GPathFinder: Identification of Ligand-Binding Pathways by a Multi-Objective Genetic Algorithm.
Protein-ligand docking is a widely used method to generate solutions for the binding of a small molecule with its target in a short amount of time. However, these methods provide identification of physically sound protein-ligand complexes without a complete view of the binding process dynamics, which has been recognized to be a major discriminant in binding affinity and ligand selectivity. In this paper, a novel piece of open-source software to approach this problem is presented, called GPathFinder. It is built as an extension of the modular GaudiMM platform and is able to simulate ligand diffusion pathways at atomistic level. The method has been benchmarked on a set of 20 systems whose ligand-binding routes were studied by other computational tools or suggested from experimental "snapshots". In all of this set, GPathFinder identifies those channels that were already reported in the literature. Interestingly, the low-energy pathways in some cases indicate novel possible binding routes. To show the usefulness of GPathFinder, the analysis of three case systems is reported. We believe that GPathFinder is a software solution with a good balance between accuracy and computational cost, and represents a step forward in extending protein-ligand docking capacities, with implications in several fields such as drug or enzyme design.


Whole Blood Adsorber During CPB and Need for Vasoactive Treatment After Valve Surgery in Acute Endocarditis: A Randomized Controlled Study.
Patients with endocarditis requiring urgent valvular surgery with cardiopulmonary bypass are at a high risk of developing systemic inflammatory response syndrome and septic shock, necessitating intensive use of vasopressors after surgery. The use of a cytokine hemoadsorber (CytoSorb, CytoSorbents Europe GmbH, Germany) during cardiac surgery has been suggested to reduce the risk of inflammatory activation. The study authors hypothesized that adding a cytokine adsorber would reduce cytokine burden, which would translate into improved hemodynamic stability. A randomized, controlled, nonblinded clinical trial. At a university hospital, tertiary referral center. Nineteen patients with endocarditis undergoing valve surgery. A cytokine hemoadsorber integrated into the cardiopulmonary bypass circuit. The accumulated norepinephrine dose in the intervention group was half or less at all postoperative time points compared to the control group, although it did not reach statistical significance; at 24 and 48 hours (median 36 [25-75 percentiles; 12-57] μg v 114 [25-559] μg, p = 0.11 and 36 [12-99] μg v 261 [25-689] μg, p = 0.09). There was no significant difference in chest tube output, but there was a significantly lower need for the transfusion of red blood cells (285 [0-657] mL v 1,940 [883-2,148] mL, p = 0.03). There was no statistically significant difference between the groups with regard to vasopressor use after surgery for endocarditis with the use of a cytokine hemoadsorber during cardiopulmonary bypass. Additional, larger randomized controlled trials are needed to definitely assess the potential effect.


Electrochemical sensor based on gold nanoparticles fabricated molecularly imprinted polymer film at chitosan-platinum nanoparticles/graphene-gold nanoparticles double nanocomposites modified electrode for detection of erythromycin.
A molecularly imprinted electrochemical sensor was fabricated based on gold electrode decorated by chitosan-platinum nanoparticles (CS-PtNPs) and graphene-gold nanoparticles (GR-AuNPs) nanocomposites for convenient and sensitive determination of erythromycin. The synergistic effects of CS-PtNPs and GR-AuNPs nanocomposites improved the electrochemical response and the sensitivity of the sensor. The molecularly imprinted polymers (MIPs) were prepared by HAuCl(4), 2-mercaptonicotinic acid (MNA) and erythromycin. Erythromycin and MNA were used as template molecule and functional monomer, respectively. They were first assembled on the surface of GR-AuNPs/CS-PtNPs/gold electrode by the formation of Au-S bonds and hydrogen-bonding interactions. Then the MIPs were formed by electropolymerization of HAuCl(4), MNA and erythromycin. The sensor was characterized by cyclic voltammetry (CV), scanning electron microscope (SEM), UV-visible (UV-vis) absorption speactra and amperometry. The linear range of the sensor was from 7.0 × 10(-8)mol/L-9.0 × 10(-5)mol/L, with the limit of detection (LOD) of 2.3 × 10(-8)mol/L (S/N=3). The sensor showed high selectivity, excellent stability and good reproducibility for the determination of erythromycin, and it was successfully applied to the detection of erythromycin in real spiked samples.


The impact of resident involvement in minimally-invasive urologic oncology procedures.
Robotic and laparoscopic surgical training is an integral part of resident education in urology, yet the effect of resident involvement on outcomes of minimally-invasive urologic procedures remains largely unknown. We assess the impact of resident participation on surgical outcomes using a large multi-institutional prospective database. Relying on the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Participant User Files (2005-2011), we abstracted the 3 most frequently performed minimally-invasive urologic oncology procedures. These included radical prostatectomy, radical nephrectomy and partial nephrectomy. Multivariable logistic regression models were constructed to assess the impact of trainee involvement (PGY 1-2: junior, PGY 3-4: senior, PGY ≥5: chief) versus attending-only on operative time, length-of-stay, 30-day complication, reoperation and readmission rates. A total of 5459 minimally-invasive radical prostatectomies, 1740 minimally-invasive radical nephrectomies and 786 minimally-invasive partial nephrectomies were performed during the study period, for which data on resident surgeon involvement was available. In multivariable analyses, resident involvement was not associated with increased odds of overall complications, reoperation, or readmission rates for minimally-invasive prostatectomy, radical and partial nephrectomy. However, operative time was prolonged when residents were involved irrespective of the type of procedure. Length-of-stay was decreased with senior resident involvement in minimally-invasive partial nephrectomies (odds ratio [OR] 0.49, p = 0.04) and prostatectomies (OR 0.68, p = 0.01). The major limitations of this study include its retrospective observational design, inability to adjust for the case complexity and surgeon/hospital characteristics, and the lack of information regarding the minimally-invasive approach utilized (whether robotic or laparoscopic). Resident involvement is associated with increased operative time in minimally-invasive urologic oncology procedures. However, it does not adversely affect the complication, reoperation or readmission rates, as well as length-of-stay.


Association between diastolic blood pressure and cumulative work time.
Diastolic blood pressure was viewed as a generic indicator of aging, and its association with cumulative work time was studied after controlling for age as a potential confounding factor. The study was conducted among production line workers at a Brazilian tannery in July 1993. The association between diastolic blood pressure and cumulative work time was verified by fitting a second-order linear regression model, where diastolic blood pressure was a function of worker's age and cumulative work time. By fitting the model, one can predict that, from the beginning of working life at the tannery, on average each 1-year period is associated with an increase of about 1. 5 mmHg in diastolic blood pressure. The fit obtained highlights a component directly associated with work as part of the rate of pressure increase in the study group. This component is twice as high as that directly associated with age.


Assuring the privacy and security of transmitting sensitive electronic health information.
The interchange of electronic health records between healthcare providers and public health organizations has become an increasingly desirable tool in reducing healthcare costs, improving healthcare quality, and protecting population health. Assuring privacy and security in nationwide sharing of Electronic Health Records (EHR) in an environment such as GRID has become a top challenge and concern. The Centers for Disease Control and Prevention's (CDC) and The Science Application International Corporation (SAIC) have jointly conducted a proof of concept study to find and build a common secure and reliable messaging platform (the SRM Platform) to handle this challenge. The SRM Platform is built on the open standards of OASIS, World Wide Web Consortium (W3C) web-services standards, and Web Services Interoperability (WS-I) specifications to provide the secure transport of sensitive EHR or electronic medical records (EMR). Transmitted data may be in any digital form including text, data, and binary files, such as images. This paper identifies the business use cases, architecture, test results, and new connectivity options for disparate health networks among PHIN, NHIN, Grid, and others.


Encoding and high-speed memory scanning of retarded and nonretarded adolescents.
A choice reaction-time experiment was performed in order to assess the encoding and memory-scanning processes of nonretarded and retarded adolescents. Random forms were used as stimuli, with stimulus-set sizes of 2, 3, and 4. The encoding process was evaluated by means of a stimulus-quality manipulation. The results indicated that both the rate of encoding and memory scanning are related to level of intellectual functioning. In addition, evidence suggesting an interdependence of these memory processes, at least for the retarded subjects, was revealed.


Scaling of morphogen gradients by an expansion-repression integral feedback control.
Despite substantial size variations, proportions of the developing body plan are maintained with a remarkable precision. Little is known about the mechanisms that ensure this adaptation (scaling) of pattern with size. Most models of patterning by morphogen gradients do not support scaling. In contrast, we show that scaling arises naturally in a general feedback topology, in which the range of the morphogen gradient increases with the abundance of some diffusible molecule, whose production, in turn, is repressed by morphogen signaling. We term this mechanism "expansion-repression" and show that it can function within a wide range of biological scenarios. The expansion-repression scaling mechanism is analogous to an integral-feedback controller, a key concept in engineering that is likely to be instrumental also in maintaining biological homeostasis.


Lateral control assistance for car drivers: a comparison of motor priming and warning systems.
This paper's first objective is to determine whether motor priming assistance (consisting of directional steering wheel vibrations) can be of some benefit compared with more traditional auditory (lateralized sound) or vibratory (symmetric steering wheel oscillation) warning devices. We hypothesize that warning devices favor driving situation diagnosis, whereas motor priming can improve the initiation of action even further. Another objective is to assess the possible benefits of using multimodal information by combining auditory warning with simple steering wheel vibration or motor priming. Within the context of active safety devices, the experiment dealt with moderately intrusive driving assistance devices that intervene when a certain level of risk in terms of lane departure is reached. An analysis of the steering behavior of 20 participants following episodes of visual occlusion was carried out. Five warning and motor priming devices were compared. All tested devices improved the drivers' steering performance, although their effects were modulated by the drivers' risk assessment. However, performance improvements were found to be greater with a motor priming device. No additional performance enhancement was observed when auditory warning was added to steering wheel vibration or motor priming devices. This study confirms the hypothesis that the direct intervention of motor priming at the action level is more effective than a simple warning, which intervenes upstream in situation diagnosis. Multimodal information did not seem to improve driver performance. This study proposes a new kind of lateral control assistance, which acts at a sensorimotor level, in contrast with traditional warning devices.


