Development of contractile properties in avian embryonic skeletal muscle.
The development of the twitch and tetanic responses of the embryonic chick posterior latissimus dorsi muscle has been studied during the last week in ovo. Normalized twitch and tetanic forces increased 3- and 12-fold, respectively, during this period. The changes in the kinetics of the twitch and tetanic responses differed during this developmental period. The time to peak twitch force progressively decreased. The decrease in time to half-peak tetanic force and the increase in the time differential of force production of the tetanic response did not continue after day 18. A prolonged tonic contractile component was described for both the twitch and tetanic responses, particularly in muscles from the younger embryos (days 14-18). A large decrease in the time to one-half relaxation of the twitch response also takes place during the final week in ovo. This detailed description of the development of the contractile properties provides a model system of fast-twitch muscle development in which neurogenic and myogenic components of muscular differentiation can be studied from several approaches.


Diagnostic potential of serum proteomic patterns in prostate cancer.
The serum prostate specific antigen test has been widely used in the last decade as an effective screening tool for prostate cancer (CaP). However, the high false-positive rate of the serum prostate specific antigen test necessitates the development of more accurate diagnostic and prognostic biomarkers for CaP. Promising diagnostic potential of serum protein patterns detected by surface enhanced laser desorption/ionization time of flight mass spectrometry for CaP has recently been reported. Independent evaluation of this new technology is warranted to realize its translational utility. We determined whether serum protein profiling by surface enhanced laser desorption/ionization time of flight mass spectrometry and a decision tree algorithm classification system could accurately discriminate between patients with CaP and unaffected individuals. Proteomic spectra of crude serum were generated using the Ciphergen ProteinChip System and pattern detection was performed using Biomarker Patterns Software (Ciphergen Biosystems, Inc., Fremont, California). A total of 106 patients with CaP and 56 controls were randomly allocated to a training set and a test set. The training set, which consisted of 44 patients with cancer and 30 controls, was used to build a decision tree algorithm. The test set, which consisted of 62 patients with cancer and 26 controls, was used in blinded fashion to validate the decision tree. Accuracy of classification using the test set was 67% and 42% for the weak cation exchange array and the copper metal affinity capture array, respectively. Combined spectral data from the weak cation exchange and copper metal affinity capture arrays generated an algorithm that achieved 85% sensitivity and 85% specificity for the detection of CaP. These preliminary findings support recent observations that complex protein profiles have promising potential for the early detection of CaP and warrant future studies with streamlined technology. Furthermore, the combined effect of using 2 array types can greatly enhance the ability of protein profile patterns, suggesting the potential usefulness of alternative approaches to evaluate this new emerging technology.


Controlling fibroblast adhesion and proliferation by 1D Al2O3 nanostructures.
The fibrotic encapsulation, which is mainly accompanied by an excessive proliferation of fibroblasts, is an undesired phenomenon after the implantation of various medical devices. Beside the surface chemistry, the topography plays also a major role in the fibroblast-surface interaction. In the present study, one-dimensional aluminium oxide (1D Al2O3) nanostructures with different distribution densities were prepared to reveal the response of human fibroblasts to the surface topography. The cell size, the cell number and the ability to form well-defined actin fibres and focal adhesions were significantly impaired with increasing distribution density of the 1D Al2O3 nanostructures on the substratum.


Interaction of LY171883 and other peroxisome proliferators with fatty-acid-binding protein isolated from rat liver.
Fatty-acid-binding protein (FABP) is a 14 kDa protein found in hepatic cytosol which binds and transports fatty acids and other hydrophobic ligands throughout the cell. The purpose of this investigation was to determine whether LY171883, a leukotriene D4 antagonist, and other peroxisome proliferators bind to FABP and displace an endogenous fatty acid. [3H]Oleic acid was used to monitor the elution of FABP during chromatographic purification. [14C]LY171883 had a similar elution profile when substituted in the purification, indicating a common interaction with FABP. LY171883 and its structural analogue, LY189585, as well as the hypolipidaemic peroxisome proliferators clofibric acid, ciprofibrate, bezafibrate and WY14,643, displaced [3H]oleic acid binding to FABP. Analogues of LY171883 that do not induce peroxisome proliferation only weakly displaced oleate binding. [3H]Ly171883 bound directly to FABP with a Kd of 10.8 microM, compared with a Kd of 0.96 microM for [3H]oleate. LY171883 binding was inhibited by LY189585, clofibric acid, ciprofibrate and bezafibrate. These findings demonstrate that peroxisome proliferators, presumably due to their structural similarity to fatty acids, are able to bind to FABP and displace an endogenous ligand from its binding site. Interaction of peroxisome proliferators with FABP may be involved in perturbations of fatty acid metabolism caused by these agents as well as in the development of the pleiotropic response of peroxisome proliferation.


Fate of combat nerve injury.
Assess a cohort of combat-related type III open tibia fractures with peripheral nerve injury to determine the injury mechanism and likelihood for recovery or improvement in nerve function. Retrospective study. Three military medical centers. Out of a study cohort of 213 type III open tibia fractures, 32 fractures (in 32 patients) with a total of 43 peripheral nerve injuries (peroneal or tibial) distal to the popliteal fossa met inclusion criteria and were available for follow-up at an average of 20 months (range, 2-48 months). Clinical assessment of motor and sensory nerve improvement. There was a 22% incidence of peripheral nerve injury in the study cohort. At an average follow-up of 20 months (range, 2-48 months), 89% of injured motor nerves were functional, whereas the injured sensory nerves had function in 93%. Fifty percent and 27% of motor and sensory injuries demonstrated improvement, respectively (P = 0.043). With the numbers available, there was no difference in motor or sensory improvement based on mechanism of injury, fracture severity or location, soft tissue injury, or specific nerve injured. In the subset of patients with an initially impaired sensory examination, full improvement was related to fracture location (P = 0.0164). Type III open tibia fractures sustained in combat are associated with a 22% incidence of peripheral nerve injury, and the majority are due to multiple projectile penetrating injury. Despite the severe nature of these injuries, the vast majority of patients had a functional nerve status by an average of 2-year follow-up. Based on these findings, discussions regarding limb salvage and amputation should not be overly influenced by the patient's peripheral nerve status. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Decomposition of magnetoencephalographic data into components corresponding to deep and superficial sources.
We extend the signal space separation (SSS) method to decompose multichannel magnetoencephalographic (MEG) data into regions of interest inside the head. It has been shown that the SSS method can transform MEG data into a signal component generated by neurobiological sources and a noise component generated by external sources outside the head. In this paper, we show that the signal component obtained by the SSS method can be further decomposed by a simple operation into signals originating from deep and superficial sources within the brain. This is achieved by using a scheme that exploits the beamspace methodology that relies on a linear transformation that maximizes the power of the source space of interest. The efficiency and accuracy of the algorithm are demonstrated by experiments utilizing both simulated and real MEG data.


Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer's disease.
One of the hallmarks of Alzheimer's disease (AD) are deposits of amyloid-beta (Aβ) protein in amyloid plaques in the brain. The Aβ peptide exists in several forms, including full-length Aβ1-42 and Aβ1-40 - and the N-truncated species, pyroglutamate Aβ3-42 and Aβ4-42, which appear to play a major role in neurodegeneration. We previously identified a murine antibody (TAP01), which binds specifically to soluble, non-plaque N-truncated Aβ species. By solving crystal structures for TAP01 family antibodies bound to pyroglutamate Aβ3-14, we identified a novel pseudo β-hairpin structure in the N-terminal region of Aβ and show that this underpins its unique binding properties. We engineered a stabilised cyclic form of Aβ1-14 (N-Truncated Amyloid Peptide AntibodieS; the 'TAPAS' vaccine) and showed that this adopts the same 3-dimensional conformation as the native sequence when bound to TAP01. Active immunisation of two mouse models of AD with the TAPAS vaccine led to a striking reduction in amyloid-plaque formation, a rescue of brain glucose metabolism, a stabilisation in neuron loss, and a rescue of memory deficiencies. Treating both models with the humanised version of the TAP01 antibody had similar positive effects. Here we report the discovery of a unique conformational epitope in the N-terminal region of Aβ, which offers new routes for active and passive immunisation against AD.


How German and Italian Laypeople Reason about Distributive Shortages during COVID-19.
(1) Background: The COVID-19 pandemic provided a unique opportunity to investigate how moral reasoning is influenced by individuals' exposure to a crisis and by personal, societal and temporal proximity. We examined how Italians and Germans judged different behaviors that arose because of the pandemic, which affected health and societal matters. (2) Methods: Over the course of four months and three assessment periods, we used an observational online survey to assess participants' judgments regarding seven scenarios that addressed distributive shortages during the pandemic. (3) Results: Overall, there was no clear answering pattern across all scenarios. For a variation of triage and pandemic restrictions, most participants selected a mean value, which can be interpreted as deferring the choice. For the other scenarios, most participants used the extremes of the scale, thereby reflecting a clear opinion of the public regarding the moral issue. In addition, moral reasoning varied across the two countries, assessment periods, fear, and age. (4) Conclusions: By using scenarios that were taken from real-life experiences, the current study addresses criticism that moral research mostly relies on unrealistic scenarios that lack in external validity, plausibility, and proximity to everyday situations. In addition, it shows how lay people regard measures of public health and societal decision-making.


The interdisciplinary approach to the treatment of multiple sclerosis patients in Italy: an aspiration or a reality?
The aim of the study was to assess whether the components necessary for an interdisciplinary approach to the treatment of multiple sclerosis (MS) patients exist in Italian MS clinics and to identify factors that make the difference between reality and aspiration for this type of approach. One hundred two out of 147 neurology departments with MS clinics throughout Italy compiled a questionnaire about characteristics and organizational structure of the clinic, type and number of professionals and resource needs. Eight hundred twenty-three healthcare professionals are currently working in MS clinics: 50% (412) neurologists, 28.7% (236) nurses, 15.1% (124) physical therapists, 3.4% (28) psychologists and 2.8% (23) social workers. Neurologists are evenly distributed between northern and southern parts of the country even though there are nearly double the number of patients followed in northern dinics compared to those in the south. Physicians reported themselves as most in need of continuing education, twice that which the same physicians reported for any other professional. The study has identified issues that contribute to the difficulty in developing and applying an interdisciplinary approach to providing care and services to Italian MS patients. Several factors have been delineated that require significant reshaping in order for this approach to begin to develop.


