Color Doppler ultrasonography in pediatric intussusception.
CDU was used in 11 children with intussusception. Demonstration of vascular images within the "pseudokidney" mass was possible in none of 11 cases. Of them, eight could be treated by hydrostatic reduction. In the remaining case, marked edema of the bowel wall did not allow reduction, and surgery had to be performed: no necrosis was observed in the surgical specimen. Both patients in whom CDU failed to demonstrate vascular signals had necrosis at surgery, and bowel resection was performed. Because of the limited number of patients examined at this time, no firm conclusions can be drawn from our experience. However, CDU seems a promising technique in detecting vascular changes occurring in intussusception, with a possible role as a predictive tool of bowel necrosis.


Can children catch up in growth after living donor liver transplantation?
Several studies have shown improved growth after liver transplantation, but long-term follow-up data have been lacking. This study was aimed at evaluating the ability of children to catch up in height after living donor liver transplantation (LDLT) and at clarifying factors affecting growth. Growth was assessed by serial height measurements performed during follow-up. Standardized height scores (z scores) were calculated for each patient preoperatively (at the baseline) and at 1, 2, 3, 5, 10, and 15 years after LDLT. The risk potential of several preoperative and postoperative variables was evaluated. A total of 237 patients, including 159 females (67.1%), met the inclusion criteria. The mean age at the time of transplant was 3.89 +/- 0.28 years. The mean z score was -1.70 +/- 0.09, whereas the baseline height deficit was -6.50 +/- 0.39 cm. After LDLT, the z score improved significantly and reached -0.64 +/- 0.14 by the end of the first year. The best height improvement was seen after 10 years (-0.33 +/- 0.16). However, significant growth retardation remained at 15 years (-0.47 +/- 0.17). Height showed 3 distinct phases after transplantation: a growth spurt, a plateau phase, and a late declining phase. Univariate and multivariate analyses showed that children under 2 years and those with the most growth retardation at the time of LDLT achieved the best height gain in the first year. Late growth retardation was related to the baseline z score, ABO-incompatible grafts, and graft dysfunction. In conclusion, children have the potential ability to catch up in growth to normal levels after LDLT; they can show impressive height gains in the first year followed by protracted improvement over 10 years and then late growth retardation. Young age is a determinant for early height gain, whereas ABO-incompatible grafts and graft dysfunction are determinants for late growth retardation. In contrast, the baseline z score is a determinant for both.


[Establishment of protein fingerprint database of Salmonella paratyphi A using SELDI-TOF-MS].
To establish a protein fingerprint database of Salmonella paratyphi A by surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Thirty-six clinical bacterial isolates and 96 control bacteria isolates were collected and identified using 16S rDNA sequencing. Bacterial proteins were detected by SELDI-TOF-MS, and all protein fingerprints were analyzed by ProteinChip and Biomarker Wizard software. The analysis results were used to set up a classification tree model by means of BioMarker Patterns software. At the same time, the data were tested by a blinded validation. In the range of M(r); 3 000-20 000, we obtained 104 protein peaks, of which 90 were of statistical significance (P<0.01). A protein peak with mass-to-charge ratio(M/Z) 10 061.7 was chosen to establish the classification tree model of Salmonella paratyphi A, and the sensitivity and specificity of Salmonella paratyphi A diagnosis was 100% as shown by the blinded validation. The classification tree model of Salmonella paratyphi A can be not only established using SELDI-TOF-MS technology, but also used for the rapid identification of Salmonella paratyphi A.


Archival tagging of subadult and adult common thresher sharks (Alopias vulpinus) off the coast of southern California.
The common thresher shark (Alopias vulpinus) is a secondary target species of the California drift gillnet fishery (CA-DGN) and supports a growing recreational fishery in California waters. This study used archival tags to examine the movement patterns and habitat preferences of common threshers of the size range captured in the CA-DGN (>120 cm fork length). Depth and temperature-logging archival tags were deployed on 57 subadult and adult common threshers in the Southern California Bight. Tags from five individuals (8.8%) were recovered, and 154 days of data were successfully obtained from four of these. By night, shark movements were primarily limited to waters above the thermocline, which ranged in depth from 15 to 20 m. Sharks were significantly deeper by day, and daytime vertical distribution consisted of two distinct modes: a 'shallow mode' (wherein sharks occupied only the upper 20 m of the water column) and a 'deep mode' (characterized by frequent vertical excursions below the thermocline). This modal switch is interpreted as relating to regional differences in abundance of surface-oriented prey and prey in deeper water. Maximum dive depth was 320 m, greatest dive duration was 712 min, minimum temperature experienced during a dive was 9.1°C, and dive descent rate was significantly greater than ascent rate. Sharks inhabited waters corresponding to a sea surface temperature range of 16 to 21°C. The nocturnal depth distribution of common threshers has implications for management of drift gillnet deployment depths in the CA-DGN.


The fibrinolysis inhibitor α2-antiplasmin restricts lymphatic remodelling and metastasis in a mouse model of cancer.
Remodelling of lymphatic vessels in tumours facilitates metastasis to lymph nodes. The growth factors VEGF-C and VEGF-D are well known inducers of lymphatic remodelling and metastasis in cancer. They are initially produced as full-length proteins requiring proteolytic processing in order to bind VEGF receptors with high affinity and thereby promote lymphatic remodelling. The fibrinolytic protease plasmin promotes processing of VEGF-C and VEGF-D in vitro, but its role in processing them in cancer was unknown. Here we explore plasmin's role in proteolytically activating VEGF-D in vivo, and promoting lymphatic remodelling and metastasis in cancer, by co-expressing the plasmin inhibitor α2-antiplasmin with VEGF-D in a mouse tumour model. We show that α2-antiplasmin restricts activation of VEGF-D, enlargement of intra-tumoural lymphatics and occurrence of lymph node metastasis. Our findings indicate that the fibrinolytic system influences lymphatic remodelling in tumours which is consistent with previous clinicopathological observations correlating fibrinolytic components with cancer metastasis.


