Possible involvement of ERK 1/2 in UVA-induced melanogenesis in cultured normal human epidermal melanocytes.
UV-induced melanogenesis is a well known physiological response of human skin exposed to solar radiation; however, the signaling molecules involved in the stimulation of melanogenesis in melanocytes following UV exposure remain unclear. In this study we induced melanogenesis in vitro in normal human epidermal melanocytes using a single irradiation with UVA at 1 kJ/m2 and examined the potential involvement of mitogen-activated protein kinases (MAPK) as UVA-responsive signaling molecules in those cells. UVA irradiation did not affect the proliferation of melanocytes, but it did increase tyrosinase mRNA expression, which reached a maximum level 4 hr after UVA irradiation. The amount of tyrosinase protein, as quantitated by immunoblotting, was also increased at 24 hr following UVA irradiation. Among the MAPK examined, extracellular signal-related kinase (ERK) 1/2 was phosphorylated within 15 min of UVA irradiation, but no such phosphorylation was observed for c-Jun N-terminal kinases (JNK) or p38. Accordingly, the activity of ERK1/2 was also increased shortly after UVA irradiation. These responses of ERK1/2 to UVA irradiation were markedly inhibited when cells were pre-treated with N-acetyl-L-cysteine, an antioxidant, or with suramin, a tyrosine kinase receptor inhibitor. The formation of (6-4)photoproducts or cyclobutane pyrimidine dimers was not detected in cellular DNA after UVA irradiation. These findings suggest that a single UVA irradiation-induced melanogenesis is associated with the activation of ERK1/2 by upstream signals that originate from reactive oxygen species or from activated tyrosine kinase receptors, but not from damaged DNA.


Evaluation of conventional and non-conventional biomarkers of liver toxicity in greenhouse workers occupationally exposed to pesticides.
The liver plays a prominent role in maintenance of homeostasis and is the major organ for xenobiotic metabolism, including pesticides. Conventional liver function tests are widely used to assess hepatocellular and biliary system dysfunction by measuring serum levels of aminotransferases (ALT, AST) and cholestasis enzymes (alkaline phosphatase -ALP- and γ-glutamyl transferase -GGT-), respectively. Although these tests are not entirely specific for liver damage, their specificity increases when measured concurrently, but still have limited usefulness to predict early liver dysfunction. Hence, non-conventional biomarkers may have a better performance for the early detection of biochemical hepatotoxicity with a greater specificity and sensitivity. A cross-sectional study with a follow-up component was conducted on 175 greenhouse workers regularly exposed to pesticides under integrated production system, and 91 controls living in the same geographical area. All individuals were evaluated for conventional (ALT, AST, ALP, GGT) and non-conventional biomarkers of hepatotoxicity (ornithine transcarbamylase (-OTC-), Arginase-1 -ARG1- and glutathione S-transferase alpha -GSTα-) over two periods of the same crop season, one of high pesticide exposure and other of low exposure. A slight increase in AST was observed in greenhouse workers relative to controls, suggestive of subtle hepatocellular toxicity. Although ALP, ARG1 and GST-α levels were decreased in greenhouse workers, this might be related to a potential homeostatic mechanism that regulates their expression. Altogether, these findings do not represent unambiguous evidence of liver dysfunction (e.g., hepatocellular or biliary system impairment) but may be the result of the low-toxicity pesticides used by greenhouse workers.


Optimization of transmission and reconstruction parameters in angular displacement compounding using plane wave ultrasound.
In ultrasound elastography, plane-wave acquisitions and angular displacement compounding (ADC) are often used and combined to allow high frame rates and to improve accuracy of lateral displacement estimates, respectively. This study investigates the performance of displacement and strain estimation for ADC as a function of; the main-to-grating-lobe-amplitude ratio which decreases as a function of steering angle; plane-wave acquisition and Delay-and-Sum (DaS)-related parameters; and grating-lobe filter cut-off frequency. Three experiments were conducted with a block phantom to test ADC performance for displacement fields of varying complexity: a lateral transducer shift, phantom rotation and phantom deformation. Experiments were repeated for four linear array transducers (pitch-to-lambda ratios between 0.6 and 1.4). Best ADC performance was found for steering angles that resulted in a theoretically derived main-to-grating-lobe-amplitude ratio of 1.7 dB for pure lateral translation and 6 dB for predominately lateral strain or rotation. Temporal filtering to reduce grating lobe signal or shifting of the receive aperture to receive angles below or above the optimal angle, as dictated by the main-to-grating-lobe-amplitude ratio, did not improve results. The accuracy of lateral displacement and strain estimates was improved by apodization in transmission and a dedicated F-number in DaS (0.75) allowing incidence angles within ± 33° in the active aperture. ADC with the optimized settings as found in this study improves the accuracy of displacements and strain estimates up to 80.7% compared to non-ADC. Compared to ADC settings described in current literature, our optimization improved the accuracy by 11.9% to 75.3% for lateral displacement and strain, and by 89.3% to 96.2% for rotation. The accuracy of ADC in rotation seemed to depend highly on plane-wave and DaS-related parameters which may explain the major improvement compared to settings in current literature. The overall improvement by optimized ADC was statistically significant compared to non-ADC (p = 0.003) and literature (p = 0.002).


Association Mapping of Verticillium Wilt Disease in a Worldwide Collection of Cotton (Gossypium hirsutum L.).
Cotton (Gossypium spp.) is the best plant fiber source in the world and provides the raw material for industry. Verticillium wilt caused by Verticillium dahliae Kleb. is accepted as a major disease of cotton production. The most practical way to deal with verticillium wilt is to develop resistant/tolerant varieties after cultural practices. One of the effective selections in plant breeding is the use of marker-assisted selection (MAS) via quantitative trait loci (QTL). Therefore, in this study, we aimed to discover the genetic markers associated with the disease. Through the association mapping analysis, common single nucleotide polymorphism (SNP) markers were obtained using 4730 SNP alleles. As a result, twenty-three markers were associated with defoliating (PYDV6 isolate) pathotype, twenty-one markers with non-defoliating (Vd11 isolate) pathotype, ten QTL with Disease Severity Index (DSI) of the leaves at the 50-60% boll opening period and eight markers were associated with DSI in the stem section. Some of the markers that show significant associations are located on protein coding genes such as protein Mpv17-like, 21 kDa protein-like, transcription factor MYB113-like, protein dehydration-induced 19 homolog 3-like, F-box protein CPR30-like, extracellular ribonuclease LE-like, putative E3 ubiquitin-protein ligase LIN, pentatricopeptide repeat-containing protein At3g62890-like, fructose-1,6-bisphosphatase, tubby-like F-box protein 8, endoglucanase 16-like, glucose-6-phosphate/phosphate translocator 2, metal tolerance protein 11-like, VAN3-binding protein-like, transformation/transcription domain-associated protein-like, pyruvate kinase isozyme A, ethylene-responsive transcription factor CRF2-like, molybdate transporter 2-like, IRK-interacting protein-like, glycosylphosphatidylinositol anchor attachment 1 protein, U3 small nucleolar RNA-associated protein 4-like, microtubule-associated protein futsch-like, transport and Golgi organization 2 homolog, splicing factor 3B subunit 3-like, mediator of RNA polymerase II transcription subunit 15a-like, putative ankyrin repeat protein, and protein networked 1D-like. It has been reported in previous studies that most of these genes are associated with biotic and abiotic stress factors. As a result, once validated, it would be possible to use the markers obtained in the study in Marker Assisted Selection (MAS) breeding.


Juvenile Psammomatoid Ossifying Fibroma (JPOF) of Proximal Radius: A Rare Entity.
Juvenile psammomatoid ossifying fibroma (JPOF) is a rare fibro-osseous lesion that usually occurs in the facial bones. The pathognomonic histopathologic feature is the presence of spherical ossicles, which are similar to psammoma bodies. It is considered to be a unique lesion because of its reported tendency to occur in children and adolescents and its tendency for locally aggressive growth. Because this lesion is aggressive in nature with high recurrence rate, early detection and complete surgical excision are essential. Herein, we present a case of 11 year old girl, who presented to our clinic with history of gradual onset pain around right elbow associated with limitation of right forearm rotation for 3 months. After getting informed consent, we performed needle biopsy and histopathologically it was diagnosed as Psammomatoid type juvenile ossifying fibroma (JPOF) of proximal radius. We performed extensive debridement, curettage of entire cystic lesion involving the proximal radius and filled the cavity with allograft bone granules and intramedullary titanium elastic nail through fibular strut graft, bridging the cystic lesion. As far as our knowledge there is no reported case of psammomatoid type of juvenile ossifying fibroma of proximal radius. We believe that such tumors in long bones are aggressive and have tendency for recurrence. Definitive diagnosis is utmost important for proper planning, surgical excision and reconstruction of long bones and need regular follow up to look for any recurrence or malignant transformation.


Effect of laundry surfactants on surface charge and colloidal stability of silver nanoparticles.
The stability of silver nanoparticles (Ag NPs) potentially released from clothing during a laundry cycle and their interactions with laundry-relevant surfactants [anionic (LAS), cationic (DTAC), and nonionic (Berol)] have been investigated. Surface interactions between Ag NPs and surfactants influence their speciation and stability. In the absence of surfactants as well as in the presence of LAS, the negatively charged Ag NPs were stable in solution for more than 1 day. At low DTAC concentrations (≤1 mM), DTAC-Ag NP interactions resulted in charge neutralization and formation of agglomerates. The surface charge of the particles became positive at higher concentrations due to a bilayer type formation of DTAC that prevents from agglomeration due to repulsive electrostatic forces between the positively charged colloids. The adsorption of Berol was enhanced when above its critical micelle concentration (cmc). This resulted in a surface charge close to zero and subsequent agglomeration. Extended DLVO theory calculations were in compliance with observed findings. The stability of the Ag NPs was shown to depend on the charge and concentration of the adsorbed surfactants. Such knowledge is important as it may influence the subsequent transport of Ag NPs through different chemical transients and thus their potential bioavailability and toxicity.


GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families.
The Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder affecting limb and craniofacial development in humans. GCPS-affected individuals are characterized by postaxial polysyndactyly of hands, preaxial polysyndactyly of feet, macroephaly, a broad base of the nose with mild hypertelorism and a prominent forehead. The genetic locus has been pinpointed to chromosome 7p13 by three balanced translocations associated with GCPS in different families. This assignment is corroborated by the detection of two sporadic GCPS cases carrying overlapping deletions in 7p13 (ref. 7), as well as by tight linkage of GCPS to the epidermal growth factor receptor gene in 7p12-13 (ref. 8). Of the genes that map to this region, those encoding T cell receptor-gamma, interferon-beta 2, epidermal growth factor receptor, and Hox1.4, a potential candidate gene for GCPS, have been excluded from the region in which the deletions overlap. Here we show that two of the three translocations interup the GLI3 gene, a zinc-finger gene of the GLI-Krüppel family already localized to 7p13 (refs 5, 6). The breakpoints are within the first third of the coding sequence. In the third translocation, chromosome 7 is broken at about 10 kilobases downstream of the 3' end of GLI3. Our results indicate that mutations disturbing normal GLI3 expression may have a causative role in GCPS.


Minilaparoscopic varicocelectomy with preservation of testicular artery and lymphatic vessels by using intracorporeal knot-tying technique: five-year experience.
In this study we present our experience using minilaparoscopic intracorporeal knot tying to ligate internal spermatic veins (ISV) while sparing the spermatic artery and lymphatics. Minilaparoscopic varicocelectomies were performed in 87 patients between January 2004 and January 2009. All varicoceles were detected clinically according to the World Health Organization (WHO) classification and confirmed by scrotal color Doppler ultrasonography. The surgical indications were scrotal symptoms in 71, infertility in 16, and both conditions in 2. Three 3.5 mm minilaparoscopic ports were used for the operation. The ISVs were dissected and then ligated with intracorporeal knot-tying. The testicular artery and lymphatic vessels were carefully preserved to minimize procedure-related complications. Unilateral laparoscopic varicocelectomy was performed in 21 (24.2%) patients and bilateral in 66 (75.8%). Mean operative time was 71.1 ± 29.2 and 46.8 ± 12.6 min for bilateral and unilateral varicocelectomies, respectively. All patients were discharged within 24 h after surgery. Neither immediate major nor late procedure-related complications were noted. Of the 71 patients with scrotal symptoms, the symptoms completely subsided in 55 (77.5%) and partially subsided in 10 (14.1%). Only one (1.2%) recurrent varicocele was detected within a mean follow-up of 21 months (range = 3-42). Neither hydrocele formation nor testicular atrophy was found during the follow-up period. Our 5-year experience revealed that minilaparoscopic varicocelectomy with sparing of artery and lymphatic vessels could safely and effectively ligate all spermatic veins and preserve spermatic arteries and lymphatic channels without leading to a high varicocele persistence or recurrence.


Hypertonic Lactate to Improve Cerebral Perfusion and Glucose Availability After Acute Brain Injury.
Lactate promotes cerebral blood flow and is an efficient substrate for the brain, particularly at times of glucose shortage. Hypertonic lactate is neuroprotective after experimental brain injury; however, human data are limited. Prospective study (clinicaltrials.gov NCT01573507). Academic ICU. Twenty-three brain-injured subjects (13 traumatic brain injury/10 subarachnoid hemorrhage; median age, 59 yr [41-65 yr]; median Glasgow Coma Scale, 6 [3-7]). Three-hour IV infusion of hypertonic lactate (sodium lactate, 1,000 mmol/L; concentration, 30 µmol/kg/min) administered 39 hours (26-49 hr) from injury. We examined the effect of hypertonic lactate on cerebral perfusion (using transcranial Doppler) and brain energy metabolism (using cerebral microdialysis). The majority of subjects (13/23 = 57%) had reduced brain glucose availability (baseline pretreatment cerebral microdialysis glucose, < 1 mmol/L) despite normal baseline intracranial pressure (10 [7-15] mm Hg). Hypertonic lactate was associated with increased cerebral microdialysis lactate (+55% [31-80%]) that was paralleled by an increase in middle cerebral artery mean cerebral blood flow velocities (+36% [21-66%]) and a decrease in pulsatility index (-21% [13-26%]; all p < 0.001). Cerebral microdialysis glucose increased above normal range during hypertonic lactate (+42% [30-78%]; p < 0.05); reduced brain glucose availability correlated with a greater improvement of cerebral microdialysis glucose (Spearman r = -0.53; p = 0.009). No significant changes in cerebral perfusion pressure, mean arterial pressure, systemic carbon dioxide, and blood glucose were observed during hypertonic lactate (all p > 0.1). This is the first clinical demonstration that hypertonic lactate resuscitation improves both cerebral perfusion and brain glucose availability after brain injury. These cerebral vascular and metabolic effects appeared related to brain lactate supplementation rather than to systemic effects.


[Intramuscular route for the administration of the anti-flu vaccine in patients receiving oral anticoagulation therapy].
Comparison of safety and effectiveness of the intramuscular (IM) (deltoid) vs subcutaneous (s.c.) administration of the flu vaccine (FV) in patients on oral anticoagulation therapy. It was a phase IV, simple blind, 2-parallel groups, randomized trial developed in an urban primary care setting. We included patients taking oral anticoagulation therapy without FV contraindications. The IM administration of the FV in the experimental group was compared with a SC administration in the control group. 59 patients were included. The two groups were comparable at the beginning of the study. INR was not modified following s.c. (p = 0.38) or i.m. (p = 0.49) administration. No systemic side effects were observed. More cutaneous lesions were observed in the S.C. group (71.4%) when compared with the i.m. group (25.8%; p < 0.0001). For the remaining variables, we observed a tendency towards more reported pain in the SC group (35.7 vs 22.6%) and a larger brachial diameter (42 vs 29%) without significant differences. 3.2% of patients in the i.m. group and 7.1% in the s.c. group developed influenza symptoms without significant differences. Even though the results must be interpreted with caution, currently there appears to be no apparent contraindication for the i.m. administration of the FV. When it is administered subcutaneously, it tends to cause more side effects.


Identification of genomic features in environmentally induced epigenetic transgenerational inherited sperm epimutations.
A variety of environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. The process involves exposure of a gestating female and the developing fetus to environmental factors that promote permanent alterations in the epigenetic programming of the germline. The molecular aspects of the phenomenon involve epigenetic modifications (epimutations) in the germline (e.g. sperm) that are transmitted to subsequent generations. The current study integrates previously described experimental epigenomic transgenerational data and web-based bioinformatic analyses to identify genomic features associated with these transgenerationally transmitted epimutations. A previously identified genomic feature associated with these epimutations is a low CpG density (<12/100bp). The current observations suggest the transgenerational differential DNA methylation regions (DMR) in sperm contain unique consensus DNA sequence motifs, zinc finger motifs and G-quadruplex sequences. Interaction of molecular factors with these sequences could alter chromatin structure and accessibility of proteins with DNA methyltransferases to alter de novo DNA methylation patterns. G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks. Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA. The current study identified genomic features associated with sperm epimutations that may explain in part how these sites become susceptible for transgenerational programming.


The direct simulation of acoustics on Earth, Mars, and Titan.
With the recent success of the Huygens lander on Titan, a moon of Saturn, there has been renewed interest in further exploring the acoustic environments of the other planets in the solar system. The direct simulation Monte Carlo (DSMC) method is used here for modeling sound propagation in the atmospheres of Earth, Mars, and Titan at a variety of altitudes above the surface. DSMC is a particle method that describes gas dynamics through direct physical modeling of particle motions and collisions. The validity of DSMC for the entire range of Knudsen numbers (Kn), where Kn is defined as the mean free path divided by the wavelength, allows for the exploration of sound propagation in planetary environments for all values of Kn. DSMC results at a variety of altitudes on Earth, Mars, and Titan including the details of nonlinearity, absorption, dispersion, and molecular relaxation in gas mixtures are given for a wide range of Kn showing agreement with various continuum theories at low Kn and deviation from continuum theory at high Kn. Despite large computation time and memory requirements, DSMC is the method best suited to study high altitude effects or where continuum theory is not valid.


Neonatal sleep stage identification using long short-term memory learning system.
Neonatal sleep analysis at the neonatal intensive care units (NICU) is critical for the diagnosis of any brain growth risks during the early stages of life. In this paper, an investigation is carried out on the use of a long short-term memory (LSTM) learning system in automatic sleep stage scoring in neonates. The developed algorithm automatically classifies sleep stages based on inputs from a single channel EEG recording. Up to this date, only a single study have developed an approach for automatic sleep stage scoring in neonatal sleep signals using deep neural network (DNN). A total of 5095 sleep stages signals acquired from EEG recordings of the University of Pittsburgh are used in this study. The sleep stages are annotated by a medical doctor from the Pediatric Neurology Department of Case Western Reserve University for three neonatal sleep stages including the awake (W), active sleep (AS), and quiet sleep (QS) stages on every 60-s epoch. The signals are pre-processed through normalization and filtering. The resulted signals are divided following 4-, 6-, and 10-fold cross-validation schemes. The training and classification process is done using a bi-directional LSTM network classifier built with pre-defined training parameters. At the end, the developed algorithm is evaluated along with a complete summary table that reports the results of this study and other state-of-the-art studies. The current study achieved high levels of Cohen's kappa (κ), accuracy, and F1 score with 91.37%, 96.81%, and 94.43%, respectively. Based on the confusion matrix, the overall true positives percentage reached 95.21%. The developed algorithm gave promising results in automatic sleep stage scoring in neonatal sleep signals. Future work include LSTM architecture and training parameters improvements to enhance the overall accuracy of the classifier.