Impact of Open Reduction on Surgical Strategies for Missed Monteggia Fracture in Children.
The aims of this study were to review our cases of missed Monteggia fracture treated by open reduction of the radial head with or without ulnar osteotomy and to investigate the indications for open reduction alone in surgical treatment of missed Monteggia fracture. We retrospectively reviewed 22 patients who presented with missed Monteggia fracture. The patients' mean age at the time of surgery was 7.6 years. The mean interval from injury to surgery was 16.1 months. The surgical procedure consisted of open reduction of the radiocapitellar joint followed by ulnar osteotomy without reconstruction of the annular ligament. The mean period of follow-up was 3.8 years. Radiographic assessment was performed for the maximum ulnar bow (MUB) and the location of the MUB. Clinical results were evaluated with the Mayo Elbow Performance Index and Kim's scores. Five patients underwent open reduction alone, and 17 patients underwent open reduction and ulnar osteotomy. When the MUB was less than 4 mm and the location of the MUB was in the distal 40% of the ulna, we could achieve reduction of the radial head without ulnar osteotomy. The radial head was maintained in a completely reduced position in 21 patients and was dislocated in one patient at final follow-up. Open reduction alone can be an attractive surgical option in select patients with missed Monteggia fracture with minimal bowing of the distal ulna. However, ulnar osteotomy should be considered in patients with a definite ulnar deformity.


In Situ Control of Crystallinity of 3D Colloidal Crystals by Tuning the Growth Kinetics of Nanoparticle Building Blocks.
Colloidal crystals (CCs) constructed from inorganic nanoparticle (NP) building blocks exhibit properties that cannot be realized from isolated NPs or corresponding bulk counterparts. Because the arrangement of NPs in CCs is crucial in the CC's collective properties, development of a procedure to modulate the assembly of NP constituents is important. We demonstrate rapid formation of nickel (phosphide) CCs with tunable crystallinity through van der Waals force-driven spontaneous self-assembly of NPs in a facile one-pot colloidal synthesis. The quantity of size-regulating reagent (tri-n-octylphosphine) modulates the assembly of NPs from ordered close-packed to a disordered configuration in CCs. Synchrotron-based in situ small-angle X-ray scattering revealed that the size uniformity of the NPs determines the crystallinity of CCs, indicating the importance of regulating the growth kinetics of NPs during the synthesis. Our work will be useful for universal scalable preparation of CCs from a variety of materials and structures, with tunable concerted properties.


Stabilization and functional impairment of the tumor suppressor p53 by the human papillomavirus type 16 E7 oncoprotein.
The p53 tumor suppressor is stabilized in cells expressing the human papillomavirus type 16 (HPV-16) E7 oncoprotein. In contrast, expression of the HPV-16 E6 protein inactivates p53 by targeting it for proteasomal degradation. Since p53 activation is associated with protein accumulation we investigated the biochemical mechanisms and biological consequences of p53 stabilization in HPV-16 E7-expressing cells. Transcriptional reporter assays, expression profiling studies using cDNA arrays, and immunoblot analyses of known p53 target genes suggest that p53 remains transcriptionally inert in E7-expressing cells. The stabilized p53 in E7-expressing cells is in a wild-type conformation and the same number of phospho-forms is present. Furthermore, E7 expression does not alter p53 localization or generally block nuclear export or proteasomal degradation of p53. Moreover, the stabilized p53 remains susceptible to mdm2-induced proteasome-mediated degradation, and exogenous transfected p53 is transcriptionally active in E7-expressing cells. Taken together, these results suggest that E7 can interfere with the normal turnover of p53 but that the resulting increase of p53 has no detectable transcriptional consequences on the p53 targets that we investigated.


The effect of obesity management on body image in patients seeking treatment at medical centers.
Body image dissatisfaction is common in treatment-seeking patients with obesity. We aimed to investigate the effects of obesity management on body image in patients with obesity attending Italian medical centers for weight loss programs. A total of 473 obese patients seeking treatment in 13 Italian medical centers (80% females; age, 45.9 +/- standard deviation 11.0 years; BMI, 36.8 +/- 5.7 kg/m(2)) were evaluated at baseline and after a 6-month weight loss treatment. Body uneasiness, psychiatric distress, and binge eating were tested by Body Uneasiness Test (BUT, Part A), Symptom CheckList-90 (SCL-90), and Binge Eating Scale (BES), respectively. At 6-month follow-up, the percentage weight loss was significantly higher in men (9.0 +/- 6.3%) than in women (6.8 +/- 7.3%; p = 0.010). Both men and women had a significant improvement in BUT Global Severity Index and in all of the BUT subscales with the exception of the Compulsive Self-Monitoring subscale. Linear regression analysis selected baseline psychological and behavioral measures (global score of BUT and SCL-90) and improved psychiatric distress and binge eating as independent predictors of changes in basal body dissatisfaction in females, whereas in males, changes were associated only with baseline BUT-Global Severity Index score, binge eating, and its treatment-associated improvement. Pre-treatment BMI and BMI changes did not enter the regression. Obesity treatment, even with a modest degree of weight loss, is associated with a significant improvement of body image, in both females and males. This effect depends mainly on psychological factors, not on the amount of weight loss.


Identification of autoimmune thrombocytopenic purpura-related epitopes using phage-display peptide library.
A random heptapeptide phage-displayed library was screened with two serum samples from autoimmune thrombocytopenic purpura (AITP) patients to address the repertoire of autoantigenic epitopes involved in platelet destruction. We obtained a panel of affinity-selected phage clones that have been shown to react in enzyme-linked immunosorbent assay with autoantibodies from other AITP patients. None of the peptides obtained has been described previously as possibly being an epitope for antiplatelet antibodies, and the majority of them did not show any homology with known platelet glycoproteins. We conclude that peptides identified in this study could represent discontinuous epitopes or mimotopes of natural autoantigens. Also, they could be present in still-unknown proteins involved in AITP pathogenesis.


Autonomous and non-autonomous Tn3-family transposons and their role in the evolution of mobile genetic elements.
The Tn3 family of transposons includes diverse elements that encode homologous transposases and contain conserved terminal inverted repeat sequences (IRs). The recent identification of non-autonomous elements, named TIMEs (Tn3-derived Inverted-repeat Miniature Elements), has shed new light on the diversity and evolution of this transposon family. A common feature of TIMEs and other members of this family is their ability to mobilize genomic DNA for transposition as part of composite transposons. These elements significantly influence the structure and properties of plasmids and other mobile genetic elements (MGEs). They may contain and move by transposition (i) plasmid replication systems, (ii) toxin-antitoxin systems and (iii) site-specific recombination modules that can resolve plasmid multimers. Some Tn3 family elements may also transfer large segments of chromosomal DNA into plasmids, which increases the pool of mobile DNA that can take part in horizontal gene transfer.


A qualitative study comparing the assay performance characteristics between the 2007 and the 2013 American Society for Clinical Oncology and College of American Pathologists HER2 scoring methods in mucinous epithelial ovarian cancer.
The remarkable success of trastuzumab and other newly developed anti-HER2 (human epidermal growth factor receptor 2) therapies in breast, gastric, or gastroesophageal junction cancer patients has supported us to investigate the HER2 status and its possible therapeutic implication in mucinous epithelial ovarian cancer (EOC). However, there is currently no standardization of HER2 scoring criteria in mucinous EOC. In this study, we aimed to compare both the assay performance characteristics of the 2007 and the 2013 American Society for Clinical Oncology and College of American Pathologists scoring methods. Forty-nine tissue microarray samples of mucinous EOC from Asian women were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests using the 2007 and the 2013 criteria, respectively. The overall concordance between IHC and FISH by the 2007 criteria was 97.92 % (kappa = 0.921), and that by the 2013 criteria was 100% (kappa = 1.000). The percentage of Her2 FISH-amplified cases showed an increasing trend significantly through their corresponding HER2 IHC ordinals by the 2007 and the 2013 criteria, respectively (P < 0.001, P < 0.001). After excluding equivocal cases, the specificity (100%) and positive predictive value (100%) were unchanged under either the 2007 or the 2013 criteria. The sensitivity (100%), negative predictive value (NPV) (100%), and accuracy (100%) of HER2 IHC were higher under the 2013 criteria than those (sensitivity 87.5%, NPV 97.6%, and accuracy 97.9%) under the 2007 criteria. Of the total 49 cases, the number (n = 4) of HER2 IHC equivocal results under the 2013 criteria was 4-fold higher than that (n = 1) under the 2007 criteria (8.16% vs 2.04%). Conclusively, if first tested by IHC, the 2013 criteria caused more equivocal HER2 IHC cases to be referred to Her2 FISH testing than the 2007 criteria. That decreased the false-negative rate of HER2 status and increased the detection rates of HER2 positivity in mucinous EOC.


[Establishment of bisphosphonate-related osteonecrosis of the jaw model in rats and preliminary analysis of its etiological mechanism].
To establish bisphosphonate-related osteonecrosis of the jaw (BRONJ) model in rats and to make preliminary analysis of its etiological mechanisms. A BRONJ model was established in rats using pamidronate, dexamethasone combined with alveolar bone trauma (tooth extraction) method, and the ratios of CD4+ and CD90+ lymphocytes in splenocytes were also analyzed by flow cytometry in each group. For in vitro studies, the effects of pamidronate and dexamethasone on the proliferation of human osteosarcoma cell line MG-63 and mouse pre-osteoclasts cell line Raw 264.7 were investigated using CCK-8 assay. The rat BRONJ model was successfully established using the method described above. Flow cytometry results showed that the ratios of CD4+ and CD90+ lymphocytes in splenocytes were much lower in the pamidronate and dexamethasone-treated rats than those in either pamidronte alone- or dexamethasone alone-treated rats. CCK-8 assay results showed that pamidronate could inhibit the proliferation of both MG-63 and Raw 264.7 cell lines, while dexamethasone could enhance the inhibitory effect of pamidronate on Raw 264.7 cells. This study successfully established the BRONJ model in rats and verified that dexamethasone could enhance the inhibitory effect of pamidronate on pre-osteoclasts in vitro. At least three factors including alveolar bone trauma, infection and immune response induced by dexamethasone could be involved in the process of BRONJ.


Life in the orchestra.
The concert soloist and conductor are prominent figures within the orchestra. Their roles make extraordinary demands on them--demands that must often be fulfilled while dealing with the problems of travel. Maintaining one's skill is a constant concern. The orchestra musician is also constantly on guard to maintain performance excellence. Unusual work patterns, obsession with the job, and job stress can put pressure on home life. The strong emotional personality of the orchestra musician must adapt to the conductor's desires and musical tradition. The player must coordinate performance with other group members. Other factors contribute to an environment with rigid boundaries and to the isolation of orchestra members as a group. With the development of performing arts medicine, injuries are less stigmatized and better treated, and performance stress is better managed. A patient's view of medicine is offered here.