Long-term observations on the loss of bone mineral following colles' fracture.
Seventy-four women were studied at various points in time between 1 month and 12 years after a fracture of the distal end of the radius--Colles' fracture. In 50 cases the maximum loss of bone after fracture was considered to have taken place in that more than 4 months had elapsed since the accident. The bone mineral content was measured in both forearms with gamma absorptiometry. It was demonstrated that the degree of post-traumatic osteoporosis, calculated as the difference between the values obtained for the injured and the uninjured arms, decreased with time. The difference between the arms was greater in peri- and early postmenopausal and in very old women suggesting that these groups had lost more bone and/or been less able to restore lost mineral with time.


The effects of fenfluramine (hydrochloride) on the behaviors of fifteen autistic children.
Fifteen autistic individuals were involved in an investigation using fenfluramine and placebo in a double-blind crossover design. Subjects were assessed using IQ tests, the Real Life Rating Scale (RLRS), the Adaptive Behavior Scale-School Edition (ABS-SE), and videotaped play data on 8 of 12 visits, including 2 follow-up visits. Serotonin level in platelet-poor plasma was assessed on all 12 visits. Serotonin levels decreased with the administration of fenfluramine, and increased with the reinstatement of placebo. Statistical tests revealed no significant differences on the IQ scores, the RLRS, or the ABS-SE for the drug versus the placebo conditions. Videotaped data favored the subjects while on placebo. Group and individual data were analyzed over time and indicated no significant improvements due to the drug. The implications of this research make it difficult to recommend fenfluramine as a treatment for autism.


Tuning Up the Old Brain with New Tricks: Attention Training via Neurofeedback.
Neurofeedback (NF) is a form of biofeedback that uses real-time (RT) modulation of brain activity to enhance brain function and behavioral performance. Recent advances in Brain-Computer Interfaces (BCI) and cognitive training (CT) have provided new tools and evidence that NF improves cognitive functions, such as attention and working memory (WM), beyond what is provided by traditional CT. More published studies have demonstrated the efficacy of NF, particularly for treating attention deficit hyperactivity disorder (ADHD) in children. In contrast, there have been fewer studies done in older adults with or without cognitive impairment, with some notable exceptions. The focus of this review is to summarize current success in RT NF training of older brains aiming to match those of younger brains during attention/WM tasks. We also outline potential future advances in RT brainwave-based NF for improving attention training in older populations. The rapid growth in wireless recording of brain activity, machine learning classification and brain network analysis provides new tools for combating cognitive decline and brain aging in older adults. We optimistically conclude that NF, combined with new neuro-markers (event-related potentials and connectivity) and traditional features, promises to provide new hope for brain and CT in the growing older population.


Protective role of Royal Jelly (honeybee) on genotoxicity and lipid peroxidation, induced by petroleum wastewater, in Allium cepa L. root tips.
In the present study, the protective effect of Royal Jelly (RJ) on genotoxicity and lipid peroxidation, induced by petroleum wastewater, in Allium cepa L. root-tip cells was investigated. For this purpose, we used the malondialdehyde (MDA) level, mitotic index (MI), frequency of micronucleus (MN) and chromosomal aberrations (CAs) as indicators of genotoxicity and lipid peroxidation, and correlated these data with statistical parameters. In additional to the genotoxic analysis, we examined changes in the root anatomy of A. cepa seeds treated with the wastewater. Heavy metal concentrations in the wastewater were measured by atomic absorption spectrophotometry. The seeds were divided into six groups as control, wastewater and RJ treatment groups. They were treated with the wastewater alone, RJ alone (25 and 50 microm doses) and RJ + wastewater for 10 consecutive days. As a result, the mean concentrations of heavy metals in the wastewater were observed to be in the order: Pb > Fe > Al > Ni > Cu > Zn > Cr > Cd. The results showed that there was a significant alteration in MI and in the frequency of MN and CAs in the seeds exposed to the wastewater when compared with the controls. The wastewater exposure resulted in a significant increase in CAs and MN formation (P < 0.05). The wastewater also caused a decrease in MI (P < 0.05). Additionally, there was a significant increase in the MDA levels of the roots exposed to the wastewater (P < 0.05). Heavy metals in the petroleum wastewater significantly increased the MDA production, indicating lipid peroxidation. Moreover, light micrographs showed anatomical damages such as an accumulation of chemical compounds in cortex parenchyma, cell death, an unusual form of cell nucleus and unclear vascular tissue. However, the RJ treatment caused amelioration in the indices of lipid peroxidation and MI, and in the frequency of CAs and MN, when compared with the group treated with petroleum wastewater alone (P < 0.05). Also, the RJ application caused the recuperation of anatomical structural damages induced by the petroleum wastewater. Each dose of RJ provided protection against the wastewater toxicity, and the strongest protective effect was observed at dose of 50 microm. In vivo results showed that RJ is a potential protector against toxicity induced by petroleum wastewater, and its protective role is dose-dependent.


[Role of emotions in cholinergic mechanisms of formation and reproduction of a bilateral conditioned avoidance reflex].
In experiments on rats it was shown that during elaboration of a bilateral avoidance conditioned reflex against scopolamine background, facilitation of the learning process takes place only at simultaneous elimination of the emotional fear reaction expressed in a decrease of the heart-rate. The presence of non-cholinergic mechanisms participating in generation of high-frequency (8-12 c/s) hippocampal regular activity is necessary for the reproduction of instrumental avoidance reaction against the scopolamine background. A resistivity of emotional fear reaction to cholinoblocators in animals learning with difficulty, is revealed (monitored according to conditioned decreasing of the heart-rates). This fact points to the non-cholinergic nature of a definite type of emotional passive fear reaction. The theory of memory dissociation explains the inversely-proportional dependence of the reflex stability after cancelling of scopolamine administration upon the duration of reaction stabilization against the background of the drug.


Enhanced recovery after thoracic surgery in low- and middle-income countries: Feasibility and outcomes.
Enhanced Recovery After Surgery (ERAS) applies multimodal, perioperative, and evidence-based practices to decrease postoperative morbi-mortality, the length of hospital stay, and hospitalization costs. Implementing enhanced recovery after thoracic surgery (ERATS) in low- and middle-income countries (LMIC) is problematic. This randomized controlled trial evaluated the feasibility and effectiveness of an ERATS protocol adapted to LMIC conditions in Tunisia. We conducted this randomized controlled trial between December 2015 and August 2017 in the Thoracic and Cardiovascular Surgery Department at Habib Bourguiba University Hospital of Sfax, Tunisia. One hundred patients undergoing thoracic surgery were randomly allocated to the ERATS group or Control group. During the postoperative phase, 13 patients (13%) were excluded secondary. These complication rates were lower in the ERATS group: lack of reexpansion (14.63% vs 16.10%: p = 0.72), pleural effusion (0% vs 10.86%, p = 0.05), and prolonged air leak (17.07% vs 30.43%, p = 0.14). The pain level decreased significantly in the ERATS group from postoperative H3 (p = 0.006). This difference was significant at H6 (p = 0.001), H24 (p = 0.05), H48 (p = 0.01), discharge (p = 0.002), and after 15 days (p = 0.01), with a decreased analgesic consumption. The length of hospital stay was shorter in the ERAS group (median six days vs seven days, p = 0.17). This study provides an adapted ERATS protocol, applicable regardless of the surgical approach or the type of resection and suitable for LMIC hospital's conditions. This protocol can improve the postoperative outcomes of thoracic surgery.


Trends in acute leukaemia incidence in adults in the Republic of Macedonia (1993-2003)--a descriptive epidemiological study.
To analyse trends in incidence rates of acute leukaemia in patients aged 15 and over admitted to hospital. A descriptive epidemiological study. University teaching hospital, Haematology Clinic, Skopje. The crude incidence rates of acute leukaemia in adults during this period increased substantially (p for overall trend < 0.001). The lowest crude incidence rates (CIR) were observed in 1996 (CIR = 1.64/100 000; 95% Confidence Interval CI = 1.1-2.4), while the highest were noted in 2003 (CIR = 3.76/100 000; 95% CI = 2.9-4.8). In 1993 the sex ratio of the incidence rates (males to females) was Rate Ratio (RR) = 2.23, while as of 2001 the association between sexes disappeared (RR = 1). The trend in males was not significant (p = 0.160), while in females it showed a monotonic increase that was highly significant (p < 0.001). During a short period of time (11 years) we have noted an increase in the incidence rates of acute leukaemia in our population aged 15 years and above. The study suggests that this could be due to increased risk in females, and in adults over 40 years. In addition, according to the census results in 1994 and 2002 the proportion of people aged 65 and above increased by 30.5% implying that this demographic change could account for part of the relative increase in the incidence rates of acute leukaemia. Further analytic studies are needed to address the possible causes of these changes. What is already known on this topic: The risk of acute leukaemia increases by age and it is higher in males than in females. The incidence rates are equal between the sexes; the increase in risk of acute leukemia in females could be due to environmental risk factor.