The wounded maternity in the fine arts.
The historian Fielding Garrison wrote that the history of medicine is the history of mankind, as it encompasses all of human life. This means that the history of medicine encourages us to critically reflect not only on the information (the what, the world of facts) but also invites us to move towards understanding (the who, the world of stories). Next to the historical change, there is the anthropological duration with its baggage of immutable values that art brings to light. The merit of art is to focus not only on the biological aspects, but also on the social and emotional ones that define the mother/child relationship. The paintings that we have analyzed "speak" of care and caregiving, grief and suffering where maternity is experienced in solitude, in misery, in sickness. And it is to this latter aspect that we have drawn our attention. Most of the works are autobiographical or relate to events actually experienced by the artist. The theme of the wounded maternity has many facets, but all are united by the absence and loss of something precious: a son, a husband, health, affection.


Respiratory syncytial virus detection by immunofluorescence in nasal secretions with monoclonal antibodies against selected surface and internal proteins.
Specimens containing respiratory tract epithelial cells from infants and children with acute respiratory disease were evaluated by using an indirect immunofluorescence technique with two specific respiratory syncytial virus monoclonal antibodies. One (RS/HN 13-1) was directed against a cell surface viral antigen, and the other (RS/HN 25-2) was directed against viral antigen present in large cytoplasmic inclusions. The same results on presence or absence of respiratory syncytial virus were obtained by cell culture and immunofluorescence in 93% of 252 patients tested adequately by both methods. The sensitivity of indirect immunofluorescence was approximately equal to that of cell culture. A total of 84 specimens were positive for RSV by immunofluorescence; 82 of them were positive with both monoclones, and the remaining 2 were positive only with the monoclone directed against the internal protein. The fluorescence pattern of the latter monoclone was unique and easily recognized. Indirect immunofluorescence testing with monoclonal antibodies to respiratory syncytial virus proved to be a very useful diagnostic technique, and results could be obtained within 4 h of specimen collection.


Errors in the use of medication dosage equations.
Calculation errors in prescribing are a well-recognized problem; however, no systematic studies of actual errors involving calculation or other errors in the use of drug dosage equations are available. To characterize the nature and potential adverse consequences of actual prescribing errors involving dosage equations. Analysis of the characteristics of 200 consecutive prescribing errors with potentially adverse outcomes involving dosage equations. Tertiary care teaching hospital. Potential adverse outcomes, prescribing service, medication class, and the process point at which the error was made. Errors most commonly involved children (69.5%) and antibiotics (53.5%). Forty-two percent of errors were considered to put the patient at risk for a serious or severe preventable adverse outcome. Errors in decimal point placement, mathematical calculation, or expression of dosage regimen accounted for 59.5% of dosage errors. The dosage equation was wrong in 29.5% of dosage errors. The use of equations to determine medication dosages presents considerable risk to patients for errant dosing and subsequent adverse events or therapeutic failure. Errors may occur in any component of a dosage equation. Health care organizations should implement procedures to reduce the risk for errors resulting from the use of dosage equations.


Outcome of prolonged QRS interval in dilated cardiomyopathy: role of implantable cardioverter-defibrillators on mortality.
The main objectives of this study were to investigate the relationship between prolonged QRS interval and its prognosis in patients with dilated cardiomyopathy (DCM), and to determine the effects of cardiac pacing with an implantable cardioverter-defibrillator (ICD) on mortality in patients with a QRS width > 150 ms. We retrospectively queried the healthcare enterprise data warehouse and the patient medical records from January 2007 to December 2012 for 1453 cases of DCM at a university- affiliated hospital. Of the 1453 cases, 989 patients were included in the final analyses. Primary outcome variable was all-cause mortality. Of the 989 patients, 20% (n = 198) of the patients had a QRS width > 150 ms. Compared with patients who had a QRS < 120 ms, patients with a QRS > 150 ms had significantly higher rates of death (p < 0.001). Among the subgroup of 198 patients who had a QRS width > 150 ms, survival (84.3%, n = 75) was significantly higher (p < 0.001) in patients with a pacemaker inserted compared with those (45.0%, n = 49) who had not been paced. Prolonged QRS interval is significantly associated with a higher rate of mortality. However, we believe that cardiac pacing with an ICD in such patients can significantly improve outcomes.


Bilastine: in allergic rhinitis and urticaria.
Bilastine is an orally administered, second-generation antihistamine used in the symptomatic treatment of seasonal or perennial allergic rhinoconjunctivitis and urticaria. In two well designed phase III trials, 14 days' treatment with bilastine was associated with a significantly lower area under the effect curve (AUEC) for the reflective total symptom score (TSS) than placebo in patients with symptomatic seasonal allergic rhinitis. Additionally, reflective nasal symptom scores were significantly lower in bilastine than placebo recipients in patients with a history of seasonal allergic rhinitis who were challenged with grass pollen allergen in a single-centre, phase II study. Neither bilastine nor cetirizine was effective in the treatment of perennial allergic rhinitis with regard to the mean AUEC for reflective TSS in another well designed phase III trial. However, results may have been altered by differences in some baseline characteristics and placebo responses between study countries. In another well designed phase III trial, compared with placebo, bilastine was associated with a significantly greater change from baseline to day 28 in the mean reflective daily urticaria symptom score in patients with chronic urticaria. There were no significant differences in primary endpoint results between bilastine and any of the active comparators used in these trials (i.e. cetirizine, levocetirizine and desloratadine). Bilastine was generally well tolerated, with a tolerability profile that was generally similar to that of the other second-generation antihistamines included in phase III clinical trials.