[Radiation therapy of benign diseases. What's new eight years after?].
The authors present an update version of the indications for radiotherapy in the management of benign diseases. This is based on available randomized trials and recent international meetings. Validated indications remain the prevention of resected heterotopic bone ossifications, keloïds scars and pterygium and also treatment of arteriovenous malformations; the place of radiotherapy for malignant exophtalmia is more and more restricted. Randomized trials have demonstrated the efficacy of endobrachytherapy in the prevention of restenosis after angioplasty but the use of embedded stent has replaced this indication. Macular degeneration is no more an indication of radiotherapy. Quality requirements for radiotherapy are identical for benign or malignant indications.


Origin and distribution of enteric neurones in Xenopus.
In Xenopus, we investigated the origin of enteric neurones and their distribution in relation to the extracellular matrix (ECM) components, fibronectin (FN) and tenascin (TN). Enteric neurone precursor cells originate from the anterior trunk neural crest (NC). They migrate along the ventromedial NC pathway (between somites and neural tube/notochord) into the primitive gut (via the dorsal mesentery/lateral plate mesoderm) where they differentiate into enteric neurones. NC cells were identified during their migration and in the gut using the X. laevis - X. borealis nuclear marker system. The neuronal character of NC cells in the gut could be demonstrated immunohistochemically with a monoclonal antibody against the HNK-1 epitope. This antibody is superior to N-CAM and neurofilament antibodies which proved insufficient in Xenopus. In early tadpoles (stage 45), enteric neurones occurred frequently in the mesenchymal lining of the oesophagus, either singly or in groups of two to three cells. In more distal portions of the digestive tract, enteric neurones were rarely found. In metamorphosing tadpoles (stage 62/63), enteric neurones were scattered singly beneath the mucosa, or formed small aggregates between the inner and outer muscle layer throughout the length of the digestive tract. The neurones occurred in positions corresponding to the myenteric and submucosal plexus of higher vertebrates. The distribution of enteric neurones was studied in relation to fibronectin (FN) and tenascin (TN), glycoproteins of the ECM, which support (FN) and inhibit (TN) amphibian NC cell migration. Using immunohistochemistry, FN was found during NC cell migration in ECM spaces along the ventromedial pathway, and in the gut between the mucosa and the muscle layers, where it would be able to support adhesion and migration of NC cells. TN, in contrast, appeared much later than FN, both in the dorsal trunk and also ventrally, in the gut. In older tadpoles, TN was present in the mesenchyme and muscle layers of the digestive tract, where it might have an inhibiting influence on the migration of enteric neurones within the gut wall.


Laser Doppler flux characteristics at the skin of the dorsum of the foot in young and in elderly healthy human subjects.
In aged human subjects the cutaneous circulation has shown reduced vasoreactive capacity when stimulated by heat or ischemia, and autonomic dysfunction developing in the elderly was suggested. Should this autonomic dysfunction affect the arteriolar vasomotional activity, it might be demonstrated by laser Doppler fluxmetry (LDF) at rest. LDF flow motion characteristics at the dorsal foot skin were investigated under resting conditions in two subject groups differing in age. The younger group (n = 27, aged 25-29 years) showed a resting flux of 3.0 +/- 1.0 Arbitrary Units (AU) and a flux amplitude of 0.34 +/- 0.13 AU. In the elderly group (n = 22, aged 60-92 years) both these values were significantly (P < 0.05) lower (2.4 +/- 0.5 and 0.18 +/- 0.05 AU, respectively). The flux frequency, on the contrary, was similar in both age groups: 4.9 cycles min-1. We conclude that the mean resting flux and the mean flow motion amplitude under resting conditions at the skin of the dorsum of the foot are significantly reduced in an old-age group. The latter finding might be an aging phenomenon affecting the microvascular tone and reactivity, and might be one of the elements responsible for the attenuated cutaneous vasoreactivity described in elderly humans in response to heat and ischemic stress.


Iron-binding and storage proteins in sputum.
Induced sputum (IS) and bronchoalveolar lavage (BAL) sample different lung compartments, with IS obtaining secretions from the surfaces of the bronchial airways and BAL sampling secretions from the alveolar airspaces. Deposition of iron-containing particulate matter occurs preferentially in the bronchial airways compared to the distal airspaces. Iron-binding and storage proteins have been measured in BAL in healthy humans, where they act to sequester and detoxify available iron; however, their comparative levels in the airways are not well defined. Seventeen (n = 17) healthy, nonsmoking volunteers underwent sputum induction and fiber-optic bronchoscopy with lavage in order to measure and compare the levels of iron and iron-binding and storage proteins in BAL, bronchial lavage (BL), and IS. Relative to BAL and BL specimens, concentrations of total iron, ferritin, lactoferrin, and total iron binding capacity (TIBC) were significantly increased and transferrin decreased in IS. Immunohistochemical staining showed increased ferritin, lactoferrin, and TIBC in IS. Constitutive levels of iron and iron-binding and storage proteins (except for transferrin) are in greatest concentration in the bronchial airways relative to the alveolar airspaces in healthy humans. We speculate that these proteins reflect activated antioxidant defense mechanisms resulting from the preferential deposition of iron-containing particulate matter in the airways. The finding of decreased transferrin with increased ferritin suggests a local cellular response via iron-response elements (IRE) associated with the mRNAs for these two iron-binding proteins.


[From evidence to care sustainability: risk management by contrast agent in cancer patient. Experience in an italian teaching hospital].
The use of organo-iodinated contrast media (CM) in diagnostics and intervention has increased in the last 10 years. It is necessary to distinguish between the different types of contrast agent, primarily with respect to osmolarity: with low osmolarity the safety profile for the patient is higher. The risk of acute renal injury caused by contrast agent (PC-AKI) is however determined also by risk factors related to the patient. Particularly in main centers, it is advisable to have a standardized program in order to stratify patients with respect to risk, to define prevention strategies and the roles of the specialists involved. The experience described in this work consists in the application of an organizational model relating to CT, with a feasibility study of applying an evidence-based check-list in the clinical routine, as a tool to support clinical decisions (Clinical Decision Support System, CDSS) in the oncology field. A pilot evaluation was carried out on 54 patients belonging to the case series treated in a Teaching Hospital, in a day service regime with a diagnosis of solid tumor. The results of this evaluation led the working group to believe that the CDSS thus structured determines the possibility of overestimating the clinical risk of PC-AKI, and consequently to redefine the evaluation form. Experience has shown that it is not generally easy to immediately identify an algorithm useful for standardizing the management of clinically complex situations, such as PC-AKI prevention. The conduction of pilot evaluations can be a valid instrument of harmonization between the solidity of the references deriving from evidence based medicine and the tangibility of real world data. It is advisable to broaden the application of the CDSS more in a larger number of cases, as well as conduct a pre-post analysis relating to the clinical impact in terms of incidence from PC-AKI.


Centrosome amplification and chromosomal instability in human and animal parthenogenetic cell lines.
Parthenotes have been proposed as a source of embryonic stem cells but they lack the centriole which is inherited through the sperm in all mammalian species, except for rodents. We investigated the centrosome of parthenotes and parthenogenetic embryonic stem cells using parthenogenetic and biparental pig pre-implantation embryos, human and pig parthenogenetic and biparental embryonic stem cells, sheep fibroblasts derived from post implantation parthenogenetic and biparental embryos developed in vivo. We also determined the level of aneuploidy in parthenogenetic cells. Oocytes of all species were activated using ionomycin and 6-dimethylaminopurine (6-DMAP). Over 60% of parthenogenetic blastomeres were affected by an excessive number of centrioles. Centrosome amplification, was observed by microscopical and ultrastructural analysis also in parthenogenetic cell lines of all three species. Over expression of PLK2 and down regulation of CCNF, respectively involved in the stimulation and inhibition of centrosome duplication, were present in all species. We also detected down regulation of spindle assembly checkpoint components such as BUB1, CENPE and MAD2. Centrosome amplification was accompanied by multipolar mitotic spindles and all cell lines were affected by a high rate of aneuploidy. These observations indicate a link between centrosome amplification and the high incidence of aneuploidy and suggest that parthenogenetic stem cells may be a useful model to investigate how aneuploidy can be compatible with cell proliferation and differentiation.


Prenatal sonographic diagnosis of tetralogy of fallot.
The objective of this report was to emphasize the sonographic findings of tetralogy of Fallot (TOF) during the prenatal period. Four fetuses with TOF were prenatally diagnosed at gestational ages of 25, 28, 25, and 32 weeks. Based on this small series, prenatal sonographic findings suggestive of TOF may be summarized as follows: (1) a large aortic root, which is the most common prenatal sonographic finding, (2) a small pulmonary artery or stenosis of the right ventricular outflow tract, (3) a ventricular septal defect in the outlet portion of the septum, (4) an overriding aorta, which is best seen in the long-axis view, and (5) right ventricular hypertrophy. Other findings such as hydrops fetalis or polyhydramnios may also be helpful especially in the case of dysplastic pulmonary valves. The demonstration of a normal aortic root would render the presence of TOF unlikely. TOF with pulmonary atresia can be confused with truncus arteriosus, in which both pulmonary arteries arise from the ascending aorta. How-ever, with careful examination along the course of the ascending aorta, there are no branches arising from the aorta in TOF.


Treatment of pediatric convulsive status epilepticus.
Status epilepticus is one of the most common life-threatening neurological emergencies in childhood with the highest incidence in the first 5 years of life and high mortality and morbidity rates. Although it is known that a delayed treatment and a prolonged seizure can cause permanent brain damage, there is evidence that current treatments may be delayed and the medication doses administered are insufficient. Here, we summarize current knowledge on treatment of convulsive status epilepticus in childhood and propose a treatment algorithm. We performed a structured literature search via PubMed and ClinicalTrails.org and identified 35 prospective and retrospective studies on children <18 years comparing two and more treatment options for status epilepticus. The studies were divided into the commonly used treatment phases. As a first-line treatment, benzodiazepines buccal/rectal/intramuscular/intravenous are recommended. For status epilepticus treated with benzodiazepine refractory, no superiority of fosphenytoin, levetirazetam, or phenobarbital was identified. There is limited data on third-line treatments for refractory status epilepticus lasting >30 min. Our proposed treatment algorithm, especially for children with SE, is for in and out-of-hospital onset aids to promote the establishment and distribution of guidelines to address the treatment delay aggressively and to reduce putative permanent neuronal damage. Further studies are needed to evaluate if these algorithms decrease long-term damage and how to treat refractory status epilepticus lasting >30 min.