Peyer's patches and mesenteric lymph nodes cooperatively promote enteropathy in a mouse model of food allergy.
To improve the efficacy and safety of tolerance induction for food allergies, identifying the tissues responsible for inducing intestinal inflammation and subsequent oral tolerance is important. We used OVA23-3 mice, which express an ovalbumin-specific T-cell receptor, to elucidate the roles of local and systemic immune tissues in intestinal inflammation. OVA23-3 mice developed marked enteropathy after consuming a diet containing egg white (EW diet) for 10 days but overcame the enteropathy (despite continued moderate inflammation) after receiving EW diet for a total of 28 days. Injecting mice with anti-IL-4 antibody or cyclosporine A confirmed the involvement of Th2 cells in the development of the enteropathy. To assess the individual contributions of Peyer's patches (PPs), mesenteric lymph nodes (MLNs), and the spleen to the generation of effector CD4+ T-cells, we analyzed the IL-4 production, proliferation in response to ovalbumin, and CD4+ T-cell numbers of these tissues. EW feeding for 10 days induced significant IL-4 production in PPs, the infiltration of numerous CD4+ T-cells into MLNs, and a decrease in CD4+ T-cell numbers in spleen. On day 28, CD4+ T-cells from all tissues had attenuated responses to ovalbumin, suggesting tolerance acquisition, although MLN CD4+ T-cells still maintained IL-4 production with proliferation. In addition, removal of MLNs but not the spleen decreased the severity of enteropathy and PP-disrupted mice showed delayed onset of EW-induced inflammatory responses. Disruption of peripheral lymphoid tissues or of both PPs and MLNs almost completely prevented the enteropathy. PPs and MLNs coordinately promote enteropathy by generating effector T-cells during the initial and exacerbated phases, respectively; the spleen is dispensable for enteropathy and shows tolerogenic responses throughout EW-feeding. The regulation of PPs may suppress the initiation of intestinal inflammation, subsequently restricting MLNs and inhibiting the progression of food-allergic enteropathy.


The possible implication of the S250C variant of the autoimmune regulator protein in a patient with autoimmunity and immunodeficiency: in silico analysis suggests a molecular pathogenic mechanism for the variant.
Autoimmunity can develop from an often undetermined interplay of genetic and environmental factors. Rare forms of autoimmune conditions may also result from single gene mutations as for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, an autosomal recessive disease associated with mutated forms of the autoimmune regulator gene. It was proposed that genetic variability in the autoimmune regulator locus, in particular heterozygous loss-of-function mutations, might favor the development of organ-specific autoimmunity by affecting the presentation of self-antigens in the thymus. Indeed, heterozygous mutations of the autoimmune regulator gene were reported in patients with organ-specific autoimmunity. Also, in primary immunodeficiencies, a breakdown in central/peripheral tolerance frequently produces association with autoimmunity. The causative link may involve a common genetic background and several gene defects have been identified as putative culprits. We report a unique patient, a 14 year old male from Lazio region, affected by common variable immunodeficiency associated with autoimmune manifestations (alopecia, onychodystrophy) and heterozygote for the S250C variant located in the SAND domain of the autoimmune regulator gene protein. To our knowledge this is the first report of the S250C variant in a patient bearing this unusual combination of autoimmunity and immunodeficiency. To obtain insights into the possible molecular effects of the S250C variant, we have carried out an in silico analysis of the SAND domain structure of the autoimmune regulator protein. In particular, homology modeling has allowed us to observe that the cysteine introduced by the S250C variant is surrounded by cationic residues, and by means of molecular dynamics simulations together with pKa calculations, we have shown that these residues remain stably proximal to cysteine-250 lowering its pKa and thus conferring high chemical reactivity to the mutated residue. We propose that the enhanced reactivity of cysteine-250, which is likely to impair the protein function but probably insufficient to produce alone a phenotype as a heterozygous S250C variant due to compensation mechanisms, might become manifest when combined with other genetic/environmental factors. These results can provide the rationale for the patient's unusual phenotype, shedding new light into the pathogenesis of the clinical association of autoimmunity and immunodeficiency.


Diet and Behavior Modifications by Long-term Rectal Cancer Survivors to Manage Bowel Dysfunction-Associated Symptoms.
Rectal cancer (RC) survivors experience significant bowel function issues after treatment. We aimed to describe self-reported dietary and behavioral modifications among long-term (≥5 yr) RC survivors to manage bowel dysfunction. RC survivors from Kaiser Permanente Northern California and Northwest regions completed surveys either via postage-paid return mail or telephone. Summary statistics on diet/behavioral modifications data were tabulated by proportion of responses. Modifications and frequency of bowel symptoms cited and were compared by ostomy status. A total of 575 respondents were included (overall response rate = 60.5%). Fruits and vegetables were troublesome for symptoms, but was also helpful in mitigating constipation, obstruction, and frequency, as well as improving predictability. Many respondents attributed red meat (17.7%), fried foods (13.9%), spicy foods (13.1%), carbonated beverages (8.0%), and sweets (7.6%) to increased diarrhea, gas, and urgency. Common behavioral modifications included controlling meal portions (50.6%), timing regularity (25.3%), and refraining from late night eating (13.8%). Permanent ostomy survivors were more likely to report symptoms of obstruction, while anastomosis survivors were more likely to report urgency. Multiple modifications were attempted by RC survivors to manage bowel symptoms. Identifying diet changes among RC survivors can improve symptom management and survivorship care.


Lectin-Mediated Bacterial Modulation by the Intestinal Nematode Ascaris suum.
Ascariasis is a global health problem for humans and animals. Adult Ascaris nematodes are long-lived in the host intestine where they interact with host cells as well as members of the microbiota resulting in chronic infections. Nematode interactions with host cells and the microbial environment are prominently mediated by parasite-secreted proteins and peptides possessing immunomodulatory and antimicrobial activities. Previously, we discovered the C-type lectin protein AsCTL-42 in the secreted products of adult Ascaris worms. Here we tested recombinant AsCTL-42 for its ability to interact with bacterial and host cells. We found that AsCTL-42 lacks bactericidal activity but neutralized bacterial cells without killing them. Treatment of bacterial cells with AsCTL-42 reduced invasion of intestinal epithelial cells by Salmonella. Furthermore, AsCTL-42 interacted with host myeloid C-type lectin receptors. Thus, AsCTL-42 is a parasite protein involved in the triad relationship between Ascaris, host cells, and the microbiota.


Triterpene glycosides from the roots of Codonopsis lanceolata.
In the course of the development of new designer foods using the roots of Codonopsis lanceolata, we found that hot-water extracts of C. lanceolata recovered decreased testosterone levels in the blood and accelerated the restoration of reproductive dysfunction induced by hyperthermic treatment in male mice. Thus we studied the constituents of the polar fraction of the roots of C. lanceolata and identified six new triterpene saponins, lancemasides B (2), C (3), D (4), E (5), F (6), and G (7), along with the known saponin lancemasaide A (1) and phenylpropanoid glycosides 8-10. The structures of the new compounds 2-7 were determined by means of spectral data including 2D-NMR studies and chemical reactions to be oleanan-type bisdesmoside with sugars at C-3 and C-28. Compounds 2-6 have echinocystic acid as an aglycone, and compound 7 has asterogenic acid as an aglycone. Identification of the sugars and determination of their D,L-chiralities were carried out by application of the exciton chirality method to the per-O-p-bromobenzoylmethyl sugar derived from saponins.


Selective modulation of left primary motor cortex excitability after continuous theta burst stimulation to right primary motor cortex and bimanual training.
Bimanual movement training (BMT) enhances the excitability of human preparatory premotor and primary motor (M1) cortices. We have shown that activity in M1 is enhanced after BMT involving simultaneous activation of homologous muscles (in-phase). Potential neural mechanisms underlying this effect could be input from premotor areas (i.e. dorsal premotor cortex (PMd)) and/or the homologous M1 representation. Recently, we showed that increasing PMd activity using theta burst stimulation (TBS) followed by BMT enhanced the corticospinal excitability of M1 compared to BMT alone. The purpose of this study was to investigate the effects of continuous TBS (cTBS) to right hemisphere M1 (rM1) on the homologous wrist extensor representation in left M1 (lM1), and its potential combined effects when followed by BMT. We used transcranial magnetic stimulation (TMS) to measure cortical excitability of extensor carpi radialis (ECR) representation at multiple time points in three conditions: (1) BMT, (2) cTBS to rM1 or (3) cTBS to rM1 and BMT. The combination of cTBS to rM1 and BMT resulted in an increased shift in the centre of gravity (CoG) compared to either intervention alone, along with an increased muscle topographical representation up to 60 min when cTBS to rM1 was combined with BMT compared to cTBS to rM1 alone. These results suggest that modulation of M1 may reduce ongoing interhemispheric inhibition (or increase facilitation indirectly) to the opposite homologous M1 region in healthy individuals via transcallosal or subcortical connections. Critically, this work may guide rehabilitation training and stimulation techniques that modulate cortical plasticity after brain injury.


Babbling in a vocal learning bat resembles human infant babbling.
Babbling is a production milestone in infant speech development. Evidence for babbling in nonhuman mammals is scarce, which has prevented cross-species comparisons. In this study, we investigated the conspicuous babbling behavior of Saccopteryx bilineata, a bat capable of vocal production learning. We analyzed the babbling of 20 bat pups in the field during their 3-month ontogeny and compared its features to those that characterize babbling in human infants. Our findings demonstrate that babbling in bat pups is characterized by the same eight features as babbling in human infants, including the conspicuous features reduplication and rhythmicity. These parallels in vocal ontogeny between two mammalian species offer future possibilities for comparison of cognitive and neuromolecular mechanisms and adaptive functions of babbling in bats and humans.


Noninvasive prenatal testing in the general obstetric population: clinical performance and counseling considerations in over 85 000 cases.
The primary goal of this study was to provide clinically relevant information for appropriate patient counseling. Demographics and test metrics were reviewed for 86 658 clinical cases. Outcome information was requested for samples reported as aneuploidy detected or suspected for chromosomes 21, 18, or 13; voluntary outcome reporting was encouraged for all discordant outcomes. Of 86 658 cases, 85 298 (98.4%) met inclusion criteria for result reporting. Of the 1360 (1.6%) cancellations, only 101 (0.1%) were for technical reasons. Average time to result was 3.3 business days. Aneuploidy was detected or suspected in 2142 (2.5%) samples. For aneuploidy detected cases with known clinical outcomes, the overall positive predictive value (PPV) was 83.5% (608/728); observed PPVs for trisomies 21, 18, and 13 ranged from 50.0 to 92.8%. As individual PPVs are determined by a patient's prior risk, we developed a chart for counseling patients on positive predictive value based on maternal age. This large-scale report reinforces that noninvasive prenatal testing is a highly accurate screen for fetal aneuploidy in the general obstetric population. Test improvements have facilitated a reduction in failure rates, time to result, and borderline results/unclassifiable results. We have developed a positive predictive value counseling tool to ensure appropriate patient education, counseling, and clinical utilization.


