Pharmacoeconomics of antihypertensive drug treatment: an analysis of how long patients remain on various antihypertensive therapies.
The objective of the research was to perform a clinical practice-based analysis of how long patients remain on various antihypertensive drugs. An administrative database listing of patient baseline characteristics, drug prescriptions, and hospital admissions was used. All new users of antihypertensive drugs, > or =20 years of age, receiving a first prescription for diuretics, beta blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor antagonists between January 1, 2000, and December 31, 2000, were included and observed for 365 days. Persistence was defined as a duration of therapy <273 days. A total of 14,062 patients were included in the study, 39.7% of whom remained on treatment (persistent patients). Persistent patients were more likely to be older, taking other drugs for concurrent disorders, hospitalized for cardiovascular diseases, and initially prescribed angiotensin II receptor antagonists. Persistent patients accounted for 80.6% of the overall cost for antihypertensive drugs. Factors associated with drug cost were age, pattern of persistence, number of prescribed classes, and specific medication at enrollment. Measuring persistence with treatment is needed to evaluate the appropriateness and the cost-effectiveness of drug use.


Effects of Seizures on Autonomic and Cardiovascular Function.
Parial and generalized seizures often affect autonomic function during seizures as well as during the interictal and postictal periods. Activation or inhibition of areas in the central autonomic network can cause cardiovascular, gastrointestinal, cutaneous, pupillary, urinary, and genital manifestations. Autonomic dysfunction during or after seizures may cause cardiac and pulmonary changes that contribute to sudden unexplained death in epilepsy.


Basophil-derived IL-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy.
Exaggerated thymic stromal lymphopoietin (TSLP) production and infiltration of basophils are associated with the pathogenesis of atopic dermatitis (AD), a recognized risk factor for the development of food allergies. Although TSLP and basophils have been implicated in promotion of food-induced allergic disorders in response to epicutaneous sensitization, the mechanisms by which TSLP-elicited basophils guide the progression of allergic inflammation in the skin to distant mucosal sites, such as the gastrointestinal tract, are poorly understood. We sought to test the role of basophil-intrinsic IL-4 production in TH2 sensitization to food antigens in the skin and effector food-induced allergic responses in the gut. Mice were epicutaneously sensitized with ovalbumin on an AD-like skin lesion, followed by intragastric antigen challenge to induce IgE-mediated food allergy. The requirement for basophil-derived IL-4 production for TH2 polarization and the pathogenesis of IgE-mediated food allergy was assessed in vitro by using coculture experiments with naive T cells and in vivo by using Il4 3'UTR mice that selectively lack IL-4 production in basophils. Epicutaneous food antigen sensitization is associated with infiltration of IL-4-competent innate immune cells to the skin, with basophils and eosinophils representing the predominant populations. In contrast to basophils, absence of eosinophils did not alter disease outcome. Coculture of IL-4-competent basophils together with dendritic cells and naive T cells was sufficient to promote TH2 polarization in an IL-4-dependent manner in vitro, whereas absence of basophil-intrinsic IL-4 production in vivo was associated with reduced food-induced allergic responses. TSLP-elicited basophils promote epicutaneous sensitization to food antigens and subsequent IgE-mediated food allergy through IL-4. Strategies to target the TSLP-basophil-IL-4 axis in patients with AD might lead to innovative therapies that can prevent the progression of allergies to distant mucosal sites.


Stereotactic third ventriculostomy in patients with nontumoral adolescent/adult onset aqueductal stenosis and symptomatic hydrocephalus.
Sixteen consecutive patients with obstructive hydrocephalus due to nontumoral aqueductal stenosis of adolescent or adult onset underwent computerized tomography-guided stereotactic third ventriculostomy. Computer-assisted angiographic target-point cross-registration was used in surgical planning to reduce morbidity. The procedure was used as primary treatment in five previously unshunted patients and in 11 patients who had previously received shunts and who presented when their shunts became obstructed (five patients), became infected (five patients), or required multiple revisions (one patient). At the time of third ventriculostomy, shunt hardware was removed in patients with infected shunts and the distal element of the shunt was ligated in all patients with obstructed shunts except one, who later required repeat third ventriculostomy; the distal shunt was ligated at that time. Follow-up data (range 1 to 5 years, mean 3 1/2 years, after surgery) showed that only one of the 16 patients had undergone a shunting procedure after the third ventriculostomy. The other 15 patients are asymptomatic and shunt-independent. In previously shunt-dependent patients, the peripheral subarachnoid space and cerebrospinal fluid absorption mechanism remained patent in spite of shunts placed earlier. Therefore, in patients with obstructive hydrocephalus due to aqueductal stenosis of adolescent or adult onset, stereotactic third ventriculostomy should be seriously considered as primary surgical management in previously unshunted patients and in shunt-dependent patients with obstructed or infected shunts.


Previous uterine artery embolization increases the rate of repeat embolization in a subsequent pregnancy.
This study aimed to determine the rate of repeat uterine artery embolization (UAE) in women with a previous UAE. Study data were collected from the Korea National Health Insurance Claims Database of the Health Insurance Review and Assessment Service for 2009-2013. We enrolled women who had a first delivery in 2009 and a second delivery between 2010 and 2013. Among 226,408 women who had a first delivery in 2009, 296 underwent UAE. A total of 127,506 women had a second delivery between 2010 and 2013. Of 296 women who underwent UAE after the first delivery, 94 had a second delivery between 2010 and 2013. Women with a previous UAE had a higher rate of UAE at the second delivery than women without a previous UAE. Multivariate adjusted analysis showed that a UAE at the first delivery increased the rate of UAE at the second delivery (odds ratio 25.56, 95% confidence interval 9.86-66.23). Women with a previous UAE should be appropriately counseled and monitored for the need for a repeat UAE.


Inner and outer retinal pathways both contribute to surround inhibition of salamander ganglion cells.
Illumination of the receptive-field surround reduces the sensitivity of a retinal ganglion cell to centre illumination. The steady, antagonistic receptive-field surround of retinal ganglion cells is classically attributed to the signalling of horizontal cells in the outer plexiform layer (OPL). However, amacrine cell signalling in the inner plexiform layer (IPL) also contributes to the steady receptive-field surround of the ganglion cell. We examined the contributions of these two forms of presynaptic lateral inhibition to ganglion cell light sensitivity by measuring the effects of surround illumination on EPSCs evoked by centre illumination. GABA(C) receptor antagonists reduced inhibition attributed to dim surround illumination, suggesting that this inhibition was mediated by signalling to bipolar cell axon terminals. Brighter surround illumination further reduced the light sensitivity of the ganglion cell. The bright surround effects on the EPSCs were insensitive to GABA receptor blockers. Perturbing outer retinal signalling with either carbenoxolone or cobalt blocked the effects of the bright surround illumination, but not the effects of dim surround illumination. We found that the light sensitivities of presynaptic, inhibitory pathways in the IPL and OPL were different. GABA(C) receptor blockers reduced dim surround inhibition, suggesting it was mediated in the IPL. By contrast, carbenoxolone and cobalt reduced bright surround, suggesting it was mediated by horizontal cells in the OPL. Direct amacrine cell input to ganglion cells, mediated by GABA(A) receptors, comprised another surround pathway that was most effectively activated by bright illumination. Our results suggest that surround activation of lateral pathways in the IPL and OPL differently modulate the sensitivity of the ganglion cell to centre illumination.


Acupuncture analgesia: a review of its mechanisms of actions.
The mechanism of acupuncture analgesia (AA) has been widely explored since the 1970s. Early studies investigated the relationship between acupuncture and endogenous opiates (beta-endorphin, enkephalin, endomorphin and dynorphin). Before the 1990s, most experts agreed on the concept that in normal animal models, lower frequency electroacupuncture (EA) stimulates the release of beta-endorphin, enkephalin and endomorphin, which in turn activates the mu- and delta-opioid receptors, and that higher frequency EA stimulates dynorphin which activates the kappa-opioid receptor. Besides endogenous opiates, our studies have focused on serotonin. The serotoninergic descending inhibitory pathway is suggested to be an important mechanism of acupuncture analgesic, collaborating with endogenous opiates. Many efforts have been made to clarify these mechanisms, but to date no satisfactory consensus has been reached. In the late 1990s, researchers began to focus on the different analgesic effects of EA between normal and hyperalgesic animal models. Published data from these studies imply that normal and hyperalgesic animals respond differently to EA. Results from experiments on the anti-hyperalgesia effect of EA have raised a new issue about the influences of EA on receptors to excitatory amino acid in the spinal cord level. Results from various studies have shown that these receptors play a role in the mechanism of AA. Recently, research on the autonomic nervous system (ANS) seem to indicate its connection with acupuncture. The inflammatory reflex (via the ANS) might be a crucial part of anti-hyperalgesia elicited by acupuncture, and this reflex, which regulates the immune system in the organism, can elucidate not only the mechanism of AA but also the mechanism of acupuncture applied to other inflammatory conditions. Innovation of functional image study enables us to analyze the responses of cortex on living human body to acupuncture. However, results of these experiments are still controversial. After 30 years of acupuncture research, there are still many puzzles left to be solved regarding the mechanism of AA.


Collective Choice, Collaboration, and Communication.
This article reviews recent empirical research on collective choice and collaborative problem solving. Much of the collective choice research focuses on hidden profiles. A hidden profile exists when group members individually have information favoring suboptimal choices but the group collectively has information favoring an optimal choice. Groups are notoriously bad at discovering optimal choices when information is distributed to create a hidden profile. Reviewed work identifies informational structures, individual processing biases, and social motivations that inhibit and facilitate the discovery of hidden profiles. The review of collaborative problem-solving research is framed by Larson's concept of synergy. Synergy refers to performance gains that are attributable to collaboration. Recent research has addressed factors that result in groups performing as well as their best member (weak synergy) and better than their best member (strong synergy). Communication dynamics underlying both collective choice and collaborative problem solving are discussed.


Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia.
HIT is an acquired antibody-mediated disorder strongly associated with thrombosis, including microthrombosis secondary to disseminated intravascular dissemination (DIC). The clinical features of HIT are reviewed from the perspective of the 4Ts scoring system for HIT, which emphasises its characteristic timing of onset of thrombocytopenia. HIT antibodies recognize multimolecular complexes of platelet factor 4 (PF4)/heparin. However, a subset of HIT sera recognise PF4 bound to platelet chondroitin sulfate; these antibodies activate platelets in vitro and in vivo even in the absence of heparin, thus explaining: delayed-onset HIT (where HIT begins or worsens after stopping heparin); persisting HIT (where HIT takes several weeks to recover); spontaneous HIT syndrome (a disorder clinically and serologically resembling HIT but without proximate heparin exposure); and fondaparinux-associated HIT (four distinct syndromes featuring thrombocytopenia that begins or worsens during treatment with fondaparinux), with a new patient case presented with ongoing thrombocytopenia (and fatal haemorrhage) during treatment of HIT with fondaparinux, with fondaparinux-dependent platelet activation induced by patient serum ("fondaparinux cross-reactivity"). Ironically, despite existence of fondaparinux-associated HIT, this pentasaccharide anticoagulant is a frequent treatment for HIT (including one used by the author). HIT can be confused with other disorders, including those with a) timing similar to HIT (e. g. abciximab-associated thrombocytopenia of delayed-onset); b) combined thrombocytopenia/thrombosis (e. g. symmetrical peripheral gangrene secondary to acute DIC and shock liver); and c) both timing of onset and thrombosis (e. g. warfarin-associated venous limb gangrene complicating cancer-associated DIC). By understanding clinical and pathophysiological similarities and differences between HIT and non-HIT mimicking disorders, the clinician is better able to make the correct diagnosis.


Reversible Fronto-occipitotemporal Signaling Complements Task Encoding and Switching under Ambiguous Cues.
Adaptation to changing environments involves the appropriate extraction of environmental information to achieve a behavioral goal. It remains unclear how behavioral flexibility is guided under situations where the relevant behavior is ambiguous. Using functional brain mapping of machine learning decoders and directional functional connectivity, we show that brain-wide reversible neural signaling underpins task encoding and behavioral flexibility in ambiguously changing environments. When relevant behavior is cued ambiguously during behavioral shifting, neural coding is attenuated in distributed cortical regions, but top-down signals from the prefrontal cortex complement the coding. When behavioral shifting is cued more explicitly, modality-specialized occipitotemporal regions implement distinct neural coding about relevant behavior, and bottom-up signals from the occipitotemporal region to the prefrontal cortex supplement the behavioral shift. These results suggest that our adaptation to an ever-changing world is orchestrated by the alternation of top-down and bottom-up signaling in the fronto-occipitotemporal circuit depending on the availability of environmental information.


Prevalence, course, and comorbidity of insomnia and depression in young adults.
(1) To describe the prevalence and prospective course of insomnia in a representative young-adult sample and (2) to describe the cross-sectional and longitudinal associations between insomnia and depression. Longitudinal cohort study. Community of Zurich, Switzerland. Representative stratified population sample. None. The Zurich Study prospectively assessed psychiatric, physical, and sleep symptoms in a community sample of young adults (n=591) with 6 interviews spanning 20 years. We distinguished 4 duration-based subtypes of insomnia: 1-month insomnia associated with significant distress, 2- to 3-week insomnia, recurrent brief insomnia, and occasional brief insomnia. The annual prevalence of 1-month insomnia increased gradually over time, with a cumulative prevalence rate of 20% and a greater than 2-fold risk among women. In 40% of subjects, insomnia developed into more chronic forms over time. Insomnia either with or without comorbid depression was highly stable over time. Insomnia lasting 2 weeks or longer predicted major depressive episodes and major depressive disorder at subsequent interviews; 17% to 50% of subjects with insomnia lasting 2 weeks or longer developed a major depressive episode in a later interview. "Pure" insomnia and "pure" depression were not longitudinally related to each other, whereas insomnia comorbid with depression was longitudinally related to both. This longitudinal study confirms the persistent nature of insomnia and the increased risk of subsequent depression among individuals with insomnia. The data support a spectrum of insomnia (defined by duration and frequency) comorbid with, rather than secondary to, depression.


SIFTING FOR SAPPHIRES: SYSTEMATIC SELECTION OF TIDAL DISRUPTION EVENTS IN iPTF.
We present results from a systematic selection of tidal disruption events (TDEs) in a wide-area (4800 deg2), g + R band, Intermediate Palomar Transient Factory (iPTF) experiment. Our selection targets typical optically-selected TDEs: bright (>60% flux increase) and blue transients residing in the center of red galaxies. Using photometric selection criteria to down-select from a total of 493 nuclear transients to a sample of 26 sources, we then use follow-up UV imaging with the Neil Gehrels Swift Telescope, ground-based optical spectroscopy, and light curve fitting to classify them as 14 Type Ia supernovae (SNe Ia), 9 highly variable active galactic nuclei (AGNs), 2 confirmed TDEs, and 1 potential core-collapse supernova. We find it possible to filter AGNs by employing a more stringent transient color cut (g - r < -0.2 mag); further, UV imaging is the best discriminator for filtering SNe, since SNe Ia can appear as blue, optically, as TDEs in their early phases. However, when UV-optical color is unavailable, higher precision astrometry can also effectively reduce SNe contamination in the optical. Our most stringent optical photometric selection criteria yields a 4.5:1 contamination rate, allowing for a manageable number of TDE candidates for complete spectroscopic follow-up and real-time classification in the ZTF era. We measure a TDE per galaxy rate of 1.7 - 1.3 + 2.9 × 10 - 4 gal - 1 yr - 1 (90% CL in Poisson statistics). This does not account for TDEs outside our selection criteria, thus may not reflect the total TDE population, which is yet to be fully mapped.


[Partial parietal cystectomy and cystoplasty using a lyophilized human dura mater patch as an alternative in palliative surgery for bladder cancer].
Fifteen patients with infiltrating bladder carcinoma underwent partial cystectomy and cystoplasty with lyophilized human dura at our hospital from 1983 to 1988. The 5-year survival rate was 75% for stage B1, 60% for B2, 40% for C and 0% for D1. There were no intra- or post-operative deaths and the post-operative complications were few. This procedure may be useful in selected patients with bladder tumors who cannot be submitted to more radical procedures due to a coexisting pathological condition representing a high surgical risk or in elderly patients.


Outer membrane of gram-negative bacteria. XVIII. Electron microscopic studies on porin insertion sites and growth of cell surface of Salmonella typhimurium.
Salmonella typhimurium contains three "major proteins" or "porins" (34K, 35K, and 36K) in the outer membrane. A mutant strain producing only the 35K porin was first grown in media containing high concentrations of NaCl to "repress" the porin synthesis and then was shifted into a medium without NaCl. The newly made porin molecules were then labeled with the ferritin-coupled antibody at various times after the shift, and the samples were examined by whole-mount, freeze-etching, and thin-section electron microscopy. These experiments showed that newly inserted porins appeared as discrete patches uniformly distributed over the surface of the cell and, furthermore, that the sites of adhesion between the inner and outer membrane were most probably the pathway by which the newly made porin molecules appeared on cell surface. The 34K and 36K porins were also inserted in the same manner, since the appearance of new porins at discrete sites all over the cell surface was also observed when cells with wild-type porin phenotype were treated with unlabeled antibody to block existing antigenic sites, subsequently regrown, and labeled with the ferritin-coupled antibody. Since porins comprise a major portion of the densely packed, relatively immobile, "protein framework" of the outer membrane, these results lead us to conclude that the outer membrane grows predominantly by diffuse intercalation rather than by the zonal growth mechanism.


Clinical efficacy of ciprofloxacin in lower respiratory tract infections.
The sputum pharmacokinetics and clinical efficacy of ciprofloxacin in lower respiratory tract infections is reviewed. Following intravenous administration, ciprofloxacin penetrates rapidly into bronchial tissue; the elimination half life is between 3 and 4 h and a dose dependency is seen. Following oral intake, the time to reach maximal concentrations is approximately two hours and after a dose of 750 mg the concentration may reach 1.7 mg/l in patients without cystic fibrosis and range from 0.5 to 3.4 mg/l in cystic fibrosis patients. Coadministration of ciprofloxacin increases serum levels and decreases total body clearance of theophylline. In controlled comparative clinical trials, ciprofloxacin has been found to have similar clinical efficacy as amoxycillin, ampicillin, cefalexin, doxycycline, co-trimoxazole, imipenem-cilastatin and ceftazidime for the treatment of a range of lower respiratory tract infections. Ciprofloxacin has been found to be superior in clinical efficacy to cefaclor. Experimental animal models suggest a role for ciprofloxacin in infections caused by Legionella pneumophila and Mycoplasma pneumoniae. The clinical and bacteriological efficacy of ciprofloxacin is less pronounced in lung infections caused by Pseudomonas aeruginosa, but is comparable to the combination of beta-lactams and aminoglycosides. Development of resistance is frequently observed during ciprofloxacin treatment of Ps. aeruginosa. Because of the availability of other oral and effective agents, ciprofloxacin is not recommended for empirical treatment of community acquired lower respiratory infections, but should be reserved for infections caused by multiply resistant organisms.


Selective autophagy as a potential therapeutic target for neurodegenerative disorders.
Cells rely on surveillance systems such as autophagy to handle protein alterations and organelle damage. Dysfunctional autophagy, an evolutionarily conserved cellular mechanism for degradation of intracellular components in lysosomes, frequently leads to neurodegeneration. The neuroprotective effect of autophagy stems from its ability to eliminate pathogenic forms of proteins such as α-synuclein or tau. However, the same pathogenic proteins often affect different types and steps of the autophagic process. Furthermore, genetic studies have shown that some proteins related to neurodegeneration, such as huntingtin, participate in autophagy as one of their physiological functions. This complex interplay between autophagy and neurodegeneration suggests that targeting autophagy as a whole might have limited applicability in neurodegenerative diseases, and that future efforts should focus instead on targeting specific types and steps of the autophagic process. This change of strategy in the modulation of autophagy might hold promise for future disease-modifying therapies for patients with neurodegenerative disorders.


Influence of spatiotemporal coupling induced by an ultrashort laser pulse shaper on a focused beam profile.
4f pulse shapers have been widely used to temporally manipulate femtosecond optical pulses by spectral filtering. When the temporal waveform is manipulated with a spatial light modulator consisting of segmented pixels, the spatial profile of the output beam also varies because of diffraction at the pixel array, which is known as a spatiotemporal coupling effect. This effect produces a complicated spatio-temporal profile near the focus of the ultrashort pulses, which may affect the interpretation of experimental results obtained with shaped ultrashort pulses. We investigate the spatial intensity distribution at the focus of temporally shaped pulses through ablation experiments. The three-dimensional space-time beam profile is also numerically calculated.


