Plant-borne human contamination by fascioliasis.
Contamination by fasciolids takes place through ingestion of metacercariae attached to vegetables. Experimental studies were performed with plant-made foods suggesting a role in human contamination in Iran and on the usefulness of potassium permanganate as a preventive tool for killing metacercariae attached to vegetables used in salads in Egypt. In the foods assayed, although viability decreases with time, a high percentage of the metacercariae were still alive 2 and 4 weeks after preparation. Infection of laboratory animals proved that metacercariae kept their infectivity. The 5-minute tests of potassium permanganate effects showed that metacercarial viability was not affected even at the very high doses of 300, 600, and 1,200 mg/L. Careful, subsequent washing of leaves and vegetables with water is therefore needed after its application. A review on similar studies performed with metacercariae belonging to fasciolid and other trematode species affecting humans is included.


ALS-causing SOD1 mutants regulate occludin phosphorylation/ubiquitination and endocytic trafficking via the ITCH/Eps15/Rab5 axis.
It is increasingly recognized that blood-spinal cord barrier (BSCB) breakdown is a hallmark of amyotrophic lateral sclerosis (ALS). BSCB integrity is disrupted prior to disease onset. Occludin, as the functional component of the endothelial barrier, is downregulated in mouse models expressing ALS-linked superoxide dismutase-1 (SOD1) mutants. However, the molecular mechanisms underlying the regulation of occludin expression remain elusive. Here, using SOD1G93A transgenic mice and endothelial cells expressing SOD1 mutants of different biochemical characteristics, we found that the SOD1 mutation disrupted endothelial barrier integrity and that the occludin expression level was downregulated with disease progression. Our mechanistic studies revealed that abnormal reactive oxygen species (ROS) in mutant SOD1-expressing cells induced occludin phosphorylation, which facilitated the subsequent occludin ubiquitination mediated by the E3 ligase ITCH. Moreover, ubiquitinated occludin interacted with Eps15 to initiate its internalization, then trafficked to Rab5-positive vesicles and be degraded by proteasomes, resulting in a reduction in cell surface localization and total abundance. Notably, either ITCH or Eps15 knockdown was sufficient to rescue occludin degradation and ameliorate endothelial barrier disruption. In conclusion, our study reveals a novel mechanism of occludin degradation mediated by ALS-causing SOD1 mutants and demonstrates a role for occludin in regulating BSCB integrity.


Sulphation pattern analysis of chemically sulphated polysaccharide LbGp1 from Lycium barbarum by GC-MS.
The polysaccharide LbGp1 from Lycium barbarum L. was sulphated with sulphur trioxide-pyridine complex in DMF, yielding two sulphated polysaccharides, which were LbGp1-OL-SL with 13.7% sulphate content, and LbGp1-OL-SH with 27.4% sulphate content. The sulphation patterns were analysed using a GC-MS strategy. After a series of sequential chemical derivatisations, the sulphated polysaccharides were converted to partially methylated alditol acetates. All the sulphate groups were replaced by acetyl groups, maintaining the positional information of the original sulphation pattern. The number and position of sulphate substitutions were deduced by comparing the relative molar ratio from methylation analysis between native polysaccharide and sulphated derivatives. In LbGp1-OL-SL, 12.65% of sulphation located on C-5 of Ara, only 0.69% and 0.34% of sulphation occurred on C-4 and C-6 Gal, respectively; while in LbGp1-OL-SH, 24.96% of sulphate groups were found at C-5 of Ara, and 0.40% and 2.02% of sulphate groups were found at C-4 and C-6 Gal, respectively.


The politics of nutrition in North America.
In the 100-odd years since the rise of modern nutritional science, North American' ideas about food and health have been influenced by much more than the scientists' findings. They have invariably been affected by political considerations. War, fear of revolution, leftist ideology, and the enormous financial stakes of giant food producers have all played important roles in shaping ideas about nutrition.


Ultrasonographic and histopathological findings in equine superficial digital flexor tendon injury.
The ultrasonographic and histopathological findings in 12 normal and 28 injured superficial digital flexor tendons, with lesions ranging in duration from 2 days to 15 months, were compared. A consistent relationship between the ultrasonographic and histological findings was demonstrated. The echogenicity of lesions, the distinctness of their delineation from the surrounding tissue, and the presence and arrangement of the linear echoes were useful features by which to assess the ultrasonograms. Acute lesions were anechoic, a complex mixture of anechoic and hypoechoic areas, or diffusely hypoechoic. These appearances represented haemorrhage, fibrolysis and early granulation tissue. Fibroplasia and granulation tissue produced well to moderately well defined hypoechoic lesions. Chronic fibrosis was characterised by heterogeneously echogenic areas which were poorly defined from the surrounding tissue and had irregularly-arranged linear echoes on longitudinal images. Intratendinous scar formation resulted in multiple hyperechoic foci. Extensive peritendinous lesions were readily apparent on ultrasonograms, but intertendinous adhesions were more difficult to assess, and produced ill-definition of the borders between the superficial and deep digital flexor tendons.


Intra- and inter-rater reliabilities of measurement of ultrasound imaging for muscle thickness and pennation angle of tibialis anterior muscle in stroke patients.
Dysfunction of skeletal muscle has been commonly reported in stroke patients. The purpose of this study was to investigate the intra- and inter-rater reliabilities of measurement of ultrasound imaging (USI) for pennation angle (PA) and muscle thickness (MT) of tibialis anterior muscle in stroke patients. Thirty-four stroke patients (19 men) participated in this study. USI was used for measurement of PA and MT of the tibialis anterior muscles at rest and during maximum voluntary contraction (MVC). Two examiners acquired images from all participants during two separate testing sessions, seven days apart. Intra-class correlation coefficients (ICCs), confidence interval (CI), standard error of measurement, minimal detectable change, and Bland-Altman plots were used for estimation of reliability. In the intra-rater reliability between measures, for all variables (PA and MT of the paretic and non-paretic sides of tibialis anterior muscles at rest and during MVC), the ICCs ranged between 0.639 and 0.998 and the CI was within an acceptable range of 0.388-0.999. In inter-rater reliability between examiners for the two tests, for all variables, the ICCs ranged between 0.690 and 0.995 and the CI was within an acceptable range of 0.463-0.997. In addition, significant difference was observed between the paretic and non-paretic sides of the tibialis anterior muscle architecture (p < 0.05). These finding demonstrate that measurements of the tibialis anterior muscle using USI can be useful for clinical assessment in stroke patients. In addition, objective and quantitative measurements of tibialis anterior muscle using USI may provide appropriate management for the walking recovery of stroke patients.


Decree No. 87-010 creating a National Literacy Council, 21 January 1987.
This Decree creates a National Literacy Council under the Mauritania Secretariat of State charged with the battle against illiteracy. The Objectives of the Council are 1) to propose the large outlines of literacy and education programs, as well as the elements of an implementation strategy; 2) to give its advice on any problem that is submitted to it by the Secretariat of State; 3) to mobilize and coordinate national, material, human, and technical forces to be placed at the service of literacy; and 4) to evaluate the progress accomplished in the field of literacy. Decree No. 87-027 of 25 February 1987 creates a special account to record the receipts and expenses in the battle against illiteracy (Journal Officiel de la Republique Islamique de Mauritanie, Nos. 690-691, 29 July 1987, pp. 328-329). Decree No. 87-028 of 25 February 1987 sets up regional literacy coordinators to carry out duties related to fighting illiteracy (Journal Officiel de la Republique Islamique de Mauritanie, Nos. 684-685, 29 April 1987, pp. 209-210).


Evolution of the larval cuticle proteins coded by the secondary sex chromosome pair: X2 and neo-Y of Drosophila miranda: II. Comparison at the amino acid sequence level.
The larval cuticle proteins (LCPs) are encoded by a multigene family, Lcp1-4, located at the right arm of the metacentric autosome 2 (2R) in Drosophila melanogaster. Due to a chromosome fusion the Lcp locus of Drosophila miranda is situated on a pair of secondary sex chromosomes, the X2 and neo-Y chromosomes. Comparing the deduced amino acid sequences of the autosomal D. melanogaster loci with the sex-chromosomal loci of D. miranda, we were able to trace the evolution of the Lcp loci with respect to their different chromosomal inheritance. The length of the signal peptide is conserved in all four LCPs, while the size of the mature LCPs varies. Conserved protein motifs became obvious from the alignment, indicating regions of structural and functional importance. Analyzing intra- and interspecific sequence similarities of the Lcp gene families allowed us to reconstruct the phylogeny of the gene cluster. Alignment with cuticle amino acid sequences originating from divergent insect species reveals motifs already present in the primordial insect LCPs. These motifs indicate different levels of constraint acting during the evolution of the LCPs.


Basal cell carcinoma of the scalp with destruction and invasion into the calvarium and dura mater: Report of 7 cases and review of literature.
Basal cell carcinoma (BCC) is the most common skin malignancy in humans. Giant BCC is a rarer entity that is characterised by aggressive biological behaviour. Intracranial invasion by a BCC on the scalp is extremely rare. The gold standard treatment of BCCs is represented by surgical excision with a wide variety of reconstructive techniques. In this paper, we describe the largest series to date of recurrent BCCs with intracranial extension involving the dura mater. We report recurrent giant BCC of the scalp with dura mater invasion in 7 patients. All patients in this series previously had more than 2 operations. Gadolinium-enhanced MRI revealed neoplastic invasion of the meninges and brain tissues. All patients had a multi-disciplinary team approach with the surgical margins ranging between 1 and 2 cm depending on the location and the size of the tumour. 5 of the patients underwent reconstruction of the skin defect by antero-lateral thigh flap, 1 patient underwent reconstruction with pedicled myocutaneous (trapezius) flap, and 1 with a pedicled myocutaneous latissimus dorsi flap. There was a mean follow-up of 5.3 years. 2 patients died due to cardio-pulmonary complications in the neuro-intensive care unit. A multi-disciplinary team approach and early aggressive tumour resection followed by sophisticated reconstructive and aesthetic procedures appears to be a reliable and realistic treatment modality for invasive BCC.