Mechanism of Fluoride Ion Encapsulation by Magnesium Ions in a Bacterial Riboswitch.
Riboswitches sense various ions in bacteria and activate gene expression to synthesize proteins that help maintain ion homeostasis. The crystal structure of the aptamer domain (AD) of the fluoride riboswitch shows that the F- ion is encapsulated by three Mg2+ ions bound to the ligand-binding domain (LBD) located at the core of the AD. The assembly mechanism of this intricate structure is unknown. To this end, we performed computer simulations using coarse-grained and all-atom RNA models to bridge multiple time scales involved in riboswitch folding and ion binding. We show that F- encapsulation by the Mg2+ ions bound to the riboswitch involves multiple sequential steps. Broadly, two Mg2+ ions initially interact with the phosphate groups of the LBD using water-mediated outer-shell coordination and transition to a direct inner-shell interaction through dehydration to strengthen their interaction with the LBD. We propose that the efficient binding mode of the third Mg2+ and F- is that they form a water-mediated ion pair and bind to the LBD simultaneously to minimize the electrostatic repulsion between three Mg2+ bound to the LBD. The tertiary stacking interactions among the LBD nucleobases alone are insufficient to stabilize the alignment of the phosphate groups to facilitate Mg2+ binding. We show that the stability of the whole assembly is an intricate balance of the interactions among the five phosphate groups, three Mg2+, and the encapsulated F- ion aided by the Mg2+ solvated water. These insights are helpful in the rational design of RNA-based ion sensors and fast-switching logic gates.


Pichia pastoris-expressed dengue 3 envelope-based virus-like particles elicit predominantly domain III-focused high titer neutralizing antibodies.
Dengue poses a serious public health risk to nearly half the global population. It causes ~400 million infections annually and is considered to be one of the fastest spreading vector-borne diseases. Four distinct serotypes of dengue viruses (DENV-1, -2, -3, and -4) cause dengue disease, which may be either mild or extremely severe. Antibody-dependent enhancement (ADE), by pre-existing cross-reactive antibodies, is considered to be the major mechanism underlying severe disease. This mandates that a preventive vaccine must confer simultaneous and durable immunity to each of the four prevalent DENV serotypes. Recently, we used Pichia pastoris, to express recombinant DENV-2 E ectodomain, and found that it assembled into virus-like particles (VLPs), in the absence of prM, implicated in the elicitation of ADE-mediating antibodies. These VLPs elicited predominantly type-specific neutralizing antibodies that conferred significant protection against lethal DENV-2 challenge, in a mouse model. The current work is an extension of this approach to develop prM-lacking DENV-3 E VLPs. Our data reveal that P. pastoris-produced DENV-3 E VLPs not only preserve the antigenic integrity of the major neutralizing epitopes, but also elicit potent DENV-3 virus-neutralizing antibodies. Further, these neutralizing antibodies appear to be exclusively directed toward domain III of the DENV-3 E VLPs. Significantly, they also lack discernible ADE potential toward heterotypic DENVs. Taken together with the high productivity of the P. pastoris expression system, this approach could potentially pave the way toward developing a DENV E-based, inexpensive, safe, and efficacious tetravalent sub-unit vaccine, for use in resource-poor dengue endemic countries.


Conotoxin gene superfamilies.
Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency and selectivity profiles for a range of neuronal targets have made several conotoxins valuable as research tools, drug leads and even therapeutics, and has resulted in a concerted and increasing drive to identify and characterise new conotoxins. Conotoxins are translated from mRNA as peptide precursors, and cDNA sequencing is now the primary method for identification of new conotoxin sequences. As a result, gene superfamily, a classification based on precursor signal peptide identity, has become the most convenient method of conotoxin classification. Here we review each of the described conotoxin gene superfamilies, with a focus on the structural and functional diversity present in each. This review is intended to serve as a practical guide to conotoxin superfamilies and to facilitate interpretation of the increasing number of conotoxin precursor sequences being identified by targeted-cDNA sequencing and more recently high-throughput transcriptome sequencing.


Is the occurrence of back pain in Germany decreasing? Two regional postal surveys a decade apart.
Back pain is often perceived as an epidemic disorder with an ever-increasing prevalence. The objective of this paper is to estimate and compare point and period prevalence rates of back pain from two highly comparable postal surveys, a decade apart within a single regional population in the north of Germany. In 1991/1992 and 2003 two systematic random samples of German residents of Lübeck aged 25-74 years were independently drawn from the municipal population registry. They received a short postal questionnaire with maximally two reminders. All data were directly standardised on the age, sex, and educational distribution of the merged samples. A sharp decrease in response rates from 81% in the early 1990s to 60% in 2003 required complex considerations of non-response bias. Both the overall and gender-specific point and 1 year prevalence rates of back pain remained fairly stable as well as the rate of severe disabling back pain. The overall prevalence (adjusted for age, sex, and education) of 'back pain today' was 39.2% (1991/92) and 38.2% (2003), the 1 year prevalence was 75.3% (1991/92) and 73.8% (2003), and the prevalence of severe pain was 9.9% (1991/92) and 10.2% (2003). The data do not support the widespread public notion of a growing epidemic of back pain in Germany.


Butterfly-packaged multi-channel interference widely tunable semiconductor laser with improved performance.
A multi-channel interference (MCI) widely tunable semiconductor laser is described in detail with improved performance in this paper. The MCI laser without the common phase section was packaged into a standard 14-pin butterfly package. The device realized a tuning range of more than 40 nm with side mode suppression ratios (SMSRs) higher than 48 dB and about 7 dBm fiber power. By making the gain section and the phase sections to be surface ridge waveguides, threshold currents of the laser have become less than 18 mA across the tuning range. Besides, tuning characteristics of the MCI laser were experimentally studied in detail for the first time. The MCI laser can be treated as a combination of eight Fabry-Pérot (FP) cavity lasers which share the same gain section. It is found that when the eight arm phase sections are completely in phase at the lasing wavelength, the operating currents are at maxima of the output power curves. The relationship between the lasing wavelength and the injection currents of the eight arm phase sections has been introduced and analyzed.


Current practice in acute flexor tendon repair in Israel.
Various methods of core suture and suture material are used successfully in acute flexor tendon repair. To assess the current practice in acute flexor tendon repair among Israeli hand surgeons. A five-question survey was conducted among certified hand surgeons in Israel regarding their preferred materials and method for performing acute flexor tendon repair. Forty-eight hand surgeons participated in the survey. The most widely used core suture in zone 2 (58.3%), as well as in zones 3 and 4 (62.5%), was the modified Kessler type. The most widely used suture material was nylon. All surgeons incorporated epitendinous sutures to augment their core sutures. The modified Kessler core suture technique is the most widely used technique among Israeli hand surgeons for repairing acute flexor tendon lacerations in zones 2, 3 and 4. This finding agrees with worldwide data and with emerging data attesting to the lower risk of adhesion formation and postoperative tendon ruptures with this method. The core suture technique initially popularized by the late Prof. Isidor Kessler, who headed our department during the years 1973-92, remains the most practiced acute flexor tendon repair technique among hand surgeons in Israel.