IS THE NEW PROCORE 20G DOUBLE FORWARD-BEVEL NEEDLE CAPABLE TO OBTAIN BETTER HISTOLOGICAL SAMPLES BY ENDOSCOPIC ULTRASOUND FOR DIAGNOSING SOLID PANCREATIC LESIONS?
Fine needle biopsy (FNB) histological samples by endoscopic ultrasound. It is important to obtain representative histological samples of solid biliopancreatic lesions without a clear indication for resection. The role of new needles in such task is yet to be determined. To compare performance assessment between 20G double fine needle biopsy (FNB) and conventional 22G fine needle aspiration (FNA) needles for endoscopic ultrasound (EUS)-guided biopsy. This prospective study examined 20 patients who underwent the random puncture of solid pancreatic lesions with both needles and the analysis of tissue samples by a single pathologist. The ProCore 20G FNB needle provided more adequate tissue samples (16 vs. 9, p=0.039) with better cellularity quantitative scores (11 vs. 5, p=0.002) and larger diameter of the histological sample (1.51±1.3 mm vs. 0.94±0.55 mm, p=0.032) than the 22G needle. The technical success, puncture difficulty, and sample bleeding were similar between groups. The sensitivity, specificity, and diagnostic accuracy were 88.9%, 100%, and 90% and 77.8%, 100%, and 78.9% for the 20G and 22G needles, respectively. The samples obtained with the ProCore 20G FNB showed better histological parameters; although there was no difference in the diagnostic performance between the two needles, these findings may improve pathologist performance.


Mutational spectrum of N-hydroxy-N-acetyl-4-aminobiphenyl at exon 3 of the HPRT gene.
4-Aminobiphenyl is a human bladder carcinogen present in many environmental sources, including cigarette smoke. It can be metabolized in two steps to the mutagen N-hydroxy-N-acetyl-4-aminobiphenyl (N-OH-AABP). In this study the mutational spectrum of N-OH-AABP-exposed human lymphoblastoid cells (TK6) was determined using HPRT.


Reduced risk of back pain following teriparatide treatment: a meta-analysis.
Vertebral fractures are the most common osteoporotic fracture and may result in back pain with functional limitations and diminished quality of life. Teriparatide [rhPTH (1-34)] has been shown to increase bone mass and reduce the risk of vertebral and other osteoporotic fractures. The aim of this study was to evaluate the effects of teriparatide on the risk of back pain in patients with osteoporosis. A systematic review of the literature was performed, and five trials were identified and included in our analyses. All trials were randomized, double-blinded, and parallel with either new vertebral fracture (n=1) or bone mineral density as the primary endpoint (n=4). Four studies were in postmenopausal women with osteoporosis, and one was in men with idiopathic or hypogonadal osteoporosis. Two trials were placebo controlled, two trials were alendronate controlled, and one trial involved teriparatide plus hormone replacement therapy versus hormone replacement therapy alone. Reports of back pain, defined as new or worsened back pain after initiating the study drug, were obtained from adverse event databases, and the risk of back pain was analyzed using a multivariate Cox proportional hazards model. Results were not statistically heterogeneous (P=0.60) across trials, and there were no differences between groups administered teriparatide 20 or 40 mcg/day doses (P=0.64). The rates of back pain, moderate or severe back pain, and severe back pain per 100 patient-years were numerically lower in the teriparatide versus comparator groups in each study. Compared with the pooled comparator, patients in the pooled teriparatide group had reduced risk for any back pain [relative risk, 0.66 (95% CI, 0.55-0.80)], moderate or severe back pain [relative risk, 0.60 (95% CI, 0.48-0.75)] and severe back pain [relative risk, 0.44 (95% CI, 0.28-0.68)]. Separate meta-analyses comparing teriparatide versus placebo or antiresorptive drugs gave similar results. In conclusion, patients randomized to teriparatide had a reduced risk of new or worsening back pain compared to patients randomized to placebo, hormone replacement therapy or alendronate.


Intoxication of host cells by the T3SS phospholipase ExoU: PI(4,5)P2-associated, cytoskeletal collapse and late phase membrane blebbing.
Pseudomonas aeruginosa is an opportunistic pathogen that is associated with hospital-acquired infections, ventilator-associated pneumonia, and morbidity of immunocompromised individuals. A subpopulation of P. aeruginosa encodes a protein, ExoU, which exhibits acute cytotoxicity. Toxicity is directly related to the phospholipase A2 activity of the protein after injection into the host cytoplasm via a type III secretion system. ExoU enzymatic activity requires eukaryotic cofactors, ubiquitin or ubiquitin-modified proteins. When administered extracellularly, ExoU is unable to intoxicate epithelial cells in culture, even in the presence of the cofactor. Injection or transfection of ExoU is necessary to observe the acute cytotoxic response. Biochemical approaches indicate that ExoU possesses high affinity to a multifunctional phosphoinositide, phosphatidylinositol 4,5-bisphosphate or PI(4,5)P2 and that it is capable of utilizing this phospholipid as a substrate. In eukaryotic cells, PI(4,5)P2 is mainly located in the cytoplasmic side of the plasma membrane and anchors adaptor proteins that are involved in cytoskeletal structures, focal adhesions, and plasma membranes. Time-lapse fluorescent microscopy analyses of infected live cells demonstrate that ExoU intoxication correlates with intracellular damage in the early phases of infection, such as disruption of focal adhesions, cytoskeletal collapse, actin depolymerization, and cell rounding. At later time points, a membrane blebbing phenotype was prominent prior to the loss of the plasma membrane integrity and barrier function. Membrane blebbing appears to accelerate membrane rupture and the release of intracellular markers. Our data suggest that in eukaryotic host cells, intracellular ExoU targets and hydrolyzes PI(4,5)P2 on the plasma membrane, causing a subsequent disruption of cellular structures and membrane integrity.


[Current concepts of the biology of the development of the human head. Observations and hypotheses].
Morphological dynamics controlling vertebrate embryo development, which takes place in flotation in a liquid medium, leads to the hypothesis that the pentameric symmetry of echinodermes, ancestors of the vertebrates, is conserved during evolution. This embryogenesis consists of morphological repetitions: synchronous growth of five expansions specialized in exploration and spatial deplacements (head and four limbs); each of these five expansions consists of five buds or five radii (facial buds, fingers and toes). Homomorphism of the mouth, of the hands, and of the feet--which are capture catastrophes over the environment, installed early during development--allows later functional and sensory connections. These morphological repetitions are also demonstrated by the association of facial, hand, and foot buds, malformations for which a topological correspondance can be shown. During vertebrate morphogenesis by flotation in a liquid medium, other phenomena take place. For instance, the palate is formed anteriorly by a triple junction resulting from the fusion of its three constitutive buds.


AGenDA: gene prediction by cross-species sequence comparison.
Automatic gene prediction is one of the major challenges in computational sequence analysis. Traditional approaches to gene finding rely on statistical models derived from previously known genes. By contrast, a new class of comparative methods relies on comparing genomic sequences from evolutionary related organisms to each other. These methods are based on the concept of phylogenetic footprinting: they exploit the fact that functionally important regions in genomic sequences are usually more conserved than non-functional regions. We created a WWW-based software program for homology-based gene prediction at BiBiServ (Bielefeld Bioinformatics Server). Our tool takes pairs of evolutionary related genomic sequences as input data, e.g. from human and mouse. The server runs CHAOS and DIALIGN to create an alignment of the input sequences and subsequently searches for conserved splicing signals and start/stop codons near regions of local sequence conservation. Genes are predicted based on local homology information and splice signals. The server returns predicted genes together with a graphical representation of the underlying alignment. The program is available at http://bibiserv.TechFak.Uni-Bielefeld.DE/agenda/.


Clinical experience and patient outcomes associated with the TandemHeart percutaneous transseptal assist device among a heterogeneous patient population.
There is a paucity of literature describing the outcomes associated with the use of TandemHeart percutaneous ventricular assist device (PVAD). The literature is limited by analyzing only subsets of patients. We present the clinical outcomes and safety associated with the use of TandemHeart among a series of heterogeneous patients requiring PVAD support. We reviewed the clinical experience, hemodynamic variables, survival outcomes, and complications associated with the implantation of TandemHeart support device among 25 patients presenting to our institution. Indications for PVAD implantation were cardiogenic shock (56%), ST-segment elevation myocardial infarction (STEMI) (20%), postpericardiotomy (16%), and high-risk percutaneous coronary interventions (PCI) or ventricular tachycardia (VT) ablation (8%). TandemHeart was used for an average of 4.8 ± 2.1 days and demonstrated significant hemodynamic improvements (pre- and postimplantation left ventricular ejection fractions were 21.5% ± 15% and 24.5% ± 10.5%, respectively [p = 0.06]). The cardiac index improved from a mean 2.04 ± 075 L/min/m² to 2.45 ± 073 L/min/m² (p = 0.09). The mixed venous oxygen saturation (SVO2) increased from 55.14 ± 13.34 to 66.43 ± 7.43 (p = 0.008) after implantation. TandemHeart was used as a bridge to left ventricular assist device implantation (44%) or recovery (20%). Thirty-six percent of patients died on support or shortly after PVAD removal. Thirty, 90-day, and long-term (>90 days) survival rates were 56%, 52%, and 36%, respectively. Procedure-related complications were reported in 13 patients (56%), and the majority (90%) was related to vascular access (bleeding or pseudoaneurysm). The TandemHeart device is a safe therapeutic option as a bridge-to-recovery or bridge-to-bridge for patients with hemodynamic compromise regardless of the etiology. The favorable hemodynamic profile, postimplantation survival rates, and manageable complications support its use to assist hemodynamic recovery in patients refractory to conventional therapy.