Cortactin regulates endo-lysosomal sorting of AMPARs via direct interaction with GluA2 subunit.
AMPA receptor (AMPAR) trafficking is a key determinant of synaptic strength and synaptic plasticity. Under basal conditions, constitutive trafficking maintains surface AMPARs by internalization into the endosomal system, where the majority are sorted and targeted for recycling back to the plasma membrane. NMDA receptor (NMDAR)-dependent Long-Term Depression (LTD) is characterised by a reduction in synaptic strength, and involves endosomal sorting of AMPARs away from recycling pathways to lysosomes. The mechanisms that determine whether AMPARs are trafficked to lysosomes or to recycling endosomes, especially in response to NMDAR stimulation, are unclear. Here, we define a role for the actin-regulatory protein cortactin as a mediator of AMPAR endosomal sorting by direct interaction with the GluA2 subunit. Disrupting GluA2-cortactin binding in neurons causes the targeting of GluA2/A3-containing receptors to lysosomes and their consequent degradation, resulting in a loss of surface and synaptic GluA2 under basal conditions and an occlusion of subsequent LTD expression. Furthermore, we show that NMDAR stimulation causes a dissociation of endogenous cortactin from GluA2 via tyrosine phosphorylation of cortactin. These results demonstrate that cortactin maintains GluA2/A3 levels by directing receptors away from lysosomes, and that disrupting GluA2-cortactin interactions to target GluA2/A3 to lysosomes is an essential component of LTD expression.


Cysteine cathepsins in human cancer.
Proteases play causal roles in the malignant progression of human tumors. This review centers on the roles in this process of cysteine cathepsins, i.e., peptidases belonging to the papain family (C1) of the CA clan of cysteine proteases. Cysteine cathepsins, most likely along with matrix metalloproteases (MMPs) and serine proteases, degrade the extracellular matrix, thereby facilitating growth and invasion into surrounding tissue and vasculature. Studies on tumor tissues and cell lines have shown changes in expression, activity and distribution of cysteine cathepsins in numerous human cancers. Molecular, immunologic and pharmacological strategies to modulate expression and activity of cysteine cathepsins have provided evidence for a causal role for these enzymes in tumor progression and invasion. Clinically, the levels, activities and localization of cysteine cathepsins and their endogenous inhibitors have been shown to be of diagnostic and prognostic value. Understanding the roles that cysteine proteases play in cancer could lead to the development of more efficacious therapies.


Dynamics of glyphosate-induced conformational changes of Mycobacterium tuberculosis 5-enolpyruvylshikimate-3-phosphate synthase (EC 220.127.116.11) determined by hydrogen-deuterium exchange and electrospray mass spectrometry.
The enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) catalyzes the reaction between shikimate 3-phosphate and phosphoenolpyruvate to form 5-enolpyruvylshikimate 3-phosphate, an intermediate in the shikimate pathway, which leads to the biosynthesis of aromatic amino acids. EPSPS exists in an open conformation in the absence of substrates and/or inhibitors and in a closed conformation when bound to the substrate and/or inhibitor. In the present report, the H/D exchange properties of EPSPS from Mycobacterium tuberculosis ( Mt) were investigated for both enzyme conformations using ESI mass spectrometry and circular dichroism (CD). When the conformational changes identified by H/D exchanges were mapped on the 3-D structure, it was observed that the apoenzyme underwent extensive conformational changes due to glyphosate complexation, characterized by an increase in the content of alpha-helices from 40% to 57%, while the beta-sheet content decreased from 30% to 23%. These results indicate that the enzyme underwent a series of rearrangements of its secondary structure that were accompanied by a large decrease in solvent access to many different regions of the protein. This was attributed to the compaction of 71% of alpha-helices and 57% of beta-sheets as a consequence of glyphosate binding to the enzyme. Apparently, MtEPSPS undergoes a series of inhibitor-induced conformational changes, which seem to have caused synergistic effects in preventing solvent access to the core of molecule, especially in the cleft region. This may be part of the mechanism of inhibition of the enzyme, which is required to prevent the hydration of the substrate binding site and also to induce the cleft closure to avoid entrance of the substrates.


Role of the yeast acetyltransferase Mpr1 in oxidative stress: regulation of oxygen reactive species caused by a toxic proline catabolism intermediate.
The MPR1 gene, which is found in the Sigma1278b strain but is not present in the sequenced laboratory strain S288C, of the budding yeast Saccharomyces cerevisiae encodes a previously uncharacterized N-acetyltransferase that detoxifies the proline analogue azetidine-2-carboxylate (AZC). However, it is unlikely that AZC is a natural substrate of Mpr1 because AZC is found only in some plant species. In our search for the physiological function of Mpr1, we found that mpr1-disrupted cells were hypersensitive to oxidative stresses and contained increased levels of reactive oxygen species (ROS). In contrast, overexpression of MPR1 leads to an increase in cell viability and a decrease in ROS level after oxidative treatments. These results indicate that Mpr1 can reduce intracellular oxidation levels. Because put2-disrupted yeast cells lacking Delta(1)-pyrroline-5-carboxylate (P5C) dehydrogenase have increased ROS, we examined the role of Mpr1 in put2-disrupted strains. When grown on media containing urea and proline as the nitrogen source, put2-disrupted cells did not grow as well as WT cells and accumulated intracellular levels of P5C that were first detected in yeast cells and ROS. On the other hand, put2-disrupted cells that overexpressed MPR1 had considerably lower ROS levels. In vitro studies with bacterially expressed Mpr1 demonstrated that Mpr1 can acetylate P5C, or, more likely, its equilibrium compound glutamate-gamma-semialdehyde, at neutral pH. These results suggest that the proline catabolism intermediate P5C is toxic to yeast cells because of the formation of ROS, and Mpr1 regulates the ROS level under P5C-induced oxidative stress.


Effects of systematic variation of amino acid sequence on the mechanical properties of a self-assembling, oligopeptide biomaterial.
In order to elucidate design principles for biocompatible materials that can be created by in situ transformation from self-assembling oligopeptides, we investigate a class of oligopeptides that can self-assemble in salt solutions to form three-dimensional matrices. This class of peptides possesses a repeated sequence of amino acid residues with the type: hydrophobic/negatively-charged/hydrophobic/positively-charged. We systematically vary three chief aspects of this sequence type: (1) the hydrophobic side chains; (2) the charged side chains; and (3) the number of repeats. Each of these has been previously shown to influence the self-assembly properties of these materials. Employing a rheometric assay we measure the shear modulus of gels created from variants of each of these aspects. First, we observe order-of-magnitude changes in shear moduli when we vary oligopeptide length, with biphasic dependence on length. This result may be due to competition between, in short oligopeptides, additional repeats either increasing the diameter of the filaments or increasing the area of interaction between individual molecules and, in large oligopeptides, additional repeats allowing the oligopeptides to fold back upon themselves and decrease their effective length. Second, no statistically significant difference is observed among the hydrophobic variants, suggesting that hydrophobicity and steric overlap are unlikely to play a significant role in filament mechanical properties. Finally, in variation of the charged side chains we observe a small difference in the shear moduli that, if significant, may mean that decreasing the energetic penalty for dehydrating the charged side chains can lead to a stiffer matrix. Overall, we demonstrate that it is possible to achieve order-of-magnitude changes in shear modulus by simple variations of oligopeptide length, while the residue substitutions affect only self-assembly properties. Thus, diverse aspects of these molecules can be designed rationally to yield desirable materials properties of different types.


Improving Cancer Patient Outcomes and Cost-Effectiveness: A Markov Simulation of Improved Early Detection, Side Effect Management, and Palliative Care.
I employed a Markov model to simulate outcomes for a cohort of 1,000 hypothetical patients, comparing improvements in early detection, side effect management, and palliative care over a ten-year period. This model showed benefits in early detection and proactive health management, improving disease stability and reducing mortality rates. This protocol resulted in an 85.8% five-year survival rate, compared to 69.5% under standard protocol. Cost-effectiveness analysis showed significantly reduced costs and improved quality-adjusted life years. Our findings underscore the importance of comprehensive cancer care. These improvements not only reduce simulated healthcare costs but also significantly improve patient outcomes.


Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry.
Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ∼ 83% and ∼ 6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy.


Seasonal variation in the activity of systemic lupus erythematosus.
To determine whether there is any seasonal variation in the activity of systemic lupus erythematosus (SLE) overall and by individual organs. The study group comprised 2102 patients with SLE who were followed in a prospective longitudinal cohort study. In this cohort, 92.3% of the patients were women. The mean ± SD age of the patients was 47.9 ± 13.9 years, 56.3% were white, 37.1% were African American, and 3.1% were Asian. Global disease activity was recorded by the Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and the physician's global assessment. Activity of each organ was also recorded using SLEDAI terms and a visual analog scale (VAS; 0 to 3). There was significant seasonal variation in photosensitive rash (p < 0.0001), which was more frequent in the spring and summer months (p < 0.0001). There was significantly more arthritis activity in spring and summer, as measured by both SELENA-SLEDAI (p = 0.0057) and the joint VAS (p = 0.0047). A decrease in renal activity was found in the summer months compared to the rest of the year (p = 0.0397). Serositis recorded by VAS had higher activity from August to October (p = 0.0392). Anti-dsDNA levels were significantly higher during October and November (p < 0.0001). There was significant seasonal variation in antiphospholipid antibody levels (p < 0.0001) and lupus anticoagulant (p = 0.0003). We found a significant variation in activity through the year in global disease activity as measured by SELENA-SLEDAI (p = 0.048). In the Hopkins Lupus Cohort, skin and joint activity is increased during the spring and summer, but other organs have different patterns. These seasonal variations likely reflect environmental factors that influence disease activity, including ultraviolet light and infections.