Helicobacter pylori increases expression of proapoptotic markers Fas and FasL on CD4 lymphocytes in children.
The pathomechanism of Helicobacter pylori action upon gastric mucosa and its role in the pathogenesis of gastritis have not been fully elucidated. The aim of this study was to evaluate the most prevalent lymphocyte subpopulations of the gastric mucosa in gastritis in children, as well as to evaluate the expression of Fas and Fas ligand receptors (FasL), periapoptotic markers of gastric mucosa lymphocytes before and after H. pylori eradication. Forty nine patients aged 6 to 17 years, investigated due to chronic abdominal pain, were studied. The obtained tissue samples were analysed by immunohistochemistry. Different lymphocyte subsets were quantified on the basis of surface antigen expression (CD3, CD4, CD8, CD20), secreted cytokines (IL-4, IL-6, IFNgamma) and Fas and FasL proteins in the gastric mucosa. B and T helper lymphocytes were found to play a major role in the inflammatory infiltration in the gastric mucosa in children during H. pylori infection. Their expression was found to decrease after eradication. The enhanced expression of Fas receptor on lymphocytes before treatment and a decrease of this expression after eradication of H. pylori were shown. It was demonstrated that there is a correlation between CD4 and Fas receptor expression that may induce apoptosis of the helper lymphocytes in infected children.


The case for human factors training.
The Association for Perioperative Practice has taken a leading role in raising awareness of the importance of human factors in healthcare. We at Atrainability (2011) have been privileged to run training courses on human factors to association members at the last two annual conferences and also at venues throughout the UK. The funding has been provided by the Hilda Mears trust.


Patients' Perspectives on the Impact of Genital Psoriasis: A Qualitative Study.
Plaque psoriasis is a chronic skin disease where genital involvement is relatively common. Yet health care providers do not routinely evaluate psoriasis patients for genital involvement and patients do not readily initiate discussion of it. A qualitative study of 20 US patients with dermatologist-confirmed genital psoriasis (GenPs) and self-reported moderate-to-severe GenPs at screening was conducted to identify key GenPs symptoms and their impacts on health-related quality of life (HRQoL). Patients had a mean age of 45 years, 55% were female, and patients had high rates of current/recent moderate-to-severe overall (65%) and genital (70%) psoriasis. Patients reported the following GenPs symptoms: genital itch (100%), discomfort (100%), redness (95%), stinging/burning (95%), pain (85%), and scaling (75%). Genital itching (40%) and stinging/burning (40%) were the most bothersome symptoms. Impacts on sexual health included impaired sexual experience during sexual activity (80%), worsening of symptoms after sexual activity (80%), decreased frequency of sexual activity (80%), avoidance of sexual relationships (75%), and reduced sexual desire (55%). Negative effects on sexual experience encompassed physical effects such as mechanical friction, cracking, and pain as well as psychosocial effects such as embarrassment and feeling stigmatized. Males reported a higher burden of symptoms and sexual impacts. Other HRQoL impacts were on mood/emotion (95%), physical activities (70%), daily activities (60%), and relationships with friends and family (45%). These impacts significantly affected daily activities. Physical activities were affected by symptoms and flares, and increased sweat and friction worsened symptoms. Patients reported daily practices to control outcomes. The high level of reported symptoms and sexual and nonsexual impacts reflects the potential burden of moderate-to-severe GenPs. GenPs can impact many facets of HRQoL and providers should evaluate their patients for the presence of genital psoriasis and its impact on their quality of life. Eli Lilly and Company.


Trajectory modeling of gestational weight: A functional principal component analysis approach.
Suboptimal gestational weight gain (GWG), which is linked to increased risk of adverse outcomes for a pregnant woman and her infant, is prevalent. In the study of a large cohort of Canadian pregnant women, our goals are to estimate the individual weight growth trajectory using sparsely collected bodyweight data, and to identify the factors affecting the weight change during pregnancy, such as prepregnancy body mass index (BMI), dietary intakes and physical activity. The first goal was achieved through functional principal component analysis (FPCA) by conditional expectation. For the second goal, we used linear regression with the total weight gain as the response variable. The trajectory modeling through FPCA had a significantly smaller root mean square error (RMSE) and improved adaptability than the classic nonlinear mixed-effect models, demonstrating a novel tool that can be used to facilitate real time monitoring and interventions of GWG. Our regression analysis showed that prepregnancy BMI had a high predictive value for the weight changes during pregnancy, which agrees with the published weight gain guideline.


Clinical Implication of the C Allele of the ITPKC Gene SNP rs28493229 in Kawasaki Disease: Association With Disease Susceptibility and BCG Scar Reactivation.
a functional single nucleotide polymorphism (SNP) (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene has been linked to the susceptibility to Kawasaki disease (KD). The implication remains unclear. genotyping for the ITPKC polymorphism was conducted on 280 unrelated Taiwanese children with KD and 492 healthy ethnically and gender-matched controls. The clinical manifestations and laboratory data were systemically collected. the GC and CC genotypes of ITPKC gene SNP rs28493229 were overrepresented in KD patients (GG:GC:CC was 236:43:1, C allele frequency: 8.04%) than those in the controls (GG:GC:CC was 454:37:1, C allele frequency: 3.96%; OR: 2.23, P = 0.001). In KD patients, those with GC or CC genotypes of SNP rs28493229 (19/44) were more likely to have reactivation at the Bacille Calmette-Guérin (BCG) inoculation site than those with GG genotypes (66/236; OR: 1.96, P = 0.044). Such association was particularly strong in patients aged <20 months (OR: 3.26, P = 0.017). The other clinical manifestations were not related to this SNP. There were 160 (57.1%) patients with coronary arterial lesions. The development and the severity of coronary arterial lesion were also not associated with this SNP. Comparison between patients with and without BCG reactivation revealed only one difference: patients with reactivation were younger. in a cohort from a population with the world's third highest incidence of KD, we demonstrated that the C-allele of ITPKC SNP rs28493229 is associated with KD susceptibility and BCG scar reactivation during the acute phase, although its frequency is lower than that in the Japanese cohort (22.6%), suggesting this SNP contributes to KD susceptibility through induced hyperimmune function reflected in the BCG reactivation.


A cluster randomised controlled trial of an intervention to promote healthy lifestyle habits to school leavers: study rationale, design, and methods.
Physical inactivity and a poor diet predict lifestyle diseases such as diabetes, cardiovascular disease, and certain types of cancer. Marked declines in physical activity occur during late adolescence, coinciding with the point at which many young people leave school and enter the workforce and begin to take greater control over their lifestyle behaviours. The work outlined within this paper sought to test a theoretically-informed intervention aimed at supporting increased engagement in physical activity and healthy eating habits in young people at the point of transition from school to work or work-based learning. As actively engaging young people in initiatives based on health messages is challenging, we also tested the efficacy of financial incentives in promoting initial engagement with the programme. A three-arm cluster-randomised design was used. Participants were school pupils from Year 11 and 13 (i.e., in their final year of study), aged 16-18 years. To reduce contamination effects, the unit of randomisation was school. Participants were randomly allocated to receive (i) a 12-week behavioural support intervention consisting of six appointments, (ii) a behavioural support intervention plus incentives (totalling £40), or (iii) an information-only control group. Behavioural support was provided by fitness advisors at local leisure centres following an initial consultation with a dietician. Sessions focused on promoting habit formation through setting implementation intentions as part of an incremental goal setting process. Consistent with self-determination theory, all advisors were trained to provide guidance in an autonomy-supportive manner so that they were equipped to create a social context supportive of autonomous forms of participant motivation. The primary outcome was objectively assessed physical activity (via GT1M accelerometers). Secondary outcome measures were diet, motivation and habit strength. Data were collected at baseline, post-intervention (12 weeks) and 12 months. Findings of this trial will provide valuable insight into the feasibility of promoting autonomous engagement in healthy physical activity and dietary habits among school leavers. The research also provides much needed data and detailed information related to the use of incentives for the initial promotion of young peoples' behaviour change during this important transition. The trial is registered as Current Controlled Trials ISRCTN55839517.


Intraspecific genotypic characterization of Lactobacillus rhamnosus strains intended for probiotic use and isolates of human origin.
A set of 118 strains of the species Lactobacillus rhamnosus was collected, including probiotic strains, research strains with potential probiotic properties, food starter cultures, and human isolates. The majority of the strains were collected from companies, hospitals, or culture collections or were obtained after contacting authors who reported clinical case studies in the literature. The present work aimed to reveal the genotypic relationships between strains of these diverse sources. All strains were initially investigated using fluorescent amplified fragment length polymorphism (FAFLP) with three different primer combinations. Numerical analysis of FAFLP data allowed (i) confirmation of the identification of all strains as members of L. rhamnosus and (ii) delineation of seven stable intraspecific FAFLP clusters. Most of these clusters contained both (potentially) probiotic strains and isolates of human origin. For each of the clusters, strains of different sources were selected for pulsed-field gel electrophoresis (PFGE) of macrorestriction fragments obtained with the enzymes NotI and AscI. Analysis of PFGE data indicated that (i) some (potentially) probiotic strains were indistinguishable from other probiotic strains, suggesting that several companies may use duplicate cultures of the same probiotic strain, and (ii) in a number of cases human isolates from sterile body sites were indistinguishable from a particular probiotic strain, suggesting that some of these isolates may be reisolations of commercial strains.


[The clinico-morphological characteristics of glomerulonephritis in infectious endocarditis].
Clinicomorphological characteristics of glomerulonephritis in infectious endocarditis (IEGN) were studied in 62 patients (with samples of autopsy material being used in 52 instances). IEGN presents with dissaminated and focal proliferative alterations involving extracapillary and/or tubulointerstitial components, and is characterized by a broad variability of indices for proteinuria, hematuria and cylindruria. In diffuse prolipherative glomerulonephritis the degree of proteinuria and cylindruria appear to be significantly higher than in focal segmental proliferative glomerulonephritis, as is the incidence rate of development of renal insufficiency and its gravity.


Palladium Single-Atom (In)Stability Under Aqueous Reductive Conditions.
Here, we investigate the stability and performance of single-atom Pd on TiO2 for the selective dechlorination of 4-chlorophenol. A challenge inherent to single atoms is their high surface free energy, which results in a tendency for the surface migration and aggregation of metal atoms. This work evaluates various factors affecting the stability of Pd single-atoms, including atomic dispersion, coordination environment, and substrate properties, under reductive aqueous conditions. The transition from single atoms to clusters vastly enhanced dechlorination kinetics without diminishing carbon-chlorine bond selectivity. X-ray absorption spectroscopy analysis using both in situ and ex situ conditions followed the dynamic transformation of single atoms into amorphous clusters, which consist of a unique unsaturated coordination environment and few nanometer diameter. The intricate relationship between stability and performance underscores the vital role of detailed characterization to properly determine the true active species for dehalogenation reactions.