Initial effects of a treatment by fixed partial dentures supported by mini dental implants from a patient's point of view.
Mini dental implants (MDIs) in dentistry are recommended for cases with adequate bone quality and height, but a lack of alveolar bone width. Some studies well documented successful usage of MDIs for a removable denture support, but studies of MDIs supporting fixed prosthodontic restorations are scarce. We aimed to study the effect of fixed partial dentures (FPD) therapy supported by MDIs or by MDIs and natural teeth, on patients self perceived oral health related quality of life (OHRQoL), self perceived oral aesthetics and self perceived chewing function. A total of 23 patients (10 female and 13 men, age range from 54 to 78 years) were included and 61 MDIs were inserted, 10 in the maxilla and 51 in the mandible. In 14 patients FPDs were constructed only on MDIs and in 9 patients FPDs were constructed on both, MDIs and natural teeth. FPDs on MDIs were replacing mostly mandibular incisors, the second maxillary incisors and the first maxillary premolars. Those FPDs supported by both, MDIs and natural teeth had some MDIs inserted in frontal regions to allow a FPD construction. The three questionnaires: the OHIP-CRO14 for the assessment of OHRQoL, the OES-CRO for assessment of oral aesthetics and the Chewing function questionnaire (CFQ) for assessment of chewing function have been administrated twice:prior to the MDIs insertion and three months after the FPD treatment supported by MDIs had been finished. The CFQ and the OHIP summary scores significantly decreased revealing better OHRQoL and better chewing ability after treatment, and the OES scores significantly increased indicating increased self perceived oral aesthetics (p < 0.01). Clinical examination revealed no periimplant inflammation. Patients' data supplement the initially promising clinical findings. However, further follow ups will be necessary to finally confirm the long term clinical benefit of MDIs.


Polymorphism in glassy silicon: inherited from liquid-liquid phase transition in supercooled liquid.
Combining molecular dynamics (MD) simulation and Voronoi polyhedral analyses, we discussed the microstructure evolution in liquid and glassy silicon during cooling by focusing on the fraction of various clusters. Liquid-liquid phase transition (LLPT) is detected in supercooled liquid silicon However, freezing the high-density liquid (HDL) to the glassy state is not achieved as the quenching rate goes up to 10(14) K/s. The polyamorphism in glassy silicon is found to be mainly associated with low-density liquid (LDL).


Structure determination of soybean and wheat glucosylceramides by tandem mass spectrometry.
Glucosylceramide (GluCer) is a major sphingolipid of plant tissue and, thus, abundant in nature and in dietary food sources. The lipid backbones of mammalian GluCer (sphingosine, d18:1(delta4), and ceramide) induce cell death (apoptosis) and inhibit colon carcinogenesis, it is critical to know the structures of GluCer present in plants as a first step toward understanding this potential link between diet and cancer. This study characterized the molecular species of GluCer from soybean and wheat by low-resolution, high-resolution and tandem mass spectrometry. Soybean GluCer was comprised primarily (>95%) of ceramide with 4,8-sphingadiene (d18:2(delta4,delta8)) and alpha-hydroxypalmitic acid (h16:0); the remainder had the same backbone with h18:0, h20:0, h22:0 and h24:0 fatty acids. Wheat GluCer had three major ceramide, d18:2(delta4,delta8) with h16:0, d18:1(delta8) with h16:0 and d18: 2(delta4,delta8) with h20:0, and smaller amounts of other homologs. These backbones differ from those of mammalian sphingolipids, which often have a delta4-double bond (but rarely a delta8-double bond), and have alpha-hydroxy fatty acids in only some cases. Previously unexplained fragmentations that were diagnostic for the type of sphingoid base backbone (i.e. by homolytic cleavage of the doubly allylic C-6-C-7 bond to yield a stable distonic allylic radical cation and an allylic radical neutral) were also identified. Hence this method should be useful in the identification of double bonds in sphingolipids, and structure-function relationships between sphingolipids and colon carcinogenesis.


More on pseudoscience in science and the case for psychiatric diagnosis. A critique of D.L. Rosenhan's "On Being Sane in Insane Places" and "The Contestual Nature of Psychiatric Diagnosis".
Rosenhan's 1973 article, "On Being Sane in Insane Places," was pseudoscience presented as science. Just as his pseudopatients were diagnosed at discharge as having "schizophrenia in remission", so a careful examination of this study's methods, results, and conclusions leads to a diagnosis of "logic in remission." Rosenhan's study proves that pseudopatients are not detected by psychiatrists as having simulated signs of mental illness and that the implementation of certain invalid research designs can make psychiatrists appear foolish. These rather unremarkable findings are irrelevant to the real problems of the reliability and validity of psychiatric diagnosis and only serve to obscure them. A correct interpretation of his own data contradicts his conclusions. There are purposes to psychiatric diagnosis that Rosenhan's article ignores. His more recent suggestion that certain requirements be met prior to the adoption of a new psychiatric classification system is unrealistic.


[The rehabilitative treatment of the frequently ill children presenting with chronic infectious foci in the nasopharynx].
The objective of the present study was to elucidate the influence of the combined physiotherapeutic remedial treatment on the effectiveness of rehabilitation of the frequently ill children (FIC) and children presenting with chronic infectious foci inthe nasopharynx taking into consideration their microelemental and immunological status. A total of 80 frequently ill children and children presenting with chronic infectious foci inthe nasopharynx were available for the observation with special reference to dynamics of clinical conditions, immunological processes, and microelement composition. The combined treatment including the intake of "Asonovklyuch" mineral water enhanced the resistance of the children to the causative factors of respiratory infections and increased selenium content in their body. It is concluded that the treatment of the children presenting with chronic infectious foci inthe nasopharynx with the use of the specialized dietary product "Clinutren Junior" produces an anti-inflammatory and immunoregulatory effect and thereby promotes the correction of disorders of microelement nutrition.


Facile Method for Specifically Sensing Sphingomyelinase in Cells and Human Urine Based on a Ratiometric Fluorescent Nanoliposome Probe.
Sphingomyelinase (SMase) is closely related to diseases like Niemann-Pick disease and atherosclerosis, and the development of a simple method for the assay of SMase activity is very useful to screen new potential inhibitors or stimulators of SMase or biomarkers of disease. Fluorophore-encapsulated nanoliposomes (FENs) are emerging as a new fluorescent probe for sensing the enzymatic activity. In this work, two fluorochromes (cy7 and IR780) were encapsulated into the liposome of sphingomyelin, and therefore, a sphingomyelin-based ratiometric FEN probe for the SMase activity assay was constructed. The probe shows high selectivity and sensitivity to acid SMase with a detection limit of 4.8 × 10-4 U/mL. Sphingomyelin is the natural substrate of SMase; therefore, the probe has native ability for all kinds of SMase activity assays. Moreover, the probe has been successfully applied to the analysis of acid SMase activity in cells and urine samples. As far as we know, this is the first example of a nanoliposome fluorescence method for assaying acid SMase, and the method is biocompatible and much simpler than the existing ones, which might provide a new strategy for developing new methods for other important esterases.


Construction of Bacillus anthracis mutant strains producing a single toxin component.
The two protein exotoxins secreted by Bacillus anthracis are composed of three distinct components: protective antigen (PA), lethal factor (LF), and (o)edema factor (EF). We have developed a genetic strategy that permits us selectively to inactivate each of the genes coding for PA, EF or LF. This strategy involved the deletion of a portion of the structural gene and the insertion of an antibiotic resistance cassette. With this technique, double mutant strains of B. anthracis producing only one toxin component have been constructed. Characterization of the mutant strains indicated that they produced the expected single toxin protein. Using a simple, two-step protocol, we have purified PA, LF and EF to homogeneity from culture supernatants. These three mutant strains are potentially powerful tools for studying the individual effect of each toxin component in vitro and in vivo.


[Haemophilus spp. antimicrobial susceptibility in Health Area 6 in Madrid, Spain (2000-2004)].
The aim of this study was to assess the antimicrobial susceptibility of 1370 Haemophilus spp. (1051 H. influenzae and 319 H. parainfluenzae) isolated during a 4-year period (July 2000 to June 2004) and to compare the results with other nationwide Spanish surveillance studies. The rate of isolation of H. parainfluenzae was significantly higher in clinical samples from the genitourinary tract (p <0.00001) and skin and soft tissues (p <0.00001), whereas H. influenzae was significantly more frequent in clinical respiratory tract samples (p <0.00001). A total of 46.2% and 31.8% of H. influenzae were isolated in infants and children of 2-6 years old, respectively; whereas 73.3% of H. parainfluenzae was isolated in patients older than age 14. Overall, 22.2% and 18.5% of the H. influenzae and H. parainfluenzae, respectively, were found to produce betalactamase. A total of 1.9% of betalactamase-negative H. influenzae were found to be resistant to ampicillin. Four strains (0.4%) of betalactamase-producing H. influenzae were resistant to amoxicillin-clavulanic acid, all isolated from infants. The rate of ampicillin susceptibility was significantly higher (p <0.01) in H. parainfluenzae than in H. influenzae. All of the 1370 strains of Haemophilus spp. were susceptible to cefotaxime and ciprofloxacin. The susceptibility to clarithromycin, trimethoprim-sulfamethoxazole, tetracycline, chloramphenicol and rifampin were 86.9%, 61.5%, 96.7%, 99.1% and 95.2% for H. influenzae versus 81.2%, 55.8%, 76.5%, 90,9% and 733% for H. parainfluenzae. In conclusion, H. influenzae is more resistant to ampicillin and H. parainfluenzae to non-betalactam antimicrobials. All isolates were susceptible to cefotaxime and ciprofloxacin.


Responses of mixed methanotrophic consortia to variable Cu2+/Fe2+ ratios.
Methane mitigation in landfill top cover soils is mediated by methanotrophs whose optimal methane (CH4) oxidation capacity is governed by environmental and complex microbial community interactions. Optimization of CH4 remediating bio-filters need to take microbial responses into account. Divalent copper (Cu2+) and iron (Fe2+) are present in landfills at variable ratios and play a vital role in methane oxidation capacity and growth of methanotrophs. This study, as a first of its kind, therefore quantified effects of variable Cu2+ and Fe2+ (5:5, 5:25 and 5:50 μM) ratios on mixed methanotrophic communities enriched from landfill top cover (LB) and compost soils (CB). CH4 oxidation capacity, CH4 removal efficiencies, fatty acids content/profiles and polyhydroxybutyrate (PHB; a biopolymer) contents were also analysed to quantify performance and potential co-product development. Mixed methanotroph cultures were raised in 10 L continuous stirred tank reactors (CSTRs, Bioflo® & Celligen® 310 Fermentor/Bioreactor; John Morris Scientific, Chatswood, NSW, Australia). Community structure was determined by amplifying the V3-V4 region of 16s rRNA gene. Community structure and, consequently, fatty acid-profiles changed significantly with increasing Cu2+/Fe2+ ratios, and responses were different for LB and CB. Effects on methane oxidation capacities and PHB content were similar in the LB- and CB-CSTR, decreasing with increasing Cu2+/Fe2+ ratios, while biomass growth was unaffected. In general, high Fe2+ concentration favored growth of the type -II methanotroph Methylosinus in the CB-CSTR, but methanotroph abundances decreased in the LB-CSTR. Increase in Cu2+/Fe2+ ratio increased the growth of Sphingopyxis in both systems, while Azospirllum was co-dominant in the LB- but absent in the CB-CSTR. After 13 days, methane oxidation capacities and PHB content decreased by ∼50% and more in response to increasing Fe2+ concentrations. Although methanotroph abundance was ∼2% in the LB- (compared to >50% in CB-CSTR), methane oxidation capacities were comparable in the two systems, suggesting that methane oxidation capacity was maintained by the dominant Azospirllum and Sphingopyxis in the LB-CSTR. Despite similar methanotroph inoculum community composition and controlled environmental variables, increasing Cu2+/Fe2+ ratios resulted in significantly different microbial community structures in the LB- and CB-CSTR, indicative of complex microbial interactions. In summary, our results suggest that a detailed understanding of allelopathic interactions in mixed methanotrophic consortia is vital for constructing robust bio-filters for CH4 emission abatement.