Mediterranean diet, physical activity and their combined effect on all-cause mortality: The Seguimiento Universidad de Navarra (SUN) cohort.
The health benefits of the Mediterranean diet (MedDiet) and of physical activity (PA) have been widely documented. However, no longitudinal studies have investigated their combined effect on mortality. We assessed the individual and combined effects of adherence to the MedDiet and PA on all-cause mortality. We used data from 19,467 participants from a prospective cohort of Spanish university graduates, the SUN cohort, followed-up between December 1999 and February 2016. Adherence to the MedDiet was assessed using four different dietary scores, categorizing the quantitative scores into tertiles of adherence. To assess multiple dimensions of PA, an 8-item score was built. Multivariable Cox regression models were used to study the individual and combined relationship of adherence to the MedDiet and PA with all-cause mortality. During a median follow-up of 10.3years, we registered 305 deaths. Compared with the lowest adherence to the MedDiet (<20 in the modified Mediterranean diet score), better adherence (23-30 points) was associated with lower mortality (multivariable-adjusted hazard ratio [HR]=0.66, 95% confidence interval [CI]: 0.46-0.96). Engaging in moderate or high levels of PA (versus lower levels) was associated with 44% and 52% relative reductions in mortality, respectively. High adherence to the MedDiet combined with engaging in higher amounts of PA showed a HR=0.36 (95% CI: 0.19-0.67). We documented that the combined effect of better adherence to the MedDiet and increased PA had multiplicative effects on mortality risk reduction.


The first year as a graduate nurse--an experience of growth and development.
The aim of this paper was to illuminate how recently graduated nurses experience their first year as a nurse. Graduate nurses are expected to identify themselves as members of an interdisciplinary team, to feel comfortable in chaos and to make and defend decisions. By graduation nurses expect to have the necessary competence to perform nursing. Recently graduated nurses lack competence, especially relating to leadership. A qualitative design was chosen and 12 nurses working in hospitals and home care were individually interviewed. The interviews were transcribed verbatim and the texts were analysed using manifest and latent content analysis. The nurses gave descriptions covering numerous experiences, interpreted and categorised in the following eight subcategories: uncertainty and chaos; need for induction; need for a supportive environment; need for recognition; awareness of responsibility; need for positive experiences; becoming experienced; and managing challenges. These subcategories gave reason for the three categories: experience of being new; gaining nurse experience; and gaining competence. The nurses described a tough start as a nurse, but they most of all gave descriptions interpreted as an experience of growth and development, which constituted the theme in this study. Recently graduated nurses have a positive attitude to the challenges of being a new nurse. Although the initial period as a nurse was tough, the nurses appreciated their experiences because they learnt from them. Recently graduated nurses should be spared from being the only nurse on duty. Employers both in hospital and home care should facilitate induction programmes for new graduate nurses.


Phenotypic convergence in a natural Daphnia population acclimated to low temperature.
Fluidity of a given membrane decreases at lower ambient temperatures, whereas it rises at increasing temperatures, which is achieved through changes in membrane lipid composition. In consistence with homeoviscous adaptation theory, lower temperatures result in increased tissue concentrations of polyunsaturated fatty acids (PUFAs) in Daphnia magna, suggesting a higher PUFA requirement at lower temperatures. However, so far homeoviscous adaptation has been suggested for single or geographically separated Daphnia genotypes only. Here, we investigated changes in relative fatty acid (FA) tissue concentrations in response to a lower temperature (15°C) within a D. magna population. We determined juvenile growth rates (JGR) and FA patterns of 14 genotypes that were grown on Chlamydomonas klinobasis at 15°C and 20°C. We report significant differences of JGR and the relative body content of various FAs between genotypes at either temperature and between temperatures. Based on slopes of reaction norms, we found genotype-specific changes in FA profiles between temperatures suggesting that genotypes have different strategies to cope with changing temperatures. In a hierarchical clustering analysis, we grouped genotypes according to differences in direction and magnitude of changes in relative FA content, which resulted in three clusters of genotypes following different patterns of changes in FA composition. These patterns suggest a lower importance of the PUFA eicosapentaenoic acid (EPA, C20:5ω3) than previously assumed. We calculated an unsaturation index (UI) as a proxy for membrane fluidity at 15°C, and we neither found significant differences for this UI nor for fitness, measured as JGR, between the three genotype clusters. We conclude that these three genotype clusters represent different physiological solutions to temperature changes by altering the relative share of different FAs, but that their phenotypes converge with respect to membrane fluidity and JGR. These clusters will be subjected to different degrees of PUFA limitation when sharing the same diet.


Comparative analysis of DNA word abundances in four yeast genomes using a novel statistical background model.
Previous studies have shown that the identification and analysis of both abundant and rare k-mers or "DNA words of length k" in genomic sequences using suitable statistical background models can reveal biologically significant sequence elements. Other studies have investigated the uni/multimodal distribution of k-mer abundances or "k-mer spectra" in different DNA sequences. However, the existing background models are affected to varying extents by compositional bias. Moreover, the distribution of k-mer abundances in the context of related genomes has not been studied previously. Here, we present a novel statistical background model for calculating k-mer enrichment in DNA sequences based on the average of the frequencies of the two (k-1) mers for each k-mer. Comparison of our null model with the commonly used ones, including Markov models of different orders and the single mismatch model, shows that our method is more robust to compositional AT-rich bias and detects many additional, repeat-poor over-abundant k-mers that are biologically meaningful. Analysis of overrepresented genomic k-mers (4≤k≤16) from four yeast species using this model showed that the fraction of overrepresented DNA words falls linearly as k increases; however, a significant number of overabundant k-mers exists at higher values of k. Finally, comparative analysis of k-mer abundance scores across four yeast species revealed a mixture of unimodal and multimodal spectra for the various genomic sub-regions analyzed.


Lipodystrophy in patients with juvenile dermatomyositis--evaluation of clinical and metabolic abnormalities.
Lipodystrophy and associated metabolic abnormalities are being increasingly recognized as complications of juvenile dermatomyositis (JDM). We investigated the prevalence of lipodystrophy and the extent of metabolic abnormalities related to lipoatrophic diabetes mellitus in patients with JDM. Twenty patients with JDM were evaluated for evidence of lipodystrophy and associated lipoatrophic diabetes mellitus. All patients underwent clinical assessment, laboratory investigations, and metabolic studies (oral glucose tolerance test, lipid studies, insulin antibodies). We found clinical evidence of lipodystrophy and lipoatrophic diabetes mellitus in 4 of 20 patients with JDM and metabolic abnormalities known to be associated with lipodystrophy in another 8 patients. The 20 patients with JDM were categorized as follows: Group 1 (Patients 1-4) consisted of patients with lipodystrophy and either diabetes mellitus (2 patients) or impaired glucose tolerance (2 patients); Group 2 (Patients 5-12): no lipodystrophy but abnormal glucose and/or lipid studies; Group 3 (Patients 13-20): no lipodystrophy and no abnormalities of glucose and lipid studies. We found 25% of patients with JDM have lipodystrophy, and 50% present with hypertriglyceridemia and insulin resistance. Screening for metabolic abnormalities in JDM should be included in routine followup because of the effect of lipodystrophy on longterm prognosis.


Heavy atom vibrational modes and low-energy vibrational autodetachment in nitromethane anions.
We report infrared spectra of nitromethane anion, CH3NO2 (-), in the region 700-2150 cm(-1), obtained by Ar predissociation spectroscopy and electron detachment spectroscopy. The data are interpreted in the framework of second-order vibrational perturbation theory based on coupled-cluster electronic structure calculations. The modes in the spectroscopic region studied here are mainly based on vibrations involving the heavier atoms; this work complements earlier studies on nitromethane anion that focused on the CH stretching region of the spectrum. Electron detachment begins at photon energies far below the adiabatic electron affinity due to thermal population of excited vibrational states.


Homology between cellulase genes of Trichoderma reesei: complete nucleotide sequence of the endoglucanase I gene.
The filamentous fungus Trichoderma reesei produces several endoglucanases (EG) and cellobiohydrolases (CBH) which are involved in cellulose hydrolysis in a complex synergistic manner. We have cloned and sequenced the gene and the full-length cDNA coding for the major endoglucanase EG-I, and compared this to the cbh1 gene sequence to clarify the relationship between the EG and CBH classes of cellulases. The deduced 437-amino acids (aa) long EG-I protein with a 22-aa long signal peptide is 45% identical in aa sequence with CBH-I. The best conserved region is found at the C terminus and shows about 70% homology. The data suggest that the two enzymes have arisen from a common ancestor by gene duplication. Despite this, the intron positions have not been conserved in these genes which both contain two short introns. The deduced EG-I sequence contains six putative N-glycosylation sites, and a putative O-glycosylated region is found near the C terminus, closely resembling a similar region at the C terminus of CBH-I. Comparison of the aa sequences suggests that the evolutionary divergence of EG-I from CBH-I has involved four separate 10-20 aa "deletions" from the ancestral protein.


[Malignant stromal tumor of the transverse colon. Case report].
Case report of a malignant stromal tumor of the transverse colon. Colon sarcomas are rare; the most frequent presentation is the leiomyosarcoma. Forty five cases of malignant stromal tumor have been reported in the international literature. The histogenesis of these mesenchymatous neoplasms is determined by ultrastructural analysis and immunohistochemical stains, nevertheless when special techniques are negative and there is uncertainty related to the cellular differentiation line (smooth muscle, neural or undifferentiated) it is preferable to call them stromal tumors of gastrointestinal tract. A 46 year old patient with the diagnosis of malignant stromal tumor of transverse colon and the prescribed treatment was reported. A case of a patient with the diagnosis of malignant stromal tumor in transverse colon is presented, who had as the main clinical features abdominal pain, transanal hemorrhage and finally intestinal occlusion. He was submitted to exploratory laparotomy finding a transverse colon intussusception, which was treated with an extended right hemicolectomy and a post surgical satisfactory recovery. Follow-up to three years hasn't found tumoral activity. Stromal tumors are rare in colon, treatment is a wide surgical resection with curative or palliative purposes.


Influence of exercise intensity on training-induced tendon mechanical properties changes in older individuals.
This study compared the effects of low vs. high intensity training on tendon properties in an elderly population. Participants were pair-matched (gender, habitual physical activity, anthropometrics, and baseline knee extension strength) and then randomly assigned to low (LowR, i.e., ~40 % 1RM) or high (High R, i.e., ~80 % 1RM) intensity resistance training programmes for 12 weeks, 3× per week (LowR, n = 9, age 74 ± 5 years; HighR, n = 8, age 68 ± 6 years). Patellar tendon properties (stiffness [K], Young's modulus [YM], cross-sectional area [T CSA], and tendon length [T L]) were measured pre and post training using a combination of magnetic resonance imaging (MRI), B-mode ultrasonography, dynamometry, electromyography and ramped isometric knee extensions. With training K showed no significant change in the LowR group while it incremented by 57.7 % in the HighR group (p < 0.05). The 51.1 % group difference was significant (p < 0.05). These differences were still apparent when the data was normalized for T CSA and T L, i.e., significant increase in YM post-intervention in HighR (p < 0.05), but no change in LowR. These findings suggest that when prescribing exercise for a mixed genders elderly population, exercise intensities of ≤40 % 1RM may not be sufficient to affect tendon properties.