PSI relieves the pressure of membrane fusion.
Some plant proteases contain a latent sequence known as the plant-specific insert (PSI) that, upon release from the full protease sequence, initiates membrane fusion to defend from pathogens. However, the mechanism by which it exerts its effects has been unclear. Zhao et al. report an elegant integration of biophysical experiments and molecular dynamics simulations to reveal events leading up to PSI-mediated membrane fusion. Their results demonstrate a pH-dependent monomer-to-dimer transition, clear evidence of membrane association, and probable structures of prefusion intermediates. These data expand our understanding of the elusive PSIs and may provide new directions for antimicrobial development.


The use of Breast Milk Fortifier in Preterm Infants by paediatric dietitians in the UK.
Breast milk is the feed of choice for premature infants, although its nutritional composition is not always sufficient to meet their raised nutritional requirements. The addition of a multi-nutrient breast milk fortifier (BMF) to breastmilk is recommended; however, international guidelines on the use of BMF are inconsistent. The present study aimed to explore the use of BMF in preterm infants by paediatric dietitians in the UK. A questionnaire was designed and sent to members of the British Dietetic Association neonatal specialist group (n = 100) using a secure online platform. Descriptive statistics were calculated. Forty dietitians completed the survey, all of whom used BMF. Local hospital BMF guidelines were available to 77.5% (n = 31). The most commonly used criteria for commencing BMF were: tolerating a feed volume of 150 mL kg-1 day-1 (72.5%, n = 29), a gestational age <34 weeks (67.5%, n = 27) and a birth weight <1500 g (60%, n = 24). The primary contraindication for the use of BMF was necrotising enterocolitis (NEC). The majority of respondents used standard fortification, with individualised fortification available to only 12.5% (n = 5). The most common indicators for discontinuing BMF were on discharge home (67.5%, n = 27), satisfactory growth (65%, n = 26) or feeding directly from the breast (62.5%, n = 25). Although BMF is used more proactively in UK neonatal units than previously, variation in practice remains. Individualised fortification is very uncommon and caution remains regarding risk of NEC. The development of national guidelines on the use of BMF would help to standardise nutritional care in neonatal units.


Detection of the major mutation M467T causing cystinuria by single-strand conformation polymorphism analysis using capillary electrophoresis.
We present a fast detection of M467T, the major mutation causing cystinuria, by capillary electrophoresis version of single-strand conformation polymorphism (SSCP). The DNA fragment (317 bp) carrying the point mutation was amplified by polymerase chain reaction (PCR) on the exon 8 of the SLC3A1 gene, which encodes for the transmembrane glycoprotein rBAT, a part of the active cystine and dibasic amino acids transporter. The complementary strands of the fragment were labeled by fluorescein and TAMRA, respectively. Thus, the electromigration of both strands was recorded independently as a laser-induced fluorescence (LIF) signal, what enabled an effective optimization of separation conditions. The injected sample was denatured by immersing the inlet of the separation capillary into a vial with 0.1 M solution of NaOH prior to analysis. Under optimum conditions, the SSCP analysis in poly(vinyl alcohol) (PVA)-coated silica-fused capillary of an effective length of 15 cm, filled with 4% linear polyacrylamide (LPA) solution, was accomplished in approximately 6 min. The experimentally observed mobility shifts of single-stranded DNA (ssDNA) fragments were compared to the appearance of their calculated two-dimensional conformations using Version 3.0 of MFOLD software. The number of nucleotides involved in the duplex regions of theoretical structures correlates well with their real migration order in the sieving medium.


MMP-7 knock-in corneal fibroblast cell lines secrete MMP-7 with proteolytic activity towards collagen XVIII.
To determine whether matrix metalloproteinase-7 (MMP-7) that is stably overexpressed by mouse corneal fibroblast cell lines exhibits proteolytic activity against the NC1 fragment of collagen XVIII. Corneal fibroblasts isolated from MMP-7 knockout (7ko) mice were subjected to SV40 T-antigen immortalization and stably transfected with a bicistronic retroviral vector encoding green fluorescence protein and active MMP-7. The resulting MMP-7 knock-in fibroblasts (7ko-MMP-7 cells) were isolated and enriched by fluorescence activated cell sorting (FACS). Culture media samples from 7ko and 7ko-MMP-7 cells were then incubated with the recombinant NC1 fragment of collagen XVIII, and NC1 degradation was monitored by immunoblotting. Immunoblot analysis revealed that MMP-7 was present in lysates and culture media from 7ko-MMP-7 fibroblasts, but not media from immortalized 7ko fibroblasts. Importantly, lower amounts of the NC1 fragment were present in in vitro enzymatic reaction mixtures containing concentrated 7ko-MMP-7 media than in those containing concentrated 7ko media. Immortalized fibroblasts stably transfected with MMP-7 secrete active MMP-7 with proteolytic activity towards the NC1 fragment of collagen XVIII.


Goal-congruent default network activity facilitates cognitive control.
Substantial neuroimaging evidence suggests that spontaneous engagement of the default network impairs performance on tasks requiring executive control. We investigated whether this impairment depends on the congruence between executive control demands and internal mentation. We hypothesized that activation of the default network might enhance performance on an executive control task if control processes engage long-term memory representations that are supported by the default network. Using fMRI, we scanned 36 healthy young adult humans on a novel two-back task requiring working memory for famous and anonymous faces. In this task, participants (1) matched anonymous faces interleaved with anonymous face, (2) matched anonymous faces interleaved with a famous face, or (3) matched a famous faces interleaved with an anonymous face. As predicted, we observed a facilitation effect when matching famous faces, compared with anonymous faces. We also observed greater activation of the default network during these famous face-matching trials. The results suggest that activation of the default network can contribute to task performance during an externally directed executive control task. Our findings provide evidence that successful activation of the default network in a contextually relevant manner facilitates goal-directed cognition.


Hydrothermal synthesis and electrochemical properties of Li₃V₂(PO₄)₃/C-based composites for lithium-ion batteries.
To improve performance at higher rates, we developed a hydrothermal method to prepare carbon-coated monoclinic lithium vanadium phosphate (Li(3)V(2)(PO(4))(3)) powder to be used as a cathode material for Li-ion batteries. The structural, morphological and electrochemical properties were characterized by X-ray diffraction (XRD), scanning and transmission electron microscopy (SEM and TEM), and galvanostatic charge-discharge cycling. A superior cycle and rate behavior are demonstrated for Li(3)V(1.85)Sc(0.15)(PO(4))(3)/C and Li(2.96)Ca(0.02)V(2)(PO(4))(3)/C electrodes at charge-discharge current rates above 5C.


[Demonstration and properties of a Cl-/HCO3--ATPase in the avian salt gland (author's transl)].
An anion-stimulated, Mg2+-dependent, ouabain-insensitive ATPase is present in salt gland homogenates of domestic ducks (Anas platyrhynchos). The enzyme is unspecifically stimulated by various inorganic and organic anions including amino and sulfonic acids which are often used as buffer components (e. g. histidine, Bicin, PIPES, MES and HEPES). Therefore, the demonstration of ATPase stimulation by chloride strongly depends on the type and concentration of the buffer used and may also largely interfere with the stimulation caused by other anions present in the incubation medium. Of the inorganic anions tested chloride and bicarbonate appear to be the favorite physiological activators, but the possible role of carbonic acids in the stimulation of the anion-dependent ATPase should not be neglected. Km values are approximately 5.8 mM for Cl- and approximately 8.7 mM for HCO-3-activation. Maximal ATPase stimulation is obtained at 25 mM Cl- and approximately 30 mM HCO-3, respectively. The simultaneous presence of bicarbonate decreases chloride affinity and Vmax, and shifts the chloride optimum to lower concentrations. ATP is the most preferred substrate. Maximal activation by Cl- and HCO-3 occurs at ATP concentrations between 0.5 and 1 mM. ATP affinity increases in the presence of Cl- and HCO-3, respectively. Both chloride and bicarbonate require a Mg2+ to ATP ratio of approximately 0.5 and a pH value of 8.0 to 8.5 for optimal stimulation. Stimulation by Cl- and HCO-3 is inhibited by thiocyanate, cyanate and by the diuretic drugs furosemide, ethacrynic acid and mersalyl. Incubation media adapted for the simultaneous demonstration of both chloride and bicarbonate activation contained 10 to 20 mM histidine-Tris buffer at pH 8.0 to 8.5, 150 mM sucrose, 0.2 mM ouabain, 0.5 mM magnesium acetate, 1 mM ATP, (pH adjusted to 8.0-8.5 with Tris or NaOH), with and without 25 mM sodium chloride or 25 mM sodium bicarbonate.


αCP Poly(C) binding proteins act as global regulators of alternative polyadenylation.
We have previously demonstrated that the KH-domain protein αCP binds to a 3' untranslated region (3'UTR) C-rich motif of the nascent human alpha-globin (hα-globin) transcript and enhances the efficiency of 3' processing. Here we assess the genome-wide impact of αCP RNA-protein (RNP) complexes on 3' processing with a specific focus on its role in alternative polyadenylation (APA) site utilization. The major isoforms of αCP were acutely depleted from a human hematopoietic cell line, and the impact on mRNA representation and poly(A) site utilization was determined by direct RNA sequencing (DRS). Bioinformatic analysis revealed 357 significant alterations in poly(A) site utilization that could be specifically linked to the αCP depletion. These APA events correlated strongly with the presence of C-rich sequences in close proximity to the impacted poly(A) addition sites. The most significant linkage was the presence of a C-rich motif within a window 30 to 40 bases 5' to poly(A) signals (AAUAAA) that were repressed upon αCP depletion. This linkage is consistent with a general role for αCPs as enhancers of 3' processing. These findings predict a role for αCPs in posttranscriptional control pathways that can alter the coding potential and/or levels of expression of subsets of mRNAs in the mammalian transcriptome.


[Indications for Retinal Laser Therapy Revisited].
Laser therapy is an important treatment option in retinal diseases, especially in cases of vascular involvement. Most approaches are based on coagulation of retinal structures. As there is increasing use of agents targetting vascular endothelial growth factor in the treatment of macular diseases, indications for the use of laser treatment need to be reviewed carefully, especially with respect to their significance in first line therapy. This article explains recent strategies and treatment protocols. Review of current literature in PubMed as well as synopsis of relevant guidelines. Retinal laser therapy is still widely used within retinal opthalmology and covers a large spectrum of indications. Despite the success of medical approaches, retinal laser therapy remains an indispensable treatment option for proliferative diabetic retinopathy, central or peripheral vein occlusion and less frequent pathologies, such as retinopathy of prematurity or Coats's disease.


