, effectively enhances the production of functional human iPSC-derived platelets at 37°C, which is an important step toward their clinical application. Stem Cells Translational Medicine 2017;6:720-730.


Comparison of longitudinal phenotypes based on number and timing of assessments: a systematic comparison of trajectory approaches II.
The popularity of trajectory-based research to characterize developmental courses of alcohol (and other drug) involvement is growing rapidly. Given the increasing use of these methods, there is a need to identify methodological factors that affect course shape and prevalence. Using growth mixture models, the authors characterized the developmental course of 2 indices of alcohol involvement, alcohol use disorder and frequency of heavy drinking, with a prospective sample of 489 young adults (Year 1 age = 18.52; 55% female; 51% with family history of alcoholism) assessed 6 times over 11 years. Then, the authors explored the extent to which trajectory models that eliminated an assessment (at the beginning, middle, or end of the study interval) were similar to the full 6-wave model. Although classifications showed relatively high concordance, trajectory shape and predicted prevalences varied. Misclassification was associated with methodological factors such as probability of class membership and missing data. Findings suggest that researchers thoughtfully consider the nature of the phenomena being studied and the developmental period of interest when designing prospective studies.


Anti-G protein antibodies targeting the RSV G protein CX3C chemokine region improve the interferon response.
Respiratory syncytial virus (RSV) is a poor inducer of antiviral interferon (IFN) responses which result in incomplete immunity and RSV disease. Several RSV proteins alter antiviral responses, including the non-structural proteins (NS1, NS2) and the major viral surface proteins, that is, fusion (F) and attachment (G) proteins. The G protein modifies the host immune response to infection linked in part through a CX3 C chemokine motif. Anti-G protein monoclonal antibodies (mAbs), that is, clones 3D3 and 2D10 that target the G protein CX3C chemokine motif can neutralize RSV and inhibit G protein-CX3CR1 mediated chemotaxis. Determine how monoclonal antibodies against the RSV F and G proteins modify the type I and III IFN responses to RSV infection. As the G protein CX3 C motif is implicated in IFN antagonism, we evaluated two mAbs that block G protein CX3C-CX3CR1 interaction and compared responses to isotype mAb control using a functional cellular assay and mouse model. Mouse lung epithelial cells (MLE-15 cells) and BALB/c mice were infected with RSV Line19 F following prophylactic mAb treatment. Cell supernatant or bronchoalveolar lavage fluid (BALF) were assayed for types I and III IFNs. Cells were interrogated for changes in IFN-related gene expression. Treatment with an anti-G protein mAb (3D3) resulted in improved IFN responses compared with isotype control following infection with RSV, partially independently of neutralization, and this was linked to upregulated SOCS1 expression. These findings show that anti-G protein antibodies improve the protective early antiviral response, which has important implications for vaccine and therapeutic design. RSV is a leading cause of respiratory disease in infants and the elderly. The only Food and Drug Administration-approved prophylactic treatment is limited to an anti-F protein monoclonal antibody (mAb), that is, palivizumab which has modest efficacy against RSV disease. Accumulating evidence suggests that targeting the RSV attachment (G) protein may provide improved protection from RSV disease. It is known that the G protein is an IFN antagonist, and IFN has been shown to be protective against RSV disease. In this study, we compared IFN responses in mouse lung epithelial (MLE-15) cells and in mice infected with RSV Line19 F treated with anti-G protein or anti-F protein mAbs. The levels of type I and III IFNs were determined. Anti-G protein mAbs improved the levels of IFNs compared with isotype-treated controls. These findings support the concept that anti-G protein mAbs mediate improved IFN responses against RSV disease, which may enable improved treatment of RSV infections.


Esketamine Nasal Spray for the Rapid Reduction of Depressive Symptoms in Major Depressive Disorder With Acute Suicidal Ideation or Behavior.
Numerous health authority approvals of esketamine nasal spray, combined with oral antidepressant, to treat depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior were based on 2 identically designed, double-blind, phase 3 studies. Across both ASPIRE studies (NCT03039192, NCT03097133), patients (N = 456) were randomized to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks plus comprehensive standard of care, including hospitalization and newly initiated or optimized antidepressant(s). In post hoc analyses of pooled data, changes from baseline at 24 hours after the first dose in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity of Suicidality-Revised, in the full cohort and in subgroups, were analyzed using analysis of covariance. Esketamine plus standard of care demonstrated significantly greater improvement in Montgomery-Åsberg Depression Rating Scale total score versus placebo plus standard of care at 24 hours (least square mean difference [95% confidence interval], -3.8 [-5.75 to -1.89]) and at earlier (4 hours: -3.4 [-5.05 to -1.71]) and later time points (day 25: -3.4 [-5.36 to -1.36]). The between-group difference (95% confidence interval) for change in Clinical Global Impression-Severity of Suicidality-Revised at 24 hours was -0.20 (-0.43 to 0.04) for all patients and -0.31 (-0.61 to -0.01) for those with a history of suicide attempt. Common adverse events (≥20%) during esketamine treatment were dizziness, dissociation, nausea, somnolence, and headache. Esketamine plus comprehensive standard of care rapidly reduces depressive symptoms in patients with major depressive disorder who have acute suicidal ideation or behavior, especially in those with a history of suicide attempt, providing a new treatment option for this particularly ill and vulnerable population.


Clinical and echocardiographic features of children with rheumatic heart disease and their serum cytokine profile.
Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) constitute important public health problems in developing countries. Children with ARF and RHD seen at Children's Hospital-Sudan from May 2008-2009 were examined clinically and by echocardiography. Blood cytokines (interleukin 10 (IL10), Tumor necrosis factor alpha (TNF- alpha) and interferon gamma (IFN-gamma) were done. Thirty six children were enrolled; 63% had established RHD, and 37% ARF. Mitral regurgitation (MR) was the most common lesion (94%).Ninety five percent of the valve lesions were severe. The serum interleukin IL10 level ranged between 3-6 pg/ml. TNF alpha levels were 9- 100 pg/ml in 12 patients (40%), 101-1000 pg/ml in 10 patients (33%), more than 1000 in 8 patients (26%). The level of IFN gamma ranged between 2-7 pg/m in all patients except 2 (84 and 135 pg/ml). RHD is manifested with severe valvular lesions and a high TNF alpha indicating and ongoing inflammation.


Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers.
To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib. A single dose of 12 mg copanlisib containing 2.76 MBq [14C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days. Blood, plasma, urine and feces were collected to monitor total radioactivity, parent compound and metabolites. Copanlisib treatment was well tolerated. Copanlisib was rapidly distributed throughout the body with a volume distribution of 1870 L and an elimination half-life of 52.1-h (range 40.4-67.5-h). Copanlisib was the predominant component in human plasma (84% of total radioactivity AUC) and the morpholinone metabolite M1 was the only circulating metabolite (about 5%). Excretion of drug-derived radioactivity based on all 6 subjects was 86% of the dose within a collection interval of 20-34 days with 64% excreted into feces as major route of elimination and 22% into urine. Unchanged copanlisib was the main component excreted into urine (15% of dose) and feces (30% of dose). Excreted metabolites (41% of dose) of copanlisib resulted from oxidative biotransformation. Copanlisib was eliminated predominantly in the feces compared to urine as well as by hepatic biotransformation, suggesting that the clearance of copanlisib would more likely be affected by hepatic impairment than by renal dysfunction. The dual mode of elimination via unchanged excretion of copanlisib and oxidative metabolism decreases the risk of clinically relevant PK-related drug-drug interactions.


Localized prior knowledge and optimal interpolation in high-resolution tomography.
The problem of electromagnetic tomographic reconstruction is approached in terms of the derivation of a minimum norm interpolator, incorporating a priori knowledge gained from a previous reconstruction. An algorithm is suggested for the initial estimate and both images are compared to that of bilinear interpolation.


Modified Peroral Endoscopic Myotomy Technique for Type II Achalasia: A Multicenter Retrospective Study.
This retrospective study is aimed at evaluating the outcomes of a modified peroral endoscopic myotomy (POEM) technique in patients with type II achalasia. We performed a modified POEM procedure, which involved a shorter (total myotomy length = 4 cm), full-thickness myotomy, on 31 patients with type II achalasia. Clinical success rates, technical success rates, pre- and postoperative esophageal manometry results, complications, and reflux-related adverse events were evaluated. The clinical success (Eckardt score ≤ 3) rates were 100% and 88.9% within 2 years and beyond 2 years postoperatively, respectively. The median lower esophageal sphincter pressures (LESP) decreased from 31.6 (26.7-49.7) mmHg preoperatively to 13.4 (10.5-21.6) and 11.8 (7.4-16.7) mmHg (P < 0.001) at 6 and 12 months postoperatively, respectively. The median integrated relaxation pressure (IRP) decreased from 27.8 (20.6-37.5) mmHg preoperatively to 12.9 (11.3-23.4) and 11.6 (9.6-16.8) mmHg (P < 0.001) at 6 and 12 months after POEM, respectively. Only one case (3.2%) of mucosal injury, four (12.9%) cases of reflux esophagitis, and two (6.5%) cases of gastroesophageal reflux symptoms were reported. The modified POEM technique showed excellent outcomes in patients with type II achalasia.


Impact of LR11 as Residual Risk on Long-Term Clinical Outcomes in Patients with Coronary Artery Disease Treated with Statins after First Percutaneous Coronary Intervention.
Cardiovascular events still occur despite statin-based lipid-lowering therapy in patients with coronary artery disease (CAD). LR11, a member of the low-density lipoprotein receptor family, is a novel marker for the proliferation of intimal smooth muscle cells, which are critical to atherosclerotic plaque formation. We evaluated the impact of LR11 on long-term clinical outcomes in CAD patients treated with statins after percutaneous coronary intervention (PCI).This study included 223 consecutive CAD patients (age, 64.5 ± 9.6 years; male, 81.2%) treated with statin after first PCI between March 2003 and December 2004 at our institution. Patients were stratified to two groups according to LR11 levels (median). Composite cardiovascular disease (CVD) endpoints that included cardiovascular death, non-fatal acute coronary syndrome and non-fatal stroke were compared between groups.The rate of CVD endpoints was significantly higher in the high LR11 group (log-rank, P = 0.0029) during the median follow-up period of 2844 days. Multivariate Cox regression analysis showed that a higher LR11 level was significantly associated with adverse clinical outcomes (adjusted hazard ratio for composite CVD endpoints, 2.47; 95% confidence interval, 1.29-4.92; P = 0.006).Elevated levels of LR11 were significantly associated with long-term clinical outcomes among CAD patients treated with statins after first PCI.


Mechanism of protein sorting during erythroblast enucleation: role of cytoskeletal connectivity.
During erythroblast enucleation, nuclei surrounded by plasma membrane separate from erythroblast cytoplasm. A key aspect of this process is sorting of erythroblast plasma membrane components to reticulocytes and expelled nuclei. Although it is known that cytoskeletal elements actin and spectrin partition to reticulocytes, little is understood about molecular mechanisms governing plasma membrane protein sorting. We chose glycophorin A (GPA) as a model integral protein to begin investigating protein-sorting mechanisms. Using immunofluorescence microscopy and Western blotting we found that GPA sorted predominantly to reticulocytes. We hypothesized that the degree of skeletal linkage might control the sorting pattern of transmembrane proteins. To explore this hypothesis, we quantified the extent of GPA association to the cytoskeleton in erythroblasts, young reticulocytes, and mature erythrocytes using fluorescence imaged microdeformation (FIMD) and observed that GPA underwent dramatic reorganization during terminal differentiation. We discovered that GPA was more connected to the membrane cytoskeleton, either directly or indirectly, in erythroblasts and young reticulocytes than in mature cells. We conclude that skeletal protein association can regulate protein sorting during enucleation. Further, we suggest that the enhanced rigidity of reticulocyte membranes observed in earlier investigations results, at least in part, from increased connectivity of GPA with the spectrin-based skeleton.


Identification of free-living amoebae and amoeba-associated bacteria from reservoirs and water treatment plants by molecular techniques.
The occurrence of free-living amoebae (FLA) was investigated in 83 water samples from reservoirs and water treatment plants, with culture positive in 64 of them (77.1%). Polymerase chain reaction (PCR) of partial 18S rRNA gene and ITS region was performed in order to identify amoeba isolates, and the presence of Legionella pneumophila , Mycobacterium spp., Pseudomonas spp., and Microcystis aeruginosa was investigated in 43 isolates of amoebae by multiplex PCR. Of the isolated amoebae, 31 were Acanthamoeba spp., 21 were Hartmannella vermiformis, 13 were Naegleria spp., and one was Vanella spp. T2, T4, and T5 genotypes of Acanthamoeba have been identified, and T4 isolates were grouped into five subgenotypes and graphically represented with a Weblog application. Inside amoebae, L. pneumophila was detected in 13.9% (6/43) of the isolates, and Pseudomonas spp. and Mycobacterium spp. were detected in 32.6% (14/43) and 41.9% (18/43), respectively. No statistical correlation was demonstrated between FLA isolation and seasonality, but the presence of intracellular bacteria was associated with warm water temperatures, and also the intracellular presence of Mycobacterium spp. and Pseudomonas spp. were associated. These results highlight the importance of amoebae in natural waters as reservoirs of potential pathogens and its possible role in the spread of bacterial genera with interest in public and environmental health.