Avirulence gene mapping in the Hessian fly (Mayetiola destructor) reveals a protein phosphatase 2C effector gene family.
The genetic tractability of the Hessian fly (HF, Mayetiola destructor) provides an opportunity to investigate the mechanisms insects use to induce plant gall formation. Here we demonstrate that capacity using the newly sequenced HF genome by identifying the gene (vH24) that elicits effector-triggered immunity in wheat (Triticum spp.) seedlings carrying HF resistance gene H24. vH24 was mapped within a 230-kb genomic fragment near the telomere of HF chromosome X1. That fragment contains only 21 putative genes. The best candidate vH24 gene in this region encodes a protein containing a secretion signal and a type-2 serine/threonine protein phosphatase (PP2C) domain. This gene has an H24-virulence associated insertion in its promoter that appears to silence transcription of the gene in H24-virulent larvae. Candidate vH24 is a member of a small family of genes that encode secretion signals and PP2C domains. It belongs to the fraction of genes in the HF genome previously predicted to encode effector proteins. Because PP2C proteins are not normally secreted, our results suggest that these are PP2C effectors that HF larvae inject into wheat cells to redirect, or interfere, with wheat signal transduction pathways.


K-space substitution: a novel dynamic imaging technique.
A rapid dynamic imaging sequence has been developed in which only the 32 phase encoding steps that encode low spatial frequencies are collected for each dynamic image. These are substituted into a previously acquired, 128 x 128 raw data set prior to image reconstruction. In this way the dynamic information is retained while the overall appearance is improved in comparison with images obtained by zero filling to 128 x 128, leading to better qualitative evaluation. The limited k-space sampling means that the technique is most effective for large homogeneous areas of signal change since fine changes in contrast are imperfectly recorded.


Frigidibacter oleivorans sp. nov., isolated from a deep well with oil reservoir water.
A Gram-stain-negative, rod-shaped bacterium, designated XJ4T, was isolated from oil-contaminated water, collected from Xinjiang Province, north-west PR China (45° 1' 27″ N, 85° 6' 14″ E). Growth occurred at 20-45 °C (optimum, 30 °C) and pH 6.0-10.0 (optimum, pH 6.0-7.0). Strain XJ4T could tolerate up to 7 % (w/v) NaCl and grow optimally in the absence of NaCl. Phylogenetic analysis based on comparative sequence analysis of 16S rRNA gene sequences indicated that strain XJ4T belonged to the genus Frigidibacter, and that was closely related to Frigidibacter mobilis cai42T (97.2 %), Frigidibacter albus SP32T (97.0 %) and Rhodobacter aestuarii JA296T (97.0 %). The average nucleotide identity values between XJ4T and three type strains were 77.9, 77.6 and 71.9 %, respectively. The DNA G+C content of strain XJ4T was 69.5 mol%. The sole respiratory quinone was Q-10. The major cellular fatty acid was summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c), C18 : 0 and 11-methyl C18 : 1 ω7c. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, unidentified phospholipids, an unidentified aminolipid and unidentified lipids. On the basis of phenotypic, chemotaxonomic and phylogenetic analyses, strain XJ4T represents a novel species of the genus Frigidibacter, for which the name Frigidibacter oleivorans sp. nov. is proposed. The type strain is XJ4T (=CGMCC 1.13778T=LMG 30952T).


Recent Advances in Solid Dispersion Technology for Efficient Delivery of Poorly Water-Soluble Drugs.
Drug discovery is generally considered as a costly affair and it takes approximately 15 years to reach a new chemical entity into the market. Among the recent potent drug molecules with most effective pharmacological properties, very few reached for Phase I clinical trial in humans. Unfortunately, the historical average reveals an almost 90% overall attrition rate in clinical trials. The solubility and permeability of a drug are the critical factors influencing the success of a drug. Oral drug delivery systems still continue to exist as the most favored, simplest and easiest administration route. A huge number of potential clinical candidates won't make it to the market or accomplish their maximum capacity except if their solubility and oral bioavailability are enhanced by formulation. The solubility of drugs will continue to exist as important aspects of formulation development. With the emergence of synthetic methods for new molecule synthesis in chemistry and better screening methods, the number of poorly water soluble compounds has dramatically expanded in the last few years. Solid dispersion is one of the most important techniques as it can be prepared by several methods. It is mostly prepared with a drug having poor water solubility and it explores hydrophilic polymers either individually or in combination for the enhancement of solubility. In comparison to the conventional formulations such as tablets or capsules, there are different methods with which solid dispersions can be prepared and also have many benefits over conventional drug delivery approaches. Solid dispersion systems are potential for increasing the solubility, oral absorption and bioavailability of drugs and the significance of the solid dispersion technology is constantly increasing. The main focus of this review is to present recent advancements in the area of solid dispersion. This review also includes an account of recent patents on solid dispersion and clinical status of solid dispersion based formulations.


Allan Urho Paivio (1925-2016).
Presents an obituary for Allan Urho Paivio, who passed away on June 19, 2016. One of his many accomplishments was the development of a dual-coding theory. Dual-coding theory, while very influential, has, unfortunately, been discussed all too often as a theory of mental imagery, and not within its larger context wherein mental imagery and verbal processes are separable but interconnected representational systems, an academic battle in clarification that Paivio waged much of his life. He published prodigiously, even in the decades after retirement. Among his many honors, he served as president of the Canadian Psychological Association (1975) and was appointed a fellow of the Royal Society of Canada (1978). (PsycINFO Database Record