Effectiveness of nitric-NPG as a conditioning agent for enamel.
This in vitro study was designed to measure the bond strength of composite resin to enamel treated with various regimes of HNO3-NPG (N-phenylglycine and glycidylmethacrylate) followed by application of PMDM (pyromellitic dianhydride and 2-hydroxyethyl methacrylate). Forty freshly extracted human teeth were prepared with a flat area entirely in enamel on the proximal surface and then divided into five groups. Group 1 was treated with 37% H3PO4, Group 2 with 2.5% HNO3-NPG while rubbing the enamel with the solution, Group 3 with 2.5% HNO3-NPG without rubbing, Group 4 with 37% H3PO4 plus 2.5% HNO3-NPG with rubbing, and Group 5 with 5% HNO3-NPG without rubbing. After drying, PMDM solution was applied to each specimen for 60 seconds. Unfilled resin was applied, cured for 20 seconds, and the composite resin was placed and cured from all sides for a total of 120 seconds. After water bath storage for 7 days, specimens were tested on an Instron machine at a crosshead speed of 2.0mm/min. The highest shear bond strengths measured were for Group 1 (22.7 MPa), followed by Group 2 (20.92 MPa). The lowest bond strength recorded was for Group 3 (14.43 MPa). The results of this study indicate that enamel surfaces treated with 2.5% HNO3-NPG solution, if the solution is rubbed during application, produce a bond strength comparable to that achieved by H3PO4 conditioning.


Dual-Stimuli-Responsive Nanotheranostics for Dual-Targeting Photothermal-Enhanced Chemotherapy of Tumor.
Stimuli-responsive nanotheranostics have been widely explored for precision medicine. Here, we developed a pH/light dual-stimuli-responsive nanotheranostic agent for biological/physical dual-targeting photothermal-enhanced chemotherapy of U87MG tumor. This nanotheranostic agent was composed of the RGD (Arg-Gly-Asp) peptide, melanin-coated magnetic nanoparticles (MMNs), doxorubicin (DOX), and indocyanine green (ICG), denoted as RMDI. The tumor accumulation of RMDI was simultaneously improved through biological active targeting by RGD and physical magnetic targeting by an external magnetic field at tumor tissues, which was proven by in vivo photoacoustic/magnetic resonance/fluorescence (PA/MR/FL) trimodal imaging. Under dual stimuli of the tumor acidic microenvironment and laser irradiation, both DOX and ICG were released in a controlled fashion, demonstrating impressive therapeutic outcomes against U87MG tumor both in vitro and in vivo, respectively. Owing to the synergistic photothermal/chemotherapy, the dual-stimuli-responsive and dual-targeting nanotheranostic agent completely ablated U87MG tumor in vivo without any tumor recurrence and biotoxicity. This nanotheranostic agent exhibited great potential in multimodal imaging-guided synergistic therapy of cancer.


Role of alternative pre-mRNA splicing in temperature signaling.
Developmental plasticity enables plants to respond rapidly to changing environmental conditions, such as temperature fluctuations. Understanding how plants measure temperature and integrate this information into developmental programs at the molecular level will be essential to breed thermo-tolerant crop varieties. Recent studies identified alternative splicing (AS) as a possible 'molecular thermometer', allowing plants to quickly adjust the abundance of functional transcripts to environmental perturbations. In this review, recent advances regarding the effects of temperature-responsive AS on plant development will be discussed, with emphasis on the circadian clock and flowering time control. The challenge for the near future will be to understand the molecular mechanisms by which temperature can influence AS regulation.


Evaluating a moving target: Using Practical Participatory Evaluation (P-PE) in hospital settings.
This article describes lessons learned about implementing evaluations in hospital settings. In order to overcome the methodological dilemmas inherent in this environment, we used a practical participatory evaluation strategy to engage as many stakeholders as possible in the process of evaluating a clinical demonstration project. Demonstration projects, in this context, push the envelope about what is known about effectiveness in novel settings, and turnover of staff and patient populations can present challenges to gathering optimal data. By using P-PE, we built capacity in the environment while expanding possibilities for data collection. Suggestions are made based on our experience.


The effect of hyperosmolality on the rate of heat production of quiescent trabeculae isolated from the rat heart.
We have measured the rate of heat production of isolated, quiescent, right ventricular trabeculae of the rat under isosmotic and hyperosmotic conditions, using a microcalorimetric technique. In parallel experiments, we measured force production and intracellular calcium concentration ([Ca2+]i). The rate of resting heat production under isosmotic conditions (mean +/- SEM, n = 32) was 100 +/- 7 mW (g dry wt)-1; it increased sigmoidally with osmolality, reaching a peak that was about four times the isosmotic value at about twice normal osmotic pressure. The hyperosmotic thermal response was: (a) abolished by anoxia, (b) attenuated by procaine, (c) insensitive to verapamil, ouabain, and external calcium concentration, and (d) absent in chemically skinned trabeculae bathed in low-Ca2+ "relaxing solution." Active force production was inhibited at all osmolalities above isosmotic. Passive (tonic) force increased to, at most, 15% of the peak active force developed under isosmotic conditions while [Ca2+]i increased, at most, 30% above its isosmotic value. We infer that hyperosmotic stimulation of resting cardiac heat production reflects, in large part, greatly increased activity of the sarcoplasmic reticular Ca2+ ATPase in the face of increased efflux via a procaine-inhibitable Ca(2+)-release channel.


Induction of c-fos expression in spinal neurons by nociceptive and nonnociceptive stimulation of LUT.
Expression of c-fos gene in spinal neurons was detected with an immunocytochemical technique to study the spinal processing of nociceptive and nonnociceptive input from the lower urinary tract (LUT) of the urethan-anesthetized rat. Two preparations were used to activate afferent pathways in the LUT: 1) the urinary bladder was exposed through an abdominal incision, and saline or 1% acetic acid solution was infused directly into the bladder lumen and expelled through the urethra; and 2) the bladder was catheterized through the urethra, and the urethral outlet was ligated to allow distension and reflex contractions to occur under isovolumetric conditions. The first preparation mimicked the physiological changes occurring during normal voiding, whereas the second preparation generated high (presumably nociceptive) pressures when the bladder contracted against a closed outlet. The results indicate that distension-induced voiding increased c-fos expression largely in the region of the sacral parasympathetic nucleus (52% of the total number of cells/L6 section) and the dorsal commissure (25% of the total number of cells), whereas nociceptive stimuli markedly increased the number of c-fos-positive cells in the dorsal commissure (3.5 x increase above the number induced by distension, representing 50% of the total number of cells/L6 section). Bladder contractions against a closed outlet elicited a distribution of c-fos-positive cells similar to that induced by chemical irritation. Drugs that suppressed bladder reflexes did not reduce c-fos induced by distension, indicating that voiding reflexes do not contribute to c-fos expression.


Problematic topic transitions in dysarthric conversation.
This study examined the nature of topic transition problems associated with acquired progressive dysarthric speech in the everyday conversation of people with motor neurone disease. Using conversation analytic methods, a video collection of five naturally occurring problematic topic transitions was identified, transcribed and analysed. These were extracted from a main collection of over 200 other-initiated repair sequences and a sub-set of 15 problematic topic transition sequences. The sequences were analysed with reference to how the participants both identified and resolved the problems. Analysis revealed that topic transition by people with dysarthria can prove problematic. Conversation partners may find transitions problematic not only because of speech intelligibility but also because of a sequential disjuncture between the dysarthric speech turn and whatever topic has come prior. In addition the treatment of problematic topic transition as a complaint reveals the potential vulnerability of people with dysarthria to judgements of competence. These findings have implications for how dysarthria is conceptualized and how specific actions in conversation, such as topic transition, might be suitable targets for clinical intervention.


Community perceptions of home environments that lead children & youth to the street in semi-rural Kenya.
Research with street-involved children and youth (SICY) in Sub-Saharan Africa over the past three decades has established a complex web of both micro and macro-level factors that simultaneously "push" and "pull" children and youth to the street. There is still little research with adult family and community members in communities from which SICY originate. Forty men and women from five semi-rural villages in Meru County, Kenya participated in a Rapid Rural Appraisal utilizing a fishbone diagram to explore main and underlying reasons for why children may be or may feel unwelcome in the home and thus migrate to the street. Responses were analyzed in terms of ecological levels, child or parent perspective, and the push/pull framework. Overall, community members identified families and households experiencing stress and lacking the necessary resources to successfully adjust and adapt. Four ecological levels of influence were proposed as main reasons, with parent and caregiver factors mentioned most often, followed by household factors, children's intrapersonal factors, and interpersonal (family) factors. Community and environmental level factors were also proposed as underlying factors. Analysis by gender revealed that both men and women emphasized push factors over pull factors, though men proposed more pull factors (from peers and street life) than women did. Men placed more responsibility on the children than women did, citing children's negative behaviors, dissatisfaction with home, and a desire for independence and work/income. Women, in contrast, emphasized children's feelings of being unloved and the experience of harsh punishment or abuse from caregivers. Findings suggest that interventions to reduce street involvement should support economically, medically, and psychologically vulnerable families and households through comprehensive family strengthening programs that build financial capacity, improve parenting and communication skills, and promote education over child work and labor.