What do we mean by social networking sites?
The purpose of this study was to explore people's conceptual understanding of Social Networking Sites (SNSs) through exploring the combined use of a range of popular SNSs, including Facebook, Twitter, Myspace, Instagram, Tumblr, LinkedIn and Google Plus. Seventy-three adults, aged 18 to 63, participated in an online survey that used open-ended questions to ask how participants define and use different SNSs. Four themes were identified, including the explicit presentation and interpretation of different selves, the love-hate relationship with SNSs, privacy and danger concerns, and limited SNS knowledge. The findings from this study suggest that researchers need to consider how people use SNSs in combination as this influences the decisions people make about which SNS accounts they use and how they present themselves on these sites.


Transcription-dependent radial distribution of TCF7L2 regulated genes in chromosome territories.
Human chromosomes occupy distinct territories in the interphase nucleus. Such chromosome territories (CTs) are positioned according to gene density. Gene-rich CTs are generally located in the center of the nucleus, while gene-poor CTs are positioned more towards the nuclear periphery. However, the association between gene expression levels and the radial positioning of genes within the CT is still under debate. In the present study, we performed three-dimensional fluorescence in situ hybridization experiments in the colorectal cancer cell lines DLD-1 and LoVo using whole chromosome painting probes for chromosomes 8 and 11 and BAC clones targeting four genes with different expression levels assessed by gene expression arrays and RT-PCR. Our results confirmed that the two over-expressed genes, MYC on chromosome 8 and CCND1 on chromosome 11, are located significantly further away from the center of the CT compared to under-expressed genes on the same chromosomes, i.e., DLC1 and SCN3B. When CCND1 expression was reduced after silencing the major transcription factor of the WNT/β-catenin signaling pathway, TCF7L2, the gene was repositioned and mostly detected in the interior of the CT. Thus, we suggest a non-random distribution in which over-expressed genes are located more towards the periphery of the respective CTs.


Mothers used wider vocabulary and talked to their six-month-old infants more during shared book reading than when they played with toys.
We compared mothers reading books to six-month-old infants or playing with toys and measured whether the maternal language input influenced the children's spoken vocabulary at 18 months of age. This Taiwanese study recruited 46 dyads and video recorded them while the mothers read books to their infants and played with them with toys at 6 months of age. The mothers' lexical diversity, which is the ratio of different unique words to the total number of words, was measured. We then assessed the children's spoken vocabulary at 18 months. The mother used more diverse vocabulary and a higher number of words when they were reading books than playing with toys with their children (p = 0.001). Maternal lexical diversity at 6 months of age accounted for 14.4% of the unique variance in the number of different words used by the child at 18 months. We believe that this is a novel finding. Mothers used wider vocabulary and talked to their infants more during book reading than when they played with toys. Diverse maternal vocabulary at 6 months of age positively influenced the number of different words their children used at 18 months of age.


¿Qué Pasa Con Papá? Exploring Paternal Responsibilities and Physical Activity in Mexican-Heritage Families.
Mexican-heritage children often achieve less physical activity (PA) than their counterparts and are at greater risk for associated comorbidities. Child PA is greatly influenced by their parents, yet researchers have rarely involved fathers in community health promotion. The purpose of this study is to examine Mexican-heritage fathers' perceptions of responsibilities and self-reported activities. Promotoras recruited fathers (n = 300) from colonies on the Texas-Mexico border and administered Spanish-language surveys including paternal responsibilities, father PA, and PA co-participation. Two researchers coded responses. Open-ended items were coded and cross-tabulations between responsibilities and activities with children were examined. Fathers reported feeling monetary responsibilities most often. Fathers reported engaging in more activities with their sons than daughters; however, fathers engaged in very few activities specifically with their children. Feeling responsible for family expenses was associated with paternal PA co-participation with family and children. This study adds clarity to the role of Mexican-heritage fathers in child PA. Findings highlight potential areas for intervention including supporting fathers to take an active role in their children's PA.


Highly Branched VS4 Nanodendrites with 1D Atomic-Chain Structure as a Promising Cathode Material for Long-Cycling Magnesium Batteries.
Rechargeable magnesium batteries have attracted increasing attention due to the high theoretical volumetric capacities, dendrite formation-free characteristic and low cost of Mg metal anodes. However, the development of magnesium batteries is seriously hindered by the lack of capable cathode materials with long cycling life and fast solid-state diffusion kinetics for highly-polarized divalent Mg2+ ions. Herein, vanadium tetrasulfide (VS4 ) with special one-dimensional atomic-chain structure is reported to be able to serve as a favorable cathode material for high-performance magnesium batteries. Through a surfactant-assisted solution-phase process, sea-urchin-like VS4 nanodendrites are controllably prepared. Benefiting from the chain-like crystalline structure of VS4 , the S22- dimers in the VS4 nanodendrites provide abundant sites for Mg2+ insertion. Moreover, the VS4 atomic-chains bonded by weak van der Waals forces are beneficial to the diffusion kinetics of Mg2+ ions inside the open channels of VS4 . Through a series of systematic ex situ characterizations and density functional theory calculations, the magnesiation/demagnesiation mechanism of VS4 are elucidated. The VS4 nanodendrites present remarkable performance for Mg2+ storage among existing cathode materials, exhibiting a remarkable initial discharge capacity of 251 mAh g-1 at 100 mA g-1 and an impressive long-term cyclability at large current density of 500 mA g-1 (74 mAh g-1 after 800 cycles).


Guideline-Based Cardiovascular Risk Assessment Delivered by an mHealth App: Development Study.
Identifying high-risk individuals is crucial for preventing cardiovascular diseases (CVDs). Currently, risk assessment is mostly performed by physicians. Mobile health apps could help decouple the determination of risk from medical resources by allowing unrestricted self-assessment. The respective test results need to be interpretable for laypersons. Together with a patient organization, we aimed to design a digital risk calculator that allows people to individually assess and optimize their CVD risk. The risk calculator was integrated into the mobile health app HerzFit, which provides the respective background information. To cover a broad spectrum of individuals for both primary and secondary prevention, we integrated the respective scores (Framingham 10-year CVD, Systematic Coronary Risk Evaluation 2, Systematic Coronary Risk Evaluation 2 in Older Persons, and Secondary Manifestations Of Arterial Disease) into a single risk calculator that was recalibrated for the German population. In primary prevention, an individual's heart age is estimated, which gives the user an easy-to-understand metric for assessing cardiac health. For secondary prevention, the risk of recurrence was assessed. In addition, a comparison of expected to mean and optimal risk levels was determined. The risk calculator is available free of charge. Data safety is ensured by processing the data locally on the users' smartphones. Offering a risk calculator to the general population requires the use of multiple instruments, as each provides only a limited spectrum in terms of age and risk distribution. The integration of 4 internationally recommended scores allows risk calculation in individuals aged 30 to 90 years with and without CVD. Such integration requires recalibration and harmonization to provide consistent and plausible estimates. In the first 14 months after the launch, the HerzFit calculator was downloaded more than 96,000 times, indicating great demand. Public information campaigns proved effective in publicizing the risk calculator and contributed significantly to download numbers. The HerzFit calculator provides CVD risk assessment for the general population. The public demonstrated great demand for such a risk calculator as it was downloaded up to 10,000 times per month, depending on campaigns creating awareness for the instrument.


Mild Cognitive Impairment Subtype Performance in Comparison to Healthy Older Controls on the NIH Toolbox and Cogstate.
Early detection is necessary for the treatment of dementia. Computerized testing has become more widely used in clinical trials; however, it is unclear how sensitive these measures are to early signs of neurodegeneration. We investigated the use of the NIH Toolbox-Cognition (NIHTB-CB) and Cogstate-Brief computerized neuropsychological batteries in the identification of mild cognitive impairment (MCI) versus healthy older adults [healthy control (HC)] and amnestic (aMCI) versus nonamnestic MCI (naMCI). Exploratory analyses include investigating potential racial differences. Two hundred six older adults were diagnosed as aMCI (n = 58), naMCI (n = 15), or cognitively healthy (HC; n = 133). The NIH Toolbox-CB subtests of Flanker, Picture Sequence Memory, and Picture Vocabulary significantly differentiated MCI from HC. Further, subtests from both computerized batteries differentiated patients with aMCI from those with naMCI. Although the main effect of race differences was noted on tests and in diagnostic groups was significant, there were no significant race-by-test interactions. Computer-based subtests vary in their ability to help distinguish MCI subtypes, though these tests provide less expensive and easier-to-administer clinical screeners to help identify patients early who may qualify for more comprehensive evaluations. Further work is needed, however, to refine computerized tests to achieve better precision in distinguishing impairment subtypes.


Face Perception and Pareidolia Production in Patients With Parkinson's Disease.
In Parkinson's disease (PD) patients, visual misperceptions are a major problem within the non-motor symptoms. Pareidolia, i.e., the tendency to perceive a specific, meaningful image in an ambiguous visual pattern, is a phenomenon that occurs also in healthy subjects. Literature suggests that the perception of face pareidolia may be increased in patients with neurodegenerative diseases. We aimed to examine, within the same experiment, face perception and the production of face pareidolia in PD patients and healthy controls (HC). Thirty participants (15 PD patients and 15 HC) were presented with 47 naturalistic photographs in which faces were embedded or not. The likelihood to perceive the embedded faces was modified by manipulating their transparency. Participants were asked to decide for each photograph whether a face was embedded or not. We found that PD patients were significantly less likely to recognize embedded faces than controls. However, PD patients also perceived faces significantly more often in locations where none were actually present than controls. Linear regression analyses showed that gender, age, hallucinations, and Multiple-Choice Vocabulary Intelligence Test (MWT) score were significant predictors of face pareidolia production in PD patients. Montreal Cognitive Assessment (MoCA) was a significant predictor for pareidolia production in PD patients in trials in which a face was embedded in another region [F (1, 13) = 24.4, p = <0.001]. We conclude that our new embedded faces paradigm is a useful tool to distinguish face perception performance between HC and PD patients. Furthermore, we speculate that our results observed in PD patients rely on disturbed interactions between the Dorsal (DAN) and Ventral Attention Networks (VAN). In photographs in which a face is present, the VAN may detect this as a behaviourally relevant stimulus. However, due to the deficient communication with the DAN in PD patients, the DAN would not direct attention to the correct location, identifying a face at a location where actually none is present.