Technique of using Cionni-modified capsular tension ring in the management of severely traumatic lens subluxation.
To investigate the effect of Cionni-modified capsular tension ring (CTR) implantation in patients with severely traumatic subluxated cataracts. All patients who totally had traumatic cataracts and lost zonule support and underwent cataract surgery were retrospectively analyzed. Corrected distance visual acuity (CDVA), extent of zonulysis, intraocular lens (IOL) position, intraoperative presentation, and complications were assessed. The primary outcomes included IOL centration stability and other postoperative complications. Twenty patients (20 eyes) were included in this study. The mean age in this study was 58.0±11.3y, and the average follow-up time was 17.3±12.8mo. Capsule bags were saved by Cionni-modified CTR. Nine eyes (45%) underwent simultaneously anterior vitrectomy due to the presence of vitreous in the anterior chamber. The preoperative mean CDVA was 0.83±0.24 logMAR, and the postoperative average CDVA was 0.23±0.30 logMAR (P<0.05). The horizontal and vertical IOL decentration after surgery was 0.27±0.12 mm and 0.41±0.19 mm, respectively; the vertical and horizontal IOL tilt after surgery was 5.5°±2.5° and 6.1°±2.2°, respectively. None of the eyes had obvious IOL decentration during the follow-up time. Eight eyes (40%) had posterior capsule opacification (PCO) that was severe enough to cause poor vision. Neodymium: YAG laser capsulotomy were performed on these eyes when the CTR was stabilized. With the help of Cionni-modified CTR, capsular bag preservation and better IOL concentration can be achieved without major complications in patients with severely traumatic subluxated cataracts.


Completion of multiple-dose travel vaccine series and the availability of pharmacist immunizers: A retrospective analysis of administrative data in Alberta, Canada.
Pharmacists in a number of countries are being trained in the administration of injections with the aim of improving access and adherence to vaccinations. However, little is known about population-level adherence to multiple-dose travel vaccines, and whether the availability of pharmacist immunizers is associated with adherence. Health administrative data from Alberta, Canada, from April 2008 to May 2017 identified adults dispensed at least one vaccine for hepatitis A, hepatitis B, Japanese encephalitis, or rabies. Individuals were coded as completers or non-completers of the vaccine series based on the number of doses dispensed over a time period comprising the duration of the standard series plus 6 months to account for late doses. The association between the proportion of Alberta pharmacists with injection authorization (according to pharmacist registration data) and completion of vaccine series was assessed using linear regression. Over the study period, 24,164 patients initiated a vaccine series for hepatitis A monovalent, 195,480 for hepatitis B monovalent, 169,802 for combined hepatitis A&B, 1,726 for Japanese encephalitis, and 1,908 for rabies. There were fewer than 5 individuals receiving Japanese encephalitis vaccine per year from 2008-2010 or rabies vaccine from 2008-2009. While statistically significant positive associations were seen across all vaccines except for Japanese encephalitis, the magnitude of these associations was small. Each 1% increase in the proportion of injections-authorized pharmacists saw a corresponding increase in the proportion of individuals with completed vaccine series by 0.31% for hepatitis A monovalent, 0.19% for hepatitis B monovalent, 0.22% for combined hepatitis A&B, and 0.21% for rabies. This may suggest that challenges remain with implementing reminder systems to ensure adherence among travellers. Strategies to develop or improve patient and clinician reminder systems in pharmacies for travel vaccines should therefore be explored.


Evaluating the Effect of Peptoid Lipophilicity on Antimicrobial Potency, Cytotoxicity, and Combinatorial Library Design.
Growing prevalence of antibiotic resistant bacterial infections necessitates novel antimicrobials, which could be rapidly identified from combinatorial libraries. We report the use of the peptoid library agar diffusion (PLAD) assay to screen peptoid libraries against the ESKAPE pathogens, including the optimization of assay conditions for each pathogen. Work presented here focuses on the tailoring of combinatorial peptoid library design through a detailed study of how peptoid lipophilicity relates to antibacterial potency and mammalian cell toxicity. The information gleaned from this optimization was then applied using the aforementioned screening method to examine the relative potency of peptoid libraries against Staphylococcus aureus, Acinetobacter baumannii, and Enterococcus faecalis prior to and following functionalization with long alkyl tails. The data indicate that overall peptoid hydrophobicity and not simply alkyl tail length is strongly correlated with mammalian cell toxicity. Furthermore, this work demonstrates the utility of the PLAD assay in rapidly evaluating the effect of molecular property changes in similar libraries.


Improved Neural Regeneration with Olfactory Ensheathing Cell Inoculated PLGA Scaffolds in Spinal Cord Injury Adult Rats.
Every year, around the world, between 250000 and 500000 people suffer from spinal cord injury (SCI). This study investigated the potential for poly (lactic-co-glycolic acid) (PLGA) complex inoculated with olfactory ensheathing cells (OECs) to treat spinal cord injury in a rat model. OECs were identified by immunofluorescence based on the nerve growth factor receptor (NGFR) p75. The Basso, Beattie, and Bresnahan (BBB) score, together with an inclined plane (IP) test were used to detect functional recovery. Nissl staining along with the luxol fast blue (LFB) staining were independently employed to illustrate morphological alterations. More so, immunofluorescence labeling of the glial fibrillary acidic protein (GFAP) and the microtubule-associated protein-2 (MAP-2), representing astrocytes and neurons respectively, were investigated at time points of weeks 2 and 8 post-operation. The findings showed enhanced locomotor recovery, axon myelination and better protected neurons post SCI when compared with either PLGA or untreated groups (P < 0.05). PLGA complexes inoculated with OECs improve locomotor functional recovery in transected spinal cord injured rat models, which is most likely due to the fact it is conducive to a relatively benevolent microenvironment, has nerve protective effects, as well as the ability to enhance remyelination, via a promotion of cell differentiation and inhibition of astrocyte formation.


An intrinsic reaction coordinate calculation of the torsion-internal rotation potential of hydrogen peroxide and its isotopomers.
Intrinsic reaction coordinate (IRC) calculations of the internal rotation (torsional) potentials for H(2)O(2) and its isotopomers HDO(2) and D(2)O(2) were carried out at the CCSD(T)/CBS//aug-cc-pVDZ level. Two extrapolation methods were used to obtain energies in the complete basis set (CBS) limit. The full IRC potential was constructed from scans from the C(2v) (cis) and C(2h) (trans) transition states to the equilibrium C(2) (gauche) structure. The IRC potential for H(2)O(2) was fit to a five-term Fourier function; coefficients were compared with values obtained from spectroscopic data. The twofold IRC torsional potentials were used to obtain torsional eigenvalues, which yielded values of the transitions between various ntau states. These results compare favorably with Raman and near-infrared data. Our calculations provide values of the cis and trans barriers of 2495 and 364 cm(-1), respectively, which are in good agreement with both previously calculated and experimentally derived values. It appears that coupling between torsional motion and other degrees of freedom is not significant in these molecules.