Sympathetic nervous activity and renal and systemic hemodynamics in cirrhosis: plasma norepinephrine concentration, hepatic extraction, and renal release.
Systemic and renal neurovascular reactivity was investigated in eight patients with cirrhosis and in eight control subjects with fatty liver during postural changes. In the supine position, mean renal blood flow averaged 1.51 and 2.97 ml per gm per min in patients and controls, respectively (p less than 0.02). During tilting, renal blood flow changed significantly (p less than 0.05) and equally in patients and controls (15 degrees head-down tilt: 12 and 13% increase, respectively; 60 degrees head-up tilt: 27 and 32% decrease, respectively). Mean arterial blood pressure was significantly lower in patients than controls (82 vs. 95 mm Hg, p less than 0.05) but did not change during the tilt. Plasma norepinephrine (NE) concentration was significantly higher in another eight patients with cirrhosis than in eight healthy controls (mean: 0.45 vs. 0.21 ng per ml in recumbency, p less than 0.02). Following 60 degrees head-up tilt, the increase in NE was similar in both groups. In another 10 patients with cirrhosis in recumbency, the splanchnic arterial-hepatic venous extraction of NE averaged 0.43 (p less than 0.01), and the hepatic clearance of NE averaged 315 ml per min which is of the same order as previously reported in healthy controls. The right kidney released NE into the systemic circulation. Renal venous plasma NE exceeded arterial concentration by 34% (p less than 0.01). It is concluded that sympathetic nervous activity is enhanced in patients with cirrhosis, and that this hyperactivity may be responsible for renal vasoconstriction in these patients. However, systemic and renal neurovascular reactivity seems to be maintained even at an advanced stage of the disease.


[Dynamics of biometal distribution in breast milk].
The results of 352 atomic-absorption measurements of the concentrations of 8 basic biometals in breast milk samples from women of different age were investigated by variation-statistical and correlative analysis. It was found that in all the cases the distribution patterns of biometals were asymmetric. K, Na, Fe and Mn were marked by logarithmic distributions, whereas Ca, Mg, Zn and Cu by power distributions with the index 1/2. That was determined most likely by the physicochemical nature of the mechanisms by which milk homeostasis was controlled. It was shown that in assumption about the normal distribution pattern, commonly accepted in practice, might lead to noticeable errors in quantitative assessments and to erroneous qualitative conclusions. The most probable concentrations of the metals and the width of their distribution showed alterations in time, dissimilar for different metals, including extremal alterations, with the concentrations of the test metals changing 1-5-fold and elementary relations up to 10-fold. For K-Na, Fe-Mn, Zn-Cu and Fe-Cu pairs the interelementary relations of the presumably biochemical nature were discovered, with the stability of those relations being dependent on the time of lactation. The data on variations in the balance of biometals can be used in the design of improved substitutes of breast milk and formula feeding adapted to babies of different age.


[Optimal inoculation doses of meningococcal chemical polyvalent ABC-vaccine for immunizing children of different ages. II. A study of the immunological effectiveness of different doses of the preparation].
The study of meningococcal chemical polyvalent ABC-vaccine, manufactured by the Mechnikov Research Institute for Vaccines and Sera (Moscow), was carried out with the aim of finding the optimum vaccination doses for the immunization of children aged 0.5-15 years. In this study the effectiveness of the vaccine was evaluated by the determination of the titers of specific bactericidal antibodies in paired serum samples obtained before and 30 days after immunization. The analysis of the frequency of positive seroconversions and the levels of the geometric mean antibody titers allowed the authors to reveal the presence of a distinct relationship between the intensity of antibody production and the dose of the vaccine under test, used for immunization, as well as to establish that pronounced immune response to the optimum dose developed in 95-100% of the vaccinees. Taking into account the results obtained in the earlier studies of the safety and reactogenicity of the preparation (see Communication I), the optimum vaccination doses for the immunization of children of different age groups were established. On the basis of the statistical analysis of the characteristics of immune response to different doses of the preparation the following doses were chosen as optimum: 80 micrograms for children aged 0.5-2 years, 100 micrograms for children aged 3-7 years, 120 micrograms for children aged 8-11 years, 160 micrograms for children aged 12-15 years.


Herbal extracts used for upper respiratory tract infections: are there clinically relevant interactions with the cytochrome P450 enzyme system?
The regulatory requirements for assessing potential interactions between herbal medicinal products and other medicines can cause specific, additional phytopharmaceutical problems. In this short review we assess the state of our knowledge for herbal extracts commonly used as over the counter (OTC) products for upper respiratory infections and which in many cases are considered to have immunomodulatory effects. Overall, the data on the safety of these products is still limited and only in the case of Echinacea preparations can preliminary conclusions be drawn. The available evidence points to weak cytochrome P450 inhibition which is unlikely to be of clinical relevance.


Extensor mechanism disruption after total knee arthroplasty.
Extensor mechanism disruption is a rare and potentially devastating complication associated with total knee arthroplasty. Disruption can occur at the quadriceps or patellar tendons or, in the setting of a fracture, at the patella. Recognition of the risk factors for disruption and prevention via meticulous surgical technique are critical to avoid this complication. Various management techniques and the challenges associated with treatment have been described. Nonsurgical management consists of the use of walking aids and/or knee braces, which may not be acceptable for the active patient. Surgical options include primary repair and reconstructive techniques using allograft, autograft, synthetic material, and gastrocnemius rotational flaps. However, no single method has reliably demonstrated satisfactory outcomes. Although research on reconstructive procedures with synthetic materials has been promising, further study is need to assess the use of these materials.


The Effect of Local Anesthetics on Neutrophils in the Context of Different Isolation Techniques.
Various functions of polymorphonuclear neutrophils (PMNs) are related to diseases and postoperative plasma changes. The influence of some local anesthetics (LAs) on PMNs obtained by conventional isolation methods and their functions has already been demonstrated. This study investigates the effect of selected LAs on PMNs, comparing a new isolation method with conventional ones. To obtain the PMNs, we performed either gelafundin sedimentation, hypotonic lysis or density gradient centrifugation. Subsequently, PMNs were mixed with different concentrations of bupivacaine, levobupivacaine, lidocaine or ropivacaine. Live cell imaging and flow cytometry were performed to quantify the migration, ROS production, NETosis and antigen expression of PMNs. We found the inhibition of chemotaxis and ROS production by LAs. PMNs showed a strong reduction in time to half maximal NETosis in response to bupivacaine and lidocaine, but not to levobupivacaine and ropivacaine. We also found distinct differences in survival time and migration duration between the isolation methods. This suggests that the careful selection of LAs has a short-term impact on in vitro PMNs.


Suggested improvements for the allergenicity assessment of genetically modified plants used in foods.
Genetically modified (GM) plants are increasingly used for food production and industrial applications. As the global population has surpassed 7 billion and per capita consumption rises, food production is challenged by loss of arable land, changing weather patterns, and evolving plant pests and disease. Previous gains in quantity and quality relied on natural or artificial breeding, random mutagenesis, increased pesticide and fertilizer use, and improved farming techniques, all without a formal safety evaluation. However, the direct introduction of novel genes raised questions regarding safety that are being addressed by an evaluation process that considers potential increases in the allergenicity, toxicity, and nutrient availability of foods derived from the GM plants. Opinions vary regarding the adequacy of the assessment, but there is no documented proof of an adverse effect resulting from foods produced from GM plants. This review and opinion discusses current practices and new regulatory demands related to food safety.


[Wilm's tumor in children: review of 38 cases].
Analysis of the incidence of the Nephroblastoma and of its clinic, echographic and radiologic aspects. Review of 38 cases handled in the Pediatric Surgery Service of Santa Maria Hospital between January 1960 and January 1987. In addition to the distribution by age and stadiation, the results were studied in 3 groupings corresponding to successive therapeutic phases along this period. The survival is more favourable in the etary group under 3 years old and does not differ substantially in stages I and II. In the analysis of the prognostic to the therapeutic sequences, there was an evident improvement of survival from 0% before 1966 (Surgery and Radiotherapy) to 46.15% in the second phase, 1966-76, with the introduction of Chemotherapy (Actinomycina D). In the last phase after 1977, using the therapeutic scheme of National Wilms Tumour Study (NWTS) survival reached 80.95%. Trying to correlate the prognostic with the histologic type, it turns out to be difficult to make a criterious characterization in the cases submitted to pre-operative Radio and/or Chemotherapy. The advantage of this therapeutic attitude in parallel with the faulaification of the histologic type and the Tumour stadiation is hereby discussed.


A case of acute-onset paraplegia due to spinal tuberculosis in term pregnancy.
Acute paraplegia in pregnancy is uncommon but can result from pathology including Guillain-Barre syndrome, acute transverse myelitis, and spinal tuberculosis, also known as Pott's disease of the spine. India has a high incidence of tuberculosis (2.8 million cases annually) therefore spinal tuberculosis is a particularly important disease to consider during pregnancy. Management of spinal tuberculosis in pregnancy poses a challenge especially at term gestation as immobilization of the spine and maintaining supination is difficult, particularly at delivery.


An unusual case of fatty liver in a patient with desmoid tumor.
A desmoid tumor, also known as aggressive fibromatosis, is a rare benign neoplasm that arises from fascial or musculoaponeurotic tissues. It can occur in any anatomical location, most commonly the abdominal wall, shoulder girdle and retroperitoneum. The typical clinical presentation is a painless mass with a slow and progressive invasion of contiguous structures. It is associated with a high local recurrence rate after resection. Many issues regarding the optimal treatment of desmoid tumors remain controversial. Aggressive surgical resection with a wide margin (2-3 cm) remains the gold standard treatment with regard to preserving quality of life. Radiotherapy alone has been shown to be effective for the control of unresectable or recurrent lesions. Desmoid tumors tend to be locally infiltrative, therefore, the fields must be generous to prevent marginal recurrence. The radiation dose appropriate for treating desmoid tumors remains controversial. We present a 25-year-old Caucasian man with local recurrence of a desmoid tumor after repeated surgical resection, treated with radiotherapy. The patient achieved complete tumor regression at 4 mo after radiotherapy, and he is clinically free of disease at 12 mo after the end of treatment, with an acceptable quality of life. The patient developed short bowel syndrome as a complication of second surgical resection. Consequently, radiotherapy might have worsened an already present malabsorption and so led to steatohepatitis.