Localizing colorectal cancer by colonoscopy.
Colonoscopic localization of colorectal carcinoma is frequently inaccurate and unreliable. Consecutive case series. Tertiary care teaching hospital. Three hundred fourteen consecutive patients undergoing surgical resection for colorectal cancer from January 1, 2000, to December 31, 2003. Surgical resection for colorectal cancer. Incidence of erroneous site localization. Two hundred thirty-six patients had complete endoscopic, pathologic, and operative records. Colonoscopy was inaccurate for tumor localization in 49 cases (21%). In 27 (11%) of these cases, a different procedure was required than initially planned; in an additional 10 cases (4%), the surgical approach required modification. Inaccurate localization was associated with previous colorectal procedures on both univariate analysis (odds ratio, 3.94; 95% confidence interval, 1.50-10.32; P<.005) and multivariate analysis (odds ratio, 4.47; 95% confidence interval, 1.64-12.08; P = .003). Having the colonoscopy performed by a surgeon trended toward protection from error on multivariate analysis (odds ratio, 0.47; 95% confidence interval, 0.20-1.08; P = .07). Age, sex, diverticular disease, endoscopist volume and years of training, and bowel preparation had no significant effect. Colonoscopy has a considerable error rate for localization of colorectal cancer, especially when previous colorectal procedures have been performed. Adjunctive localizing techniques, such as endoscopic tattooing, should be strongly considered.


[Pathobiological determinants of atherosclerosis in youths: data from a macromorphometric and histomorphometric investigation of the aorta and coronary arteries].
We present a review of data from epidemiological and morphological studies carried out in Kaunas of atherosclerosis in youths. Since 1985, Kaunas has been a Collaborating Center involved with the World Health Organization and International Society and Federation of Cardiology studying the pathobiological determinants of atherosclerosis in youth. During the pilot study (1985-1987), we estimated the prevalence and extent of atherosclerotic lesions in the aorta and coronary arteries correlated to various risk factors in Kaunas residents aged 5 to 44 years. Within the framework of this international study, we compared histomorphometric characteristics of arteries collected from trauma victims aged 5 to 34 years in Budapest (Hungary), Heidelberg (Germany), Kaunas (Lithuania), Yaounde (Cameroon), and Mexico City (Mexico). These data revealed that males from countries with a high mortality from ischemic heart disease (Hungary, Lithuania, Germany) tended to have thicker intima in the thoracic and abdominal aorta and left anterior descending coronary artery than did males from countries with low mortality from ischemic heart disease (Mexico, Cameroon). We detected an increased mean intimal thickness of the abdominal aorta in male smokers aged 25-34 years. Males with hypertension aged 15-24 and 25-34 years had a thicker intima in the aorta and left anterior descending coronary artery than normotensive males. The morphological and epidemiological studies of atherosclerosis in youths carried out in Kaunas demonstrated that aortic and coronary atherosclerotic lesions appeared as early as childhood and advanced until the lesions become clinically apparent in adulthood. Histomorphometric findings support the postulate that increased intimal thickness can be considered a structural determinant of atherogenesis. These data draw attention to the means for the primary prevention of atherosclerosis in youth.


Vocal indicators of affective disorders.
Speech consists not only of linguistic elements such as phonemes - it also contains features which carry nonlinguistic information. These features, e.g. voice quality and prosody, either occur spontaneously and are related to the speaker's emotional and/or physiological state or are produced intentionally and related to the speaker's attitudes or interaction strategies (even though the latter often include features that are meant to appear as unintentional). Acoustic analysis of the human voice thus allows the identification of vocal correlates of the speaker's emotional and/or physiological state as well as of his social intentions.


Withdrawal reactions to diazepam in combined imipramine/diazepam treatment of primary nonagitated depressed outpatients.
Twenty-seven outpatients who had primary nonagitated depression that had been treated for 3.5 months with imipramine were included in the study. Of these, 14 patients were given additional diazepam treatment (10 mg/day) and 13 patients got placebo. The additional medication was stopped, and withdrawal reactions were observed after two weeks. The depression scores (both global evaluation and CPRS) increased significantly in the diazepam group, without any changes in the placebo group. Eleven patients in the diazepam group and four in the placebo group reported their condition as impaired after discontinuing their additional medication. Four patients in the placebo group and none in the diazepam group reported improvement. The level of working activity decreased significantly in the diazepam group and increased in the placebo group. The serum level of imipramine decreased in the placebo group (P = 0.07), but not in the diazepam group. Serum levels of desipramine decreased significantly in both groups (P less than 0.05). Our study indicates that the discontinuation of diazepam, even when given in moderate dosage over a relatively short period of time, may cause withdrawal reactions in combined antidepressant/diazepam treatment. This may be caused by a possible tendency for the depression to become chronic. Such chronicity may be the reason for secondary dependency to diazepam.


17-Deoxoestrone [estra-1,3,5(10)-trien-3-ol]-methanol (3/1).
Three independent mol-ecules of the title estrone derivative and a mol-ecule of methanol comprise the asymmetric unit of the title compound [systematic name: 13-methyl-6,7,8,9,11,12,13,14,15,16-deca-hydro-cyclo-penta-[a]phenanthren-3-ol-meth-an-ol (3/1)], 3C(18)H(24)O·CH(3)OH. Two of the estrone mol-ecules exhibit 50:50 disorder (one displays whole-mol-ecule disorder and the other partial disorder in the fused five- and six-membered rings) so that five (partial) mol-ecular conformations are discernable. The conformation of the six-membered ring abutting the aromatic ring is close to a half-chair in all five components. The conformation of the six-membered ring fused to the five-membered ring is based on a chair with varying degrees of distortion ranging from minor to significant. Two distinct conformations are found for the five-membered ring: in four mol-ecules, the five-membered ring is twisted about the bond linking it to the six-membered ring, and in the other, the five-membered ring is an envelope with the quaternary C atom being the flap atom. The crystal packing features O-H⋯O hydrogen bonding whereby the four mol-ecules comprising the asymmetric unit are linked into a supra-molecular chain along the b axis.


Structured Design Methodology to Achieve a High SNR Electrical Impedance Tomography.
In this paper, we present a methodology for designing the main circuit building blocks of an electrical impedance tomography (EIT) system. In particular, we derive equations that map system-level EIT specifications to the performance requirements of each circuit block. We also review the circuit architectures that are best suited for meeting a given set of performance requirements. Our proposed design methodology is focused on maximizing the EIT system's signal-to-noise ratio while minimizing total power consumption.


Tolerability to romidepsin in patients with relapsed/refractory T-cell lymphoma.
Histone deacetylase inhibitor romidepsin has demonstrated durable clinical responses and tolerability in patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma (PTCL, CTCL). Selection of novel drug therapies for patients with relapsed/refractory aggressive lymphoma requires not only considerations regarding efficacy but also careful evaluation of toxicities as well as overall clinical benefit. The purpose of this analysis was to examine common adverse events (AEs) reported in pivotal trials of romidepsin in relapsed/refractory PTCL or CTCL and to more clearly define the overall AE profile in these populations. Patients with relapsed/refractory PTCL or CTCL were treated with romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 of 28-day cycles for up to 6 cycles; patients with at least stable disease could extend therapy until progressive disease or another withdrawal criterion was met. All enrolled patients who received ≥ 1 dose of romidepsin were included in the AE analyses. Overall, safety profiles of common AEs were similar, although patients with relapsed/refractory PTCL had more frequent hematologic toxicities and grade ≥ 3 infections. In both patient populations, the greatest incidence of grade ≥ 3 AEs and the majority of discontinuations due to AEs occurred during cycles 1-2. Early discontinuations were primarily related to infection, thrombocytopenia, or electrocardiogram abnormalities, confirming the need to closely monitor patients with poor bone marrow reserve or other comorbidities. Despite this, 28% of patients with relapsed/refractory PTCL and 36% of patients with relapsed/refractory CTCL continued on romidepsin treatment for ≥ 6 cycles. This study demonstrates that patients with relapsed/refractory PTCL or CTCL have similar AE profiles with romidepsin treatment, although patients with PTCL experienced more frequent and more severe hematologic toxicities and more frequent grade ≥ 3 infections. The greatest incidence of grade ≥ 3 AEs and the majority of discontinuations due to AEs occurred during treatment cycles 1-2. Extended dosing of romidepsin can be tolerated in responding patients. NCT00426764,NCT00106431.


Behavioral effects of 6-methylene naltrexone (nalmefene) in rhesus monkeys.
Nalmefene [17-N-cyclopropylmethyl-3,14-beta-dihydroxy-4,5-alpha-epoxy-6- methylenemorphinan hydrochloride (also NIH 10365)], a 6-methylene derivative of naltrexone, was compared to naltrexone for its behavioral effects in rhesus monkeys. Nalmefene had opioid antagonist actions under all conditions, having a potency similar to that of naltrexone. In morphine-treated monkeys, discriminating between 0.01 mg/kg of naltrexone and saline, nalmefene substituted completely for naltrexone at doses larger than 0.001 mg/kg. The onset of discriminative stimulus effects was similar for nalmefene and naltrexone. A dose of 0.032 mg/kg of either antagonist occasioned > or = 90% naltrexone-level responding beginning 6 to 8 min after s.c. administration; the effects of this dose of either antagonist persisted for more than 1 hr. Like the parent compound naltrexone, nalmefene also antagonized the discriminative stimulus effects of opioid agonists. Nalmefene prevented the discriminative stimulus effects of morphine in monkeys acutely deprived of morphine and antagonized the discriminative stimulus effects of nalbuphine in a separate group of monkeys discriminating between nalbuphine and saline. At the dose of naltrexone and nalmefene that produced an equivalent antagonism of morphine when the antagonist was administered 0.25 hr before morphine (0.01 mg/kg), the duration of antagonist action was < 4 hr and > 6 hr, respectively. Nalmefene also attenuated the antinociceptive effects of the mu agonist alfentanil and the kappa agonist CI-977 [5R-(5,7,8-beta)-N-methyl- N-[7-(1-pyrrolidinyl)1-oxaspiro[4,5]dec-8-yl]-4-benzofuranaceta mide], being 55 times more potent in attenuating the antinociceptive effects of alfentanil as compared to Cl-977.(ABSTRACT TRUNCATED AT 250 WORDS)


The H3 loop of antibodies shows unique structural characteristics.
The H3 loop in the Complementarity Determining Region of antibodies plays a key role in their ability to bind the diverse space of potential antigens. It is also exceptionally difficult to model computationally causing a significant hurdle for in silico development of antibody biotherapeutics. In this article, we show that most H3s have unique structural characteristics which may explain why they are so challenging to model. We found that over 75% of H3 loops do not have a sub-Angstrom structural neighbor in the non-antibody world. Also, in a comparison with a nonredundant set of all protein fragments over 30% of H3 loops have a unique structure, with the average for all of other loops being less than 3%. We further observed that this structural difference can be seen at the level of four residue fragments where H3 loops present numerous novel conformations, and also at the level of individual residues with Tyrosine and Glycine often found in energetically unfavorable conformations. Proteins 2017; 85:1311-1318. © 2017 Wiley Periodicals, Inc.