[Metastatic Lung Tumor from Papillary Thyroid Carcinoma Suspected of Primary Lung Cancer;Report of Two Cases].
Radiological finding of pulmonary metastasis of thyroid cancer is generally known to be multiple small nodular shadow. We experienced 2 cases of lung solitary tumor, which were suspected of primary lung cancer as differential diagnosis. Patient 1:A 67-year-old man;the tumor obstructed subsegmental bronchus (B10) of the right lobe, and pathological diagnosis by transbronchial biopsy was adeno-squamous carcinoma. Fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) showed abnormal uptake in the tumor and also in the left lobe of his thyroid gland, but no malignant findings were found by the fine-needle aspiration cytology from the thyroid gland. Patient 2:A 51-year-old woman;she had a lobulated nodule in the left lower lobe, which was diagnosed as adenocarcinoma. She had undergone an operation for thyroid cancer about 30 years earlier, but after the operation, there has been no recurrence. In both cases, primary lung cancer were suspected and the tumors were resected surgically. By immunohistochemistry, both tumors were diagnosed as pulmonary metastases from papillary thyroid carcinoma.


Attometer resolution spectral analysis based on polarization pulling assisted Brillouin scattering merged with heterodyne detection.
Spectral analysis is essential for measuring and monitoring advanced optical communication systems and the characterization of active and passive devices like amplifiers, filters and especially frequency combs. Conventional devices have a limited resolution or tuning range. Therefore, the true spectral shape of the signal remains hidden. In this work, a small part of the signal under test is preselected with help of the polarization pulling effect of stimulated Brillouin scattering where all unwanted spectral components are suppressed. Subsequently, this part is analyzed more deeply through heterodyne detection. Thereby, the local oscillator is generated from a narrow linewidth fiber laser which acts also as pump wave for Brillouin scattering. By scanning the pump wave together with the local oscillator through the signal spectrum, the whole signal is measured. The method is tunable over a broad wavelength range, is not affected by unwanted mixing products and utilizes a conventional narrow bandwidth photo diode. First proof of concept experiments show the measurement of the power spectral density function with a resolution in the attometer or lower kilohertz range at 1550 nm.


Construction of Expression Shuttle Vectors for the Haloarchaeon Natrinema sp. J7 Based on Its Chromosomal Origins of Replication.
Haloarchaeon Natrinema sp. J7, the first reported archaeon harboring both plasmid and chromosome-based temperate viruses, is a useful model for investigating archaeal virus-host and virus-virus interactions. However, the lack of genetic tools has limited such studies. On the basis of the automatically replicating sequences of the J7 chromosome and the pyrF marker, we constructed seven vectors, six of which were confirmed to possess replication ability in a pyrF-deletion derivative of J7 (J7-F). Among these vectors, pFJ1, pFJ4, and pFJ6 could be transformed into the host strain with relatively high efficiency (approximately 103 colony-forming units/μg DNA) and were present at about one copy per chromosome. These three vectors could be stably maintained in J7-F without selection and were used for heterologous protein expression. Only pFJ6 was found to be present in the transformed cells in an exclusively episomal, nonintegrated state (one copy per chromosome). In contrast, some pFJ1 and pFJ4 DNA was probably integrated into the J7-F chromosome. In addition, pFJ6 was found to be compatible with pYCJ in J7 cells, suggesting that these two vectors could be used for further studies of virus-virus and virus-host interactions.


The channel kinases TRPM6 and TRPM7 are functionally nonredundant.
TRPM7 and its closest homologue, TRPM6, are the only known fusions of an ion channel pore with a kinase domain. Deletion of TRPM7 in DT40 B-lymphocytes causes growth arrest, Mg(2+) deficiency, and cell death within 24-48 h. Amazingly, in analogy to TRPM6-deficient patients who can live a normal life if provided with a Mg(2+)-rich diet, TRPM7-deficient DT40 B-lymphocytes show wild type cell growth if supplied with 5-10 mm Mg(2+) concentrations in their extracellular medium. Here we have investigated the functional relationship between TRPM6 and TRPM7. We show that TRPM7 deficiency in DT40 cells cannot be complemented by heterologously expressed TRPM6. Nevertheless, both channels can influence each other's biological activity. Our data demonstrate that TRPM6 requires TRPM7 for surface expression in HEK-293 cells and also that TRPM6 is capable of cross-phosphorylating TRPM7 as assessed using a phosphothreonine-specific antibody but not vice versa. TRPM6 and TRPM7 coexpression studies in DT40 B-cells indicate that TRPM6 can modulate TRPM7 function. In conclusion, although TRPM6 and TRPM7 are closely related and deficiency in either one of these molecules severely affects Mg(2+) homeostasis regulation, TRPM6 and TRPM7 do not appear to be functionally redundant but rather two unique and essential components of vertebrate ion homeostasis regulation.


Heart rate variability in patients with different manifestations of gastroesophageal reflux disease.
Autonomic nervous dysfunction has frequently been observed in patients with gastroesophageal reflux diseases (GERD) and impacts the pathogenesis of GERD. However, the characteristics that distinguish between GERD patients with different manifestations remain unknown. To investigate the autonomic nervous function in subgroups of GERD patients. Of the 164 participants in this study, 57 were healthy controls, 34 had non-erosive reflux disease (NERD), 40 had symptomatic esophagitis (SE), and 33 asymptomatic esophagitis (AE). Resting autonomic activity was assessed by measuring the 5-min heart rate variability (HRV) and HRV indices including time-domain parameters (standard deviation of normal-to-normal intervals [SDNN] and root mean square of successive differences [RMSSD]) and frequency-domain parameters (low-frequency power [LF; 0.04-0.15 Hz], high-frequency power [HF; 0.15-0.4 Hz], and LF/HF power ratio). Mental stress was assessed by use of a self-reported questionnaire (Brief Symptom Rating Scale [BSRS]). HF power was (ANOVA, p=0.041) but time-domain parameters, LF power, LF/HF power ratio, and BSRS parameters were not significantly different between the four groups. A higher HF power was found in examinees with NERD than in those with SE and AE (LSD methods: both p=0.02). When split into two groups (erosive vs. non-erosive), nearly all measures of autonomic tonus were significantly lower in the erosive than non-erosive group. Age and the presence of endoscopic esophagitis influenced the RMSSD and HF power results in the regression analysis. Mental stress or gender did not correlate with any HRV index. In comparison with NERD subjects, autonomic tonus in patients with endoscopically confirmed esophagitis (even without symptom) is lower. This finding may suggest that the structural state of esophagus but not symptomatology dictates autonomic function status.


Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia.
T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively active Notch1 activates the NF-kappaB pathway transcriptionally and via the IkappaB kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-kappaB in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-kappaB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These findings identify NF-kappaB as one of the major mediators of Notch1-induced transformation and suggest that the NF-kappaB pathway is a potential target of future therapies of T-ALL.


Reforms and child development.
Since their inception in the 1930s, U.S. welfare and income support programs have played an important role in providing benefits to children. Unlike programs directly targeted to children, however, welfare programs are designed to produce economic and employment impacts on adults, so that any effects on children would be indirect. This article explores the influence of such programs on children's well-being and development, first by defining goals for children's healthy development, then by proposing a framework for understanding the impact of welfare policies on children. A review of the literature within each component of this framework reveals the following: Measures of children's well-being should encompass physical, intellectual, social, and emotional development. The physical and material environment, family environment, and social and community environment can all affect a child's healthy development. Policies designed to increase maternal employment, reduce welfare use, and strengthen families do not necessarily lead to more positive environmental contexts and increased child well-being. The author concludes that to ensure positive impacts on children, welfare and income support policies must move beyond their exclusive emphasis on adults and include goals that focus on improving children's social and physical environments at home and in the community.


Customized cutoff limits for the sediMAX-2 automated analyzer reduce the number of urine culture tests.
Urinary tract infections are highly prevalent in nosocomial and community settings. Their diagnosis, although costly and time-consuming, is crucial to avoid inappropriate treatments and/or clinical complications. In this context, automated analyzers have been developed and commercialized to screen and rule out negative urine samples. Adjustments of the manufacturers' suggested cutoff values might lead to substantial diagnostic and economic advantages. We retrospectively analyzed 776 urine samples from different individuals. 546 samples (training group) were used to optimize develop new cutoffs values. The remaining 230 samples (validation group) were used to validate the optimized cutoffs. All samples were subjected to urine culture, 17% resulted positive. Escherichia coli and Enterococcus faecalis were the two most frequently identified bacteria, 95 and 9 samples, respectively. Two different cutoffs levels were obtained. Cutoff-A (bacteria>110 and/or white blood cells> 15 cell/µL), showed the same sensitivity of the manufacturers' suggested cutoff, yet leads to a large reduction of the samples to be cultured. Cutoff-B (bacteria>50 and/or white blood cells>20 cell/µL), showed an almost 100% sensitivity by subjecting only ~70% of the samples to urine culture. Cutoff-A is a good compromise between sensitivity and specificity yet allowing economic advantages by reducing the number of urinary cultures. Cutoff-B relegates urinary tract infection misdiagnosis to a rare event without the need of culturing the entire batch of samples. We believe that clinical implementation of the proposed cutoffs will help other laboratories, using similar instrumentation, to reach their most convenient balance between sensitivity and economical needs.


Echocardiographic diagnosis of partial obstruction of Blalock-Taussig shunts.
While echocardiography has previously been used to differentiate between patency and complete occlusion of aortopulmonary shunts, the echocardiographic diagnosis of partial obstruction of a shunt has not been reported. We describe a unique color flow Doppler finding that quickly and accurately diagnosed three cases of partial distal obstruction of aortopulmonary shunts.


Cancer and nutritional misconceptions: a perspective.
Misconceptions and disinformation have clouded the relevance of nutritional practices in cancer prevention. This perspective presents data from experimental and human studies, showing that, for most cancers, no convincing evidence exists to incriminate any dietary factor. The relevance of fiber and excess energy intake to the risk of colorectal cancer is also far from established. It is concluded that the significance of dietary factors in cancer prevention, is exaggerated. Even if an association does exist between nutritional practices and the risk for certain cancers, it is very small. As physicians, we should not allow nutritional misconceptions, fads, and belief systems, to mislead the public into wasting billions of dollars for ineffective dietary practices and "nutritional" supplements, in the false hope of cancer prevention.


The homing of human cord blood stem cells to sites of inflammation: unfolding mysteries of a novel therapeutic paradigm for glioblastoma multiforme.
Efficient homing of human umbilical cord blood mesenchymal stem cells (hUCBSC) to inflammation sites is crucial for therapeutic use. In glioblastoma multiforme, soluble factors released by the tumor facilitate the migratory capacity of mesenchymal stem cells toward glioma cells. These factors include chemokines and growth inducers. Nonetheless, the mechanistic details of these factors involved in hUCBSC homing have not been clearly delineated. The present study is aimed to deduce specific factors involved in hUCBSC homing by utilizing a glioma stem cell-induced inflammatory lesion model in the mouse brain. Our results show that hUCBSC do not form tumors in athymic nude mice brains and do not elicit immune responses in immunocompetent SKH1 mice. Further, hUCBSC spheroids migrate and invade glioma spheroids, while no effect was observed on rat fetal brain aggregates. Several cytokines, including GRO, MCP-1, IL-8, IL-3, IL-10, Osteopontin and TGF-β2, were constitutively secreted in the naive hUCBSC-conditioned medium, while significant increases of IL-8, GRO, GRO-α, MCP-1 and MCP-2 were observed in glioma stem cell-challenged hUCBSC culture filtrates. Furthermore, hUCBSC showed a stronger migration capacity toward glioma stem cells in vitro and exhibited enhanced migration to glioma stem cells in an intracranial human malignant glioma xenograft model. Our results indicate that multiple cytokines are involved in recruitment of hUCBSC toward glioma stem cells, and that hUCBSC are a potential candidate for glioma therapy.