Acute nasal reconstruction with forehead flap after dog bite.
This study aimed to describe immediate nasal reconstruction using a forehead flap after dog bite injuries. Dog bites to the nose can avulse multiple aesthetic subunits, making primary repair difficult, inadvisable, or impossible. Microsurgical replantation and composite grafting of the nose have been reported, but this assumes the avulsed nasal segments are salvageable even after the animal's attack. We present 2 cases of dog bites to the nose with loss of multiple aesthetic subunits. The avulsed portions of the nose were not recovered. A search of the literature (OVID MEDLINE) was also performed, reviewing acute reconstruction of nasal defects after animal bites. Acute forehead flaps were used as part of a first-stage operation to reconstruct the nasal defects. Second- and third-stage operations were performed to thin and divide the flap, respectively. Although the defects involved the full thickness of the nose, only the skin and nasal lining were acutely reconstructed. Acute cartilage grafts were not used due to concern of wound contamination; however, some resultant collapse of the nasal vestibule was noted and selectively addressed with subsequent cartilage grafting. Dog bites to the face can create immediately disfiguring injuries that may initially seem devastating. Nonetheless, soft tissue damage often can be primarily repaired, leading to roughly linear scars that can be revised later. However, nasal injuries from dog bites can be more challenging if multiple subunits are irreparably lost. Acute forehead flap reconstruction after dog bite-concomitant with initial debridement-is a reliable method of reconstruction. It remains to be seen whether acute cartilage grafts would be useful during the first-stage reconstructive operation for better long-term outcomes.


Modern treatment of Parkinson's disease.
Both general measures and a variety of drugs serve to improve the quality of life in the Parkinsonian patient. Meticulous neurological supervision is required to monitor response and the many drug-induced side-effects.


Executive dysfunction and the relation with behavioral problems in children with 47,XXY and 47,XXX.
Neuroimaging studies have shown that having an extra X chromosome is associated with abnormal structure and function of brain areas in the frontal lobe, which is crucially involved in executive functioning. However, there is little of knowledge of the type and severity of executive dysfunction, and the impact on emotional and behavioral problems. The present study aims to provide in this. In total, 40 children (23 boys with 47,XXY and 17 girls with 47,XXX) with an extra X chromosome and 100 non-clinical controls (47 boys and 53 girls) participated in the study. The participants were 9-18 years old. Processing speed and executive functioning were assessed using the Amsterdam Neuropsychological Testbattery (ANT) and the Dysexecutive Questionnaire (DEX). Problems in emotional and behavioral functioning were assessed with the Childhood Behavior Checklist (CBCL). Children with an extra X chromosome showed deficits in inhibition, mental flexibility, sustained attention and visual working memory. Parental report showed high levels of everyday manifestations of executive dysfunction. More severe inhibition difficulties were associated with higher levels of thought problems, aggression and rule breaking behavior. Boys and girls with an extra X chromosome could not be differentiated based on severity of executive dysfunction, however, girls had lower information processing speed than boys. These findings suggest that executive dysfunction may be part of the phenotype of children with an extra X chromosome, impacting the ability to function adequately in everyday life. Furthermore, children with impairments in inhibition may have more problems in regulating their thinking, emotions and behavior.


The introduction of midwifery in Ontario, Canada.
Midwives in Ontario, Canada, currently have no legal status. After an announcement in 1986 that the government would recognize them, an extensive planning period ensued. Groups of health care providers, consumers, and government representatives were active participants in formulating plans to integrate midwives into the centrally organized health care system in Ontario. Efforts to introduce legislation, establish a regulatory framework, and develop an educational program are well developed, but legalized practice must yet be realized.


Toward wearable sensors: optical sensor for detection of ammonium nitrate-based explosives, ANFO and ANNM.
Increasing security needs require compact and portable detection tools for the rapid and reliable identification of explosives used in improvised explosive devices (IEDs). We report of an easy-to-use optical sensor for both vapour-phase and solution-phase identification of explosive mixtures that uses a cross-reactive fluorimetric sensor array comprising chemically responsive fluorimetric indicators composed of aromatic aldehydes and polyethyleneimine. Ammonium nitrate-nitromethane (ANNM) was analyzed by paper microzone arrays and nanofiber sensor mats. Progress toward wearable sensors based on electrospun nanofiber mats is outlined.


Characterization of Salmonella Gallinarum from an outbreak in Raigarh, Chhattisgarh.
The present investigation was conducted to isolate and characterize Salmonella Gallinarum from an outbreak of fowl typhoid in layer birds. Clinically ill and dead layer birds from an outbreak were investigated. History, clinical signs, and postmortem lesions were suggestive of fowl typhoid. Postmortem samples including heart blood, intestinal contents, pieces of ovary, and liver were collected and processed immediately for bacterial culture, serotyping and antibiotic sensitivity tests. Isolates were further screened for the presence of extended spectrum beta lactamase (ESBL) (blaTEM) gene by polymerase chain reaction. On the basis of cultural, staining and biochemical characteristics; three bacterial isolates were confirmed as S. Gallinarum. On serotyping, somatic antigen O: 9 and 12 with nonflagellated antigen were detected in all three isolates. Isolates were intermediate sensitive to amoxycillin, amoxyclav, gentamicin and ciprofloxacin and resistant to most of the antibiotics including chloramphenicol, ampicillin, ceftazidime, cefexime, cefepime, azithromycin, nalidixin, tetracycline, oxytetracycline, and streptomycin. Two isolates were found to harbor ESBL (blaTEM) gene. Beta lactamase producer S. Gallinarum was confirmed as cause of increased mortality in layer birds during present investigation. Existence of multi drug resistant Salmonella poses serious threat to poultry industry in Chhattisgarh.


Assessment protocol for acquired apraxia of speech.
To develop an assessment protocol for speech motor planning with phonologically balanced stimuli for Brazilian Portuguese, including all necessary variables for this diagnosis. Three stages were carried out: In the first, word lists were built with the main criterion being syllabic and accentual patterns. From the survey conducted in Stage 1, the words that composed the first version of the protocol lists in Stage 2 were selected, and grouped into two fundamental tasks for diagnosing acquired apraxia of speech (AOS): repetition and Reading Aloud (RA). In Stage 3, the occurrence of words was investigated using the Brazilian Corpus (PUC-SP) - Linguateca database, and a statistical analysis was performed to verify if the repetition and RA lists were balanced in terms of the occurrences. Thus, the lists were distributed in quartiles and submitted to both descriptive and bivariate analyses. A significance level of 5% (p<0.05) was adopted. After completion of all stages, the words that composed the lists of the repetition and RA tasks were obtained. Finally, other tasks considered essential for the assessment of AOS, such as diadochokinetic rates and the board for spontaneous oral emission, were then added to the protocol. The developed protocol contains the tasks considered standard for the assessment of AOS according to the international literature, which makes this instrument important for diagnosing this disorder in speakers of Brazilian Portuguese.


Simulation of surface EMG signals for a multilayer volume conductor with a superficial bone or blood vessel.
This study analytically describes surface electromyogram (EMG) signals generated by a planar multilayer volume conductor constituted by different subdomains modeling muscle, bone (or blood vessel), fat, and skin tissues. The bone is cylindrical in shape, with a semicircular section. The flat portion of the boundary of the bone subdomain is interfaced with the fat layer tissue, the remaining part of the boundary is in contact with the muscle layer. The volume conductor is a model of physiological tissues in which the bone is superficial, as in the case of the tibia bone, backbone, and bones of the forearm. The muscle fibers are considered parallel to the axes of the bone, so that the model is space invariant in the direction of propagation of the action potential. The proposed model, being analytical, allows faster simulations of surface EMG with respect to previously developed models including bone or blood vessels based on the finite-element method. Surface EMG signals are studied by simulating a library of single-fiber action potentials (SFAP) of fibers in different locations within the muscle domain, simulating the generation, propagation, and extinction of the action potential. The decay of the amplitude of the SFAPs in the direction transversal to the fibers is assessed. The decay in the direction of the bone has a lower rate with respect to the opposite direction. Similar results are obtained by simulating motor unit action potentials (MUAPs) constituted by 100 fibers with territory 5 mm2. M waves and interference EMG signals are also simulated based on the library of SFAPs. Again, the decay of the amplitude of the simulated interference EMG signals is lower approaching the bone with respect to going farther from it. The findings of this study indicate the effect of a superficial bone in enhancing the EMG signals in the transversal direction with respect to the fibers of the considered muscle. This increases the effect of crosstalk. The same mathematical method used to simulate a superficial bone can be applied to simulate other physiological tissues. For example, superficial blood vessels (e.g., basilic vein, brachial artery) can influence the recorded EMG signals. As the electrical conductivity of blood is high (it is of the same order as the longitudinal conductivity in the muscle), the effect on EMG signals is opposite compared to the effect of a superficial bone.


Evaluation of antimitotic activity of herbal extracts using plant-based model systems and their cytotoxic potential against human colon carcinoma cells.
The aim of this study was to screen plant extracts for antimitotic activity using Vigna radiata germination inhibition assay, followed by Allium cepa root tip assay and evaluation of their cytotoxic potential on colon carcinoma (HCT-116) cell lines. Aqueous extracts of Aconitum heterophyllum, Terminalia bellirica, Bauhinia variegata, Vanda roxburghii, and Cassia angustifolia were prepared by maceration method, and preliminary screening studies to check their antimitotic activity were done by V. radiata germination inhibition assay, followed by A. cepa root tip assay. Furthermore, cytotoxic actions were evaluated by cell proliferation assay. Effect of T. bellirica aqueous extract was analyzed to induce morphological changes, cell death, lactate dehydrogenase release, and cell survival of HCT-116 cells. The data represented were analyzed by Student's t-test using SigmaStat 2.0 statistical analysis software. The normality of data was tested by the Shapiro-Wilk test before the Student's t-test. P values *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 were considered as statistically significant. All the plant extracts showed promising antimitotic activity. Out of all, T. bellirica was highly effective on HCT-116 cells and promising effect on cell proliferation assay and Annexin-propidium iodide staining revealed that T. bellirica efficiently induces apoptosis. T. bellirica inhibits cancer cell growth and induces apoptotic cell death. Collectively, it may hold potential for cancer therapeutics.