Safety and efficacy of growth hormone treatment in small for gestational age children.
Approximately 100,000 infants are born small for gestational age (birth weight <2 standard deviation) annually in the US alone. Because of catch-up growth, 10-20% of all children born small for gestational age will be eligible for growth hormone therapy. Growth hormone has been approved by the Food and Drug Administration in 2003 and by the European Agency for the Evaluation of Medical Products though at different enrollment and treatment criteria. Benefits and risks of growth hormone therapy for small for gestational age children are the purpose of the present review. Mean height increased by as much as two standard deviation over 3 years of treatment in infants born small for gestational age. Rapid catch-up growth is desirable and will only be achieved with higher growth hormone doses (0.48 mg/kg/week) Treatment should be continuous and not interrupted. The safety profile of growth hormone treatment is excellent. Transient elevation of insulin levels returned to near normal after growth hormone treatment was discontinued. Growth hormone treatment in small for gestational age children has been found to be well tolerated and is an important advance in the treatment of short stature in pediatrics. Treatment of short prematurely born infants with growth hormone may offer similar efficacy and safety as growth hormone treatment in small for gestational age infants.


[Curative radiotherapy of local advanced non-small-cell lung cancer. Eight years of experience from Odense].
No previous reports on 3-D conformal radiotherapy of Danish patients with inoperable local advanced non-small-cell lung cancer have been published. From 1995 to 2003, 158 patients with inoperable non-small-cell stage III lung cancer received radical radiotherapy in doses of 60-66 Gy in 30-33 fractions. Neoadjuvant chemotherapy was administered to 77 patients. The median survival time was 15.8 months. The one, two-, three-, four-, and five-year survival rates were 61%, 35%, 23%, 19% and 17%, respectively. Gender and age had no influence on survival, while patients in performance status 2 tended to have poorer survival rate than patients in performance status 0-1. The lung function as evaluated byh FEV1 and FVC declined by 8-9% during the first year and was reduced by 9-13% after three years. The cause of death in 90% of the cases was lung cancer. In 50% of all cases, a loco-regional relapse was found, and in 41% distant metastases existed. These results show that a significant number of stage III patients treated with modern radiotherapy with curative intent will be long-term survivors.


Polypoidal choroidal vasculopathy: evidence-based guidelines for clinical diagnosis and treatment.
Polypoidal choroidal vasculopathy (PCV) is an exudative maculopathy affecting vision, with clinical features distinct from neovascular age-related macular degeneration. Currently, no evidence-based guidelines exist for its diagnosis and treatment. A panel of experts analyzed a systematic literature search on PCV together with results of the EVEREST trial, the only published randomized controlled clinical trial in PCV. At a subsequent Roundtable meeting, recommendations for the management of PCV were agreed based on this analysis and their own expert opinion. Diagnosis of PCV should be based on early-phase nodular hyperfluorescence from choroidal vasculature visualized using indocyanine green angiography. Recommended initial treatment of juxtafoveal and subfoveal PCV is either indocyanine green angiography-guided verteporfin photodynamic therapy or verteporfin photodynamic therapy plus 3 × 0.5 mg ranibizumab intravitreal injections 1 month apart. If there is incomplete regression of polyps by indocyanine green angiography, eyes should be retreated with verteporfin photodynamic therapy monotherapy or verteporfin photodynamic therapy plus ranibizumab. If there is complete regression of polyps by indocyanine green angiography, but there is leakage on fluorescein angiography and other clinical or anatomical signs of disease activity, eyes should be retreated with ranibizumab. Practical guidance on the clinical management of PCV is proposed based on expert evaluation of current evidence.


Molecular Design of Organic Ionic Plastic Crystals Consisting of Tetracyanoborate with Ultralow Phase Transition Temperature.
Organic ionic plastic crystals (OIPCs) are a ductile soft material where the composing ions are in isotropic free rotation, while their positions are aligned in order. The rotational motion in its plastic phase promotes ion conduction by decreasing the activation energy. Here, we report novel OIPCs comprised of tetracyanoborate ([TCB]-) and various organic cations. In particular, the OIPC composed of [TCB]- and spiro-(1,1')-bipyrrolidinium ([spiropyr]+) cations can transform into its plastic phase at ultralow temperature (Tp = -55 °C) while maintaining a high melting point (Tm = 242 °C). Replacement of the cation with either tetraalkylammonium or phosphonium and comparing their phase behavior, the high Tm was attributed to the relatively small interionic distance between [spiropyr]+ and [TCB]-. At the same time, the low Tp was realized by the restricted vibrational mode of the spirostructure, allowing the initiation of isotropic rotational motion with less thermal energy input.


Nonfullerene Acceptor Molecules for Bulk Heterojunction Organic Solar Cells.
The bulk-heterojunction blend of an electron donor and an electron acceptor material is the key component in a solution-processed organic photovoltaic device. In the past decades, a p-type conjugated polymer and an n-type fullerene derivative have been the most commonly used electron donor and electron acceptor, respectively. While most advances of the device performance come from the design of new polymer donors, fullerene derivatives have almost been exclusively used as electron acceptors in organic photovoltaics. Recently, nonfullerene acceptor materials, particularly small molecules and oligomers, have emerged as a promising alternative to replace fullerene derivatives. Compared to fullerenes, these new acceptors are generally synthesized from diversified, low-cost routes based on building block materials with extraordinary chemical, thermal, and photostability. The facile functionalization of these molecules affords excellent tunability to their optoelectronic and electrochemical properties. Within the past five years, there have been over 100 nonfullerene acceptor molecules synthesized, and the power conversion efficiency of nonfullerene organic solar cells has increased dramatically, from ∼2% in 2012 to >13% in 2017. This review summarizes this progress, aiming to describe the molecular design strategy, to provide insight into the structure-property relationship, and to highlight the challenges the field is facing, with emphasis placed on most recent nonfullerene acceptors that demonstrated top-of-the-line photovoltaic performances. We also provide perspectives from a device point of view, wherein topics including ternary blend device, multijunction device, device stability, active layer morphology, and device physics are discussed.


A randomized clinical trial targeting anxiety sensitivity for patients with suicidal ideation.
Anxiety sensitivity (AS) is a well-established transdiagnostic risk factor for anxiety and mood psychopathology including suicide. A variety of interventions using cognitive-behavioral skills as well as cognitive bias modification (CBM) suggest that AS can be quickly and effectively reduced in nonclinical and nontreatment seeking samples. However, it is unclear whether AS reduction protocols will have efficacy for more severe clinical samples. Moreover, the combination of cognitive-behavioral techniques with CBM focused on changing interpretation bias (CBM-I) related to AS has not been evaluated. A patient sample with co-occurring anxiety psychopathology and active suicidal ideation (N = 74) was randomly assigned to a brief 1-session computerized treatment including: (a) psychoeducation and interoceptive exposure (i.e., cognitive anxiety sensitivity treatment [CAST]) plus CBM-I for AS; or (b) health information condition plus sham CBM for AS. Participants were assessed immediately after the 1-hr intervention as well as at 1- and 4-month follow-ups. Consistent with hypotheses, participants in the active treatment showed significantly greater AS reduction that was maintained through follow-up (effect sizes ranged from medium to large for the overall AS and the AS subscales). Mediation analyses suggested that changes in AS mediated suicide outcomes. In sum, these are the first findings to suggest that brief AS reduction protocols have efficacy both in terms of risk and symptom outcomes in patient samples showing active suicidal ideation. (PsycINFO Database Record


Uteroplacental insufficiency alters liver and skeletal muscle branched-chain amino acid metabolism in intrauterine growth-restricted fetal rats.
Uteroplacental insufficiency causes intrauterine growth restriction (IUGR) and decreases plasma levels of the branched-chain amino acids in both humans and rats. Increased fetal oxidation of these amino acids may contribute to their decline in the IUGR fetus. The rate-limiting step of branched-chain amino acid oxidation is performed by the mitochondrial enzyme branched-chain alpha-keto acid dehydrogenase (BCKAD), which is regulated by a deactivating kinase. We therefore hypothesized that uteroplacental insufficiency increases BCKAD activity through altered mRNA and protein levels of BCKAD and/or the BCKAD kinase. In IUGR fetal liver, BCKAD activity was increased 3-fold, though no difference in hepatic BCKAD protein or mRNA levels were noted. Hepatic BCKAD kinase mRNA and protein levels were significantly decreased in association with the increase in BCKAD activity. In IUGR fetal skeletal muscle, BCKAD mRNA levels were significantly increased. IUGR skeletal muscle BCKAD protein levels as well as BCKAD kinase mRNA and protein levels were unchanged. We also quantified mRNA levels of two amino acid transporters: LAT1 (system L) and rBAT (cysteine and dibasic amino acids). Both hepatic and muscle LAT1 mRNA levels were significantly increased in the IUGR fetus. We conclude that uteroplacental insufficiency significantly increases hepatic BCKAD activity in association with significantly decreased mRNA and protein levels of the deactivating kinase. We speculate that these changes contribute to the decreased serum levels of branched-chain amino acids seen in the IUGR fetus and may be an adaptation to the deprived milieu associated with uteroplacental insufficiency.