The Effect of Lithium Disilicate Opacity on Polymerization of a Dual-Cured Resin Cement.
The aim of this study was to evaluate the influence of different levels of opacity of the lithium disilicate framework upon polymerization of dual-cured resin cement. Four ceramic discs were used, one for each opacity framework covered by their respective ceramic veneering, and a cement group without a ceramic cover. The degree of conversion for each resin cement was estimated using the Knoop microhardness test. The group with the highest opacity showed the lowest hardness score at baseline. The study concluded that the opacity level of lithium disilicate framework could influence the degree of polymerization of a dual-cured resin cement.


[Exenatide: use in humans].
Exenatide is the first synthetic agonist of the GLP-1 (glucagon-like peptide 1) receptor approved for clinical use in patients with type 2 diabetes. The multiplicity of its effects over glucose metabolism, appetite, body weight and its potential capacity to preserve the ?cell mass, makes it an attractive therapeutic alternative. This article attempts to review the current literature on pharmacokinetics, pharmacodynamics, efficacy, and safety of exenatide in humans, derived from the early phase I and II studies, and from the clinical controlled trials that led to its approval for clinical use as a combination therapy with sulphonylureas and metformin.


The human PDGF receptor alpha-subunit gene maps to chromosome 4 in close proximity to c-kit.
The gene encoding the alpha-subunit of the human platelet-derived growth factor receptor (PDGFRA) maps to band q11-q12 of chromosome 4 by in situ hybridization, which was confirmed by Southern analysis of a Chinese hamster x human cell hybrid that retains only human chromosome 4.


Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation.
The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by atherosclerosis with chronic inflammation in the aortic wall. Montelukast is a selective cys-LT 1 receptor antagonist that can suppress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensin II-infused apolipoprotein E-deficient (apoE-/-) AAA mouse model. The mouse monocyte/macrophage cell line J774A.1 was used in vitro. M1 macrophages were treated with montelukast, and gene expressions of inflammatory cytokines were measured. Macrophages were cultured with montelukast, then gene expressions of arginase-1 and IL (interleukin)-10 were assessed by quantitative polymerase chain reaction, arginase-1 was measured by fluorescence-activated cell sorting, and IL-10 concentration was analyzed by enzyme-linked immunosorbent assay. In vivo, one group (Mont, n=7) received oral montelukast (10 mg/kg/day) for 28 days, and the other group (Saline, n=7) was given normal Saline as a control for the same period. Aortic diameters, activities of matrix metalloproteinases (MMPs), cytokine concentrations, and the number of M2 macrophages were analyzed. Relative to control, montelukast significantly suppressed gene expressions of MMP-2, MMP-9, and IL-1β, induced gene expressions of arginase-1 and IL-10, enhanced the expression of the arginase-1 cell surface protein, and increased the protein concentration of IL-10. In vivo, montelukast significantly decreased aortic expansion (Saline vs Mont; 2.44 ± 0.15 mm vs 1.59 ± 0.20 mm, P<.01), reduced MMP-2 activity (Saline vs Mont; 1240 μM vs 755 μM, P<.05), and induced infiltration of M2 macrophages (Saline vs Mont; 7.51 % vs 14.7 %, P<.05). Montelukast induces M2 macrophage polarization and prevents AAA formation in apoE-/- mice.


Easily processable highly ordered Langmuir-Blodgett films of quaterthiophene disiloxane dimer for monolayer organic field-effect transistors.
Self-assembly of highly soluble water-stable tetramethyldisiloxane-based dimer of α,α'-dialkylquaterthiophene on the water-air interface was investigated by Langmuir, grazing incidence X-ray diffraction, and X-ray reflectivity techniques. The conditions for formation of very homogeneous crystalline monolayer Langmuir-Blodgett (LB) films of the oligomer were found. Monolayer organic field-effect transistors (OFETs) based on these LB films as a semiconducting layer showed hole mobilities up to 3 × 10(-3) cm(2)/(V s), on-off ratio of 10(5), small hysteresis, and high long-term stability. The electrical performance of the LB films studied is close to that for the same material in the bulk or in the monolayer OFETs prepared from water vapor sensitive chlorosilyl derivatives of quaterthiophene by self-assembling from solution. These findings show high potential of disiloxane-based LB films in monolayer OFETs for large-area organic electronics.


Reaching for upper bound ROUGE score of extractive summarization methods.
The extractive text summarization (ETS) method for finding the salient information from a text automatically uses the exact sentences from the source text. In this article, we answer the question of what quality of a summary we can achieve with ETS methods? To maximize the ROUGE-1 score, we used five approaches: (1) adapted reduced variable neighborhood search (RVNS), (2) Greedy algorithm, (3) VNS initialized by Greedy algorithm results, (4) genetic algorithm, and (5) genetic algorithm initialized by the Greedy algorithm results. Furthermore, we ran experiments on articles from the arXive dataset. As a result, we found 0.59 and 0.25 scores for ROUGE-1 and ROUGE-2, respectively achievable by the approach, where the genetic algorithm initialized by the Greedy algorithm results, which happens to yield the best results out of the tested approaches. Moreover, those scores appear to be higher than scores obtained by the current state-of-the-art text summarization models: the best score in the literature for ROUGE-1 on the same data set is 0.46. Therefore, we have room for the development of ETS methods, which are now undeservedly forgotten.