The Geriatrics in Primary Care Demonstration: Integrating Comprehensive Geriatric Care into the Medical Home: Preliminary Data.
Three thousand nine hundred thirty-one veterans aged 75 and older receive primary care (PC) in two large practices of the Department of Veterans Affairs (VA) Boston Healthcare System. Cognitive and functional disabilities are endemic in this group, creating needs that predictably exceed available or appropriate resources. To address this problem, Geriatrics in Primary Care (GPC) embeds geriatric services directly into primary care. An on-site consulting geriatrician and geriatric nurse care manager work directly with PC colleagues in medicine, nursing, social work, pharmacy, and mental health within the VA medical home. This design delivers interdisciplinary geriatric care within PC that emphasizes comprehensive evaluations, care management, planned transitions, informed resource use, and a shift in care focus from multiple subspecialties to PC. Four hundred thirty-five veterans enrolled during the project's 4-year course. Complex, fragmented care was evident in a series of 50 individuals (aged 82 ± 7) enrolled during Months 1 to 6. The year before, these individuals made 372 medical or surgical subspecialty clinic visits (7.4 ± 9.8); 34% attended five or more subspecialty clinics, 48% had dementia, and 18% lacked family caregivers. During the first year after enrollment the mean number of subspecialty clinic visits declined significantly (4.7 ± 5.0, P = .01), whereas the number of PC-based visits remained stable (3.1 ± 1.5 and 3.3 ± 1.5, respectively, P = .50). Telephone contact by GPC (2.3 ± 2.0) and collaboration with PC clinicians replaced routine follow-up geriatric care. GPC facilitated planned transitions to rehabilitation centers (n = 5), home hospice (n = 2), dementia units (n = 3), and home care (n = 37). GPC provides efficient, comprehensive geriatric care and case management while preserving established relationships between patients and the PC team. Preliminary results suggest "care defragmentation," as reflected by a significant reduction in subspecialty clinic use. Model simplicity and flexibility facilitated ready implementation.


Factors affecting vaginal pH levels among female adolescents attending genitourinary medicine clinics.
Vaginal pH is related to hormonal status, and adolescents experience disturbed hormonal patterns following menarche. We assessed hormonal factors and risk of abnormal vaginal pH and bacterial vaginosis (BV) among adolescents attending genitourinary medicine (GUM) clinics. In a cross sectional study adolescents within 5 years of menarche, < or =17 years, or with oligo-amenorrhoea were recruited. Vaginal pH and BV were assessed and among those not using hormonal contraceptives, estrone-3-glucuronide (E3G) and pregnanediol-3alpha-glucuronide (P3G) concentrations were measured. Among 102 adolescents, 59.8% (61) had a high vaginal pH (>4.5), which was higher than the prevalence of BV, detected in 33% (34). No association was found between presence of sexually transmitted infections (STI) and vaginal pH. In logistic regression, after controlling for BV and condom use, vaginal pH was positively associated with cervical ectopy (OR = 2.5; 95% CI 1.0 to 6.6, p = 0.05) and STI treatment history (OR = 2.5; 95% CI 0.9 to 6.5, p = 0.07), and negatively associated with use of Depo-Provera (OR = 0.1; 95% CI 0.03 to 0.6, p = 0.003) and recent onset (<12 months) of sexual activity (OR = 0.2; 95% CI 0.1 to 0.7, p = 0.004). Among 23 adolescents not using hormonal contraceptives, a high pH occurred more often in abnormal compared to normal menstrual cycles (OR = 10.8; 95% CI 1.4 to 85.4; p = 0.026). E3G concentrations were inversely correlated with vaginal pH in the follicular phase (Spearman: r = 0.51; p = 0.024). Ectopy and abnormal menstrual cycles are common features of adolescence. Their presence is associated with increased risk of abnormal pH, and may also predispose to BV.


Structure-function analysis of the UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase. Essential residues lie in a predicted active site cleft resembling a lactose repressor fold.
Mucin-type O-glycosylation is initiated by a family of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (ppGaNTases). Based on sequence relationships with divergent proteins, the ppGaNTases can be subdivided into three putative domains: each putative domain contains a characteristic sequence motif. The 112-amino acid glycosyltransferase 1 (GT1) motif represents the first half of the catalytic unit and contains a short aspartate-any residue-histidine (DXH) or aspartate-any residue-aspartate (DXD)-like sequence. Secondary structure predictions and structural threading suggest that the GT1 motif forms a 5-stranded parallel beta-sheet flanked by 4 alpha-helices, which resembles the first domain of the lactose repressor. Four invariant carboxylates and a histidine residue are predicted to lie at the C-terminal end of three beta-strands and line the active site cleft. Site-directed mutagenesis of murine ppGaNTase-T1 reveals that conservative mutations at these 5 positions result in products with no detectable enzyme activity (D156Q, D209N, and H211D) or <1% activity (E127Q and E213Q). The second half of the catalytic unit contains a DXXXXXWGGENXE motif (positions 310-322) which is also found in beta1,4-galactosyltransferases (termed the Gal/GalNAc-T motif). Mutants of carboxylates within this motif express either no detectable activity, 1% or 2% activity (E319Q, E322Q, and D310N, respectively). Mutagenesis of highly conserved (but not invariant) carboxylates produces only modest alterations in enzyme activity. Mutations in the C-terminal 128-amino acid ricin-like lectin motif do not alter the enzyme's catalytic properties.


Iodinated analogs of trimetoquinol as highly potent and selective beta 2-adrenoceptor ligands.
A series of trimetoquinol (1, TMQ) analogs were designed and synthesized based on the lead compound 2, a diiodinated analog of trimetoquinol which exhibits improved selectivity for beta 2-versus beta 1-adrenoceptors (AR). To determine the influence of 1-benzyl substituents of trimetoquinol on beta 2-AR binding affinity and selectivity, we replaced and/or removed the 3'-, 4'-, and 5'-methoxy substituents of trimetoquinol. Replacement of the 4'-methoxy group of 2 with an amino (21c) or acetamido (15) moiety did not significantly alter beta 2-AR and thromboxane A2/prostaglandin H2 (TP) receptor affinity. Substitution with a 4'-hydroxy (18) or -iodo (21b) group did not significantly alter beta 2-AR affinity, but greatly reduced TP receptor affinity (380- and 1200-fold, respectively). Further, the beta 2-AR can accommodate larger substituents such as a benzamide at the 4'-position (26b). Other monoiodo derivatives (24, 26a) have similar or slightly lower affinity to both beta 2-AR and TP receptor compared to their diiodo analogs. Interestingly, removal of the 4'-substituent of 3',5'-diiodo analogs increased beta 2-AR affinity with little or no effect on beta 1-AR and TP binding. Thus, analog 21a displayed highly potent (pKi 9.52) and selective (beta 2/beta 1 = 600) binding affinity for beta 2-AR. On the other hand, trifluoromethyl substituents at the 3'- and 5'-positions (27) essentially abolished binding affinity at beta 2-AR and TP receptors. The differential binding effects of the aforementioned trimetoquinol modifications on the receptor systems may reflect differences in the binding pocket that interacts with the benzyl portion of trimetoquinol analogs. Thus, manipulation of the 1-benzyl moiety of trimetoquinol (1) has resulted in analogs that exhibit potent beta 2-AR binding affinity and significantly lower beta 1-AR and TP receptor affinities.


The benefit of treatment intensification is age and histology-dependent in patients with locally advanced non-small cell lung cancer (NSCLC): a quality-adjusted survival analysis of radiation therapy oncology group (RTOG) chemoradiation studies.
Currently, chemoradiation treatment strategies in locally advanced NSCLC are essentially the same irrespective of tumor histology or patient age. The purpose of this study is to analyze the impact of age, histology, Karnofsky performance status (KPS), and specific toxicities on the median survival time (MST) and quality-adjusted survival (QTime) for each treatment strategy. Nine hundred seventy-nine patients with Stage II-IIIB inoperable NSCLC were enrolled on 6 prospective Phase II and III studies from 1983 to 1995. Treatment regimens ranged from standard RT (SRT) to 60 Gy, hyperfractionated RT (HRT) to 69.6 Gy, induction chemotherapy (ICT) of cisplatin (CIS) and vinblastine (VBL) followed by SRT, ICT + concurrent CT (CCT) + SRT, and CCT + HRT; CCT consisted of etoposide or VBL + CIS. Toxicities assessed were skin, mucous membrane, lung, esophagus, neurologic, hematologic, and upper GI. QTime was calculated by weighting the time spent with a specific toxicity, as well as local or distant tumor progression. Each toxicity was weighted with increasing severity as the toxicity increased in grade. As expected, patients with the worst KPS (50-70) had the lowest MST (7.8 months) and QTime (6.7 months). Patients <70 years had improved survival with more aggressive therapy (i.e., ICT + SRT or CCT + HRT), while patients > 70 years achieved the best QTime with standard RT (SRT) alone. In patients with squamous cell carcinoma, those treated with ICT + CCT + SRT had dramatically improved MST (25.7 months) and QTime (21.8 months) compared to the other treatment regimens (11.7-12.8 and 10.7-12 months, respectively). Patients with adenocarcinoma, however, generally manifested incrementally better MST and QTime as the therapies intensified. Within the concurrent chemoradiation arms, the upper GI and lung toxicities had the greatest impact on QTime. This quality-adjusted survival analysis suggests that there is a critical relationship between the type of histology and its optimal treatment, age and the ability to tolerate intensive therapy, and the need to reduce lung and upper GI toxicities.


Multispacer sequence typing of Coxiella burnetii from milk and hard tick samples from ruminant farms in Lebanon.
his study was carried out to detect and characterize Coxiella burnetii in ruminant milk samples and in different tick species from seropositive farms in four Lebanese regions. Milk and tick samples were screened for C. burnetii presence by quantitative real-time PCR (qPCR) targeting IS1111 region followed by multispacer sequence typing (MST). The overall positive percentages of 9.6% (27/282) and 95.45% (84/88) for C. burnetii were recorded in ruminant milk and tick samples, respectively. In detail, the C. burnetii DNA was recorded in 52/54 (96.3%) of Rhipicephalus annulatus, 20/21 (95.24%) of Rhipicephalus turanicus, 6/6 (100%) of Hyalomma anatolicum, 5/6 (83.3%) of Rhipicephalus sanguineus and 1/1 of Rhipicephalus bursa. After genotyping of some IS1111-positive samples (17/111), different MST genotypes were identified. Out of 15 positive ticks, 10 were infected with MST2 genotype, 4 were infected with MST7 genotype and 1 was infected with MST57. Moreover, genotypes MST20 and MST58 were found in one cow and one goat milk samples, respectively. The present study confirmed the high genetic diversity of C. burnetii in Lebanon.