Lack of motivation: a new modifiable risk factor for peritonitis in patients undergoing peritoneal dialysis?
Can we identify modifiable risk factors for peritonitis in patients undergoing peritoneal dialysis (PD)? We aimed to determine whether housing standard, PD exchange technique or patient motivation might be modifiable risks for peritonitis. We also explored the relationship between lack of motivation and depression. Nurse home visits assessed PD exchange technique, environment and patient motivation. Motivation scores were correlated separately with an Apathy Evaluation Score and a depression score using PHQ-9 questionnaires. Home hygiene, exchange technique and motivation were above average in 53%, 56% and 60%, respectively in 104 patients undergoing PD. After 15 months, 25.9% patients developed peritonitis but nurses' ratings of homes and exchange techniques were not predictive. Low patient motivation was predictive. Patients rated to have above or below median motivation had significantly different Apathy Scores (p = 0.0002). Unmotivated depressed patients were significantly more likely to develop peritonitis compared to motivated depressed patients. Lack of motivation predicted peritonitis particularly if associated with depression. Further studies are required focusing on specific motivation scoring schemes and the psychosocial support that might lead to better outcomes.


"Critical periods" in vestibular development or adaptation of gravity sensory systems to altered gravitational conditions?
1. A feature of sensory, neuronal and motor systems is the existence of a critical period during their development. Modification of environmental conditions during this specific period of life affects development in a long-term manner, or even irreversibly. Deprivation is the prefered approach to study the existence and duration of critical periods. For gravity sensory systems, space flights offer the only opportunity for deprivation conditions. 2. Studies in a fish (Oreochromis mossambicus) and an amphibian (Xenopus laevis) revealed a significant sensitivity of their roll-induced static vestibuloocular reflex (rVOR) to a 9- to 10-day gravity deprivation (microgravity) during a spaceflight. In some instances, the rVOR was augmented after the flight as demonstrated in young Oreochromis which were launched when their rVOR had not been developed, and in Xenopus tadpoles launched after their rVOR had developed. Fish which could perform the rVOR at launch were insensitive to microgravity exposure. A similar insensitivity to microgravity was observed in Xenopus tadpoles with normal body shape which had not yet developed their rVOR at launch. Some tadpoles, however, developed an upward bended tail during their space flight; their rVOR was significantly depressed after termination of microgravity independent of the age at onset of the flight. Hypergravity depressed the rVOR for all so far tested developmental stages in both Oreochromis and Xenopus. 3. Both adaptive processes during exposure to altered gravity as well as the existence of a critical period in vestibular development might be responsible for the modulation of the rVOR recorded after exposure to altered gravity. Deprivation studies have to be extended to older developmental stages to test the possibility of a critical period; however, this approach is limited due to the low number of space flights.


Luteolin suppresses cisplatin-induced apoptosis in auditory cells: possible mediation through induction of heme oxygenase-1 expression.
Luteolin has been shown to possess antitumorigenic, antioxidant, and anti-inflammatory properties. In the present study, we investigated the protective mechanism of luteolin against cisplatin-induced apoptosis in auditory (House Ear Institute-Organ of Corti 1 [HEI-OC1]) cells. Luteolin was found to induce the expression of heme oxygenase-1 (HO-1) in a dose- and time-dependent manner. Luteolin also activated the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathway, which plays an important role in the expression of HO-1. Luteolin protected the cells against cisplatin-induced apoptotic cell death. The protective effect of luteolin was abrogated by zinc protoporphyrin IX (ZnPP IX), an HO inhibitor, and antisense oligodeoxynucleotides against the HO-1 gene. Furthermore, pretreatment with luteolin inhibited the activation of caspase-3 and the mitochondrial dysfunction, and the effect of luteolin on the activation of caspase-3 disappeared in the presence of ZnPP IX or PD098059. These results demonstrate that the expression of HO-1 by luteolin is mediated by the ERK pathway, and also that the activating of HO-1 inhibits cisplatin-induced apoptosis in HEI-OC1 1 cells.


PET/CT: Role in staging, in follow-up and in the evaluation of disease recurrence in gynecologic cancer.
18F-FDG PET/CT may facilitate improved diagnosis and treatment in gynecological fields. This method provides pretreatment prognostic information concerning the aggressiveness of tumors which may contribute to optimizing and individualizing patient therapy. Although 18F-FDG PET/CT has a limited role for local staging of primary cancer, it has an important role in staging, as it aids particularly in identifying the involvement of lymph nodes and distant metastases throughout the whole body in a single examination in patients with advanced-stage disease and also in restaging after therapy. Another major indication of the modality is the evaluation of disease recurrence, especially in clinically equivocal patients or in patients in which tumor markers are rising, and conventional imaging studies show negative or equivocal findings.


Dietary Intake Patterns of Community-Dwelling Older Adults After Acute Hospitalization.
Malnutrition and sarcopenia are a growing concern in community-dwelling older adults. Hospitalization increases the risk of malnutrition and leads to a decline in functional and nutritional status at discharge. Persistent malnutrition after hospital discharge may worsen posthospital outcomes, including readmissions. The aim of this study was to determine dietary intakes and nutrient distribution patterns of community-dwelling older adults after acute hospitalization. Participants (65 years and older, n = 85) were enrolled during acute hospitalization and dietary 24-hour recalls were collected weekly for 1 month postdischarge. Analysis included change in dietary intake over recovery timeframe; daily intake of energy, protein, fruit, vegetables, and fluids; comparison of intake to recommendations; distribution of energy and protein across mealtimes; and analysis of most common food choices. Most participants did not meet current recommendations for energy, fruit, vegetables, or fluids. Average protein consumption was significantly higher than the current recommendation of 0.8 g/kg/d; however, only 55% of participants met this goal and less than 18% met the 1.2 g/kg/d proposed optimal protein intake for older adults. The protein distribution throughout the day was skewed and no one met the 0.4 g/meal protein recommendation at all meals. Our findings indicate that community-dwelling older adults did not meet their nutritional needs during recovery after hospitalization. These data highlight the need for better nutritional evaluation and support of geriatric patients recovering from hospitalization.


Does sex matter? Effects on venous thromboembolism risk in screened trauma patients.
Sex is associated with disparate risk of venous thromboembolism (VTE) in nontrauma patients, with increased risk seen during pregnancy and in women on hormone-containing medications. Sex effects on VTE after trauma are unclear. Some studies have demonstrated no effect whereas others have instead shown a higher incidence of VTE among men. We hypothesized that male sex would increase the risk of VTE across all age groups in trauma patients undergoing standardized duplex screening. All admissions to a Level I academic trauma center 2000 to 2014 were reviewed. We excluded patients for age <18 years, pregnancy, pre-admission anticoagulant use, and hospital length of stay (LOS) <72 hours. A strict venous duplex screening protocol was followed. Female patients were subcategorized into pre- and post-menopausal groups based on age (18-44 vs. ≥ 55 years). Bivariate analysis and logistic regression were used to identify variables correlating with VTE risk. A total of 8,726 patients met inclusion criteria. The overall VTE rate was 5.3%. Bivariate analysis did not find a difference in VTE risk by sex (5.1% women vs. 5.4% men, p = 0.565), or between women and men within age-defined menopausal categories (pre-menopausal women 3.9% vs. men 4.7%, p = 0.293; post-menopausal women 5.9% vs. men 7.0%, p = 0.22). Logistic regression (see figure) did identify other risk factors for VTE including age ≥55 (adjusted odds ratio [AOR] 2.0), increasing ISS (AOR 1.5-2.1), penetrating mechanism of injury (AOR 2.2), lower extremity injury (AOR 1.7), need for mechanical ventilation (AOR 2.1), and increasing hospital length of stay (LOS 7-28 days, AOR 3.8; LOS > 28 days, AOR 9.1). There was no difference in VTE rates based on patient sex, even after controlling for menopausal status. Aggressive VTE screening of over 8,700 patients did identify several other patient populations at increased risk of developing VTE. More intensive VTE prophylaxis may be appropriate in these patients. Epidemiologic study, level III; therapeutic study, level V.


Can coil-to-globule transition of a single chain be treated as a phase transition?
The effects of the concentration (C) and heating rate on the collapse and association of poly(N-isopropylacrylamide) chains in water have been investigated by use of ultrasensitive differential scanning calorimetry. In the dilute solutions, both the phase transition temperature (Tp) and enthalpy change (DeltaH) increase with the heating rate but decrease with concentration. By extrapolation to zero heating rate and zero concentration, Tp and DeltaH for coil-to-globule transition of a single chain in thermodynamic equilibrium can be obtained. In semidilute solutions, both Tp and DeltaH increase with the heating rate but slightly vary with the concentration. Tp and DeltaH for pure interchain association in equilibrium are obtained by extrapolation to zero heating rate. Our experiments reveal that only intrachain contraction occurs when the concentration is infinitely close to zero. When the concentration is above the overlap concentration (C*), only interchain association exists. In the range 0<C<C*, both intrachain contraction and interchain association coexist.


A real-time hybrid neuron network for highly parallel cognitive systems.
For comprehensive understanding of how neurons communicate with each other, new tools need to be developed that can accurately mimic the behaviour of such neurons and neuron networks under `real-time' constraints. In this paper, we propose an easily customisable, highly pipelined, neuron network design, which executes optimally scheduled floating-point operations for maximal amount of biophysically plausible neurons per FPGA family type. To reduce the required amount of resources without adverse effect on the calculation latency, a single exponent instance is used for multiple neuron calculation operations. Experimental results indicate that the proposed network design allows the simulation of up to 1188 neurons on Virtex7 (XC7VX550T) device in brain real-time yielding a speed-up of x12.4 compared to the state-of-the art.


Clustering and enhanced activity of an inwardly rectifying potassium channel, Kir4.1, by an anchoring protein, PSD-95/SAP90.
An inwardly rectifying potassium channel predominantly expressed in glial cells, Kir4.1/KAB-2, has a sequence of Ser-Asn-Val in its carboxyl-terminal end, suggesting a possible interaction with an anchoring protein of the PSD-95 family. We examined the effects of PSD-95 on the distribution and function of Kir4.1 in a mammalian cell line. When Kir4.1 was expressed alone, the channel immunoreactivity was distributed homogeneously. In contrast, when co-expressed with PSD-95, prominent clustering of Kir4.1 in the cell membrane occurred. Kir4.1 was co-immunoprecipitated with PSD-95 in the co-expressed cells. Glutathione S-transferase-fusion protein of COOH terminus of Kir4.1 bound to PSD-95. These interactions disappeared when the Ser-Asn-Val motif was deleted. The magnitude of whole-cell Kir4.1 current was increased by 2-fold in cells co-expressing Kir4.1 and PSD-95 compared with cells expressing Kir4. 1 alone. SAP97, another member of the PSD-95 family, showed similar effects on Kir4.1. Furthermore, we found that Kir4.1 as well as SAP97 distributed not diffusely but clustered in retinal glial cells. Therefore, PSD-95 family proteins may be a physiological regulator of the distribution and function of Kir4.1 in glial cells.