Ectoparasite presence and brood size manipulation interact to accelerate telomere shortening in nestling jackdaws.
Early-life conditions impact fitness, but whether the combined effect of extrinsic stressors is additive or synergistic is not well known. This is a major knowledge gap because exposure to multiple stressors is frequent. Telomere dynamics may be instrumental when testing how stressors interact because many factors affect telomere shortening, and telomere shortening predicts survival. We evaluated the effect of manipulated brood size and natural infestation by the carnid fly Carnus hemapterus on nestling growth and telomere shortening of wild jackdaws (Corvus monedula). Telomere length, measured in blood using TRF, shortened on average by 264 bp, and on average, Carnus infection induced more telomere shortening. Further analyses showed that in enlarged broods, nestlings' telomeres shortened more when parasitized, while in reduced broods there was no effect of infection on telomere shortening. We conclude that there is a synergistic effect of number of siblings and Carnus infection on telomere shortening rate: blood-sucking parasites may negatively impact telomeres by increasing cell proliferation and/or physiological stress, and coping with infection may be less successful in enlarged broods with increased sibling competition. Larger nestlings had shorter telomeres independent of age, brood manipulation or infection. Growth was independent of infestation but in enlarged broods, nestlings were lighter at fledging. Our findings indicate that (i) evaluating consequences of early-life environmental conditions in isolation may not yield a full picture due to synergistic effects, and (ii) effects of environmental conditions may be cryptic, for example, on telomeres, with fitness consequences expressed beyond the temporal framework of the study.


A comprehensive linear programming tool to optimize formulations of ready-to-use therapeutic foods: an application to Ethiopia.
Ready-to-use therapeutic food (RUTF) is the standard of care for children suffering from noncomplicated severe acute malnutrition (SAM). The objective was to develop a comprehensive linear programming (LP) tool to create novel RUTF formulations for Ethiopia. A systematic approach that surveyed international and national crop and animal food databases was used to create a global and local candidate ingredient database. The database included information about each ingredient regarding nutrient composition, ingredient category, regional availability, and food safety, processing, and price. An LP tool was then designed to compose novel RUTF formulations. For the example case of Ethiopia, the objective was to minimize the ingredient cost of RUTF; the decision variables were ingredient weights and the extent of use of locally available ingredients, and the constraints were nutritional and product-quality related. Of the new RUTF formulations found by the LP tool for Ethiopia, 32 were predicted to be feasible for creating a paste, and these were prepared in the laboratory. Palatable final formulations contained a variety of ingredients, including fish, different dairy powders, and various seeds, grains, and legumes. Nearly all of the macronutrient values calculated by the LP tool differed by <10% from results produced by laboratory analyses, but the LP tool consistently underestimated total energy. The LP tool can be used to develop new RUTF formulations that make more use of locally available ingredients. This tool has the potential to lead to production of a variety of low-cost RUTF formulations that meet international standards and thereby potentially allow more children to be treated for SAM.


Increased transmigration of intermediate monocytes associated with atherosclerotic burden in people with HIV on antiretroviral therapy.
This study evaluated the association between the transmigration of monocyte subpopulations that contributes to atherosclerosis development, along with surrogate biomarkers of inflammation and atherosclerosis, through carotid intima-media thickness (cIMT) measurements of 72 people with HIV (PWH) on suppressive antiretroviral therapy (ART). We found that the transmigration of intermediate monocytes was positively correlated with D-dimer and cIMT, suggesting that intermediate monocytes may have a greater propensity to promote cardiovascular disease (CVD) in PWH on ART.


Knockdown of Myo-Inositol Transporter SMIT1 Normalizes Cholinergic and Glutamatergic Function in an Immortalized Cell Line Established from the Cerebral Cortex of a Trisomy 16 Fetal Mouse, an Animal Model of Human Trisomy 21 (Down Syndrome).
The Na+/myo-inositol cotransporter (SMIT1) is overexpressed in human Down syndrome (DS) and in trisomy 16 fetal mice (Ts16), an animal model of the human condition. SMIT1 overexpression determines increased levels of intracellular myo-inositol, a precursor of phophoinositide synthesis. SMIT1 is overexpressed in CTb cells, an immortalized cell line established from the cerebral cortex of a Ts16 mouse fetus. CTb cells exhibit impaired cytosolic Ca2+ signals in response to glutamatergic and cholinergic stimuli (increased amplitude and delayed time-dependent kinetics in the decay post-stimulation), compared to our CNh cell line, derived from the cerebral cortex of a euploid animal. Considering the role of myo-inositol in intracellular signaling, we normalized SMIT1 expression in CTb cells using specific mRNA antisenses. Forty-eight hours post-transfection, SMIT1 levels in CTb cells reached values comparable to those of CNh cells. At this time, decay kinetics of Ca2+ signals induced by either glutamate, nicotine, or muscarine were accelerated in transfected CTb cells, to values similar to those of CNh cells. The amplitude of glutamate-induced cytosolic Ca2+ signals in CTb cells was also normalized. The results suggest that SMIT1 overexpression contributes to abnormal cholinergic and glutamatergic Ca2+ signals in the trisomic condition, and knockdown of DS-related genes in our Ts16-derived cell line could constitute a relevant tool to study DS-related neuronal dysfunction.


Identification of NQO2 As a Protein Target in Small Molecule Modulation of Hepatocellular Function.
The utility of in vitro human disease models is mainly dependent on the availability and functional maturity of tissue-specific cell types. We have previously screened for and identified small molecules that can enhance hepatocyte function in vitro. Here, we characterize the functional effects of one of the hits, FH1, on primary human hepatocytes in vitro, and also in vivo on primary hepatocytes in a zebrafish model. Furthermore, we conducted an analogue screen to establish the structure-activity relationship of FH1. We performed affinity-purification proteomics that identified NQO2 to be a potential binding target for this small molecule, revealing a possible link between inflammatory signaling and hepatocellular function in zebrafish and human hepatocyte model systems.