Genetic variability of measles viruses circulating in the Benelux.
In Europe measles incidence remains high and in some parts the disease is likely to be still endemic due to insufficient vaccination. Luxembourg experienced an outbreak with at least 110 cases in 1996, and cases continued to be reported throughout 1997. We used molecular epidemiology to investigate this apparent endemicity. On the basis of their N gene sequences, the isolates were assigned to the typical European C2 and D6 genotypes. Sequence diversity within the outbreak was 0.2%. The nucleotide distance between the C2-viruses of the outbreak and the other C2 isolates was at least three or four times higher, suggesting an independent origin of the latter viruses. Similarly, the four D6 viruses found in Luxembourg were thought to be of at least two or three origins. Thus, we propose here to use intra-outbreak sequence diversity to differentiate between sporadic endemic cases and a "pseudo-outbreak" of multiple unrelated imported cases.


Planning of an interceptive movement in children.
In the present study, we examined the spatio-temporal organization of the walking and reaching behaviour during an interception task in younger (6-9 years old) and older (10-13 years old) children. To this end, eighteen children had to walk towards an interception point to grasp a moving ball under three visual manipulation conditions. Walking and reaching behaviour were analysed during a condition allowing full vision of the ball trajectory and during two conditions in which vision towards the ball was partly occluded (enhanced planning requirement). The velocity of the ball was adapted to 50 or 70% of the maximum walking velocity of the participant. Results revealed that both younger and older children show a less accurate performance when the ball trajectory was occluded, while the walking profile and timing of the reach was not influenced by the occlusion manipulations. The findings seem to suggest that both groups were less accurate when the necessity of planning was enhanced.


Nitrogen turnover and N2O/N2 ratio of three contrasting tropical soils amended with biochar.
Biochar has been reported to reduce emission of nitrous oxide (N2O) from soils, but the mechanisms responsible remain fragmentary. For example, it is unclear how biochar effects on N2O emissions are mediated through biochar effects on soil gross N turnover rates. Hence, we conducted an incubation study with three contrasting agricultural soils from Kenya (an Acrisol cultivated for 10-years (Acrisol10); an Acrisol cultivated for over 100-years (Acrisol100); a Ferralsol cultivated for over 100 years (Ferralsol)). The soils were amended with biochar at either 2% or 4% w/w. The 15N pool dilution technique was used to quantify gross N mineralization and nitrification and microbial consumption of extractable N over a 20-day incubation period at 25 °C and 70% water holding capacity of the soil, accompanied by N2O emissions measurements. Direct measurements of N2 emissions were conducted using the helium gas flow soil core method. N2O emissions varied across soils with higher emissions in Acrisols than in Ferralsols. Addition of 2% biochar reduced N2O emissions in all soils by 53 to 78% with no significant further reduction induced by addition at 4%. Biochar effects on soil nitrate concentrations were highly variable across soils, ranging from a reduction, no effect and an increase. Biochar addition stimulated gross N mineralization in Acrisol-10 and Acrisol-100 soils at both addition rates with no effect observed for the Ferralsol. In contrast, gross nitrification was stimulated in only one soil but only at a 4% application rate. Also, biochar effects on increased NH4 + immobilization and NO3 -consumption strongly varied across the three investigated soils. The variable and bidirectional biochar effects on gross N turnover in conjunction with the unambiguous and consistent reduction of N2O emissions suggested that the inhibiting effect of biochar on soil N2O emission seemed to be decoupled from gross microbial N turnover processes. With biochar application, N2 emissions were about an order of magnitude higher for Acrisol-10 soils compared to Acrisol-100 and Ferralsol-100 soils. Our N2O and N2 flux data thus support an explanation of direct promotion of gross N2O reduction by biochar rather than effects on soil extractable N dynamics. Effects of biochar on soil extractable N and gross N turnover, however, might be highly variable across different soils as found here for three typical agricultural soils of Kenya.


Twin optical traps for two-particle cross-correlation measurements: eliminating cross-talk.
The correlated motions of two micron-sized particles reflect the (micro-) rheological properties of a fluid and can be conveniently detected using two optical traps in combination with interferometric displacement detection. When the correlations become small, cross-talk between the two beams becomes important. We have used dual optical traps created by either two orthogonally polarized laser beams derived from one laser source, or by two independent lasers of different wavelengths for microrheology experiments. High numerical aperture lenses (objective and condenser) in the optical path can introduce depolarization, and polarizing beam splitters are not perfect, both of which can lead to optical cross-talk. We have characterized the cross-talk in our setup and demonstrate that the use of two independent laser eliminates cross-talk entirely.


6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.
Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer. We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30-90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901. 1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1-51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6-94·9) in the 12-month group and 91·1% (89·7-92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05-1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001). After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care. French National Cancer Institute.


[Comparative efficacy of various methods of treatment of chronic venous oedema in real clinical practice].
The study was aimed at assessing efficacy and safety of micronized purified flavonoid fraction (MPFF, Detralex) in comprehensive treatment of chronic venous oedema induced by lower limb varicose veins. We performed a post hoc analysis of the results of treatment of 708 patients included into the observational programme VAP-PRO-C3 (ClinicalTrials.gov. NCT03722836). These patients, depending on the type of treatment, were divided into 8 subgroups: MPFF (n=32); MPFF + compression (n=145); MPFF + compression + topical treatment (n=158); MPFF + compression + topical treatment + endovasal laser coagulation (n=197); MPFF + endovasal laser coagulation (n=3); MPFF + compression + endovasal laser coagulation (n=152), patients not receiving MPFF (n=16); MPFF + topical treatment (n=2). Due to paucity of the participants, from the subsequent analysis we excluded the groups MPFF + endovasal laser coagulation, patients not receiving MPFF (n=16) and MPFF + topical treatment. All further statistical data are shown for the remaining 687 patients. Comparing the groups of patients undergoing conservative treatment alone and those subjected to surgical intervention demonstrated no statistically significant differences in dynamics of crural oedema. In both groups at every subsequent visit there was a statistically significant decrease in the ankle volume (p<0.001). During the whole period of follow up the crural volume in patients from the group of conservative treatment totally decreased by 0.201±0.158 L and in the operated patients by 0.236±0.189 L (p=0.021). The QOL assessed by the CIVIQ-14 global index score statistically significantly improved in the unoperated patients from 31.5±19.2 to 12.0±10.1 (p<0.001). In the operated patients, the baseline and final values of the QOL of the global index score amounted to 33.4±17.8 and 7.7±9.2, respectively (p<0.001). In the groups with and without topical treatment, the baseline values of the QOL assessed by CIVIQ-14 global index score amounted to 28.5±17.4 and 36.2±18.6, respectively. During the follow-up period, we observed statistically significant positive dynamics of all parameters of quality of life. The final visit demonstrated improvement of the CIVIQ-14 global index score to 9.4±9.2 in patients without topical treatment and 10.1±10.4 in those receiving topical treatment (p=0.367), with the mean value of this parameter during treatment in both groups decreased significantly (p<0.001). A statistically significant decrease in the ankle volume in both groups was registered at every visit, finally amounting to 0.223±0.166 L and 0.248±0.174 L (p=0.118) for patients not receiving and receiving topical treatment, respectively. In groups of patients not receiving and those receiving compression therapy, the baseline values of the QOL assessed by CIVIQ-14 global index score amounted to 21.4±14.2 and 33.1±18.5 (p<0.001), respectively. At the final visit, these indices statistically significantly (p<0.001) decreased to 7.3±9.1 and 9.9±9.9 (p=0.106). Compared with the baseline values, the ankle volume at the final visit in groups of patients with and without compression therapy statistically significantly decreased by 0.187±0.14 L and 0.238±0.17 L respectively (p=0.204). During the study, there were no adverse events related to the administration of MPFF and use of Detragel. MPFF and Detragel appear to be effective and safe components of comprehensive conservative therapy of chronic oedema induced by primary varicose veins of lower extremities.


Mortality caused by intracranial bleeding in non-severe hemophilia A patients.
Essentials Data on bleeding-related causes of death in non-severe hemophilia A (HA) patients are scarce. Such data may provide new insights into areas of care that can be improved. Non-severe HA patients have an increased risk of dying from intracranial bleeding. This demonstrates the need for specialized care for non-severe HA patients. Background Non-severe hemophilia (factor VIII concentration [FVIII:C] of 2-40 IU dL-1 ) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on bleeding-related causes of death, such as fatal intracranial bleeding, in non-severe patients are scarce. Such data may provide new insights into areas of care that can be improved. Aims To describe mortality rates, risk factors and comorbidities associated with fatal intracranial bleeding in non-severe hemophilia A patients. Methods We analyzed data from the INSIGHT study, an international cohort study of all non-severe hemophilia A patients treated with FVIII concentrates during the observation period between 1980 and 2010 in 34 participating centers across Europe and Australia. Clinical data and vital status were collected from 2709 patients. We report the standardized mortality rate for patients who suffered from fatal intracranial bleeding, using a general European male population as a control population. Results Twelve per cent of the 148 deceased patients in our cohort of 2709 patients died from intracranial bleeding. The mortality rate between 1996 and 2010 for all ages was 3.5-fold higher than that in the general population (95% confidence interval [CI] 2.0-5.8). Patients who died from intracranial bleeding mostly presented with mild hemophilia without clear comorbidities. Conclusion Non-severe hemophilia A patients have an increased risk of dying from intracranial bleeding in comparison with the general population. This demonstrates the need for specialized care for non-severe hemophilia A patients.