[Resection of liver and abdominal wall metastasis 11 years after pancreatoduodenectomy. Case report].
Pancreatic cancer has adverse prognosis. Disease recurrence is typical and it occurs mainly within the first 2 years postoperatively. However late and soliter metastases are rare. This case report shows the history of a male patient, who was radically operated on for pancreatic cancer. 11 years later a solitary liver metastasis has developed and it was completely removed by resection. 1 year postoperatively the patient is doing well. Our case demonstrates that in patients after resection for pancreatic cancer, redo surgery might be justified in case of late and isolated metastasis. Orv Hetil. 2017; 158(28): 1109-1111.


Mitral stenosis due to pannus overgrowth after rigid ring annuloplasty.
Although mitral stenosis (MS) due to pannus overgrowth after mitral valve repair for rheumatic mitral regurgitation (MR) is not uncommon, it is extremely rare in relation to non-rheumatic mitral regurgitation. Whilst it has been suggested that the rigid annuloplasty ring induces pannus overgrowth in the same manner as the flexible ring, to date only in cases using the flexible ring has pannus formation been confirmed by a pathological examination after redo surgery. The case is described of a woman who had undergone mitral valve repair using a 28 mm rigid ring three years previously because of non-rheumatic MR, and subsequently suffered from MS due to pannus formation over the annuloplasty ring. To the present authors' knowledge, this is the first report of MS due to pannus formation after mitral valve repair using a rigid annuloplasty ring to treat non-rheumatic MR documented at reoperation.


Pharmacokinetics and pharmacodynamics of a new transdermal delivery system for bopindolol.
1. In two separate studies, each with 12 healthy male volunteers, the pharmacokinetic and dynamic properties of a transdermal delivery system for bopindolol were evaluated. 2. In study I it was shown that bopindolol absorption from a 14 mg patch occurred over the whole 7-day application period. No signs of a significant skin depot were found. 3. In study II, a linear pharmacokinetic behaviour but a non-linear kinetic/dynamic relationship was established for the patches over a dose range from 7 to 21 mg. Comparable peak effects of reduction in exercise-induced tachycardia were observed after different patch doses and an i.v. injection. However, the effect was significantly prolonged with the patches compared with the injection and was maintained over 7 days. 4. The patches showed a good local and systemic tolerability in both studies over a dosing interval of up to 7 days.


[Public Reporting on long-term Care Facilities in Germany: Current State and Evaluation of Quality Information].
Little is known about public reporting on long-term care facilities. In this study, we (1) identify the websites that are available for a search on long-term care facilities in Germany, (2) describe them systematically with regard to general information and range of functions, 3) capture the information on quality available on the websites and 4) evaluate the extent to which they can be useful for those in need. 1) Systematic internet search to identify the websites. 2) Analysis of the websites with regard to defined inclusion and exclusion criteria. 3) Data collection from the included websites. 4) Description of the general content and the range of functions of the websites. 5) Collection of quality-related information on long-term care facilities (structure, process and outcome quality, costs, quality inspections results, user feedback). 6) Evaluation of the usefulness of information by analyzing the information using a catalogue of criteria. A total of 24 websites were identified with information on long-term care facilities. Only 4 websites allowed a direct online comparison of several facilities and 17% allowed consumer feedback online. All websites provided information on structural quality, but none on the outcome quality. Across all websites, the usefulness of information for the consumers amounted to 19%. The thematic area on location and accessibility of a facility offered relatively detailed information (79%), while only to 9% was dedicated to the thematic area on care. There is a large number of websites that can be searched for information on long-term care facilities. They show a range of heterogeneous functions and information. More websites should offer a function of comparison of multiple facilities. With regard to the information available, consumer preferences do not yet seem to be sufficiently taken into account. Further researches should focus on the evaluation of the impact of outcome quality on decision-making and the analysis of the validity of consumer feedback.


Imaging features of peripheral neurogenic tumors.
Peripheral nerve sheath tumors (PNST) include schwannoma, neurofibroma and malignant peripheral sheath tumors. All neurogenic tumors share the same imaging characteristics, including fusiform shape, low attenuation on CT, fascicular sign, split fat sign and associated muscle atrophy. The aim of this article is to give a comprehensive overview of peripheral nerve tumors and to discuss the imaging characteristics that distinguish these masses.


Impact of pellet thickness on quantitative terahertz spectroscopy of solid samples in a polyethylene matrix.
Pellets composed of different weight-percent (wt-%) of lactose within a polyethylene (PE) matrix are used to examine how the physical thickness of solid samples impact analytical measurements performed over terahertz (THz) frequencies when using time-domain THz spectroscopy. Results indicate that the thickness of each pellet depends on the mass and physical properties of the individual components that comprise the pellet. Thickness of mixture pellets depends on the porosity of the individual pellet components. Porosity measurements presented here for PE and lactose give values of 25.6 ± 0.3 and 14.5 ± 0.1, respectively, which indicate that more air is trapped within the compressed PE matrix compared to that for lactose. This difference in porosity creates different pellet thicknesses for pellets of the same nominal mass but with different relative amounts of PE and lactose. For this binary matrix, the thickness of each pellet is found to be a linear combination of the compressed densities of the individual components. Analysis of the time-domain THz spectra reveals that thinner samples are confounded by a fringe pattern observed in the frequency-domain spectra. This fringe pattern is created by an etalon corresponding to the air/pellet interfaces for the sample in the optical path. Spectra collected from thicker pellets are confounded by a sloping baseline caused by scattering effects within the pellet matrix. The quantitative impact of pellet thickness is determined by comparing the mean standard error of calibration (MSEC) and mean standard error of prediction (MSEP) for a set of leave-three-out cross validation multivariate calibration models based on the partial least-squares (PLS) algorithm. Results indicate that PLS models are capable of analytical measurements with MSEC and MSEP values between 0.04 and 0.20 wt-%. Analysis of spectral variance captured within the corresponding spectral loadings for each model indicates that spectral variance is lowest for the 300 mg samples where the impact of scattering is minimal under conditions when the sample etalon is nonexistent.


In Silico Investigation of the Clinical Translatability of Competitive Clearance Glucose-Responsive Insulins.
The glucose-responsive insulin (GRI) MK-2640 from Merck was a pioneer in its class to enter the clinical stage, having demonstrated promising responsiveness in in vitro and preclinical studies via a novel competitive clearance mechanism (CCM). The smaller pharmacokinetic response in humans motivates the development of new predictive, computational tools that can improve the design of therapeutics such as GRIs. Herein, we develop and use a new computational model, IM3PACT, based on the intersection of human and animal model glucoregulatory systems, to investigate the clinical translatability of CCM GRIs based on existing preclinical and clinical data of MK-2640 and regular human insulin (RHI). Simulated multi-glycemic clamps not only validated the earlier hypothesis of insufficient glucose-responsive clearance capacity in humans but also uncovered an equally important mismatch between the in vivo competitiveness profile and the physiological glycemic range, which was not observed in animals. Removing the inter-species gap increases the glucose-dependent GRI clearance from 13.0% to beyond 20% for humans and up to 33.3% when both factors were corrected. The intrinsic clearance rate, potency, and distribution volume did not apparently compromise the translation. The analysis also confirms a responsive pharmacokinetics local to the liver. By scanning a large design space for CCM GRIs, we found that the mannose receptor physiology in humans remains limiting even for the most optimally designed candidate. Overall, we show that this computational approach is able to extract quantitative and mechanistic information of value from a posteriori analysis of preclinical and clinical data to assist future therapeutic discovery and development.


Measurement of plasma cell-free DNA concentrations in dogs with sepsis, trauma, and neoplasia.
To determine if cell-free DNA (cfDNA) was identifiable in canine plasma, to evaluate 3 techniques for the measurement of plasma cfDNA concentrations in dogs presented to an emergency service, and to compare the plasma cfDNA concentrations of healthy dogs to those with sepsis, trauma, and neoplasia. Retrospective study of banked canine plasma samples collected between May 2014 and December 2014. Dogs presented to the emergency service of a university veterinary teaching hospital. Plasma cfDNA was measured on residual plasma samples obtained from 15 dogs with sepsis, 15 dogs with moderate-severe trauma, 15 dogs diagnosed with a sarcoma. Plasma cfDNA was also measured in 15 healthy dogs. None. Assay linearity, repeatability, and reproducibility were evaluated. Quantification of cfDNA was performed in duplicate on diluted citrated plasma and following DNA purification using 2 fluorescence assays (SYBR-Gold; Quant-iT) and by ultraviolet absorbance spectroscopy. Fluorescence intensities (FIs) were converted to cfDNA concentrations using standard curves. Median FI values and cfDNA concentrations were compared to healthy controls using the Kruskal-Wallis test, with adjustment for multiple comparisons. Alpha was set at 0.05. Both assays had excellent linearity, and acceptable repeatability and reproducibility. Compared to controls, plasma cfDNA concentrations were significantly increased in dogs with sepsis or moderate-severe trauma with both assays (P ≤ 0.003). Dogs with neoplasia had significantly increased cfDNA concentrations with the Quant-iT assay only (P = 0.003). When measurements were performed on purified DNA, only dogs with moderate-severe trauma had significantly increased cfDNA concentrations (P < 0.001; SYBR-Gold assay). cfDNA can be readily identified in canine plasma using 2 fluorescence assays. DNA extraction offers no advantage over direct measurement. Compared to healthy controls, dogs with sepsis or moderate-severe trauma have significantly increased plasma cfDNA concentrations.


Use of Crossed Polarizers to Enhance Images of the Eyelids.
To describe imaging of the external eye with Crossed Polarizers to enhance clinically important features in digital photographs of the eyelids. External photographs with and without crossed polarizing filters were taken of patients with blepharitis and controls with no clinical eye pathology. Photographing eyelid skin through Crossed Polarizers decreased reflections on the skin surface and improved visualization of eyelid telangiectasias and blood vessels in patients with a broad range of skin pigmentation and ethnicities. The use of Crossed Polarizers in imaging the external eye reduces reflections and glare from the eyelid skin and margins, thereby allowing for a more detailed evaluation of underlying structures and analysis of images. These findings suggest that including Crossed Polarizers in clinical photography has informative applications for assessing eyelid disease.