Nitric oxide modulates the activity of the hemoproteins prostaglandin I2 synthase and thromboxane A2 synthase.
Nitric oxide modulates the activity of the hemoprotein isomerase enzymes that transform prostaglandin H2 into prostaglandin I2 and thromboxane A2. Two nitric oxide donors, 1-hexanamine, 6-(2hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-nitroso- hydrazine (MMNN) and 1,1-diethyl-2-hydroxy-2-nitrosohydrazine, modulated prostaglandin I2 synthase activity in a bidirectional manner. At moderate concentrations, they increased enzyme activity irreversibly and at higher concentrations they inhibited enzyme activity reversibly. We confirmed that these effects originated from nitric oxide. First, we showed that hemoglobin, a substance that sequesters nitric oxide, prevented both the activation and the inhibition of catalysis, stoichiometrically. Second, we showed that solutions depleted of nitric oxide had no effect on catalysis. Nitric oxide also modulated thromboxane A2 synthase activity; however, its effects on thromboxane A2 synthase differed from its effects on prostaglandin I2 synthase in three ways: (i) It inhibited thromboxane A2 synthase in a concentration-dependent manner. The IC50 = 4.2 +/- 0.8 microM MMNN corresponded to an IC50 congruent with 0.1-0.3 microM nitric oxide. (ii) It did not increase thromboxane A2 synthase activity at any concentration tested. (iii) Its irreversible inhibition of thromboxane A2 synthase contrasted with its reversible inhibition of prostaglandin I2 synthase. Nitric oxide also inhibited cellular formation of thromboxane A2 by intact platelets in a concentration-dependent manner. The IC50 = 267 +/- 26 microM MMNN corresponded to an IC50 congruent with 6-18 microM nitric oxide. We conclude that nitric oxide can modulate certain hemoprotein enzymes in the biosynthetic cascade that governs the formation of eicosanoid mediators of thrombosis and hemostasis.


Epidermal growth factor synergistically enhances interleukin-8 production in human gingival fibroblasts stimulated with interleukin-1beta.
The chemokine interleukin-8 (IL-8) has been implicated in inflammatory diseases including periodontitis. In this study the effect of epidermal growth factor (EGF) on the production and regulation of interleukin-8 (IL-8) in human gingival fibroblasts challenged with interleukin-1beta (IL-1beta) was investigated. EGF, in comparison to the effect of IL-1beta, weakly increased the mRNA and protein expression of IL-8 in gingival fibroblasts. When the cells were treated simultaneously with EGF and IL-1beta, however, EGF synergistically enhanced the mRNA expression and production of IL-8. The stimulatory effect of EGF on IL-1beta-induced IL-8 production was completely abolished by the broad range tyrosine kinase inhibitor Herbimycin A, and considerably reduced by the receptor tyrosine kinase specific inhibitor PD 153035. Herbimycin A abolished IL-8 production induced by IL-1beta, whereas PD 153035 had no effect on the cytokine-induced IL-8 production. Furthermore, the p38 mitogen-activated protein (MAP) kinase inhibitor SB 203580 reduced IL-8 production induced by IL-1beta as well as by the combination of EGF and IL-1beta but had no effect on EGF-induced IL-8 production. In conclusion, the study demonstrates that EGF synergistically stimulates IL-8 production in the presence of IL-1beta and that tyrosine kinase(s) seem to be involved in the signalling pathway of IL-1beta and EGF. The synergistic interactions between EGF and IL-1beta on IL-8 production may play an essential role in the pathogenesis of the inflammatory disease periodontitis.


[Progressive cerebral parenchyma damage caused by recurrent arterial hypotension].
To date clinical and experimental investigations have focused on acute strokes and complete infarctions. Histological and immunological staining in animal experiments and improved imaging techniques in patients suggest that selective or incomplete infarction is a common pathomechanism. Incomplete infarction can manifest as laminar necrosis at autopsy and as leukoaraiosis in imaging studies. An important mechanism in the genesis of leukoaraiosis is vascular pathology of the long penetrating arteries of the deep white matter combined with episodes of decreased perfusion pressure or hypotension. We demonstrate that the cumulative effect of repetitive, moderate hypotensive episodes on cognitive performance or cerebral tissue has not been adequately studied and appreciated.


Timing of surgery for aneurysmal subarachnoid haemorrhage.
The timing of surgery to secure a ruptured aneurysm after a subarachnoid haemorrhage is an important issue. Early clipping of an aneurysm prevents rebleeding, a major cause of death after a subarachnoid haemorrhage. However, concerns about the possible deleterious effects of early surgery raise questions about the safety and efficacy of this approach. This review examines the randomised controlled evidence addressing the effect of surgery at different time intervals on the outcome after a subarachnoid haemorrhage. To determine whether the timing of surgery after a subarachnoid haemorrhage significantly influences overall management outcome. We searched the Cochrane Stroke Review Group Trials Register and in addition searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register (CENTRAL/CCTR). Colleagues were contacted to identify further studies and unpublished trials. All completed, unconfounded, truly randomised trials comparing "best medical treatment plus early surgery" with "best medical treatment plus delayed surgery". The authors selected trials for inclusion, or exclusion, according to the above criteria. An "intention to treat" analysis strategy was utilised. Only one randomised controlled trial addressing the timing of surgery after aneurysmal subarachnoid haemorrhage was identified. Patients undergoing early surgery tended to fare better than those undergoing late surgery (death or dependency at 3 months OR 0.37 95% CI 0.13,1.02). Patients undergoing surgery in the intermediate time period appeared to fare worse than those undergoing early surgery although confidence intervals were wide (death or dependency at 3 months OR 0.34 95% CI 0.12, 0.93). Based upon the limited randomised controlled evidence available, the timing of surgery was not a critical factor in determining outcome following a subarachnoid haemorrhage. Since the publication of the only randomised controlled study in 1989, techniques for the treatment of subarachnoid haemorrhage have progressed, questioning the validity of the conclusions in the modern era. Currently, most neurovascular surgeons elect to operate within 3 or 4 days of the bleed in good grade patients to minimise the chances of a devastating rebleed. However, the treatment of patients in poorer grades warrants further scrutiny in a randomised controlled trial.


Continuous theta burst stimulation for drug-resistant epilepsy.
Repetitive transcranial magnetic stimulation (rTMS) may have anti-epileptic effects, especially in patients with neocortical lesions. Initial clinical trials demonstrated that the duration of the seizure reducing effect is relatively short-lived. In the context of a chronic condition like epilepsy, theta burst stimulation (TBS) may represent a potential solution in optimizing treatment practicality and durability as it was demonstrated to be associated with longer-lasting after-effects. TBS has been studied extensively in diverse neuropsychiatric conditions, but a therapeutic TBS protocol has not previously been applied in epilepsy patients. We performed a prospective open-label pilot study of 4-day accelerated continuous TBS (cTBS) treatment in patients with neocortical drug-resistant epilepsy (DRE). A treatment session consisted of 5 cTBS trains, each comprising 600 pulses presented in 50 Hz triplet bursts every 200 ms, delivered at 10-min intertrain-intervals, targeted over the epileptic focus (EF) using a neuronavigation-guided figure-of-8 coil. Safety and feasibility, and seizure frequency were assessed as primary and secondary endpoints, respectively, over a 4-week baseline period, a 1-week treatment period and a 7-week follow-up period, using adverse event logging, electro-encephalography, cognitive, and psychological questionnaires and a seizure diary kept by the patients and/or caregivers. Seven subjects (4M:3F; median age 48, interquartile ranges 25) underwent the treatment protocol. Adverse events were reported in all subjects but were mild and transient. No clinical or electrographic seizures were evoked during or immediately following stimulation. No deterioration was found in cognition nor in psycho-emotional well-being following treatment. Treatment burden was acceptable, but seems to depend on clinical effect, duration of ongoing effect and stimulation site. Median weekly seizure frequency and ratio of seizure-free weeks did not change significantly in this small patient cohort. We report the results of the first ever trial of cTBS as a treatment for neocortical DRE. A 4-day accelerated cTBS protocol over the EF appears safe and feasible. Although the design and sample size of this open-label pilot study is unfit to reliably identify a therapeutic effect, results encourage further exploration of cTBS as an anti-epileptic treatment and potential optimization compared to conventional rTMS in a dedicated randomized controlled trial. (clinicaltrials.gov: NCT02635633).


Peripheral mural cell recruitment requires cell-autonomous heparan sulfate.
Blood vessel maturation and stability require recruitment of mural cells (MCs) to the nascent vessel. Loss or detachment of MCs causes vascular dysfunction in diseases. N-sulfation of heparan sulfate (HS) is required for platelet-derived growth factor B (PDGF-B) retention and platelet-derived growth factor receptor-beta (PDGFR-beta) signaling during MC recruitment. To analyze the specific role of MC-derived HS in this process, we inactivated HS synthesis in MCs. MC-specific loss of HS causes embryonic lethality associated with vascular patterning defects, edema, and hemorrhages during late gestation. MC recruitment in the skin is impaired, correlating with defective PDGFR-beta and transforming growth factor-beta (TGF-beta)-SMAD signaling. Accumulation of rounded cells positive for MC markers close to the vessels indicates defective polarization and migration of local MC progenitors. In contrast, MC recruitment and signaling in the central nervous system (CNS) are unaffected by MC HS loss. Our results suggest that HS is selectively required in a cell-autonomous manner, acting in cis with PDGFR-beta and TGF-beta receptors during induction/polarization and migration of local progenitor cells to the nascent vessel. Once MCs are in contact with the vessel, as during CNS vascularization, endothelial HS appears sufficient to facilitate PDGFR-beta activation in trans.


Musculoskeletal rehabilitation and sports medicine. 1. Head and spine injuries.
This self-directed learning module focuses on head, neck, and spine injuries that are frequent occurrences in sporting activity. It is part of the chapter on musculoskeletal rehabilitation and sports medicine in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. The physiatrist must be able to recognize not only the cause of the acute injury but also the functional consequences of the impairment. This article will discuss some of the more common head, neck, and spine injuries in patients engaged in sports activity and will suggest typical management options for these patients.