Metastatic rectal cancer to papillary thyroid carcinoma: a case report and review of literature.
Tumor-to-tumor metastasis is a rare event. Rectal cancer to primary thyroid neoplasm metastasis is extremely rare. Herein, we reported a case of metastatic rectal adenocarcinoma to a papillary thyroid carcinoma. The incidence and clinicopathological characteristics of metastatic colorectal cancer to a thyroid gland neoplasm were described, and the pertinent literature was reviewed. A 34-year-old female patient had curative treatment of initial rectal adenocarcinoma in 2012, and was found to have lung metastases by follow-up CT scan 3 years later. In 2018, she was found to have thyroid metastasis by imaging due to left neck pain and hoarseness. A fine-needle aspiration biopsy (FNAB) result suggested suspicious papillary thyroid carcinoma (PTC). The patient underwent a total thyroidectomy and bilateral cervical lymph nodes dissection. The histopathology of thyroidectomy specimen revealed a rectal adenocarcinoma metastatic to the thyroid concomitant with the papillary carcinoma in metastatic adenocarcinoma. The patient received levothyroxine supplementation therapy and palliative chemotherapy with irinotecan and anti-angiogenesis for the metastatic rectal adenocarcinoma. After 1 year of thyroidectomy, no newly developed lesion evidence of recurrent PTC was observed. The patient remains still alive. The possibility of metastases should be considered in patients with a history of rectal cancer and with a thyroid lesion, particularly in those with ageing, hereditary nonpolyposis colorectal cancer (HNPCC) or long-term survival. The diagnosis should be histologically confirmed for the presence of both primary thyroid lesions and secondary thyroid neoplasms. Thyroidectomy may be a feasible treatment for symptomatic thyroid metastasis or thyroid cancer. we need to gain more available evidence from large or multi-center clinical data to help clinicians to diagnose rectal cancer to thyroid neoplasm metastases and evaluate treatment.


The mechanism of glucose-induced catecholamine stimulation.
Catecholamines are important hormones for maintaining homeostasis and may be secreted in response to several different stimuli. A report by Robertson and Porte in 1974 made the unexpected observation that acute administration of hypertonic glucose stimulates catecholamine secretion. Our study reassessed this observation by measuring individual catecholamines, explored its potential mechanism, and quantitated it relative to exercise and hypoglycemia-stimulated catecholamine secretion. We hypothesized that the mechanism of glucose-induced catecholamine secretion was related to an acute increase in plasma osmolality, which we tested with the nonmetabolizable hexose mannitol. In 56 studies, 14 normal adults underwent 4 partially randomized studies. The 4 study conditions consisted of the following: (1) rapid intravenous injection of 20 g of glucose; (2) rapid intravenous injection of 20 g of mannitol; (3) acute exercise (80 J/kg); and (4) insulin-induced hypoglycemia. Our results demonstrate that a significant increase in plasma catecholamine concentration occurs following each of the above stimuli, but its composition differs relative to the magnitude of epinephrine versus norepinephrine secretion. We conclude that the mechanism of glucose-induced catecholamine stimulation is the acute elevation in plasma osmolality induced by glucose, and that its stimulation is less than that which occurs following exercise for norepinephrine and less than that which occurs following hypoglycemia for epinephrine.


Comparative study of the cell walls of the yeastlike and mycelial phases of Histoplasma capsulatum.
Cell walls were prepared from the yeastlike and mycelial phases (YP and MP) of Histoplasma capsulatum and from Saccharomyces cerevisiae by mechanical disruption and washing. Lipids were extracted with methanol-ether, chloroform, and acidified methanol:ether; a final extraction was made with ethylenediamine. The lipid contents of H. capsulatum YP and MP walls were about the same. Qualitative and quantitative analyses were made of the products obtained from treatment of the cell walls, or fractions from them, with weak acid or with enzymatic preparations containing glucanase and chitinase activities. YP walls contained much larger quantities of chitin and smaller quantities of mannose and amino acids than the MP walls. H. capsulatum MP was shown to resemble S. cerevisiae by low chitin content and by the presence of a mannose polymer, soluble in ethylenediamine and water. H. capsulatum MP chitin appeared to be intimately associated with glucose in the wall, since enzymatic hydrolysis of the residue after mild acid hydrolysis of cell walls or fractions from them resulted in the release of glucose and acetylglucosamine; only acetylglucosamine was released from YP walls with such treatment. By electron microscopic observations, the unextracted MP cell walls were much thinner than the YP, and neither wall appeared laminated.


A dental-anthropological study of health and illness behaviour among Orang Asli of the Semai Tribe: the perspective of traditional healers.
This observational study investigates and describes the oral health beliefs and illness behaviour in the Semai tribe of Orang Asli community. Data was obtained from a "Key informant interview" method i.e. the village Tok Halaq (Traditional healer). Information about common oral diseases and conditions were illustrated with enlarged pictures of dental caries, periodontal disease, oral cancer and cleft. The most common oral problem was toothache. This is treated by self-medication. However if the pain still persist, the Tok Halaq was consulted to start traditional methods. He will identify the cause. If "germs" were thought to be the cause, he will ask the person to see a doctor. Otherwise, he attempts traditional treatment. If the effort failed after a few days, the person will be advised to see a doctor. It appears that the Tok Halaq plays an influential role in prevention, promotion and the healing process in this community. Hence any effort to promote oral health and prevent oral disease must seek their cooperation. Their beliefs on causes of common oral diseases are described in the text.


An efficient strategy for the synthesis of 1-chloroethyl phosphates and phosphoramidates.
[reaction: see text] A versatile, efficient, and simple method for the preparation of various 1-chloroethyl phosphates and phosphoramidates is described. The protected chlorophosphates or phosphoramidates are synthesized to the vinyl derivative under mild conditions, followed by conversion to the chloroethylidene phosphate or phosphoramidate by dry HCl gas, resulting in good to excellent yields. 1-Chloroethyl phosphates and phosphoramidates are excellent building blocks for the synthesis of novel ethylidene-linked phosphate prodrugs.


Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia.
7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals).


Relationship of quantitative reverse transcription polymerase chain reaction (RT-PCR) to RNA Sequencing (RNAseq) transcriptome identifies mouse preimplantation embryo reference genes†.
Numerous reference genes for use with quantitative reverse transcription polymerase chain reaction (RT-qPCR) have been used for oocytes, eggs, and preimplantation embryos. However, none are actually suitable because of their large variations in expression between developmental stages. To address this, we produced a standardized and merged RNA sequencing (RNAseq) data set by combining multiple publicly available RNAseq data sets that spanned mouse GV oocytes, MII eggs, and 1-cell, 2-cell, 4-cell, 8-cell, morula, and blastocyst stage embryos to identify transcripts with essentially constant expression across all stages. Their expression was then measured using RT-qPCR, with which they did not exhibit constant expression but instead revealed a fixed quantitative relationship between measurements by the two techniques. From this, the relative amounts of total messenger RNA at each stage from the GV oocyte through blastocyst stages were calculated. The quantitative relationship between measurements by RNAseq and RT-qPCR was then used to find genes predicted to have constant expression across stages in RT-qPCR. Candidates were assessed by RT-qPCR to confirm constant expression, identifying Hmgb3 and Rb1cc1 or the geometric mean of those plus either Taf1d or Cd320 as suitable reference genes. This work not only identified transcripts with constant expression from mouse GV oocytes to blastocysts, but also determined a general quantitative relationship between expression measured by RNAseq and RT-qPCR across stages that revealed the relative levels of total mRNA at each stage. The standardized and merged RNA data set should also prove useful in determining transcript expression in mouse oocytes, eggs, and embryos.