Transverse or longitudinal? A survey of volar wrist incision preferences.
In volar wrist surgery, the traditional longitudinal incision leaves a scar that may be considered cosmetically unpleasant. Recent studies suggest that transverse wrist incisions result in more aesthetically pleasing scars that are well hidden in the wrist crease. The aim of our study was to explore the public's perceptions of longitudinal versus transverse wrist scars. A prospective survey was conducted among the general public. Inclusion criteria were patients aged over 18 years with no prior surgery to the wrist. Survey questions assessed included: (a) longitudinal or transverse scar preference; (b) reasons for preference; and (c) demographic information. There were 107 respondents from the general public. More respondents preferred longitudinal scars. Top three reasons for longitudinal scar preference were: (a) perceived damage to wrist structures by a transverse incision; (b) better cosmesis; and (c) scar from the transverse incision appearing like a self-inflicted injury. Top three reasons for transverse scar preference were: (a) easily concealed by accessories; (b) less noticeable; and (c) better cosmesis. Respondents aged 60 years and above were most concerned about possible damage to wrist structures; younger respondents were most concerned that transverse scars appeared like self-inflicted injuries. Respondents from the general public preferred a longitudinal scar to a transverse one. Younger respondents were most concerned about how the transverse scar appeared like a self-inflicted injury while older respondents were most concerned with perceived functional implications of the incisions.


High-Flow Nasal Oxygen in Coronavirus Disease 2019 Patients With Acute Hypoxemic Respiratory Failure: A Multicenter, Retrospective Cohort Study.
An ongoing outbreak of coronavirus disease 2019 is spreading globally. Acute hypoxemic respiratory failure is the most common complication of coronavirus disease 2019. However, the clinical effectiveness of early high-flow nasal oxygen treatment in patients with coronavirus disease 2019 with acute hypoxemic respiratory failure has not been explored. This study aimed to analyze the effectiveness of high-flow nasal oxygen treatment and to identify the variables predicting high-flow nasal oxygen treatment failure in coronavirus disease 2019 patients with acute hypoxemic respiratory failure. A multicenter, retrospective cohort study. Three tertiary hospitals in Wuhan, China. Forty-three confirmed coronavirus disease 2019 adult patients with acute hypoxemic respiratory failure treated with high-flow nasal oxygen. None. Mean age of the enrolled patients was 63.0 ± 9.7 years; female patients accounted for 41.9%. High-flow nasal oxygen failure (defined as upgrading respiratory support to positive pressure ventilation or death) was observed in 20 patients (46.5%), of which 13 (30.2%) required endotracheal intubation. Patients with high-flow nasal oxygen success had a higher median oxygen saturation (96.0% vs 93.0%; p < 0.001) at admission than those with high-flow nasal oxygen failure. High-flow nasal oxygen failure was more likely in patients who were older (p = 0.030) and male (p = 0.037), had a significant increase in respiratory rate and a significant decrease in the ratio of oxygen saturation/FIO2 to respiratory rate index within 3 days of high-flow nasal oxygen treatment. In a multivariate logistic regression analysis model, male and lower oxygen saturation at admission remained independent predictors of high-flow nasal oxygen failure. The hospital mortality rate of the cohort was 32.5%; however, the hospital mortality rate in patients with high-flow nasal oxygen failure was 65%. High-flow nasal oxygen may be effective for treating coronavirus disease 2019 patients with mild to moderate acute hypoxemic respiratory failure. However, high-flow nasal oxygen failure was associated with a poor prognosis. Male and lower oxygenation at admission were the two strong predictors of high-flow nasal oxygen failure.


An Acute Ocfentanil Fatality: A Case Report with Postmortem Concentrations.
A 24-year-old man known to consume illegal drugs was found dead in his apartment. A reclosable plastic zipper bag containing several hundred milligrams of a brown powder was found close to the dead body and the first assumption of the investigators was death due to heroin intoxication. Therefore, a legal autopsy was ordered. The following toxicological analysis revealed ocfentanil in urine and in the brown powder. Four different approaches for the determination of the ocfentanil concentrations in peripheral whole blood are described. Enrichment of ocfentanil from the powder was realized. With this reference, it was possible to determine the ocfentanil concentration in the seized powder to be 0.91%. Concentrations of ocfentanil were also determined in the sampled body fluids using the standard addition procedure. In peripheral blood 9.1 µg/L, in heart blood 27.9 µg/L and in urine 480 µg/L were measured. In addition, the antidepressant citalopram, the neuroleptic quetiapine and cannabinoids were found in urine and subsequently quantified in peripheral blood.


Effects of spectral and temporal disruption on cortical encoding of gerbil vocalizations.
Animal communication sounds contain spectrotemporal fluctuations that provide powerful cues for detection and discrimination. Human perception of speech is influenced both by spectral and temporal acoustic features but is most critically dependent on envelope information. To investigate the neural coding principles underlying the perception of communication sounds, we explored the effect of disrupting the spectral or temporal content of five different gerbil call types on neural responses in the awake gerbil's primary auditory cortex (AI). The vocalizations were impoverished spectrally by reduction to 4 or 16 channels of band-passed noise. For this acoustic manipulation, an average firing rate of the neuron did not carry sufficient information to distinguish between call types. In contrast, the discharge patterns of individual AI neurons reliably categorized vocalizations composed of only four spectral bands with the appropriate natural token. The pooled responses of small populations of AI cells classified spectrally disrupted and natural calls with an accuracy that paralleled human performance on an analogous speech task. To assess whether discharge pattern was robust to temporal perturbations of an individual call, vocalizations were disrupted by time-reversing segments of variable duration. For this acoustic manipulation, cortical neurons were relatively insensitive to short reversal lengths. Consistent with human perception of speech, these results indicate that the stable representation of communication sounds in AI is more dependent on sensitivity to slow temporal envelopes than on spectral detail.


Longitudinal associations between sibling relationship qualities and risky behavior across adolescence.
This study examined the associations between sibling intimacy and conflict and youths' reports of risky behavior in a sample of adolescents ages 11-20. Participants were mothers, fathers, and sibling dyads in 393 families who were interviewed annually for 3, 4, or 5 years. Multivariate multilevel models tested longitudinal links between sibling intimacy and conflict and youths' risky behavior and whether these associations were moderated by birth order, sex, or dyad sex constellation. Controlling for parent-youth conflict, the results showed positive within-person covariation between sibling conflict and risky behavior for all youths except firstborns with younger brothers. Controlling for parent-youth intimacy, sibling intimacy was positively linked with risky behavior at the between-person level, but only in brother-brother pairs. The discussion focuses on sibling relationships as a context for adolescents' individual development and the roles of birth order, sex, and dyad sex constellation.


Satraplatin: BMS 182751, BMY 45594, JM 216.
Satraplatin [BMS 182751, BMY 45594, JM 216] belongs to a series of orally-active platinum compounds with anticancer activity. It was jointly originated by Bristol-Myers Squibb, Johnson Matthey and the Institute of Cancer Research in the UK; however, Johnson Matthey has since ceased involvement with drug development. Subsequently, the agent has been licensed to and is under development with GPC Biotech, Pharmion and Spectrum Pharmaceuticals. Clinical trials are underway to evaluate satraplatin among patients with different tumour types, including prostate, breast, cervical and lung cancers. The compound is under regulatory review with the US FDA for the treatment of hormone-refractory prostate cancer. NeoTherapeutics (now Spectrum Pharmaceuticals) granted GPC Biotech an exclusive worldwide licence to develop and market satraplatin in October 2002. Under the terms of the agreement, GPC Biotech is fully funding development costs and commercialisation requirements for the drug. The deal also involves GPC Biotech paying a signing fee, milestone and royalty payments. Spectrum is a member of a joint development committee headed by GPC Biotech to govern development of satraplatin. Previously in October 2001, NeoOncoRx (Spectrum Pharmaceuticals) gained the rights to develop and market the compound worldwide. In December 2005, GPC Biotech and Pharmion Corporation entered into a co-development and license agreement for satraplatin. Under the agreement terms, Pharmion has exclusive commercialisation rights for Europe, Turkey, the Middle East, Australia and New Zealand, while GPC Biotech retains rights to North America and all other territories. Pharmion made an upfront payment of $US37.1 million to GPC Biotech, which included reimbursement for past clinical development costs plus funding for ongoing and certain clinical development activities to be jointly conducted by the companies. In addition, both parties will pursue a joint development plan for satraplatin in a variety of tumour types and will share global development costs, for which Pharmion has made an additional commitment of $US22.2 million. GPC Biotech could also receive up to $US270 million in milestone payments and royalties on sales. Both companies will manage regulatory and commercial activities in their respective territories. A registrational phase III study is ongoing among 950 patients with HRPC. This global, multicentre, randomised study, called SPARC (Satraplatin and Prednisone Against Refractory Cancer), is assessing satraplatin plus prednisone versus prednisone alone as second-line therapy in HRPC patients. Top-line results from the trial showed that patients who received satraplatin plus prednisone had a 40% reduction in the risk of progression compared with patients who received prednisone plus placebo. In accordance with the recommendation of the independent Data Monitoring Board for the SPARC trial, patients who have not progressed will continue to be treated and all patients will be followed for overall survival. The company expects to have final overall survival results in the fall of 2007. The company intends to complete the NDA filing with the FDA before the end of 2006. In February 2006, GPC Biotech raised euro36.2 million from a private placement of shares; the funds will be used in the commercialisation of satraplatin in the US. GBC Biotech received a Scientific Advice letter from the EMEA in January 2004, enabling the company to use the SPARC trial for registrational plans in both Europe and the US. Data from the pivotal phase III trial are expected in the second half of 2006. If positive, the findings will form the basis of a MAA filing with the EMEA for satraplatin as a second-line therapy of HRPC. The EMEA has confirmed that it would accept the final analysis for progression-free survival (PFS) from the SPARC trial and the available overall survival data as the basis for the MAA submission expected in the first quarter of 2007. In December 2005, enrolment started for a phase II study of satraplatin plus paclitaxel as a first-line treatment for unresectable advanced NSCLC. This open-label study is enrolling up to 40 patients at sites in the US. In addition, GPC Biotech and Spectrum have initiated a phase I/II trial of satraplatin plus radiation therapy among patients with NSCLC. The study is expected to enrol up to 30 patients in the phase I portion to determine dose-limiting toxicities and maximum tolerated doses. Once these are established, the phase II portion will enrol patients to evaluate efficacy and safety. This trial is expected to be closely followed by phase I/II trials of satraplatin in combination with docetaxel and paclitaxel. GPC Biotech initiated a phase I trial in July 2005 investigating satraplatin plus docetaxel among patients with advanced solid tumours in the US. The study is primarily focused on establishing the toxicity and maximum tolerated doses of combination therapy to determine suitable dosages for phase II trials. Enrolment is ongoing for the open-label, single-centre study with a target of up to 48 patients. A phase I study is evaluating satraplatin in combination with gemcitabine in patients with advanced solid tumours. Previously, Bristol-Myers Squibb initiated phase III development of satraplatin in Europe and the US in 1996. The trials were being conducted in patients with ovarian, non-small cell lung and small-cell lung cancers. However, the company closed all ongoing trials of satraplatin in 1999. Satraplatin is protected by a number of patents issued in the US, EU, Japan, Canada and Australia. The patents have been assigned to Johnson Matthey, a multinational chemical company in the UK, which has exclusively sub-licensed these to GPC Biotech under a co-development and licensing agreement with Spectrum Pharmaceuticals. The patents cover the composition of matter and anticancer uses of various platinum-based compounds, including satraplatin. Two of the US patents will expire in 2008 and 2010, respectively, while patents in most other countries will expire in 2009.