Is Body Adiposity Index a Better and Easily Applicable Measure for Determination of Body Fat?
Objective: The BAI can be used to reflect %body fat. This study aimed to compare BAI with other methods used in the determination of body fat.Materials and Methods: A cross-sectional study was conducted in Turkish adults. BAI, BMI, WHR, WHtR, body weight, hip and waist circumference (WC), skinfold thicknesses (biceps, triceps, subscapular, suprailiac) were measured. Body fat was measured using Bioelectric Impedance Analysis.Results: The Bland-Altman analyses conducted in this study showed that for % body fat estimations, BIA was in excellent agreement with skinfold measurements (p = 0.131) without proportional bias (p = 0.082), but that BAI was not in agreement with BIA and skinfold measurement. There were a statistically significant positive correlation between BAI and other measurements in terms of females and males and also regardless of sex.Conclusion: BAI was not in agreement with BIA and skinfold measurement methods for % body fat estimations, it had a significantly stronger correlation with % fat calculated using BIA and skinfold thickness.


Soluble toll-like receptor 2 is significantly elevated in HIV-1 infected breast milk and inhibits HIV-1 induced cellular activation, inflammation and infection.
We previously demonstrated that immunodepletion of soluble Toll-like receptor 2 (sTLR2) from human breast milk significantly increased HIV infection in vitro. The aims of this study were to characterize sTLR2 levels in breast milk from HIV-infected and uninfected women, and identify a mechanism by which sTLR2 inhibits HIV-induced cellular activation and infection. Blinded studies of breast milk from HIV-infected and uninfected Nigerian and Canadian women were evaluated for levels of sTLR2, proinflammatory cytokines and viral antigenemia. In-vitro experiments were conducted using cell lines to assess sTLR2 function in innate responses and effect on HIV infection. Breast milk from HIV-infected women showed significantly higher levels of sTLR2 than uninfected breast milk. Further, sTLR2 levels correlated with HIV-1 p24 and interleukin (IL)-15, thus suggesting a local innate compensatory response in the HIV-infected breast. Given the significantly higher levels of sTLR2 in breast milk from HIV-infected women, we next demonstrated that mammary epithelial cells and macrophages, which are prevalent in milk, produced significantly increased levels of sTLR2 following exposure to HIV-1 proteins p17, p24 and gp41 or the TLR2 ligand, Pam3CSK4. Our results also demonstrated that sTLR2 physically interacts with p17, p24 and gp41 and inhibits HIV-induced nuclear factor kappa-light-chain-enhancer of activated B cells activation, and inflammation. Importantly, binding of sTLR2 to HIV-1 proteins inhibited a TLR2-dependent increase in chemokine receptor 5 expression, thus resulting in significantly reduced HIV-1 infection. These results indicate novel mechanisms by which sTLR2 plays a critical role in inhibiting mother-to-child HIV transmission.


Influence of water quality on the accumulation of methyl 203mercury in gill tissue of minnow (Phoxinus phoxinus).
Effects of pH and concentrations of Cl and Ca on the uptake of methyl mercury (MeHg) in the gills of the minnow (Phoxinus phoxinus) were studied. Chloride concentration and pH in the water affect the speciation of MeHg. Ca was included because it affects the permeability of the gills and could therefore indirectly affect the amount of MeHg accumulated in the tissue. The species formed differ in hydrophobicity, as reflected in their octanol/water partition coefficients (Pow). Both a reduction in pH and an increase in Cl- concentration increased the Pow of MeHg. Ca had no effect on speciation. The accumulation of MeHg in the gill tissue increased with decreasing pH (from pH 7.0 to pH 3.9). Accumulation also increased as Cl- concentrations were increased from 10(-7) to 10(-1) M at pH 7.0. An increase in Ca concentration did not alter the accumulation of MeHg beyond a decrease in MeHg accumulation as Ca increased from 20 to 50 microM. We conclude that, of the water-quality factors studied, those affecting chemical speciation were most important in determining the MeHg uptake. The Ca concentration appears to be of minor importance.


[Classification Systems to Evaluate the Clubfoot and Their Potential Use to Predict the Course and the Results of the Ponseti Method Treatment].
INTRODUCTION The clubfoot ranks among the most frequent paediatric structural deformities of the lower extremity. Currently, the Ponseti method is considered the gold standard for the treatment. To evaluate the degree and severity of the deformity, clinical classification systems have been developed, commonly used in clinical practice. This study aims to verify whether the Pirani and Dimeglio clinical scoring systems can be used to predict the results of treatment by the Ponseti method. MATERIAL AND METHODS The study included 31 patients. The patients had been referred from the neonatal departments to the Department of Paediatric Surgery, Orthopaedics and Traumatology in Brno with the diagnosed clubfoot deformity, where they were treated by an erudite orthopaedist experienced in this field according to the Ponseti treatment standards. The Pirani and Dimeglio clinical scoring of the deformity were performed always before the commencement of the therapy and after the second plaster cast fixation. The number of plaster cast fixations, the necessity to carry out achillotomy and the relapse rate were set as the parameters of treatment results. In the first stage of statistical analysis, the respective clinical systems were correlated with the treatment results, in the second part of the study the patients were based on the clinical evaluation divided into 3 groups depending on the severity of the deformity, and these groups were subsequently compared. RESULTS 22 patients from the group (71%) underwent percutaneous achillotomy and in 3 patients (9.7%) a relapse occurred. To correct deformities 7.1 corrective casts were used on average. The correlation between the number of plaster cast fixations and classification systems was significant in all the cases, with the strongest dependency shown by the correlation with the Pirani score after the second corrective cast (r = 0.594, p < 0.001). Positive correlation was found also between the necessity to perform achillotomy and both the classification systems. In this case the strongest correlation was established in the case of the Pirani clinical scoring after the second plaster cast fixation (r = 0.488, p = 0.003). Conversely, significant correlation was not established between the relapse rate and the used classification systems, not even in a single case (p ≥ 0.05). In the second stage of the statistical analysis, in the case of the Pirani scoring before the therapy no difference was found between the individual groups with diverse severity of clubfoot deformity during the evaluation of the aforementioned parameters of treatment results. In the Pirani classification after the second plaster cast fixation, a statistically significant difference was established in the number of plaster cast fixations (p = 0.003) and the necessity to perform achillotomy (p = 0.012). When the Dimeglio scoring was applied before the therapy, a statistically significant difference between the groups was found in the number of plaster cast fixations (p = 0.031) and after the second plaster cast fixation in the relapse rate (p = 0.035). DISCUSSION Although the clinical scoring systems belong to key indicators of severity of the deformity and are commonly used in clinical practice, the current literature provides only an inconsistent picture of their application in predicting the course and the results of treatment. Concurrently, the authors opinions on this issue differ. The scoring in later stages of treatment shows a better predictive value than the scoring at the beginning of the treatment, which was confirmed also by the results of our study. CONCLUSIONS Even though the clinical scoring systems show a certain dependency on the parameters of the treatment results, in practice their predictive function can be used to a limited degree only. The complexity of the evaluation of the deformity itself and subsequently of the results of treatment requires also the use of other parameters than the clinical classifications only so that the prediction of the course and results of the treatment of clubfoot according to Ponseti shows a higher degree of reliability. Key words:clubfoot, Ponseti, Pirani classification, Dimeglio classification.


Interpersonal body and neural synchronization as a marker of implicit social interaction.
One may have experienced his or her footsteps unconsciously synchronize with the footsteps of a friend while walking together, or heard an audience's clapping hands naturally synchronize into a steady rhythm. However, the mechanisms of body movement synchrony and the role of this phenomenon in implicit interpersonal interactions remain unclear. We aimed to evaluate unconscious body movement synchrony changes as an index of implicit interpersonal interaction between the participants, and also to assess the underlying neural correlates and functional connectivity among and within the brain regions. We found that synchrony of both fingertip movement and neural activity between the two participants increased after cooperative interaction. These results suggest that the increase of interpersonal body movement synchrony via interpersonal interaction can be a measurable basis of implicit social interaction. The paradigm provides a tool for identifying the behavioral and the neural correlates of implicit social interaction.


Carotid endarterectomy: the financial impact of practice changes.
New techniques in the management of extracranial carotid occlusive disease have focused attention on the outcome and economics of carotid endarterectomy (CEA). Changing practice patterns for CEA must be assessed to allow accurate comparisons. The purpose of this study was to evaluate the effect of practice modifications related to CEA on patient outcome and cost data. Data on patients undergoing CEAs at a single institution from fiscal year 1992 to 1998 were prospectively collected and entered into a computerized database. Records were reviewed for patient demographics and outcome with regard to stroke and death. Selected years that corresponded to transitions in perioperative management were audited for complete hospital financial information from. We performed 960 CEAs during the study period, with a combined stroke and death rate of 1.1%. Inflation-adjusted hospital costs per patient in 1998 dollars for the years 1992, 1996, and 1998 were $5494, $4476, and $3350, respectively. In 1998, costs for patients who required arteriography were $1825 greater than those operated on during duplex scan examination alone in 1998. Statistically significant differences occurred in the year-to-year comparisons in the use of arteriography, intensive care unit monitoring, same day admissions, and length of stay. There were no statistically significant differences in the stroke and death rate between years. Practice changes related to CEA have resulted in significant savings without detriment in patient outcome. Comparisons between CEA and endovascular techniques will need to be evaluated within this context. Given these advances in perioperative management, it will be difficult to justify carotid stenting on the basis of current economic considerations.