Effects of zuogui pill (see text) on Wnt singal transduction in rats with glucocorticoid-induced osteoporosis.
To reveal the mechanism of Zuogui Pill (see text) in treatment of glucocorticoid-induced osteoporosis from the angle of the Wnt signal transduction pathway and to provide further experimental evidence for expounding the scientific connotation of "the kidney dominating the bones" in TCM. Forty-two male Wistar rats were selected and randomly divided into three groups, control group (n = 12), model group (n = 15) and Zuogui Pill group (n = 15). Form the beginning, The rats were injected dexamethasone for eight weeks to make the model of osteoporosis, and the Zuogui Pill were administered intragastrically to the rats of Zuogui Pill group for eight weeks. The relative morphological parameters were measured in the undecalcified tibial slices. And the protein expression levels of Wnt1, LRP-5 and beta-catenin in rat tibial osteoblasts (OB) and bone marrow stromal cells (BMC) were detected by immunohistochemistry. Compared with the control group, TBV% and TFS% decreased significantly, while TRS% increased significantly, and the protein expression of Wnt1, LRP-5 and beta-catenin in OB and BMC decreased significantly in the model group. And compared with the model group, TBV% and TFS% increased significantly, and expression levels of Wnt1, LRP-5 and beta-catenin proteins increased significantly in the Zuogui pill group. Zuogui Pill can prevent and treat glucocorticoid-induced osteoporosis in rats by up-regulating the expression of the key signal molecules Wnt1, LRP-5 and beta-catenin in Wnt signal transduction pathway.


Impact and predictors of quality of life in adults diagnosed with a genetic muscle disorder: a nationwide population-based study.
To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, and symptom factors influencing quality of life. Adults (aged 16-90 years) with a confirmed clinical or molecular diagnosis of a genetic muscle disorder identified as part of a nationwide prevalence study were invited to complete an assessment of the impact of their condition. Quality of life was measured using the World Health Organization Quality of Life questionnaire. Impact was measured via the prevalence of symptoms and comparisons of quality of life against New Zealand norms. Multivariate regression models were used to identify the most significant predictors of quality of life domains. 490/596 participants completed the assessment (82.2% consent rate). Quality of life was lower than the general population on physical (t = 9.37 p < 0.0001, d = 0.54) social (t = 2.27 p = 0.02, d = 0.13) and environmental domains (t = 2.28 p = 0.02, d = 0.13), although effect sizes were small. No difference was found on the psychological domain (t = - 1.17 p = 0.24, d = 0.07). Multivariate regression models (predicting 42%-64% of the variance) revealed personal factors (younger age, being in employment and in a relationship), symptoms (lower pain, fatigue, and sleep difficulties), physical health (no need for ventilation support, fewer activity limitations and no comorbidities), and psychosocial factors (lower depression, anxiety, behavioural dyscontrol and higher self-efficacy, satisfaction with health care and social support) contributed to improved quality of life. A range of factors influence the quality of life in adults diagnosed with a genetic muscle disorder and some may serve as targets for multi-faceted intervention.


Epidemiology in protection and prevention against environmental mutagens/carcinogens. Examples from occupational medicine.
Subjects occupationally exposed to potential mutagens/carcinogens represent the most suitable groups for epidemiological studies aimed at assessing the risk for the individual or the offspring. Several cancer risks to humans have been detected by epidemiological studies performed in occupational settings. Cancer epidemiology studies have been able (a) to identify specific occupations or agents associated with the risk; (b) to verify the results of experimental studies; (c) to test the effectiveness of changes in production or preventive measures in decreasing risks. Reproductive epidemiology has suggested a risk of spontaneous abortions or of malformation in the offspring of workers exposed to some chemicals or occupations, but data are often conflicting due to methodological problems. With the aim of early assessment of risk in mind, the epidemiological use of indicators of exposure or of the early effect of exposure to genotoxic agents is increasingly applied to occupational groups. Cytological monitoring of subjects at risk of occupational cancer of lung or bladder is carried out mainly to diagnose precancerous lesions of target tissues. Cytogenetic methods (chromosome aberrations, SCE, micronuclei) in somatic cells provide a means for detecting early effects of occupational exposure to known or potential mutagens/carcinogens in selected groups of individuals, but their significance is widely debated. Monitoring of urinary mutagenicity, as applied in nurses handling cytostatic drugs, is an example of how an indicator of exposure to genotoxins can be used to evaluate the impact of preventive measures. Among the perspectives, biochemical epidemiology seems to be promising in detecting individuals genetically susceptible to cancer.


Redistribution of Intracellular Metabolic Flow in E. coli Improves Carbon Atom Economy for High-Yield 2,5-Dimethylpyrazine Production.
2,5-Dimethylpyrazine (2,5-DMP) is an important pharmaceutical intermediate and an important essence. Conventional chemical synthesis methods are often accompanied by toxic substances as by-products, and the biosynthesis efficiency of 2,5-DMP is insufficient for industrial applications. In this study, the tdh and soaao genes were overexpressed to enhance enzymatic and nonenzymatic reactions in metabolic pathways, and kbl was knocked out to block competitive branching carbon flow metabolic pathways. Finally, a genetically engineered Escherichia coli strain with the highest carbon recovery rate (30.18%) and the highest yield reported to date was successfully constructed, and 9.21 g·L-1 threonine was able to produce 1682 mg·L-1 2,5-DMP after 24 h. At the same time, an expression regulation strategy and whole-cell biocatalysis helped to eliminate the damage to cells caused by 2,5-DMP, aminoacetone, and reactive oxygen species generated by aminoacetone oxidase from S. oligofermentans, and the negative effect of 2-amino-3-ketobutyrate CoA ligase on the yield of 2,5-DMP in E. coli was also demonstrated.


Genetic programming assisted stochastic optimization strategies for optimization of glucose to gluconic acid fermentation.
This article presents two hybrid strategies for the modeling and optimization of the glucose to gluconic acid batch bioprocess. In the hybrid approaches, first a novel artificial intelligence formalism, namely, genetic programming (GP), is used to develop a process model solely from the historic process input-output data. In the next step, the input space of the GP-based model, representing process operating conditions, is optimized using two stochastic optimization (SO) formalisms, viz., genetic algorithms (GAs) and simultaneous perturbation stochastic approximation (SPSA). These SO formalisms possess certain unique advantages over the commonly used gradient-based optimization techniques. The principal advantage of the GP-GA and GP-SPSA hybrid techniques is that process modeling and optimization can be performed exclusively from the process input-output data without invoking the detailed knowledge of the process phenomenology. The GP-GA and GP-SPSA techniques have been employed for modeling and optimization of the glucose to gluconic acid bioprocess, and the optimized process operating conditions obtained thereby have been compared with those obtained using two other hybrid modeling-optimization paradigms integrating artificial neural networks (ANNs) and GA/SPSA formalisms. Finally, the overall optimized operating conditions given by the GP-GA method, when verified experimentally resulted in a significant improvement in the gluconic acid yield. The hybrid strategies presented here are generic in nature and can be employed for modeling and optimization of a wide variety of batch and continuous bioprocesses.


Detection of hippocampal pathology in intractable partial epilepsy: increased sensitivity with quantitative magnetic resonance T2 relaxometry.
Abnormal T2-weighted signal intensity in the hippocampus may be difficult to detect visually, and T2 mapping provides an objective means of assessing signal abnormality. We investigated 50 adult outpatients suffering from intractable partial epilepsy with MRI optimized to detect hippocampal and cortical gray matter abnormalities, and with MR T2 relaxation mapping. The range of normal hippocampal T2 relaxation times is small (99 to 106 msec), and the measurements are reproducible between observers. There were abnormal hippocampal T2 relaxation times in the hippocampus ipsilateral to the site of seizure origin in 70% of patients studied, with the more severe abnormality in the ipsilateral hippocampus in all cases. All hippocampal T2 measurements greater than 116 msec were associated with temporal lobe epilepsy and pathologic or MRI evidence of hippocampal sclerosis, or both. Bilateral abnormalities were present in 29% of cases with hippocampal sclerosis.


Free Methionine Levels in rin and Normal Isogenic Tomato Fruits Ripened in the Field or in Storage.
Free methionine levels in rin and normal tomato fruits were determined microbiologically. Similar levels (1750 mug/100 g fresh weight) for mature green fruits of both rin and a normal isogenic line suggest that the lack of ripening of rin fruits is not due to low methionine levels. Methionine levels of mature green rin and normal fruits were 1750 mug/ 100 g fresh weight. Normal fruits ripened either on or off the vine were 2860 and 2500 mug/100 g fresh weight, respectively. The rin fruits which were left on the plant or held in air at 20 C until soft and yellow were significantly lower in methionine than C(2)H(4)-treated rin fruits or any normal fruits. Harvested rin and normal fruits held at 20 C in continuously applied ethylene (10 mul/l) had higher methionine levels than comparable air controls; levels in treated rin fruits were significantly higher than those in normal fruits.


Longitudinal effects of FTO gene polymorphism on body composition, cardiorespiratory fitness, physical activity, inflammatory markers, and cardiovascular risk in children and adolescents. "The UP & DOWN study".
The role of polymorphism rs9939609 of the FTO gene has been related with fat mass and cardiovascular risk in adults, but it remains unclear in children and adolescents. Hence, the main aim of this study was to determine the FTO polymorphism effects on body composition, cardiorespiratory fitness (CRF), physical activity (PA), inflammatory markers, and cardiovascular risk both in cross-sectional analysis and after two-years of follow-up in children and adolescents. A total of 2129 participants were included in this study. The rs9939609 polymorphism was genotyped. Body composition measurements, CRF, and moderate-to-vigorous PA (MVPA) were determined at baseline and after two-year of follow-up. Moreover, plasma leptin and adiponectin were also determined as inflammatory markers. Furthermore, an index of cardiovascular disease risk factors (CVDRF-I) was calculated. Codominant (TT vs. TA vs. AA) and dominant (AA+AT vs. TT) models were applied for statistical analysis. The results showed a main effect of the FTO genotype on body composition measures in both first and third year (p < 0.05), with lower adiposity in TT compared with AA or AA+AT group. These differences were maintained after accounting for pubertal maturity, sex, age, VO2 max, and MVPA. Moreover, lower leptin level was observed in TT compared to AA+AT group in the third year. An interaction in Gene*Time*Sex was found in height and neck circumference in dominant model (p = 0.047; p = 0.020, respectively). No differences were found in CRF, MVPA nor CVDRF-I between groups. Hence, homozygous TT allele could be a protective factor against weight gain from early childhood.