Using body diagrams and disease protocols as part of an integrated approach to the medical consultation in Nepal.
Neither medical assistants nor doctors in Nepal receive adequate training in medical consultation techniques. Patients often leave the consultation with poor understanding of their disease. Moreover, disease management counselling and preventative health counselling are rarely done. In order to address these issues, simple body diagrams and disease protocols were developed and tested in a random cohort survey of 300 outpatients. While 72% of patients who were shown a body diagram achieved basic understanding of their disease, only 38% of patients who were not shown a body diagram understood their disease. This improvement was significant and independent of other factors. Satisfactory disease management counselling was given in 38% of cases, and preventative health counselling in 36%. There was correlation between use of body diagrams and provision of disease management counselling and preventative health counselling. These findings emphasize the need for simple consultation tools such as body diagrams and disease management protocols in developing countries.


A reexamination of the hypoglycemia-aggression hypothesis in laboratory mice.
The suggestion of a clinical link between hypoglycemia and aggression has been recently encouraged by the work of Virkkunen and others. Modern techniques have impressively established a correlation between reactive hypoglycemia (low blood sugar levels engendered by stimulation of endogenous insulin secretion) and hostility as expressed in a variety of situations. It is not surprising that blood sugar levels influence behavior, as the brain is entirely dependent on glucose reaching it via the vascular system. In spite of this impressive link, there are remarkably few successful studies involving the effects of manipulating glucose levels on fighting in infrahuman animals. As there have been several methodological developments in this area it was thought appropriate to reinvestigate such phenomena in mice. The effects of injected bovine insulin and glucose were assessed using an ethopharmacological methodology applied to social encounters by isolated male Swiss mice with docile anosmic opponents. Although manipulation of blood glucose levels did not consistently change attack or defensive behavior, these treatments did modify aspects of the interactions.


Developmental changes in lactate dehydrogenase and aldolase activity of the A2G-adr mouse with abnormal muscle function: further comparison with the 129Re-dy mutant.
Lactate dehydrogenase and aldolase activity were reduced in lateral gastrocnemius muscle from two mouse mutants, A2G-adr and 129Re-dy, with abnormal muscle function. The activities of both of these enzymes were significantly reduced in the lateral gastrocnemius muscle from the A2G-adr mice at ages varying from 2 weeks to 32 weeks, whereas the activities in the soleus, heart, liver, and brain were the same as in the control animals. The lactate dehydrogenase isoenzymes in the lateral gastrocnemius and soleus muscles from the A2G mice were quantified, and although those of the soleus were comparable in mutant and control muscle, the lateral gastrocnemius from the adr mutant had reduced activity of LDH 5 and increased activities of the other four isoenzymes. The findings suggest that the adr mutation is expressed in the white (Type II) muscle fibres and not in the red (Type I) fibres or in any of the organs studied. It is suggested that the initiation of differentiation into Type II fibres from the embryonic form is absent or delayed in the A2G mutant. The reduced activities of lactate dehydrogenase and aldolase in 129Re-dy muscle confirm the findings of other workers.


Cyanobacteria in Antarctica: ecology, physiology and cold adaptation.
Cyanobacterial species composition of fresh water and terrestrial ecosystems and chemical environment of water in Schirmacher Oasis in Continental Antarctica was investigated. Over 35 species of cyanobacteria were recorded. Diazotrophic species both heterocystous and unicellular contributed more than half to the count except in lake ecosystem. The species composition varied among the fresh water as well as terrestrial ecosystems. The physico-chemical analyses of water revealed its poor nurient content which might have supported the growth of diazotrophic cyanobacteria in an Antarctic environment. Among the cyanobacteria Oscillatoria, Phormidium and Nostoc commune were the dominant flora in most of the habitats. The physiological characteristics of isolated cyanobacteria strains indicated that N2-fixation, nitrate uptake, nitrate-reduction, ammonium-uptake, GS-transferase activity and photosynthesis was unaffected at low temperature (5 degrees C) which indicated low temperature adaptation for Antarctic cyanobacteria. This phenomenon was not evident in different strains of tropical origin. The temperature optima for N2-fixation for the different Antarctic cyanobacterial strains was in the range of 15-25 degrees C, nearly 10 degrees C lower than their respective reference strains of tropical origin. Similar results were obtained for cyanobacteria-moss association. The low endergonic activation energy exhibited by the above metabolic activities supported the view that cyanobacteria were adapted to Antarctic ecosystem.


[Nursing management of neonatal opiate abstinence syndrome].
Caring for infants with neonatal opiate abstinence syndrome is a challenge for nursing staff. These infants are at high risk for many complications. Nurses should be aware of the influences on neonates of maternal opium addiction during pregnancy. This article discusses clinical manifestations of neonatal opiate abstinence syndrome, common assessment tools for neonatal abstinence syndrome, and a variety of medical treatments and nursing interventions. In order to obtain adequate medical care for the neonates and safely alleviate their neonatal abstinence system, nurses should develop a comprehensive discharge plan and seek community support for the neonate's family.