The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats.
As circulating estrogen levels rise on the afternoon of proestrus, they stimulate the hypothalamo-pituitary axis. This estrogen positive feedback is pivotal to stimulate the luteinizing hormone (LH) surge required for ovulation and luteinization of ovarian follicles. In addition to estrogen, pre-LH surge progesterone is critical for an LH surge as was demonstrated by blocking progesterone synthesis. In ovariectomized (OVX) rats treated with trilostane, a blocker of the enzyme 3beta-hydroxysteroid dehydrogenase (3beta-HSD) that catalyzes the conversion of pregnenolone to progesterone, estrogen did not induce an LH surge. Further, estrogen induced an LH surge in OVX and adrenalectomized (ADX) rats, indicating that the source of progesterone was neither the ovary nor adrenal gland. This estrogen-only LH surge was inhibited by pretreatment with trilostane, indicating that although the adrenal gland and ovary were not necessary for positive feedback, progesterone synthesis was critical for estrogen-induced positive feedback in an OVX/ADX rat. This suggested that the LH surge is dependent on the pre-LH surge synthesis of progesterone. Estrogen-induced progesterone receptors in the hypothalamus are vital for the LH surge, so a potential location for progesterone synthesis is the hypothalamus. OVX/ADX female rats were treated with 17beta-estradiol (50 microg) and progesterone levels were assayed by RIA. Progesterone levels were elevated in hypothalamic tissue following estrogen treatment. No increases in tissue progesterone levels were found in parietal cortex, cerebellum, medulla, pituitary or plasma. Additionally, male rats that do not have an estrogen positive feedback-induced LH surge were examined. Castrated/ADX male rats had no increase in hypothalamic progesterone levels after estrogen treatment. Together, these data strongly suggest that estrogen enhances neuroprogesterone synthesis in the hypothalamus that is involved in the positive feedback regulating the LH surge.


ALE meta-analysis: controlling the false discovery rate and performing statistical contrasts.
Activation likelihood estimation (ALE) has greatly advanced voxel-based meta-analysis research in the field of functional neuroimaging. We present two improvements to the ALE method. First, we evaluate the feasibility of two techniques for correcting for multiple comparisons: the single threshold test and a procedure that controls the false discovery rate (FDR). To test these techniques, foci from four different topics within the literature were analyzed: overt speech in stuttering subjects, the color-word Stroop task, picture-naming tasks, and painful stimulation. In addition, the performance of each thresholding method was tested on randomly generated foci. We found that the FDR method more effectively controls the rate of false positives in meta-analyses of small or large numbers of foci. Second, we propose a technique for making statistical comparisons of ALE meta-analyses and investigate its efficacy on different groups of foci divided by task or response type and random groups of similarly obtained foci. We then give an example of how comparisons of this sort may lead to advanced designs in future meta-analytic research.


Ultraviolet-protected inflation.
In natural inflation, the inflaton is a pseudo-Nambu-Goldstone boson which acquires a mass by explicit breaking of a global shift symmetry at scale f. In this case, for small field values, the potential is flat and stable under radiative corrections. Nevertheless, slow roll conditions enforce f ≫ M(p), making the validity of the whole scenario questionable. In this Letter, we show that a coupling of the inflaton kinetic term to the Einstein tensor allows f ≪ M(p) by enhancing the gravitational friction acting on the inflaton during inflation. This new unique interaction (a) keeps the theory perturbative in the whole inflationary trajectory, (b) preserves the tree-level shift invariance of the pseudo-Nambu-Goldstone boson, and (c) avoids the introduction of any new degrees of freedom with respect to standard natural inflation.


NK cells in self-limited HCV infection exhibit a more extensively differentiated, but not memory-like, repertoire.
Natural killer (NK) cells have long been thought of as a purely innate immune cell population, but increasing reports have described developmental and functional qualities of NK cells that are commonly associated with cells of the adaptive immune system. Of these features, the ability of NK cells to acquire functional qualities associated with immunological memory and continuous differentiation resulting in the formation of specific NK cell repertoires has recently been highlighted in viral infection settings. By making use of a unique cohort of monitored, at-risk intravenous drug users in this study, we were able to dissect the phenotypic and functional parameters associated with NK cell differentiation and NK cell memory in patients 3 years after acute HCV infection and either the subsequent self-clearance or progression to chronicity. We observed increased expression of cytolytic mediators and markers CD56bright and NKp46+ of NK cells in patients with chronic, but not self-limited HCV infection. Patients with a self-limited infection expressed higher levels of differentiation-associated markers CD57 and KIRs, and lower levels of NKG2A. A more extensively differentiated NK cell phenotype is associated with self-clearance in HCV patients, while the NK cells of chronic patients exhibited more naïve and effector NK cell phenotypic and functional characteristics. The identification of these distinct NK cell repertoires may shed light on the role NK cells play in determining the outcome of acute HCV infections, and the underlying immunological defects that lead to chronicity.


Bioaccumulation of Per- and polyfluoroalkyl substances (PFASs) in a tropical estuarine food web.
The biomagnification of per- and polyfluoroalkyl substances (PFASs) was investigated in a tropical mangrove food web from an estuary in Bahia, Brazil. Samples of 44 organisms (21 taxa), along with biofilm, leaves, sediment and suspended particulate matter were analyzed. Sum (∑) PFAS concentrations in biota samples were dominated by perfluorooctane sulfonate (PFOS, 93% detection frequency in tissues; 0.05 to 1.97 ng g-1 ww whole-body (wb)), followed by perfluorotridecanoate (PFTrDA, 57%; 0.01 to 0.28 ng g-1 ww wb). PFOS precursors such as perfluorooctane sulfonamide (FOSA, 54%; 0.01 to 0.32 ng g-1 ww wb) and N-ethyl perfluorooctane sulfonamide (EtFOSA; 30%; 0.01 to 0.21 ng g-1 ww wb) were also detected. PFAS accumulation profiles revealed different routes of exposure among bivalve, crustacean and fish groups. Statistics for left-censored data were used in order to minimize bias on trophic magnification factors (TMFs) calculations. TMFs >1 were observed for PFOS (linear + branched isomers), EtFOSA (linear + branched isomers), and perfluorononanoate (PFNA), and in all cases, dissimilar accumulation patterns were observed among different trophic positions. The apparent biodilution of some long-chain PFCAs through the food chain (TMF < 1) may be due to exposure from multiple PFAS sources. This is the first study investigating bioaccumulation of PFASs in a tropical food web and provides new insight on the behavior of this ubiquitous class of contaminants.


Human milk oligosaccharides: Shaping the infant gut microbiota and supporting health.
Human milk oligosaccharides (HMO) are complex sugars which are found in breast milk at significant concentrations and with unique structural diversity. These sugars are the fourth most abundant component of human milk after water, lipids, and lactose and yet provide no direct nutritional value to the infant. Recent research has highlighted that HMOs have various functional roles to play in infant development. These sugars act as prebiotics by promoting growth of beneficial intestinal bacteria thereby generating short-chain fatty acids which are critical for gut health. HMOs also directly modulate host-epithelial immune responses and can selectively reduce binding of pathogenic bacteria and viruses to the gut epithelium preventing the emergence of a disease. This review covers current knowledge related to the functional biology of HMOs and their associated impact on infant gut health.


A Retrospective Study Evaluating the Effect of Low Doses of Perineural Dexamethasone on Ropivacaine Brachial Plexus Peripheral Nerve Block Analgesic Duration.
Examination of the effectiveness of perineural dexamethasone administered in very low and low doses on ropivacaine brachial plexus block duration. Retrospective evaluation of brachial plexus block duration in a large cohort of patients receiving peripheral nerve blocks with and without perineural dexamethasone in a prospectively collected quality assurance database. A single academic medical center. A total of 1,942 brachial plexus blocks placed over a 16-month period were reviewed. Demographics, nerve block location, and perineural dexamethasone utilization and dose were examined in relation to block duration. Perineural dexamethasone was examined as none (0 mg), very low dose (2 mg or less), and low dose (greater than 2 mg to 4 mg). Continuous catheter techniques, local anesthetics other than ropivacaine, and block locations with fewer than 15 subjects were excluded. Associations between block duration and predictors of interest were examined using multivariable regression models. A subgroup analysis of the impact of receiving dexamethasone on block duration within each block type was also conducted using a univariate linear regression approach. A total of 1,027 subjects were evaluated. More than 90% of brachial plexus blocks contained perineural dexamethasone (≤4 mg), with a median dose of 2 mg. Increased block duration was associated with receiving any dose of perineural dexamethasone (P < 0.0001), female gender (P = 0.022), increased age (P = 0.048), and increased local anesthetic dose (P = 0.01). In a multivariable model, block duration did not differ with very low- or low-dose perineural dexamethasone after controlling for other factors (P = 0.420). Perineural dexamethasone prolonged block duration compared with ropivacaine alone; however, duration was not greater with low-dose compared with very low-dose perineural dexamethasone.


Intracellular and extracellular phosphatidylinositol 3-phosphate produced by Phytophthora species is important for infection.
RxLR effectors produced by Phytophthora pathogens have been proposed to bind to phosphatidylinositol 3-phosphate (PtdIns(3)P) to mediate their translocation into host cells and/or to increase their stability in planta. Since the levels of PtdIns(3)P in plants are low, we examined whether Phytophthora species may produce PtdIns(3)P to promote infection. We observed that PtdIns(3)P-specific GFP biosensors could bind to P. parasitica and P. sojae hyphae during infection of Nicotiana benthamiana leaves transiently secreting the biosensors, suggesting that the hyphae exposed PtdIns(3)P on their plasma membrane and/or secreted PtdIns(3)P. Silencing of the phosphatidylinositol 3-kinases (PI3K) genes, treatment with LY294002, or expression of PtdIns(3)P-binding proteins by P. sojae reduced the virulence of the pathogen on soybean, indicating that pathogen-synthesized PtdIns(3)P was required for full virulence. Secretion of PtdIns(3)P-binding proteins or of a PI3P-5-kinase by N. benthamiana leaves significantly increased the level of resistance to infection by P. parasitica and P. capsici. Together, our results support the hypothesis that Phytophthora species produce external PtdIns(3)P to aid in infection, such as to promote entry of RxLR effectors into host cells. Our results derived from P. sojae RxLR effector Avr1b confirm that both the N-terminus and the C-terminus of this effector can bind PtdIns(3)P.