Endosomal localization of the autoantigen EEA1 is mediated by a zinc-binding FYVE finger.
EEA1, a 162-kDa autoantigen associated with subacute cutaneous systemic lupus erythematosus, is a coiled-coil protein localized to early endosomes and cytosol. At its C terminus, the protein contains a cysteine-rich motif, which is shared with Vps27, Fab1, and Vac1, yeast proteins implicated in membrane traffic (Mu, F. T., Callaghan, J. M., Steele-Mortimer, O., Stenmark, H., Parton, R. G., Campbell, P. L., McCluskey, J., Yeo, J. P., Tock, E. P., and Toh, B. H. (1995) J. Biol. Chem. 270, 13503-13511). Here we show that this motif constitutes a genuine zinc binding domain, which we term the FYVE finger (based on the first letters of four proteins containing this motif). Profile-based data base searches identified the FYVE finger in 11 distinct proteins. The FYVE finger-containing C terminus of EEA1 was found to bind 2 mol equivalents of Zn2+. Mutations of conserved histidine and cysteine residues in the FYVE motif independently reduced zinc binding to 1 mol equivalent. Confocal immunofluorescence microscopy of transfected HEp2 cells revealed that the C-terminal part (residues 1277-1411) of EEA1 colocalizes extensively with a GTPase-deficient mutant of the early endosomal GTPase Rab5, while deletion of the FYVE finger or mutations that interfere with zinc binding cause a cytosolic localization. These results implicate the FYVE finger in the specific localization of EEA1 to endosomes.


Treatment of radiation maculopathy with intravitreal injection of bevacizumab (Avastin).
To evaluate the safety and efficacy of intravitreal injection of bevacizumab as a treatment option for radiation maculopathy secondary to plaque radiotherapy. Interventional case series of five patients who developed radiation maculopathy complicating plaque radiotherapy with ruthenium 106 for choroidal melanoma. One to two intravitreal injections of bevacizumab (0.5 mL) were given, with an interval of 4 weeks between each injection. The main outcome measures were visual acuity and results of clinical ophthalmic examination and optical coherence tomography. Preinjection visual acuity ranged from hand movements to 20/25. The average preinjection central macular thickness measured by optical coherence tomography was 351 microm. Three of five patients had no improvement in macular edema after treatment with a single injection of bevacizumab at the 2-week follow-up (average postinjection central macular thickness, 287 microm). Maculopathy in these three patients was long-standing (3-5 years). Improvement in visual acuity occurred in two patients (from 20/30 to 20/25 and from 20/25 to 20/20). Maculopathy in these two patients was diagnosed 1 week before treatment was offered. Resolution of macular edema occurred after a single injection in Patient 4 and after two injections in Patient 5. Patient 4 did not receive direct radiation to the fovea. All but one patient (Patient 5; dose, 8,000 cGy) received a radiation dose of 10,000 cGy to the tumor apex. In this series, treatment of radiation maculopathy with intravitreal injection of bevacizumab was useful in two patients as measured by improvement in visual acuity due to resolution of macular edema. These patients were younger and had macular edema for a shorter duration. One patient did not receive direct radiation to the fovea, and the other had a lower dose of radiation.


Measurement of ceftazidime concentration in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry. Application to critically ill patients and patients with osteoarticular infections.
Ceftazidime is an antibiotic belonging to the third generation of the cephalosporin family. It is indicated in the treatment of serious, simple or mixed bacterial infections, and its administration in continuous or intermittent infusion allows optimization of the concentration of antibiotic to keep it above the minimum inhibitory concentration. We developed and validated a chromatographic method by ultra-performance liquid chromatography-tandem mass spectrometry to measure ceftazidime concentration in human plasma. Following extraction with acetonitrile and 1,2-dichloroethane, the chromatographic separation was achieved using an Acquity ® UPLC ® BEH(TM) (2.1 × 100 mm i.d., 1.7 µm) reverse-phase C18 column, with a water-acetonitrile linear gradient containing 0.1% formic acid at a 0.4 mL/min flow rate. Ceftazidime and its internal standard (cefotaxime) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode using mass-to-charge transitions of 547.0 → 467.9/396.1 and 456.0 → 395.8/324.1, respectively. The limit of quantification was 0.58 mg/L and linearity was observed in the range 0.58-160 mg/L. Coefficients of variation and absolute relative biases were <9.8 and 8.4%. The mean recovery for ceftazidime was 74.4 ± 8.1%. Evaluation of the matrix effect showed ion enhancement, and no carry-over was observed. The validated method could be applied to daily clinical laboratory practice to measure the concentration of ceftazidime in plasma.


Completion Time Minimization for Multi-UAV Information Collection via Trajectory Planning.
Unmanned Aerial Vehicles (UAVs) are widely used as mobile information collectors for sensors to prolong the network time in Wireless Sensor Networks (WSNs) due to their flexible deployment, high mobility, and low cost. This paper focuses on the scenario where rotary-wing UAVs complete information collection mission cooperatively. For the first time, we study the problem of minimizing the mission completion time for a multi-UAV system in a monitoring scenario when considering the information collection quality. The mission completion time includes flying time and hovering time. By optimizing the trajectories of all UAVs, we minimize the mission completion time while ensuring that the information of each sensor is collected. This problem can be formulated as a mixed-integer non-convex one which has been proved to be NP-hard. To solve the formulated problem, we first propose a hovering point selection algorithm to select appropriate hovering points where the UAVs can sequentially collect the information from multiple sensors. We model this problem as a BS coverage problem with the information collection quality in consideration. Then, we use a min-max cycle cover algorithm to assign these hovering points and get the trajectory of each UAV. Finally, with the obtained UAVs trajectories, we further consider the UAVs can also collect information when flying and optimize the time allocations. The performance of our algorithm is verified by simulations, which show that the mission completion time is minimum compared with state-of-the-art algorithms.


Intraocular pressure-lowering effects of latanoprost and brimonidine therapy in patients with open-angle glaucoma or ocular hypertension: a randomized observer-masked multicenter study.
To compare the effect of treatment with latanoprost or brimonidine on intraocular pressure in patients with glaucoma or ocular hypertension and intraocular pressure inadequately controlled by monotherapy or dual therapy. Three hundred seventy-nine patients with primary open-angle glaucoma or ocular hypertension were recruited for this 6-month prospective, randomized, observer-masked multicenter study involving 30 eye clinics. All patients were receiving monotherapy or dual therapy that did not adequately control intraocular pressure. After appropriate washout periods, patients were randomized to treatment with latanoprost once daily or brimonidine twice daily. The main outcome measure was change in mean diurnal intraocular pressure after 6 months of treatment compared with baseline. Of the 379 randomized patients, 375 were included in the intent-to-treat analysis. From an overall baseline mean intraocular pressure of 25.0 mm Hg, latanoprost monotherapy reduced mean diurnal intraocular pressure by 7.1 +/- 3.3 mm Hg (mean +/- SD, P < 0.001), whereas brimonidine monotherapy yielded an intraocular-pressure reduction of 5.2 +/- 3.5 mm Hg (P < 0.001). This 1.9 mm Hg difference in intraocular-pressure reduction was significantly in favor of latanoprost (P < 0.001). Ocular allergy (P < 0.001) and systemic side effects (P = 0.005) were reported significantly less frequently by latanoprost-treated patients compared with brimonidine-treated patients. Both latanoprost and brimonidine reduced intraocular pressure in patients with glaucoma or ocular hypertension after 6 months of treatment. However, latanoprost once daily was significantly more effective than brimonidine twice daily in reducing mean diurnal intraocular pressure. Latanoprost was better tolerated with less frequently occurring ocular allergy and systemic side effects.


Pcid2 inactivates developmental genes in human and mouse embryonic stem cells to sustain their pluripotency by modulation of EID1 stability.
Self-renewal and differentiation are the hallmarks of embryonic stem cells (ESCs). However, it is largely unknown about how the pluripotency is regulated. Here we demonstrate that Pcid2 is required for the maintenance of self-renewal both in mouse and human ESCs. Pcid2 plays a critical role in suppression of ESC differentiation. Pcid2 deficiency causes early embryonic lethality before the blastocyst stage. Pcid2 associates with EID1 and is present in the CBP/p300-EID1 complex in the ESCs. We show that MDM2 is an E3 ligase for K48-linked EID1 ubiquitination for its degradation. For the maintenance of self-renewal, Pcid2 binds to EID1 to impede the association with MDM2. Then EID1 is not degraded to sustain its stability to block the HAT activity of CBP/p300, leading to suppression of the developmental gene expression. Collectively, Pcid2 is present in the CBP/p300-EID1 complex to control the switch balance of mouse and human ESCs through modulation of EID1 degradation.


Metastatic anal sac adenocarcinoma in a dog presenting for acute paralysis.
A 4-year old, female spayed terrier was referred for hind end paresis that rapidly progressed to paralysis. Spinal radiographs revealed vertebral collapse and bony lysis. Myelography confirmed spinal cord compression and surgical exploration found an extradural soft tissue mass. Metastatic anal sac adenocarcinoma was diagnosed at postmortem examination.


Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060.
Since atrial fibrillation (AF) is associated with increased risks of cardiovascular and cerebrovascular complications, estimations on the number of individuals with AF are relevant to healthcare planning. We aimed to project the number of individuals with AF in the Netherlands and in the European Union from 2000 to 2060. Age- and sex-specific AF prevalence estimates were obtained from the prospective community-based Rotterdam Study. Population projections for the Netherlands and the European Union were obtained from the European Union's statistics office. In the age stratum of 55-59 years, the prevalence of AF was 1.3% in men (95% CI: 0.4-3.6%) and 1.7% in women (95% CI: 0.7-4.0%). The prevalence of AF increased to 24.2% in men (95% CI: 18.5-30.7%), and 16.1% in women (95% CI: 13.1-19.4%), for those >85 years of age. This age- and sex-specific prevalence remained stable during the years of follow-up. Furthermore, we estimate that in the European Union, 8.8 million adults over 55 years had AF in 2010 (95% CI: 6.5-12.3 million). We project that this number will double by 2060 to 17.9 million (95% CI: 13.6-23.7 million) if the age- and sex-specific prevalence remains stable. We estimate that from 2010 to 2060, the number of adults 55 years and over with AF in the European Union will more than double. As AF is associated with significant morbidities and mortality, this increasing number of individuals with AF may have major public health implications.


The social networks of manureshed management.
Manureshed management-the strategic use of manure nutrients that prioritizes recycling between livestock systems and cropping systems-provides a comprehensive framework for sustainable nutrient management that necessitates the collaboration of many actors. Understanding the social dimensions of collaboration is critical to implement the strategic and technological requirements of functional manuresheds. To improve this understanding, we identified aspirational networks of actors involved in manureshed management across local, regional, and national scales, principally in the United States, elucidating key relationships and highlighting the breadth of interactions essential to successful manureshed management. We concluded that, although the social networks vary with scale, the involvement of a common core set of actors and relationships appears to be universal to the successful integration of modern livestock and crop production systems necessary for functional manuresheds. Our analysis also reveals that, in addition to agricultural producers, local actors in extension and advisory services and private and public sectors ensure optimal outcomes at all scales. For manureshed management to successfully integrate crop and livestock production and sustainably manage manure nutrient resources at each scale, the full complement of actors identified in these social networks is critical to generate innovation and ensure collaboration continuity.