On radar and radio exposure and cancer in the military setting.
In 2018, we reported a case series of 47 patients diagnosed with cancer following several years of exposure to high-intensity whole-body radiofrequency radiation (RFR) using the parameter of percentage frequency (PF). Consistent high and statistically significant PFs of hematolymphoid (HL) cancers were found in this group and in four previous reports on RFR-exposed groups in Belgium, Poland and Israel together with increased all-cancers rates. In this paper we report a new series of 46 young cancer patients who were exposed during military service to such radiation. The new group of patients comprises Israeli soldiers previously exposed to occupational RFR. The patients were self-selected to enroll in the research in cooperation with an NGO assisting patients with administrative counseling and legal and social services. The new group of patients was studied with respect to distribution (proportion) of cancer types using the method of PF. When possible, cancer risk ratios (RR) were estimated too. The results are compared to those of other occupational groups in three countries. Median age at diagnosis was 23 years; duration of exposure was between 1 and 3 years and the latencies were short, median 4.6 years. The PF of HL cancers was 41.3%, 95% CI (27%-57%), versus 22.7% expected in non-exposed subjects matched for age and gender profiles, p = 0.003; 19 out of the 46 patients had HL cancers. The PF of Hodgkin lymphoma cancers was 21.7%, 95%CI (11%-36%), versus 11.6% expected, p = 0.033. For a subgroup of 6 patients, the number of soldiers in the units was known, and we were able estimate approximately the overall cancer risk ratio (RR) after 8 years as being 8.0 with 95% CI (2.9, 17), p < 0.002, with only 0.75 cases expected from the Cancer Registry data. In this subgroup, there were 3 HL cancer cases and 3 non-HL cases. Sarcoma PF was higher than expected, 7 out of the 46 patients were diagnosed with sarcoma, PF = 15.2%, 95%CI (6.3%-28.9%), p = 0.04 versus the expected PF of 7%. The HL PF was high and consistent with previous reports. Epidemiological studies on excess risk for HL and other cancers, brain tumors in cellphone users, and experimental studies on RFR and carcinogenicity strongly point to a cause-effect relationship. It is mandatory to reduce the RFR exposure of all personnel to that of the typical community levels, including the peak level of radar pulses. Radiation protection, safety instructions, cancer risk warnings and quantitative data on individual exposure together with regular medical monitoring must be instituted for all personnel exposed to such risks. The findings from our study add to the growing body of evidence underscoring the gross inadequacy of the International Commission on Non-Ionizing Radiation Protection (ICNIRP) thermal standards. Based on our findings and on the previous accumulated research, we endorse the recommendations to reclassify RFR exposure as a human carcinogen, International Agency for Research on Cancer (IARC) group 1.


Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
To update the 2004 American Academy of Neurology/Child Neurology Society practice parameter on treatment of infantile spasms in children. MEDLINE and EMBASE were searched from 2002 to 2011 and searches of reference lists of retrieved articles were performed. Sixty-eight articles were selected for detailed review; 26 were included in the analysis. RECOMMENDATIONS were based on a 4-tiered classification scheme combining pre-2002 evidence and more recent evidence. There is insufficient evidence to determine whether other forms of corticosteroids are as effective as adrenocorticotropic hormone (ACTH) for short-term treatment of infantile spasms. However, low-dose ACTH is probably as effective as high-dose ACTH. ACTH is more effective than vigabatrin (VGB) for short-term treatment of children with infantile spasms (excluding those with tuberous sclerosis complex). There is insufficient evidence to show that other agents and combination therapy are effective for short-term treatment of infantile spasms. Short lag time to treatment leads to better long-term developmental outcome. Successful short-term treatment of cryptogenic infantile spasms with ACTH or prednisolone leads to better long-term developmental outcome than treatment with VGB. Low-dose ACTH should be considered for treatment of infantile spasms. ACTH or VGB may be useful for short-term treatment of infantile spasms, with ACTH considered preferentially over VGB. Hormonal therapy (ACTH or prednisolone) may be considered for use in preference to VGB in infants with cryptogenic infantile spasms, to possibly improve developmental outcome. A shorter lag time to treatment of infantile spasms with either hormonal therapy or VGB possibly improves long-term developmental outcomes.


Anidulafungin in children: Experience in a tertiary care children's hospital in Argentina.
The experience using anidulafungin for the treatment of invasive fungal infections in pediatrics is limited. In this article, we describe our experience in 55 children. Anidulafungin was administered intravenously at a loading dose of 3 mg/kg once daily, followed by 1.5 mg/kg every 24 hours over a mean period of 14 days (range: 7-22 days). Patients' median age was 114 months old (interquartile range: 32-168 months old). All patients had underlying diseases. Among patients with bone marrow transplant, the difference in white blood cell count, transaminase levels, and renal function at baseline and at the end of anidulafungin administration was not significant. No adverse events were reported and no patient died from an anidulafungin-related cause. Anidulafungin may be considered an alternative for the prophylaxis or treatment of invasive fungal infections in pediatrics but methodologically robust studies are needed to confirm this.


Surface-induced conformational switching in amphiphilic peptide segments of apolipoproteins B and E and model peptides.
The conformational and surface-binding properties of a synthetic peptide corresponding to Tyr-apolipoprotein B-100(1000-1016) amide, SP-4, which was previously shown to mimic the focal accumulation pattern of LDL on the healing de-endothelialized rabbit aorta [Shih et al. (1990) Proc. Natl. Acad. Sci. USA 87, 1436-1440], have been investigated. SP-4 behaves as an amphiphilic alpha-helical peptide at the air-water interface and bound to siliconized quartz slides. However, its N alpha-acetylated analogue formed beta-sheet structures at the air-water interface. Nonhomologous peptide models of SP-4 also exhibited mixed alpha-helical and beta-sheet surface-binding behavior. Peptides corresponding to the cationic apolipoprotein (apo) B/E receptor binding regions of apoE (SP-2) and apoB (SP-11) were also studied. SP-2 behaved as an amphiphilic alpha helix, but, surprisingly, SP-11 formed surface-induced beta-sheets. These results demonstrate that all of the peptides studied have surface-binding properties, and suggest further that either alpha-helical or beta-sheet peptide structures may determine the binding of LDL to the arterial wall or the apoB/E receptor.


Frequency, Causes, and Places of Unintentional Injuries in a Nationally Representative Sample of Iranian Children and Adolescents: The CASPIAN-IV Study.
This study aims to assess the frequency, causes, and places of injuries in a nationally representative sample of Iranian children and adolescents, as well as the referral, places allocated for injured individuals. This nationwide study was conducted in 2011-2012 among 13486 elementary, secondary and high-school students who were selected by random cluster stratified multistage sampling from 30 provinces in Iran. The Global School-based Health Survey questionnaire of the World Health Organization was used. The study participants consisted of 50.8% boys, 75.6% urban resident with a mean age of 12.5 years. Overall, 20.25% of participants reported that they were minimally injured once in the last 12 months; this prevalence was higher in boys than in girls (25.74% vs. 14.58%, respectively, P < 0.001), without significant difference in urban (20.11%) and rural (20.69%) areas. Most of them (39.92%) were injured at homes or house yards with higher prevalence in girls than in boys (48.61% vs. 35.17%, respectively, P < 0.001) and in rural than in urban areas (27.30% vs. 20.89%, respectively, P < 0.001). Schools were reported as the second prevalent site of injury occurrence (22.50%). Emergency departments and physician offices were the most prevalent referral places for injured individuals (32.31% and 22.38%, respectively). Most of the school injuries occurred during play or sport activities (45.92%). Prevention of unintentional injuries should be considered as a health priority. Appropriate preventive strategies should be enhanced at homes and schools.