Mia40-dependent oxidation of cysteines in domain I of Ccs1 controls its distribution between mitochondria and the cytosol.
Superoxide dismutase 1 (Sod1) is an important antioxidative enzyme that converts superoxide anions to hydrogen peroxide and water. Active Sod1 is a homodimer containing one zinc ion, one copper ion, and one disulfide bond per subunit. Maturation of Sod1 depends on its copper chaperone (Ccs1). Sod1 and Ccs1 are dually localized proteins that reside in the cytosol and in the intermembrane space of mitochondria. The import of Ccs1 into mitochondria depends on the mitochondrial disulfide relay system. However, the exact mechanism of this import process has been unclear. In this study we detail the import and folding pathway of Ccs1 and characterize its interaction with the oxidoreductase of the mitochondrial disulfide relay Mia40. We identify cysteines at positions 27 and 64 in domain I of Ccs1 as critical for mitochondrial import and interaction with Mia40. On interaction with Mia40, these cysteines form a structural disulfide bond that stabilizes the overall fold of domain I. Although the cysteines are essential for the accumulation of functional Ccs1 in mitochondria, they are dispensable for the enzymatic activity of cytosolic Ccs1. We propose a model in which the Mia40-mediated oxidative folding of domain I controls the cellular distribution of Ccs1 and, consequently, active Sod1.


Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio.
Cross-sectional studies with binary outcomes analyzed by logistic regression are frequent in the epidemiological literature. However, the odds ratio can importantly overestimate the prevalence ratio, the measure of choice in these studies. Also, controlling for confounding is not equivalent for the two measures. In this paper we explore alternatives for modeling data of such studies with techniques that directly estimate the prevalence ratio. We compared Cox regression with constant time at risk, Poisson regression and log-binomial regression against the standard Mantel-Haenszel estimators. Models with robust variance estimators in Cox and Poisson regressions and variance corrected by the scale parameter in Poisson regression were also evaluated. Three outcomes, from a cross-sectional study carried out in Pelotas, Brazil, with different levels of prevalence were explored: weight-for-age deficit (4%), asthma (31%) and mother in a paid job (52%). Unadjusted Cox/Poisson regression and Poisson regression with scale parameter adjusted by deviance performed worst in terms of interval estimates. Poisson regression with scale parameter adjusted by chi2 showed variable performance depending on the outcome prevalence. Cox/Poisson regression with robust variance, and log-binomial regression performed equally well when the model was correctly specified. Cox or Poisson regression with robust variance and log-binomial regression provide correct estimates and are a better alternative for the analysis of cross-sectional studies with binary outcomes than logistic regression, since the prevalence ratio is more interpretable and easier to communicate to non-specialists than the odds ratio. However, precautions are needed to avoid estimation problems in specific situations.


The Outcome of Scleral Lens Fitting for Keratoconus With Resolved Corneal Hydrops.
To investigate the success and failure of scleral lens fitting in patients with keratoconus with resolved hydrops. Retrospective case series of patients with keratoconus who attended the Ophthalmology Department at Antwerp University Hospital, Belgium, and developed acute hydrops between January 1, 2015, and June 30, 2018. The exclusion criteria included amblyopia, mental retardation, and insufficient follow-up. Of the 25 patients with keratoconus with acute hydrops, 14 patients (16 eyes) were included in this study. Median age was 31 years (range 19-52 years). Before hydrops, the median maximum keratometry value of affected eyes was 81.3 D (range 66.3-108.3 D). Acute hydrops was managed medically in 5 eyes (31.3%), by observation in 5 eyes (31.3%), by application of bandage contact lens in 1 eye (6.3%), and compression corneal sutures in 5 eyes (31.3%). Contact lens fitting after hydrops was not necessary for 2 patients (2 eyes; 12.5%) because of excellent vision in the fellow eye. Of the remaining patients, 11 (68.8%) were successfully fitted with mini-scleral lenses, with a median visual acuity of 0.7 (0.5-0.9; decimal Snellen). Three patients (3 eyes; 18.8%) proceeded to graft surgery because of limited visual acuity with scleral lenses (n = 2) or persistent edema (n = 1). Scleral lenses are effective for providing satisfactory visual acuity after corneal hydrops in keratoconus. A scleral lens trial is advised before listing patients for graft surgery.


Autocrine regulation of biliary pathology by activated cholangiocytes.
The bile duct system of the liver is lined by epithelial cells (i.e., cholangiocytes) that respond to a large number of neuroendocrine factors through alterations in their proliferative activities and the subsequent modification of the microenvironment. As such, activation of biliary proliferation compensates for the loss of cholangiocytes due to apoptosis and slows the progression of toxic injury and cholestasis. Over the course of the last three decades, much progress has been made in identifying the factors that trigger the biliary epithelium to remodel and grow. Because a large number of autocrine factors have recently been identified as relevant clinical targets, a compiled review of their contributions and function in cholestatic liver diseases would be beneficial. In this context, it is important to define the specific processes triggered by autocrine factors that promote cholangiocytes to proliferate, activate neighboring cells, and ultimately lead to extracellular matrix deposition. In this review, we discuss the role of each of the known autocrine factors with particular emphasis on proliferation and fibrogenesis. Because many of these molecules interact with one another throughout the progression of liver fibrosis, a model speculating their involvement in the progression of cholestatic liver disease is also presented.


Ganglioside treatment and improved axonal regeneration capacity in experimental diabetic neuropathy.
The efficacy of gangliosides in enhancing axonal regeneration and maturation in the early stages of diabetic neuropathy was assessed by quantitative analysis of immunostained serial sections of the sciatic nerve. Sprague-Dawley rats were made diabetic with a single injection of alloxan (100 mg/kg). One week later they were injected daily intraperitoneally with either a highly purified ganglioside mixture (10 mg/kg) or sterile saline for 4 wk. At the end of the treatment, sciatic nerves were crushed and allowed to regenerate for 1 wk without ganglioside treatment. The animals were then killed, and the nerves were frozen and processed for immunohistochemistry and electron microscopy. The number of regrowing axons was counted with a computerized image-analysis system on cross sections taken at predefined distances along the regenerating stump and stained with monoclonal antibody iC8 specific for the 145,000-Mr subunit of the neurofilaments. In untreated diabetic animals the number of axons able to regenerate and sustain elongation for greater than or equal to 13 mm from the crush point was reduced by 40% with respect to control rats. Ganglioside treatment was effective in compensating almost completely for this dramatic reduction. Electron microscopy confirmed that the immunofluorescence counts corresponded to regenerating axons containing neurofilaments. These results suggest that gangliosides are able to compensate for the derangements of axonal transport of cytoskeletal proteins reported in experimental diabetic neuropathy.


Examining the Accuracy of Ultrasound-Guided Lumbar Transforaminal Injection Controlled by Fluoroscopic Imaging in Patients with Lumbar Radiculopathy: A Modified Technique.
To present a new sonographic approach for lumbar transforamianal injection and compared it with traditional fluoroscopicguided approach. This interventional clinical study was conducted on 30 patients with a history of radicular lowback pain and a recent MRI indicating root compression. On the prone position, with the curve of ultrasound transducer on the parasagittal oblique position, a peripheral venous catheter (# 16) was advanced to the lamina through out-of-plane technique. Then, the transducer position was changed to axial position and an epidural catheter was placed about 8 cm away from midline and advanced under sonography guide with the in-plane technique to the intervertebral foramen. The level and the situation of needle was controlled with fluoroscopy and documented when the corticosteroid (triamcinolone) was injected. Also, pain scores for patients were documented and analyzed with SPSS-22 software. After controlling with fluoroscopy, from all 38 levels of injection, 36 levels were correctly achieved. Of all 36 injections on right levels, all injections were performed in the correct position (in intervertebral foramen). The patients? pain dramatically decreased during the first month after injection (p < 0.001), but after that, it remained unchanged. In our study, transforaminal injection was administered using the modified new technique, which was found to be safe and accurate in comparison with the fluoroscopy, as the popular gold standard technique.


CytoCopasi: A Chemical Systems Biology Target and Drug Discovery Visual Data Analytics Platform.
Target discovery and drug evaluation for diseases with complex mechanisms call for a streamlined chemical systems analysis platform. Currently available tools lack the emphasis on reaction kinetics, access to relevant databases, and algorithms to visualize perturbations on a chemical scale providing quantitative details as well streamlined visual data analytics functionality. CytoCopasi, a Maven-based application for Cytoscape that combines the chemical systems analysis features of COPASI with the visualization and database access tools of Cytoscape and its plugin applications has been developed. The diverse functionality of CytoCopasi through ab initio model construction, model construction via pathway and parameter databases KEGG and BRENDA is presented. The comparative systems biology visualization analysis toolset is illustrated through a drug competence study on the cancerous RAF/MEK/ERK pathway. The COPASI files, simulation data, native libraries, and the manual are available on https://github.com/scientificomputing/CytoCopasi. Supplementary data is available at Bioinformatics online.


Effects of intravenous lipopolysaccharide infusion on glucose and insulin dynamics in horses with equine metabolic syndrome.
To test the hypothesis that glucose and insulin dynamics during endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS). 6 healthy adult mares and 6 horses with EMS. Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline insulin-modified frequently sampled IV glucose tolerance tests were performed 27 hours before and then repeated at 0.5 and 21 hours after infusion. Results were assessed via minimal model analysis and area under the curve values for plasma glucose and serum insulin concentrations. Lipopolysaccharide infusion decreased insulin sensitivity and increased area under the serum insulin concentration curve (treatment × time) in both healthy and EMS-affected horses, compared with findings following saline solution administration. The magnitude of increase in area under the plasma glucose curve following LPS administration was greater for the EMS-affected horses than it was for the healthy horses. Horses with EMS that received LPS or saline solution infusions had decreased insulin sensitivity over time. Glucose and insulin responses to endotoxemia differed between healthy horses and horses with EMS, with greater loss of glycemic control in EMS-affected horses. Horses with EMS also had greater derangements in glucose and insulin homeostasis that were potentially stress induced. It may therefore be helpful to avoid exposure of these horses to stressful situations.