Differences in prostate cancer grade, stage, and location in radical prostatectomy specimens from United States and Japan.
To compared prostate cancer at radical prostatectomy between men in the United States (US) and Japan in the modern era. Three hundred seventy consecutive totally embedded RP cases (159 US; 211 Japan) from 2010 to 2012 were reviewed. US men were significantly younger (mean age 58.8 years) than Japanese men (mean age 64.6 years; P < 0.00001). Japanese patients presented with higher PSA levels (mean = 10.9 ng/ml) compared to US patients (mean = 5.8 ng/ml, P < 0.00001) and higher clinical stage (P = 0.003). Japanese tumors were: higher grade; larger; more advanced stage; with increased lymphovascular invasion; and more commonly TZ in location (P < 0.00001). In multivariate analysis, independent predictors of high tumor volume were PSA level, clinical stage, TZ location, Gleason grade, and country of origin (Japan). Independent predictors of TZ location were clinical stage, tumor volume, and country of origin (Japan). A major factor for larger, higher grade and stage tumors in Japanese patients is the lower prevalence of screening for prostate cancer in Japan. Another contributing factor may be their TZ location, where they are not palpable until advanced and where they are difficult to sample on needle biopsy possibly leading to a delay in diagnosis. The finding of a difference in zonality of prostate cancer between US and Japanese cases is novel and may reflect differences in biology rather than different health care practice between the groups. If this data is confirmed, consideration should be given to TZ sampling as part of routine needle biopsies in Japanese men.


Hysterectomy at a Canadian tertiary care facility: results of a one year retrospective review.
BACKGROUND: The purpose of this study was to investigate the indications for and approach to hysterectomy at Kingston General Hospital (KGH), a teaching hospital affiliated with Queen's University at Kingston, Ontario. In particular, in light of current literature and government standards suggesting the superiority of vaginal versus abdominal approaches and a high number of concurrent oophorectomies, the aim was to examine the circumstances in which concurrent oophorectomies were performed and to compare abdominal and vaginal hysterectomy outcomes. METHODS: A retrospective chart audit of 372 consecutive hysterectomies performed in 2001 was completed. Data regarding patient characteristics, process of care and outcomes were collected. Data were analyzed using descriptive statistics, t-tests and linear and logistic regression. RESULTS: Average age was 48.5 years, mean body mass index (BMI) was 28.6, the mean length of stay (LOS) was 5.2 days using an abdominal approach and 3.0 days using a vaginal approach without laparoscopy. 14% of hysterectomies were performed vaginally, 5.9% were laparoscopically assisted vaginal hysterectomies and the rest were abdominal hysterectomies. The most common indication was dysfunctional or abnormal uterine bleeding (37%). The average age of those that had an oophorectomy (removal of both ovaries) was 50.8 years versus 44.3 years for those that did not (p < .05). Factors associated with LOS included surgical approach, age and the number of concurrent procedures. CONCLUSIONS: A significant reduction in LOS was found using the vaginal approach. Both the patient and the health care system may benefit from the tendency towards an increased use of vaginal hysterectomies. The audit process demonstrated the usefulness of an on-going review mechanism to examine trends associated with common surgical procedures.


Perceived family and peer invalidation as predictors of adolescent suicidal behaviors and self-mutilation.
The present study investigates the longitudinal relationship between perceived family and peer invalidation and adolescent suicidal events (SE) and self-mutilation (SM) in a 6 month follow-up (f/u) study of adolescents admitted to an inpatient psychiatric unit for suicide risk. Adolescents (n=119) and their parent(s) were administered interviews and self-report assessments at baseline and at a 6 month f/u, with 99 (83%) completing both assessments. The Adolescent Longitudinal Interval Follow-Up Evaluation (A-LIFE) was modified to provide weekly ratings (baseline and each week of f/u) for perceived family and peer invalidation. Regression analyses examined whether: 1) Prospectively rated perceived family and peer invalidation at baseline predicted SE and SM during f/u; and 2) chronicity of perceived invalidation operationalized as proportion of weeks at moderate to high invalidation during f/u was associated with SE and SM during f/u. Multiple regression analyses, controlling for previously identified covariates, revealed that perceived family invalidation predicted SE over f/u for boys only and perceived peer invalidation predicted SM over f/u in the overall sample. This was the case for both baseline and f/u ratings of perceived invalidation. Our results demonstrate the adverse impact of perceived family and peer invalidation. Specifically, boys who experienced high perceived family invalidation were more likely to have an SE over f/u. Both boys and girls who experienced high perceived peer invalidation were more likely to engage in SM over f/u.


Ultraviolet and osmotic stresses induce and regulate the synthesis of mycosporines in the cyanobacterium chlorogloeopsis PCC 6912
The cyanobacterium Chlorogloeopsis PCC 6912 was found to synthesize and accumulate two putative UV sunscreen compounds of the mycosporine (mycosporine-like amino acid; MAA) type: mycosporine-glycine and shinorine. These MAAs were not constitutively present in the cells; their synthesis could be induced specifically either by exposure to UVB radiation (280-320 nm) or by osmotic stress, but not by other stress factors such as heat or cold shock, nutrient limitation, or photooxidative stress. A significant synergistic enhancement of MAA synthesis was observed when both stress factors were applied in combination. Although osmotic stress could induce MAA synthesis, comparison of the intracellular contents of MAAs with those of sugar osmolytes (glucose and trehalose) indicated that MAAs play no significant role in attaining osmotic homeostasis. UVB strongly enhanced the accumulation of shinorine, whereas osmotic stress had a more pronounced effect on mycosporine-glycine. This differential effect on the steady-state contents of each MAA could be explained either by differential regulation of biosynthesis or by differential loss rates of MAAs (leakage) under each condition. A preferential leakage of mycosporine-glycine from the cells after a hypoosmotic shock was detected. The results are interpreted in terms of an adaptive necessity for a combined regulatory control responding to both UV and external osmotic conditions in organisms that accumulate water-soluble sunscreens intracellularly.


The Effectiveness of Ledipasvir/Sofosbuvir in Youth With Genotype 4 Hepatitis C Virus: A Single Egyptian Center Study.
Licensure of ledipasvir/sofosbuvir for chronic hepatitis C virus (HCV) infection in adolescents was based on clinical trials on patients mainly with genotype 1. We aimed to evaluate the effectiveness and short-term safety of this newly approved antiviral in adolescents with HCV genotype 4. This was a study of 51 HCV-infected adolescents, who received the adult dose of ledipasvir/sofosbuvir, once daily for 12 weeks, and were followed-up for 12 weeks post-treatment. Laboratory tests, quantitation of HCV RNA, HCV genotyping, IL-28rs gene polymorphism and transient elastography were performed at baseline. Follow-up visits were done for blood testing and adverse events recording. The mean age was 14.7 ± 1.5 years (11-17.5), with a male to female ratio of 1.7:1. All patients were genotype 4a, and 76.5% had the CC IL-28 gene polymorphism. About 50% gave a history of HCV-infected mother, and 31% were treatment-experienced. Liver stiffness was F0 in 72.5%, F0-F1 in 13.7% and F1-F2 in 13.7%. Adverse events were mainly abdominal pain in 72.5%, headache in 64.7% and diarrhea in 53% of patients; these were mild. A reversible increase in creatinine level with a concomitant decline in estimated glomerular filtration rate was observed in the first month of treatment. By the end of week 12, a significant decline in liver enzymes was observed. All patients achieved an early, end of treatment, and a sustained virologic response. Adolescent patients with genotype 4 chronic HCV infection achieved a good response rate with good ontreatment tolerability for ledipasvir/sofosbuvir therapy.


Successful treatment of rotavirus diarrhea in children with immunoglobulin from immunized bovine colostrum.
Oral ingestion of immunoglobulins in humans has been shown to be effective as prophylaxis against enteric infections. However, its therapeutic effect in children with infectious diarrhea has hitherto not been proven. We treated children with rotavirus diarrhea with immunoglobulins extracted from immunized bovine colostrum (IIBC) containing high titers of antibodies against four rotavirus serotypes. In this double blind placebo-controlled trial, 80 children with rotavirus diarrhea were randomly assigned to receive orally either 10 g of IIBC (containing 3.6 g of antirotavirus antibodies) daily for 4 days or the same amount of a placebo preparation. The daily stool output (grams/kg/day), intake of oral rehydration solution (ml/kg/day), stool frequency (number of stools/day) and presence of rotavirus in stool were monitored for the 4 days during treatment. Children who received IIBC had significantly less daily and total stool output and stool frequency and required a smaller amount of oral rehydration solution than did children who received placebo (P < 0.05). Clearance of rotavirus from the stool was also earlier in the IIBC group compared with the placebo group (mean day, 1.5 vs. 2.9, P < 0.001). No adverse reactions from the colostrum treatment were observed. Treatment with antirotavirus immunoglobulin of bovine colostral origin is effective in the management of children with acute rotavirus diarrhea.


Preoperative assessment of eloquence in neurosurgery: a systematic review.
Tumor location and eloquence are two crucial preoperative factors when deciding on the optimal treatment choice in glioma management. Consensus is currently lacking regarding the preoperative assessment and definition of eloquent areas. This systematic review aims to evaluate the existing definitions and assessment methods of eloquent areas that are used in current clinical practice. A computer-aided search of Embase, Medline (OvidSP), and Google Scholar was performed to identify relevant studies. This review includes articles describing preoperative definitions of eloquence in the study's Methods section. These definitions were compared and categorized by anatomical structure. Additionally, various techniques to preoperatively assess tumor eloquence were extracted, along with their benefits, drawbacks and ease of use. This review covers 98 articles including 12,714 participants. Evaluation of these studies indicated considerable variability in defining eloquence. Categorization of these definitions yielded a list of 32 brain regions that were considered eloquent. The most commonly used methods to preoperatively determine tumor eloquence were anatomical classification systems and structural MRI, followed by DTI-FT, functional MRI and nTMS. There were major differences in the definitions and assessment methods of eloquence, and none of them proved to be satisfactory to express eloquence as an objective, quantifiable, preoperative factor to use in glioma decision making. Therefore, we propose the development of a novel, objective, reliable, preoperative classification system to assess eloquence. This should in the future aid neurosurgeons in their preoperative decision making to facilitate personalized treatment paradigms and to improve surgical outcomes.