Antibiogram, biotyping and plasmid profile analysis of Acinetobacter calcoaceticus var. anitratus.
Antibiogram, biotyping, and plasmid profile analysis were studied on 115 isolates (40 nosocomial and 75 community strains) of Acinetobacter calcoaceticus var. anitratus isolated from clinical specimens. By disk diffusion method, we found 14 antimicrobial susceptibility patterns. Among them, the gentamicin-resistant patterns were recovered more frequently from nosocomial origin than from community-acquired origin. Fifteen patterns of biocodes were found by using GNI card of AutoMicrobic System (Vitek System). By using rapid alkaline extraction method and agarose gel electrophoresis, 102 isolates (88.7%) contained plasmids, and 72 distinct profiles were found. No particular plasmid profile correlates with specific antibiogram or biotype. However, multiple isolates with identical antibiogram and biotype recovered from the same patient were usually of identical plasmid profile. In view of the heterogeneity of the plasmid patterns that were found, the combined use of antibiogram, biotyping, and plasmid profile analysis could be satisfactory for epidemiological investigation.


Urethritis caused by group B streptococci: a case report.
We describe a case of urethritis caused by group B streptococci. The diagnosis was confirmed by examination of a Gram stained smear, isolation of the organism from the urethral discharge, and also by the clinical response to treatment with phenoxymethyl penicillin.


Reservoir function after subtotal or total gastrectomy with or without gastric substitute.
Volume and pressure characteristics as a measure of reservoir function were studied in three patient groups greater than 1 year after gastrectomy for cancer, one group with straight Roux-en-Y esophagojejunostomy, one with an s-shaped gastric substitute after total gastrectomy, and the third group with subtotal gastrectomy. A large latex balloon was introduced into the proximal jejunum, gastric substitute or gastric remnant and then filled with water at a constant, slow rate. The maximal volume capacity was 400 ml at basal pressure 13.9 cmH2O in the remnant after subtotal gastrectomy and 475 ml at 10.4 cm in the gastric substitute, but only 180 ml at basal pressure 40.4 cmH2O in the proximal Roux limb of the straight esophagojejunostomy. Maximal basal pressure and maximal pressure amplitudes throughout the study period were significantly higher in the patients with straight Roux-en-Y esophagojejunostomy. The results suggest that a gastric substitute constructed as an s-shaped pouch is characterized by pressure and volume typical of a low-pressure reservoir, similar to that achieved by leaving the proximal part of the stomach intact.


Strategies to implement evidence into practice to improve palliative care: recommendations of a nominal group approach with expert opinion leaders.
In the past decades, many new insights and best practices in palliative care, a relatively new field in health care, have been published. However, this knowledge is often not implemented. The aim of this study therefore was to identify strategies to implement improvement activities identified in a research project within daily palliative care practice. A nominal group technique was used with members of the IMPACT consortium, being international researchers and clinicians in cancer care, dementia care and palliative care. Participants identified and prioritized implementation strategies. Data was analyzed qualitatively using inductive coding. Twenty international clinicians and researchers participated in one of two parallel nominal group sessions. The recommended strategies to implement results from a research project were grouped in five common themes: 1. Dissemination of results e.g. by publishing results tailored to relevant audiences, 2. Identification and dissemination of unique selling points, 3. education e.g. by developing e-learning tools and integrating scientific evidence into core curricula, 4. Stimulation of participation of stakeholders, and 5. consideration of consequences e.g. rewarding services for their implementation successes but not services that fail to implement quality improvement activities. The added value of this nominal group study lies in the prioritisation by the experts of strategies to influence the implementation of quality improvement activities in palliative care. Efforts to ensure future use of scientific findings should be built into research projects in order to prevent waste of resources.


A large retroperitoneal lymphatic malformation successfully treated with traditional Japanese Kampo medicine in combination with surgery.
Current treatment options for lymphatic malformations (LMs) are multimodal. Recently, the effectiveness of treating LMs with Eppikajyutsuto (TJ-28) has been reported. TJ-28 is a kind of oral herbal medicine classified as the traditional Japanese Kampo medicine. A 12-year-old girl was admitted to our hospital for intermittent upper abdominal pain. Radiological examinations revealed a large (9.5 × 5.8 × 10.0 cm) retroperitoneal LM, which was suspected to adhering and stretching both pancreas head and duodenum. The large retroperitoneal tumor resection might induce involving complications because of the size and the location. Therefore, we used TJ-28 in order to diminish the tumor size before surgery. The patient received oral doses of 7.5 g/day (2.5 g × 3 times/day) of TJ-28. Six months after the medication, the tumor decreased markedly to 3.5 × 1.5 × 1.2 cm in size. Thereafter, the mass was sub-totally resected (95%) via a 3 cm trans-umbilical incision without any surgical complications. We reported a case of successfully treated retroperitoneal LM with the combination treatment of TJ-28 and surgery. Based on our experience, this TJ-28 treatment option may be very useful in treating cases of LMs having surgical difficulties because of size and/or location.


Purification and subunit structure of extracellular superoxide dismutase from mouse lung tissue.
The first purification of mouse extracellular superoxide dismutase (EC-SOD) and the analysis of the native enzyme are described. Mouse EC-SOD was purified from lung tissues with a high recovery (41%) and a specific polyclonal antibody against the purified enzyme was obtained. The purified enzyme had a strong affinity for, heparin and a molecular mass of 150 kDa (estimated by a gel filtration chromatography). The native mouse EC-SOD was composed of two different sizes of subunits, a M(r) of 33 and 35 kDa (determined by SDS-PAGE). The 35-kDa subunit had an interchain disulfide bond at the C-terminus and existed as a covalent dimer in the molecule, whereas the 33-kDa subunit resulted from the 35-kDa subunit by truncating its C-terminus as a posttranslational modification, with resultant loss of the interchain disulfide bond. These results suggest that the native mouse EC-SOD is a heterotetramer composed of two different dimers, with or without a covalent bond.


[Development of multifunctional envelope type artificial viral-like gene delivery system].
This review introduces a new concept "Programmed Packaging" to develop a non-viral gene delivery system. Based on this concept, multifunctional envelope type nano devices (MEND) were developed for in vitro, in situ and in vivo conditions. A quantitative study to identify a rate limiting step in intracellular trafficking was also shown between viral and non-viral vectors, which indicated an important role of controlled intranuclear disposition for development a safe and efficient non-viral gene delivery system. This review will provide a future direction of non-viral gene delivery system.