Inflammatory Bowel Disease Therapeutics: A Focus on Probiotic Engineering.
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of gastrointestinal (GI) tract with dysregulated mucosal immune functions and disturbed commensal ecosystem of the intestinal lumen. IBD is categorized into two major subsets: Crohn's disease (CD) and ulcerative colitis (UC). Though advent of biologics has shifted the treatment with relatively longer remission compared to small molecule pharmaceuticals, patients still suffer from long-term complications. Since gut-microbiome is now accepted as another human organ holding potential for long-lasting human health, probiotics, and its engineering hold great promises to treat several previously untreatable chronic inflammatory conditions including IBD. Several emerging biological engineering tools have unlimited potential to manipulate probiotic bacterial system. These can produce useful therapeutic biologics with a goal to either ameliorate and/or treat previously untreatable chronic inflammatory conditions. As gut-microbiome is diverse and vary in different ethnic, geographic, and cultural human population, it will be important to develop vision for personalized probiotic treatment and develop the technology thereof to make personalized probiotic options a reality. The aim of this review paper is to present an overview of the current knowledge on both pharmacological and nonpharmacological IBD treatment modalities with a special emphasis on probiotic strains that are developed through the probiotic engineering. These engineered probiotics contain the most anti-inflammatory cytokines found within the human immune response and are currently being used to treat the intestinal inflammation in IBD for the IBD treatment.


Effects of physical method and enzymatic hydrolysis on the properties of soybean fiber-rich stabilizer for oil in water emulsions.
Okara is a by-product from soybean industry and an abundant resource of insoluble soybean fiber (ISF). ISF with various properties could be obtained by different extraction methods. It is an attracting option to utilize okara by taking advantage of ISF as an emulsifier or stabilizer. Compared with the untreated ISF (ISFUT ), superfine grinding reduced the particle size and viscosity of ISF (ISFSG ). Steam explosion increased the water solubility from 17.5% to 51.7% but decreased the water holding capacity and swelling capacity of ISF (ISFSE ) from 15.0 and 14.0 g/g to 4.2 and 3.3 g/g, respectively. Emulsions prepared by ISFUT and ISFSG before or after enzymatic hydrolysis presented large oil droplets and were unstable. Although emulsions prepared by ISFSE after enzymatic hydrolysis (ISFSE-E ) showed flocculation, the volume-weighted average diameter (19.7 μm) were the smallest while the viscosity and viscoelastic modulus were the highest, and exhibited excellent physical stability during storage. ISF obtained by physical and hydrolysis treatment displayed diverging physicochemical properties while ISF prepared by steam explosion- enzymatic hydrolysis presented the best potential to stabilize emulsions. The present study could provide novel information about the utilization of okara by the application of ISF as an emulsifier or stabilizer. This article is protected by copyright. All rights reserved.


Transcription factor Fra-1 induces cholangitis and liver fibrosis.
Chronic diseases of the biliary system are common and may cause fibrosis and eventually progression to liver cirrhosis. The aim was to define a new mouse model of a cholangiopathy leading to liver fibrosis in fra-1tg mice. Liver pathology of fra-1tg mice was analyzed in detail by histology and flow cytometry. Transcript levels of fibrosis-related genes and matrix metalloproteinase (MMP) activities were quantified and immunohistochemical analysis additionally applied. The role of the immune system in this model was analyzed by crossing fra-1tg mice with rag2(-/-) mice. Furthermore, expression of Fra-1 in corresponding human liver diseases was investigated on transcription level and histologically. Fra-1tg mice spontaneously develop biliary fibrosis preceded by ductular proliferation and infiltration of inflammatory cells. Fra-1 protein is present in cholangiocytes and inflammatory cells within the liver. These findings were replicated in human biopsies of patients with advanced liver fibrosis. The inflammatory infiltrate showed a strong increase in activated T cells and decreased natural killer (NK), natural killer T cells (NKT), and B cells in fra-1tg mice as compared to wildtype mice. Moreover, fra-1tg mice develop biliary fibrosis with a time-dependent increase in hepatic collagen content and increase in relative messenger RNA (mRNA) expression of profibrotic genes. Attenuation but not complete prevention of collagen accumulation in liver was observed in the fra-1tg × rag2(-/-) mice. However, transplantation of fra-1tg bone marrow cells into wildtype mice could not induce disease. Fra-1tg mice spontaneously develop a progressive biliary disease. These mice are an attractive model for the investigation of cholangiopathies and their interaction with the immune system.


[The role of structural heterogeneity of circulating lipids in the regulation of lipoprotein metabolism in the plasma and lymph in hypercholesterolemia in dogs].
Fatty acid spectrum of lipoproteins was studied in intestinal steam lymph and blood plasma of dogs with alimentary hypercholesterolemia. Mechanism of cholesterol accumulation in blood plasma appears to relate to increase in content of cholesterol palmitate which is secreted from intestine into lymph and hydrolyzed slowly in liver tissue. Alterations in composition of fatty acid acyls of cholesterol esters, of phosphatidyl cholines and triacyl glycerides as well as effect of these alterations on the lecithin-cholesterol acyl-transferase reaction and lipoprotein lipolysis are discussed.


Simulation-based training for prostate biopsies: towards the validation of the Biopsym simulator.
Objectives: The Biopsym simulator, a virtual-reality simulator for prostate biopsies, was designed to offer enhanced teaching of the biopsy procedure. The objectives of the present article are to describe the new version of the simulator and report the results of a new validation study.Material and methods: A prospective validation study was conducted between January and March 2017. The new version of the simulator, with improved physical realism, ultrasound image deformation, and a new scoring system, was evaluated by novice and confirmed users.Results: Twenty-one users evaluated the simulator, including ten novices and 11 confirmed users. The overall realism of the biopsy procedure was rated at 7.7/10 (IQR 5.7-9). The differences between the rates given by confirmed users and novices were not statistically significant. The median overall score obtained for the performance of 12 systematic ultrasound-guided biopsies was 43% (IQR 33-55). The median score obtained by confirmed users was 54% (IQR 46-62), and the median score obtained by novices was 31% (IQR 20-35). The difference between the scores was statistically significant (p = 0.005).Conclusions: This study allowed us to gather evidence towards the validation, and particularly towards the construct validation of the new version of the Biopsym simulator.


Peroneal-nerve palsy following total knee arthroplasty. A review of The Hospital for Special Surgery experience.
Twenty-three postoperative peroneal-nerve palsies in twenty-two patients were documented in the records of 2626 consecutive knee arthroplasties that were performed at The Hospital for Special Surgery from 1974 through 1980. This is an incidence of 0.87 per cent. The preoperative knee deformities included fourteen flexion contractures, eleven valgus deformities, and five biplane deformities. In five patients a peroneal palsy developed despite a peroneal-nerve release at the time of arthroplasty. Only two patients, who initially had only a motor loss, had a complete clinical recovery. Follow-up ranged from six months to seven years (average 3.1 years). Sensory deficits, initially noted in eighteen patients, had not fully resolved in any patient at the time of writing. Although motor deficits were initially noted in all patients, only 28.6 per cent of them fully resolved. The possible causes of the nerve palsy appeared to be direct traction on the nerve, traction on the surrounding tissues resulting in vascular compromise to the nerve, direct pressure on the nerve from the postoperative dressing, or a combination of these factors. When the palsy is discovered, the suggested treatment is a change to a looser dressing and flexion of the knee. The value of surgical exploration of the nerve in the immediate postoperative period is not known.


Identification of 170 New Long Noncoding RNAs in Schistosoma mansoni.
Long noncoding RNAs (lncRNAs) are transcripts generally longer than 200 nucleotides with no or poor protein coding potential, and most of their functions are also poorly characterized. Recently, an increasing number of studies have shown that lncRNAs can be involved in various critical biological processes such as organism development or cancer progression. Little, however, is known about their effects in helminths parasites, such as Schistosoma mansoni. Here, we present a computational pipeline to identify and characterize lncRNAs from RNA-seq data with high confidence from S. mansoni adult worms. Through the utilization of different criteria such as genome localization, exon number, gene length, and stability, we identified 170 new putative lncRNAs. All novel S. mansoni lncRNAs have no conserved synteny including human and mouse. These closest protein coding genes were enriched in 10 significant Gene Ontology terms related to metabolism, transport, and biosynthesis. Fifteen putative lncRNAs showed differential expression, and three displayed sex-specific differential expressions in praziquantel sensitive and resistant adult worm couples. Together, our method can predict a set of novel lncRNAs from the RNA-seq data. Some lncRNAs are shown to be differentially expressed suggesting that those novel lncRNAs can be given high priority in further functional studies focused on praziquantel resistance.