Higher diet quality is inversely associated with mortality in African-American women.
Diet quality has been inversely associated with overall mortality in white populations, but the evidence in African-American populations is limited. The goal of the present study was to assess diet quality in relation to all-cause mortality in the Black Women's Health Study, a follow-up study of African-American women begun in 1995. Data used in this study were obtained via biennial questionnaires from 1995 to 2011. Based on food-frequency questionnaire data collected in 1995 and 2001, we calculated an index-based diet quality score [Dietary Approaches to Stop Hypertension (DASH)] and derived dietary patterns (prudent and Western) with the use of factor analysis. We followed 37,001 women who were aged 30-69 y and free of cancer, cardiovascular disease, and diabetes at baseline for mortality through 2011. Multivariable Cox regression was used to estimate HRs and 95% CIs. Analyses were conducted in 2014. Based on a total of 1678 deaths during 16 y of follow-up, higher DASH scores were associated with reduced all-cause mortality (HR: 0.75; 95% CI: 0.63, 0.89 for highest vs. lowest quintiles). The DASH components most strongly associated with lower mortality were high intake of whole grains and low intake of red and processed meat. A Western dietary pattern, characterized by high intake of red and processed meat, was associated with increased all-cause mortality rates (HR: 1.37; 95% CI: 1.17, 1.60 for highest vs. lowest quintiles of score); a prudent dietary pattern was not associated with risk. A DASH-style diet high in intake of whole grains and low in consumption of red meat is associated with reduced mortality rates in healthy African-American women.


Total RNA, rRNA and poly(A)+RNA abundances during aging in Caenorhabditis elegans.
This is the second in a series of studies in which we characterize gene expression at the level of RNA during aging in the nematode Caenorhabditis elegans. Here, we quantitatively analyzed total RNA, poly(A)+ RNA, and ribosomal RNA as a function of chronological age in two different strains (TJ1060 and TJ1061) having wild-type life spans and in a long-lived age-1 mutant strain (TJ1062). In addition, we compared the age-dependent abundance patterns of these RNAs in two different culture environments. Total RNA yield did not show a consistent pattern of age-related changes. However, total RNA yield was significantly higher in all three strains when grown on agar than when grown in liquid. In addition, total RNA yield was significantly lower from strain TJ1061 than from strain TJ1060 and TJ1062. Relative to total RNA, rRNA did not exhibit any consistent differences with age, strain or environment. Poly(A)+ RNA decreased by 23-43% in old animals from the long-lived strain and one of the wild-type strains, but was not changed in the second wild-type strain. In addition, control experiments to determine the amount of RNA contributed by E. coli bacteria (present in the nematode culture medium as a food source) suggest that the age-1 mutant strain has a lower bacterial infection rate, which may contribute to the increased life span of this strain.


Cognitive enhancers for the treatment of ADHD.
Attention-deficit hyperactivity disorder (ADHD) is associated with multiple cognition-related phenotypic features in both children and adults. This review aims to clarify the role of cognition in ADHD and how prevailing treatments, which are often highly effective at reducing the clinical symptoms of the disorder, fare in modulating ADHD-related cognitive processes. First, we consider how the broad construct of cognition can be conceptualized in the context of ADHD. Second, we review the available evidence for how a range of both pharmacological and non-pharmacological interventions have fared with respect to enhancing cognition in individuals affected by this pervasive disorder. Findings from the literature suggest that the effects across a broad range of pharmacological and non-pharmacological interventions on the characteristic symptoms of ADHD can be distinguished from their effects on cognitive impairments. As such the direct clinical relevance of cognition enhancing effects of different interventions is somewhat limited. Recommendations for future research are discussed, including the identification of cognition-related endophenotypes, the refinement of the ADHD clinical phenotype, and studying the difference between acute and chronic treatment regimens.


"Top of the basilar" syndrome.
Infarction of rostral brainstem and cerebral hemispheral regions fed by the distal basilar artery causes a clinically recognizable syndrome characterized by visual, oculomotor, and behavioral abnormalities, often without significant motor dysfunction. Rostral brainstem infarction produces oculomotor and pupillary signs that are identical to those in thalamic hemorrhage. Somnolence, vivid hallucinations and dreamlike behavior may also accompany rostral brainstem infarction. Temporal and occipital infarctions are frequently accompanied by hemianopia with distinctive characteristics, fragments of the Balint syndrome, amnestic dysfunction, and agitated behavior. The "top of the basilar" syndrome is most often due to an embolus.


The role of Bruton's tyrosine kinase in B-cell development and function: a genetic perspective.
Mutations in Bruton's tyrosine kinase (Btk) result in the B-cell immunodeficiencies X-linked agammaglobulinemia in humans and X-linked immunodeficiency in mice. These diseases are characterized by blocks in B-cell development at multiple stages and impaired function of residual mature B cells. This review focuses on a series of in vivo genetic studies that have begun to define the mechanism by which Btk regulates B-cell development and function. The functional interactions between Btk and other signaling molecules defined by this approach are more complex than initially appreciated from in vitro biochemical and cell culture studies.


The Pivotal Role of the Lymphovascular System in Cancer Metastasis: future perspectives.
Nodal status is the most important predictor in patients with solid cancer. In general, sentinel lymph node is the gateway to regional nodal metastasis and beyond. Biomarkers and gene profiles are being developed to stage and subgroup cancer patients more accurately for more effective personalized therapy.


Acute lung injury complicating acute kidney injury: A model of endogenous αKlotho deficiency and distant organ dysfunction.
The lung interfaces with atmospheric oxygen via a large surface area and is perfused by the entire venous return bearing waste products collected from the whole body. It is logical that the lung is endowed with generous anti-oxidative capacity derived both locally and from the circulation. The single-pass pleiotropic alpha-Klotho (αKlotho) protein was discovered when its genetic disruption led to premature multi-organ degeneration and early death. The extracellular domain of αKlotho is cleaved by secretases and released into circulation as endocrine soluble αKlotho protein, exerting wide-ranging cytoprotective effects including anti-oxidation on distant organs including the lung, which exhibits high sensitivity to circulating αKlotho insufficiency. Because circulating αKlotho is derived mainly from the kidney, acute kidney injury (AKI) leads to systemic αKlotho deficiency that in turn increases the risks of pulmonary complications, i.e., edema and inflammation, culminating in the acute respiratory distress syndrome. Exogenous αKlotho increases endogenous anti-oxidative capacity partly via activation of the Nrf2 pathway to protect lungs against injury caused by direct hyperoxia exposure or AKI. This article reviews the current knowledge of αKlotho antioxidation in the lung in the setting of AKI as a model of circulating αKlotho deficiency, an under-recognized condition that weakens innate cytoprotective defenses and contributes to the dysfunction in distant organs.


Abcb and Abcc transporter homologs are expressed and active in larvae and adults of zebra mussel and induced by chemical stress.
Multixenobiotic resistance (MXR) of aquatic invertebrates has so far been associated with cellular efflux activity mediated by P-glycoprotein (ABCB1) and MRP (multidrug resistance protein; ABCC) type ABC (ATP binding cassette) transporters. Expression and activity of an abcb1/Abcb1 homolog has been shown in eggs and larvae of the zebra mussel Dreissena polymorpha. Here we report identification of a partial cDNA sequence of an abcc/Abcc homolog from zebra mussel that is transcribed and active as a cellular efflux transporter in embryos and gill tissue of adult mussels. Transcript expression levels were comparatively low in eggs and sharply increased after fertilization, then maintaining high expression levels in 1 and 2 dpf (days post fertilization) larvae. MK571, a known inhibitor of mammalian ABCC transporters, blocks efflux of calcein-am in larvae and gill tissue as indicated by elevated calcein fluorescence; this indicates the presence of active Abcc protein in cells of the larvae and gills. Dacthal and mercury used as chemical stressors both induced expression of abcb1 and abcc mRNAs in larvae; accordingly, assays with calcein-am and ABCB1 inhibitor reversin 205 and ABCC inhibitor MK571 indicated enhanced Abcb1 and Abcc efflux activities. Responses to chemicals were different in gills, where abcb1 transcript abundances were enhanced in dacthal and mercury treatments, whereas abcc mRNA was only increased with mercury. Abcb1 and Abcc activities did not in all cases show increases that were according to respective mRNA levels; thus, Abcc activity was significantly higher with dacthal, whereas Abcb1 activity was unchanged with mercury. Our data indicate that abcb1/Abcb1 and abcc/Abcc transporters are expressed and active in larvae and adult stages of zebra mussel. Expression of both genes is induced as cellular stress response, but regulation appears to differ in larvae and tissue of adult stages.


The impact of HIV on infectiousness of pulmonary tuberculosis: a community study in Zambia.
To examine the impact of HIV on infectiousness of pulmonary tuberculosis (TB). A cross-sectional tuberculin survey carried out among household contacts of HIV-1-positive and negative patients with bacteriologically confirmed pulmonary TB. Contacts were also examined for active TB. Index cases were recruited from patients attending the University Teaching Hospital in Lusaka, Zambia and household contacts were examined during visits to their homes within Lusaka. A total of 207 contacts of 43 HIV-positive patients, and 141 contacts of 28 HIV-negative patients with pulmonary TB were examined. Proportion of contacts of HIV-positive and negative index cases with a positive tuberculin response (diameter of induration > or = 5 mm to a dose of 2 tuberculin units). Fifty-two per cent of contacts of HIV-positive pulmonary TB patients had a positive tuberculin response compared with 71% of contacts of HIV-negative patients (odds ratio, 0.43; 95% CI, 0.26-0.72; P < 0.001). This difference persisted after allowing for between-household variations in the tuberculin response. Tuberculin response in the contact was related to age of contact, intimacy with the index case and crowding in the household. However, the effect of HIV status of the index case was not confounded by these variables. Tuberculin response in the contact was also related to the number of bacilli seen in the sputum smear of the index case which partially explained the effect of HIV status of the index case. Active TB was diagnosed in 4% of contacts of HIV-positive and 3% of contacts of HIV-negative cases, respectively (P = 0.8). HIV-positive patients with pulmonary TB may be less infectious than their HIV-negative counterparts and this may partly be explained by lower bacillary load in the sputum.


Birefringence and polarization effects in fiber gyroscopes.
A formalism is presented for treating birefringence and polarization in fiber optic sensors. This formalism is applied to study theoretical characteristics of fiber gyroscopes which are operated with various states of polarization of the input light including nonpolarized and partially polarized light, which have potentially useful characteristics. Measurements supporting the theoretical predictions are described.