Controlled ultrasound tissue erosion.
The ability of ultrasound to produce highly controlled tissue erosion was investigated. This study is motivated by the need to develop a noninvasive procedure to perforate the neonatal atrial septum as the first step in treatment of hypoplastic left heart syndrome. A total of 232 holes were generated in 40 pieces of excised porcine atrial wall by a 788 kHz single-element transducer. The effects of various parameters [e.g., pulse repetition frequency (PRF), pulse duration (PD), and gas content of liquid] on the erosion rate and energy efficiency were explored. An Isppa of 9000 W/cm2, PDs of 3, 6, 12, and 24 cycles; PRFs between 1.34 kHz and 66.7 kHz; and gas saturation of 40-55% and 79-85% were used. The results show that very short pulses delivered at certain PRFs could maximize the erosion rate and energy efficiency. We show that well-defined perforations can be precisely located in the atrial wall through the controlled ultrasound tissue erosion (CUTE) process. A preliminary in vivo experiment was conducted on a canine subject, and the atrial septum was perforated using CUTE.


Functioning gonadotroph adenoma with hyperestrogenemia and ovarian hyperstimulation in a reproductive-aged woman: A case report and review of literature.
Functioning gonadotroph adenomas are extremely rare pituitary tumors that secrete gonadotropins and exhibit distinct clinical manifestations. Here, we report a case of functioning gonadotroph adenoma in a reproductive-aged woman and discuss its diagnosis and management. A 21-year-old female patient with abdominal pain, irregular menstruation, hyperestrogenemia, and an ovarian mass was included. Brain magnetic resonance imaging (MRI) revealed a pituitary macroadenoma, and transsphenoidal surgery relieved her clinical symptoms. Before transsphenoidal surgery, plasma CA125, estradiol levels were elevated, while prolactin, luteinizing hormone, follicle-stimulating hormone, PROG, cortisol, FT4, thyroid-stimulating hormone, parathyroid hormone, and GH levels were maintained at normal levels. After transsphenoidal surgery, the patient was diagnosed with a functioning gonadotroph adenoma. During follow-up, pelvic ultrasound confirmed normal-sized ovaries in the patient, the menstrual cycle returned to regular, and her hormones were maintained within a normal range. There was no evidence of tumor recurrence after two years of follow-up. Early diagnosis of functioning gonadotroph adenomas should be considered in patients with hyperestrogenism, irregular menstruation, large or recurrent ovarian cysts, and visual field defects. Pituitary MRI should be performed, and transsphenoidal surgery is recommended for the management of this disease.


Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation Impairs Trophoblast Invasion and Spiral Artery Remodelling during Pregnancy in Mice.
The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Trophoblast cell proliferation, migration and invasion into the endometrium are fundamental events in the initiation of placentation. Leukemia inhibitory factor (LIF) has been shown to promote trophoblast invasion in vitro, however its precise role in trophoblast invasion in vivo is unknown. We hypothesized that LIF would be required for normal trophoblast invasion and spiral artery remodeling in mice. Both LIF and its receptor (LIFRα) co-localized with cytokeratin-positive invasive endovascular extravillous trophoblasts (EVT) in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via administration of our unique LIFRα antagonist, PEGLA, resulted in abnormal trophoblast invasion and impaired spiral artery remodeling compared to PEG control. PEGLA-treated mouse decidual vessels were characterized by retention of α-smooth muscle actin (αSMA)-positive vascular smooth muscle cells (VSMCs), while PEG control decidual vessels were remodelled by cytokeratin-positive trophoblasts. LIF blockade did not alter F4/80-positive decidual macrophage numbers between treatment groups, but resulted in down-regulation of decidual transcript levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10), which are important immune cell activation factors that promote spiral artery remodeling during pregnancy. Our data suggest that LIF plays an important role in trophoblast invasion in vivo and may facilitate trophoblast-decidual-immune cell cross talk to enable adequate spiral artery remodeling.


Reversible dilated cardiomyopathy following treatment of atopic eczema with Chinese herbal medicine.
Chinese herbal medicines are increasingly being used as an alternative treatment for chronic skin disease. Most patients and many doctors remain insufficiently aware of their potential toxicity. We report a patient with eczema who developed a severe cardiomyopathy following a 2-week course of Chinese herbal medicine. The connection between the two conditions was not made until 2 weeks after presentation when the patient was specifically asked if she had ingested any unusual substances. The belief that herbs, as natural products available without prescription, are harmless, is commonplace and patients may not consider them worthy of mention during a standard medical history.


Highly fluctuating thrombocytopenia developing in a patient with immune thrombocytopenia (ITP) while administering romiplostim.
A patient with immune thrombocytopenia (ITP) was administered a thrombopoietin (TPO) receptor agonist, romiplostim. After a step-wise increase the dose of romiplostim, the platelet count was highly fluctuated; it initially markedly increased, but then it subsequently steeply dropped. These fluctuations were observed three consecutive times. The administration of romipolostin was then discontinued. After the re-administration of romiplostim, the dose was gradually increased, and the platelet count rose steadily. The highly fluctuating platelet count in the present patient indicates the need for careful monitoring of the platelet count at the beginning of romiplostim administration.


DNMT1-microRNA126 epigenetic circuit contributes to esophageal squamous cell carcinoma growth via ADAM9-EGFR-AKT signaling.
MicroRNAs (miRNA) are involved in and are controlled by epigenetic regulation, and thereby form a reciprocal regulatory circuit. Using next-generation sequencing (NGS)-based miRNA profiling, this study aimed to discover esophageal squamous cell carcinoma (ESCC)-specific miRNAs and miRNA-related epigenetic modulations. NGS-based miRNA profiles were generated for four pairs of ESCC tissues and adjacent normal tissues. In situ hybridization was used to assess miRNA expression and its correlation with prognosis. miRNA-related DNA methylations were identified using bisulfite genomic sequencing, and the role of DNA methyltransferase 1 (DNMT1) was investigated using RNA interference. miRNA targets were screened by mRNA sequencing, and functional validation was performed in vitro and in vivo. NGS-based miRNA profiling identified 78 differentially expressed miRNAs in ESCC. Among them, microRNA126-3p (miR-126) was significantly downregulated, and its downregulation correlated with poor ESCC prognosis. Downregulation of miR-126 was due to promoter hypermethylation of its host gene, Egfl7. DNMT1 was aberrantly upregulated in ESCC and responsible for the hypermethylation of Egfl7. Intriguingly, DNMT1 was suppressed by overexpression of miR-126, indicating the existence of a regulatory feedback circuit. ADAM9 was identified as a key target of miR-126. Ectopic expression of miR-126 or silencing of ADAM9 reduced ESCC cell proliferation and migration by inhibiting epidermal growth factor receptor-AKT signaling. Our results indicate that miR-126 is a potential prognostic indicator for ESCC and suggest that a novel "DNMT1-miR-126 epigenetic circuit" is involved in ESCC progression. Consequently, miR-126-based epigenetic modulations may provide a basic rationale for new approaches to antitumor therapeutics.


Alzheimer's disease: diagnosis and treatment across the spectrum of disease severity.
Alzheimer's disease exists along a spectrum, from early memory changes to functional dependence and death. Using a case illustration, we review the evaluation and diagnosis of mild cognitive impairment and the diagnosis and management of Alzheimer's disease at each stage, including the management of both cognitive and behavioral/psychiatric aspects of the disease and end-stage and end-of-life care.


Asbestos ingestion and gastrointestinal cancer: a possible underestimated hazard.
The presence of asbestos fibres (AFs) in drinking water could be linked with gastrointestinal cancers. However, it is not regulated in several countries due to conflicting evidence. Areas covered: Some reports mainly associated AF ingestion with gastric and colorectal cancer. Experimental evidence suggested a role for timing and extent of exposure, and showed that ingested AFs induce toxic effects on the stomach, ileum and colon, histological alterations and negative effects at a molecular level, cross the placenta and enter foetal organs (including the liver), and seem able to act as a co-carcinogen agent. Occupational studies suggest associations between asbestos exposure and intrahepatic cholangiocarcinoma, and observations exist indicating the possibility that AFs could enter the liver and bile through enteric absorption. Expert commentary: A risk threshold (AF concentration in drinking water) for digestive cancers has not been convincingly identified so far and regulations, where adopted, have weak scientific basis and may not be adequate. With further and more definitive studies, evidence might become sufficient to justify monitoring plans, persuade countries with no current limits to set a maximum level of AFs in drinking water and might induce a revision of the existing legislations, pointing to efficient primary prevention policies.


Depth estimation for speckle projection system using progressive reliable points growing matching.
In this paper, we propose a progressive reliable points growing matching scheme to estimate the depth from the speckle projection image. First a self-adapting binarization is introduced to reduce the influence of inconsistent intensity. Then we apply local window-based correlation matching to get the initial disparity map. After the initialization, we formulate a progressive updating scheme to update the disparity estimation. There are two main steps in each round of updation. At first new reliable points are progressively selected based on three aspects of criterion including matching degree, confidence, and left-right consistency; then prediction-based growing matching is adopted to recalculate the disparity map from the reliable points. Finally, the more accurate depth map can be obtained by subpixel interpolation and transformation. The experimental results well demonstrate the effectiveness and low computational cost of our scheme.


[Functional organization of the intermediate and deep layers of the superior colliculus of the monkey].
Single neurons and polispike activity were recorded from the superior colliculus of anesthetized, behaving monkeys. In agreement with previous findings neurons of the superficial layers responded exclusively to visual stimuli. In the intermediate layers most neurons were oculomotor, although some of them showed also a visual receptive field. No neurons responding to tactile or auditory stimuli were found. Occasionally the discharge of an oculomotor neuron increased if the ocular movement was triggered by a visual or an acoustical stimulus. Rare tacticle and auditory neurons were recorded in deep layers. However their receptive fields were difficult to map and their responses lacked the precision of the responses of the specific acoustic and tactile areas. Electrical stimulation of the SC produced contralateral eye and head movements, the threshold being high in the superficial layers and low in the intermediate and deep ones. In the deep layers complex limb and trunk movements could be also elicited. In conclusion, in contrast with carnivores and other mammals, the primate superior colliculus appears to be dominated by the visual modality.