Polycomb protein family member CBX7 plays a critical role in cancer progression.
CBX7 is a polycomb protein that participates in the formation of polycomb repressive complex 1. Apart from few exceptions, CBX7 expression is lost in human malignant neoplasias and a clear correlation between its downregulated expression and a cancer aggressiveness and poor prognosis has been observed. These findings indicate a critical role of CBX7 in cancer progression. Consistently, CBX7 is able to differentially regulate crucial genes involved in cancer progression and in epithelial-mesenchymal transition, as osteopontin and E-cadherin. Recent evidences indicate a role of CBX7 also in the modulation of response to therapy. In conclusion, CBX7 represents an important prognostic factor, whose loss of expression in general indicates a bad prognosis and a progression towards a fully malignant phenotype.


Small intestine bacterial overgrowth is frequent in cystic fibrosis: combined hydrogen and methane measurements are required for its detection.
Hydrogen breath test (BT) is commonly used as a diagnostic tool for the detection of small intestine bacterial overgrowth (SIBO). It was reported that colonic methane production is far more frequent in cystic fibrosis (CF) patients than in other subjects. Therefore, measuring exclusively hydrogen in the diagnostic breath test for diagnosing SIBO might be of limited value. We aimed to assess the usefulness of combined measurement of hydrogen and methane expiration for the diagnosis of SIBO in CF. The study comprised 62 CF patients aged 5 to 18 years. Three-hundred-ninety subjects assessed due to gastrointestinal symptoms for the presence of SIBO served as a comparative group. In all subjects hydrogen/methane BT using glucose was performed. A positive BT was defined as fasting hydrogen > or = 20 ppm or fasting methane > or = 10 ppm or a rise of > or = 12 ppm hydrogen or > or = 6 ppm methane over baseline during the test. In 23 (37.1%) CF patients and in 52 (13.3%) subjects from the comparative group abnormal BT results were found. In seven (11.3%) CF patients and 29 (7.4%) of the other subjects studied methane measurement allowed diagnosis of SIBO. Small intestine bacterial overgrowth is frequent in cystic fibrosis. For its detection in cystic fibrosis and other gastrointestinal patients, combined hydrogen and methane measurement instead of hydrogen breath test should be applied. Without the additional measurement of methane a significant percentage of SIBO will be missed.


Smooth pursuit of nonvisual motion.
Unlike saccades, smooth pursuit eye movements (SPEMs) are not under voluntary control and their initiation generally requires a moving visual target. However, there are various reports of limited smooth pursuit of the motion of a subject's own finger in total darkness (pursuit based on proprioceptive feedback) and to the combination of proprioception and tactile motion as an unseen finger was moved voluntarily over a smooth surface. In contrast, SPEMs to auditory motion are not distinguishable from pursuit of imagined motion. These reports of smooth pursuit of nonvisual motion cues used a variety of paradigms and different stimuli. In addition, the results have often relied primarily on qualitative descriptions of the smooth pursuit. Here, we directly compare measurements of smooth pursuit gain (eye velocity/stimulus velocity) to visual, auditory, proprioceptive, tactile, and combined tactile + proprioceptive motion stimuli. The results demonstrate high gains for visual pursuit, low gains for auditory pursuit, and intermediate, statistically indistinguishable gains for tactile, proprioceptive, and proprioceptive + tactile pursuit.


Phospholipid/fatty acid-induced secondary structural change in beta-lactoglobulin during heat-induced gelation.
Effects of phosphatidylcholine (PC) and the predominant fatty acids (FAs) in milk, butyrate, oleate, and palmitate, on secondary structural changes in beta-lactoglobulin (beta-LG) during heat-induced gelation were analyzed on the basis of circular dichroism (CD) spectra. Small-strain oscillatory measurements were carried out to characterize viscoelastic properties of the heat-induced gels. In the absence of added salt, PC and FAs induced helix formation of beta-LG on heating to 80 degrees C and increased the storage moduli (G') of heat-induced gels. In the presence of 500 mM NaCl, PC did not change the CD spectrum of beta-LG but decreased G'. In contrast, butyrate substantially unfolded beta-LG in 500 mM NaCl on heating, forming very elastic gels with increased G' values. Palmitate and oleate induced beta-LG gel formation at 25 degrees C without heating; heating to 80 degrees C almost completely unfolded beta-LG in 500 mM NaCl.


Osteopetrosis ('marble bone' disease).
Osteopetrosis is a hereditary disorder in which pathologic alteration of osteoclast resorption of bone results in thickening of cortical and lamellar bone. Before bone marrow transplantation, the infantile recessive form was uniformly fatal within the first two decades of life as a result of invasion of the marrow space by abnormal bone formation. The adult autosomal dominant form causes minimal morbidity and is usually diagnosed incidentally on routine radiographs. Although osteopetrosis is an extremely rare disorder, the study of this disease can provide insights into the formation of bone and the inheritance of disease.


A novel approach to local reliability of sequence alignments.
The pairwise alignment of biological sequences obtained from an algorithm will in general contain both correct and incorrect parts. Hence, to allow for a valid interpretation of the alignment, the local trustworthiness of the alignment has to be quantified. We present a novel approach that attributes a reliability index to every pair of residues, including gapped regions, in the optimal alignment of two protein sequences. The method is based on a fuzzy recast of the dynamic programming algorithm for sequence alignment in terms of mean field annealing. An extensive evaluation with structural reference alignments not only shows that the probability for a pair of residues to be correctly aligned grows consistently with increasing reliability index, but moreover demonstrates that the value of the reliability index can directly be translated into an estimate of the probability for a correct alignment.


The virtual desktop: the remote access solution.
The increasing expectation for easy, yet full remote access to library materials necessitates innovative thinking on the part of libraries. Other traditional methods of providing access don't always meet the needs of the library or the patrons. This paper describes the project of one library to develop a Virtual Desktop, making access easy to grant or withhold, and also making available a wider array of resources.


Neoadjuvant Therapy Using Checkpoint Inhibitors before Radical Cystectomy for Muscle Invasive Bladder Cancer: A Systematic Review.
Neoadjuvant chemotherapy is the standard of care before radical cystectomy for muscle invasive bladder cancer. Recently, checkpoint inhibitors have been investigated as a neoadjuvant treatment after the reported efficacy of checkpoint inhibitors in metastatic urothelial carcinoma. The aim of this systematic review is to investigate the role of checkpoint inhibitors as a neoadjuvant treatment for muscle invasive bladder cancer before radical cystectomy. Based on the PRISMA statement, a systematic review of the literature was conducted through online databases and the American Society of Clinical Oncology (ASCO) Meeting Library. Suitable publications were subjected to full-text assessment. The primary outcome of this review was to identify the impact of neoadjuvant immunotherapy on the oncological outcomes and survival benefits. From the retrieved 254 results, 8 studies including 404 patients were included. Complete response varied between 30% and 50%. Downstaging varied between 50% and 74%. ≥Grade 3 AEs were recorded in 8.6% of patients who received monotherapy with either Atezolizumab or Pembrolizumab. In patients who received combination treatment, the incidence of ≥Grade 3 AEs was 16.3% for chemoimmunotherapy and 36.5% for combined immunotherapy. A total of 373 patients (92%) underwent radical cystectomy. ≥Grade 3 Clavien-Dindo surgical complications were reported in 21.7% of the patients. One-year overall survival (OS) and relapse-free survival (RFS) varied between 81% and 92%, and 70% and 88%, respectively. The evidence on the use of immune checkpoint inhibitors in the setting of pre-radical cystectomy is quite limited, with noted variability within published trials. Combination with chemotherapy or another checkpoint inhibitor may boost response, although prospective studies with extended follow-up are needed to report on the survival advantages.


Rem2 signaling affects neuronal structure and function in part by regulation of gene expression.
The central nervous system has the remarkable ability to convert changes in the environment in the form of sensory experience into long-term alterations in synaptic connections and dendritic arborization, in part through changes in gene expression. Surprisingly, the molecular mechanisms that translate neuronal activity into changes in neuronal connectivity and morphology remain elusive. Rem2, a member of the Rad/Rem/Rem2/Gem/Kir (RGK) subfamily of small Ras-like GTPases, is a positive regulator of synapse formation and negative regulator of dendritic arborization. Here we identify that one output of Rem2 signaling is the regulation of gene expression. Specifically, we demonstrate that Rem2 signaling modulates the expression of genes required for a variety of cellular processes from neurite extension to synapse formation and synaptic function. Our results highlight Rem2 as a unique molecule that transduces changes in neuronal activity detected at the cell membrane to morphologically relevant changes in gene expression in the nucleus.


Regulation of matrix metalloproteinases and their inhibitors by interferon-beta: a longitudinal study in multiple sclerosis patients.
Matrix metalloproteinases (MMPs) represent a large family of proteolytic enzymes, with some members being implicated in the immunopathogenesis of multiple sclerosis (MS). Interferon (IFN)-beta is one of the current mainstays in MS therapy and known to downregulate the expression of MMP-9. However, only sparse information is available on the effects of IFN-beta on the other 20 members of the MMP family. This is a longitudinal analysis on the RNA expression pattern of all known MMPs and their endogenous inhibitors before and after 1 and 6 months of IFN-beta therapy. RNA expression levels were assessed in peripheral venous blood cells from 14 MS patients and 8 matched controls by real time-PCR. RNA expression levels before treatment differed in part in MS patients compared to healthy controls (MMP-9, MMP-14, MMP-19, TIMP-1, TIMP-2). Some of the MMPs responded to therapy specifically (MMP-8, MMP-9, MMP-19), whereas others remained unchanged over time. These data suggest that MMPs may differ in their expression levels in MS patients and that this group of enzymes is differentially regulated during the treatment with IFN-beta in MS for at least 6 months.


To Read More Papers, or to Read Papers Better? A Crucial Point for the Reproducibility Crisis.
The overflow of scientific literature stimulates poor reading habits which can aggravate science's reproducibility crisis. Thus, solving the reproducibility crisis demands not only methodological changes, but also changes in our relationship with the scientific literature, especially our reading habits. Importantly, this does not mean reading more, it means reading better.