Chest pain, troponin rise, and ST-elevation in an adolescent boy following the use of the synthetic cannabis product K2.
"Legal highs" such as K2, which typically contain synthetic cannabinoids, are increasingly popular with adolescents around the world. We have limited knowledge concerning their toxicity or adverse effects and their mechanism of action is poorly understood. While synthetic cannabinoids have been linked to adverse cardiovascular effects, cases of ST-elevation myocardial infarction (STEMI) associated with K2 use are exceedingly rare. We report a case of a 14-year-old boy who suffered an STEMI after smoking K2. To our knowledge, this is not only the youngest case of an STEMI associated with K2 use, but also the first case to be reported outside of the United States of America. Pediatricians worldwide must be aware of the clinical significance and potential harm associated with the use of synthetic cannabinoids, to better educate patients and their families regarding the dangers of using such "legal" substances.


Highly localized divergence within supergenes in Atlantic cod (Gadus morhua) within the Gulf of Maine.
Atlantic cod (Gadus morhua), is known to vary genetically across the North Atlantic, Greenland, and Newfoundland. This genetic variation occurs both spatially and temporally through decades of heavy fishing, and is concentrated in three linkage disequilibrium blocks, previously defined by pedigreed linkage mapping analysis. Variation within these genomic regions is correlated with both seawater temperature and behavioral ecotype. The full extent and nature of these linkage groups is important information for interpreting cod genetic structure as a tool for future fisheries management. We conducted whole genome sequencing for 31 individual cod from three sub-populations in the Gulf of Maine. Across the genome, we found 3,390,654 intermediate to high frequency Single Nucleotide Polymorphisms (SNPs). We show that pairwise linkage analysis among these SNPs is a powerful tool to detect linkage disequilibrium clusters by recovering the three previously detected linkage groups and identifying the 1031 genes contained therein. Across these genes, we found significant population differentiation among spawning groups in the Gulf of Maine and between Georges Bank and Gulf of Maine. Coordinated divergence among these genes and their differentiation at both short and long spatial scales suggests that they are acting as linked supergenes in local adaptation of cod populations. Differentiation between SNPs in linkage disequilibrium blocks is the major signal of genetic differentiation between all groups tested within the Gulf of Maine. Our data provide a map of genes contained in these blocks, allowing an enhanced search for neutral genetic structure for demographic inference and fisheries modeling. Patterns of selection and the history of populations may be possible to identify in cod using this description of linkage disequilibrium blocks and future data sets to robustly separate neutral and selected genetic markers.


Effectiveness of virtual reality in the management of paediatric anxiety during the peri‑operative period: A systematic review and meta-analysis.
Children undergoing surgery generally experience anxiety during the perioperative period, which could impact the surgical outcome, cause long-term psychological consequences and result in later healthcare avoidance. Preoperative anxiety in children is managed using both pharmacological and non-pharmacological therapies. The latter include distraction, a tour of the operating room and parental presence until the induction of anaesthesia. A novel and effective non-pharmacological therapies is the use of virtual reality to reduce anxiety and pain in children scheduled for medical procedures. However, the effectiveness of virtual reality in paediatric surgery has yet to be evaluated in a systematic review. To evaluate the effectiveness of virtual reality in the management of anxiety in paediatric patients during the perioperative period. Both a systematic review and a meta-analysis of randomised controlled trials were performed according to the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions Section 8.5 and in accordance with the Cochrane Effective Practice and Organisation of Care. The results are reported as prescribed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. A systematic search of randomised controlled trials was conducted using Medline, SCOPUS, Web of Science, Ovid MEDLINE and CINAHL. Two researchers screened potentially eligible articles and then assessed the quality of the reported studies using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions Section 8.5 and according to Cochrane Effective Practice and Organisation of Care. The data were synthesised using the random-effects models to incorporate the estimated heterogeneity in the weighting. Heterogeneity was tested using the Q and I2 statistics. The τ2 statistic, an estimate of the amount of variation between the included studies, was also determined. Studies whose heterogeneity with respect to primary outcome measurements hindered pooling of the results for meta-analysis were summarised narratively. Seven studies were eligible for inclusion in this systematic review. An effect size for anxiety could be determined in six. The results support the effectiveness of virtual reality in reducing anxiety in paediatric patients undergoing elective surgery. The overall effect was supported by a confidence interval < 0 (PL = -0.341, 95% confidence interval: -0.620 to -0.107) and by heterogenity indexes that were non significant (Q = 9.49, p = 0.091) or not important (I2 = 38.64%). Paediatric patients undergoing elective surgery may benefit from virtual reality as a distraction method that can reduce anxiety. PROSPERO register, number: (blinded for Referee).


Development of a decision-making tool to predict risk of prostate cancer: the Cancer of the Prostate Risk Index (CAPRI) test.
To provide a simple and reliable clinical prediction for an individual patient's overall risk of cancer at biopsy by deriving an easily implemented test based on a generalizable model. Four variables are analyzed for inclusion in the model: prostate-specific antigen (PSA) level, digital rectal examination (DRE) results, race, and age. Two populations were used to develop and validate the test: a model (n = 633) and an independent, geographically separate, external population (n = 766). Pathology records for patients who underwent prostate biopsy between 1991 and 1995 were reviewed and screened for the presence of PSA and DRE results. Records where age and race could be determined were extracted. Multiple logistic regression was used with an iterative approach to optimize each test factor. The Wald chi-square test, receiver operating characteristic (ROC) curve, and Hosmer-Lemingshaw test were used to evaluate the model's predictive capability in the two populations. The model and external populations were significantly different for racial mix, PSA level, age, and biopsy detection rate, providing diverse populations to validate the test. Within a combined model, PSA, DRE, race, and age all demonstrated independent capability to predict cancer at biopsy. Predictive power of the overall test was high within the model population (ROC 80.8%), with minimal loss of power in the external population. The test demonstrated no significant lack of fit in either population. Within a combined test, PSA, DRE, race, and age all contribute significantly to prediction of prostate cancer at biopsy in an individual patient. The test depicts individual risk in an easily understood, visually provocative manner and should assist the clinician and patient in reaching a decision as to whether biopsy is appropriate.


Risks and features of secondary infections in severe and critical ill COVID-19 patients.
Objectives Severe or critical COVID-19 is associated with intensive care unit admission, increased secondary infection rate, and would lead to significant worsened prognosis. Risks and characteristics relating to secondary infections in severe COVID-19 have not been described. Methods Severe and critical COVID-19 patients from Shanghai were included. We collected lower respiratory, urine, catheters, and blood samples according to clinical necessity and culture and mNGS were performed. Clinical and laboratory data were archived. Results We found 57.89% (22/38) patients developed secondary infections. The patient receiving invasive mechanical ventilation or in critical state has a higher chance of secondary infections (P<0.0001). The most common infections were respiratory, blood-stream and urinary infections, and in respiratory infections, the most detected pathogens were gram-negative bacteria (26, 50.00%), following by gram-positive bacteria (14, 26.92%), virus (6, 11.54%), fungi (4, 7.69%), and others (2, 3.85%). Respiratory Infection rate post high flow, tracheal intubation, and tracheotomy were 12.90% (4/31), 30.43% (7/23), and 92.31% (12/13) respectively. Secondary infections would lead to lower discharge rate and higher mortality rate. Conclusion Our study originally illustrated secondary infection proportion in severe and critical COVID-19 patients. Culture accompanied with metagenomics sequencing increased pathogen diagnostic rate. Secondary infections risks increased after receiving invasive respiratory ventilations and intravascular devices, and would lead to a lower discharge rate and a higher mortality rate.


Immune responses of pigs after experimental infection with a European strain of Porcine reproductive and respiratory syndrome virus.
The purpose of this experiment was to study the immune response of pigs during an experimental infection with a European strain of Porcine reproductive and respiratory syndrome virus (PRRSV). Five pigs were challenged intranasally with PRRSV strain VP21 and another five were kept as controls. Clinical course and humoral and cell-mediated responses were monitored for 70 days post-infection (p.i.). Infected pigs developed mild signs at 24 h p.i. Viraemia was detectable by nested RT-PCR until day 14 p.i. Earliest seroconversions (ELISA) were seen by day 7 p.i. (three of five animals) and, by day 14, all inoculated pigs had seroconverted (ELISA and immunoperoxidase monolayer assay). Virus-neutralizing antibodies were undetectable until day 56 p.i. and, by day 70 p.i., two inoculated pigs still were negative. Flow-cytometry assays using peripheral blood mononuclear cells (PBMC) showed an upshift in CD8(+) cells (day 7 p.i.) and a downshift of CD21(+) cells (days 7 and 28 p.i.). Regarding cell-mediated responses, development of PRRSV-specific gamma interferon-secreting cells (IFN-gamma-SC) and interleukin 4-secreting cells (IL4-SC) in PBMC was examined by ELISPOT assay. IFN-gamma-SC were not detected significantly until day 14 p.i., whereas, for IL4-SC, no differences between groups were seen. Concurrently with the onset of viraemia and the development of clinical signs, serum haptoglobin levels and interleukin 10 (IL10) in PRRSV-stimulated PBMC-culture supernatants increased significantly. These differences disappeared later on. For IL2, IL4, IL8 or transforming growth factor beta, no differences were seen among groups. These results are compatible with a model in which the immune response does not fully control the outcome of the infection.


Structural insights of lincosamides targeting the ribosome of Staphylococcus aureus.
Antimicrobial resistance within a wide range of pathogenic bacteria is an increasingly serious threat to global public health. Among these pathogenic bacteria are the highly resistant, versatile and possibly aggressive bacteria, Staphylococcus aureus. Lincosamide antibiotics were proved to be effective against this pathogen. This small, albeit important group of antibiotics is mostly active against Gram-positive bacteria, but also used against selected Gram-negative anaerobes and protozoa. S. aureus resistance to lincosamides can be acquired by modifications and/or mutations in the rRNA and rProteins. Here, we present the crystal structures of the large ribosomal subunit of S. aureus in complex with the lincosamides lincomycin and RB02, a novel semisynthetic derivative and discuss the biochemical aspects of the in vitro potency of various lincosamides. These results allow better understanding of the drugs selectivity as well as the importance of the various chemical moieties of the drug for binding and inhibition.