Implication of nitric oxide in the increased islet-cells vulnerability of adult progeny from protein-restricted mothers and its prevention by taurine.
An increased vulnerability of adult beta-cells seems to be programmed in early life as adult islets from the progeny of dams fed a low-protein diet exhibited an increased apoptotic rate after cytokine stimulation. This was prevented by maternal taurine supplementation. Here, we investigated the mechanisms implicated in such an increased vulnerability and how taurine exerts its protective role. Throughout gestation and lactation, Wistar rats were fed a 20% (control (C group)) or an isocaloric 8% protein diet (recovery (R group)) supplemented or not with taurine (control+taurine and recovery+taurine groups respectively). Offspring received a 20% protein diet after weaning. Islets from 3-month-old females were isolated and cultured for 48 h before being incubated with or without cytokines for 24 h. In unstimulated islets, apoptotic rate and NO(.) secretion were higher in R than in C. Both GADD153 mRNA and protein were increased, whereas mRNA of mitochondrial gene ATPase6 was downregulated in R group compared with C. In the RT group, taurine prevented apoptosis and restored a normal NO(.) production in GADD153 as well as ATPase6 mRNA expression. After cytokines-induction, apoptosis and NO(.) secretion were still increased in R compared with C but both parameters were normalized in the RT group. In conclusion, a maternal low-protein diet programmes a different pattern of gene expression in islet-cells of adult progeny. Higher NO(.) production by these islets could be an important factor in the subsequent cell death. The prevention of these events by maternal taurine supplementation emphasizes the importance of taurine during endocrine pancreas development.


Definition of brainstem afferents to gonadotropin-releasing hormone neurons in the mouse using conditional viral tract tracing.
Brainstem monoamines have long been considered to play a role in regulating the activity of GnRH neurons, although their neuroanatomical relationship with these cells has remained unclear. Using a Cre-dependent pseudorabies virus (Ba2001) technique that permits retrograde tracing selectively from GnRH neurons in the mouse, we have examined the organization of brainstem inputs to rostral preoptic area (rPOA) GnRH neurons. Two days after injection of Ba2001 into the rPOA of adult female GnRH-Cre transgenic mice, five to nine GnRH neurons located immediately adjacent to the injection site were found to express green fluorescent protein (GFP), the marker of virus infection, with no GFP expression anywhere else in the brain. In mice killed 24 h later (3 d after injection), GFP-expressing cells were identified (in order of density) in the raphe nuclei, periaqueductal grey, locus coeruleus, nucleus tractus solitarius, and area postrema. This time course is compatible with these neurons representing primary afferent inputs to the GnRH neurons. Four and 6 d after Ba2001 injection, GFP-expressing cells were found in additional brain regions. Dual-label immunofluorescence experiments in 3-d postinjection mice demonstrated that 100% of GFP-expressing neurons in the raphe were positive for tryptophan hydroxylase, whereas 100% and approximately 50% of GFP neurons in the locus coeruleus and nucleus tractus solitarius, respectively, expressed tyrosine hydroxylase. These observations demonstrate that rPOA GnRH neurons receive direct projections from brainstem A2 and A6 noradrenergic neurons and that, surprisingly, the largest afferent input from the brainstem originates from raphe serotonin neurons in the mouse.


A Cross-Sectional Clinic-Based Study in Patients With Side-Locked Unilateral Headache and Facial Pain.
To undertake the epidemiological evaluation of the patients presenting with side-locked headache and facial pain in a tertiary neurology outpatient clinic. Side-locked unilateral headache and facial pain include a large number of primary and secondary headaches and cranial neuropathies. A diagnostic approach for the patients presenting with strictly unilateral headaches is important as many of these headache disorders respond to a highly selective drug. Epidemiological data may guide us to formulate a proper approach for such patients. However, the literature is sparse on strictly unilateral headache and facial pain. We prospectively recruited 307 consecutive adult patients (>18 years) with side-locked headache and facial pain presenting to a neurology outpatient clinic between July 2014 and December 2015. All patients were subjected to MRI brain and other investigations to find out the different secondary causes. The diagnosis was carried out by at least two headache specialists together. All patients were classified according to the International Classification of Headache Disorder-third edition (ICHD-3β). The mean age at the time of examination was 42.4 ± 13.6 years (range 18-80 years). Forty-eight percent of patients were male. Strictly unilateral headaches accounted for 19.2% of the total headaches seen in the clinic. Headaches were classified as primary in 58%, secondary in 18%, and cranial neuropathies and other facial pain in 16% patients. Five percent of patients could not be classified. Three percent of patients were classified as per the Appendix section of ICHD-3β. The prevalence of secondary headaches and painful cranial neuropathies increased with age. A total of 36 different diagnoses were made. Only two diseases (migraine and cluster headache) had a prevalence of more than 10%. The prevalence of 13 diseases varied between 6 and 9%. The prevalence of other 14 groups was ≤1%. Migraine was the most common diagnosis (15%). Cervicogenic headache was the most common secondary headache. Classical trigeminal neuralgias and persistent idiopathic facial pain were two most common diagnoses in the painful cranial neuropathies and other facial pain groups. Sixty-one percent fulfilled the definition of chronic daily headaches, and hemicrania continua and cervicogenic headache were the two most common diagnoses in this group. A large number of primary and secondary headaches and cranial neuropathies may present as side-locked headache and facial pain syndromes. Therefore, a sound knowledge of diagnostic approach is required for the optimal management of side locked headaches and facial pain.


Continental phylogeography of an ecologically and morphologically diverse Neotropical songbird, Zonotrichia capensis.
The Neotropics are exceptionally diverse, containing roughly one third of all extant bird species on Earth. This remarkable species richness is thought to be a consequence of processes associated with both Andean orogenesis throughout the Tertiary, and climatic fluctuations during the Quaternary. Phylogeographic studies allow insights into how such events might have influenced evolutionary trajectories of species and ultimately contribute to a better understanding of speciation. Studies on continentally distributed species are of particular interest because different populations of such taxa may show genetic signatures of events that impacted the continent-wide biota. Here we evaluate the genealogical history of one of the world's most broadly-distributed and polytypic passerines, the rufous-collared sparrow (Zonotrichia capensis). We obtained control region DNA sequences from 92 Zonotrichia capensis individuals sampled across the species' range (Central and South America). Six additional molecular markers, both nuclear and mitochondrial, were sequenced for a subset of individuals with divergent control region haplotypes. Median-joining network analysis, and Bayesian and maximum parsimony phylogenetic analyses all recovered three lineages: one spanning Middle America, the Dominican Republic, and north-western South America; one encompassing the Dominican Republic, Roraima (Venezuela) and La Paz (Bolivia) south to Tierra del Fuego, Argentina; and a third, including eastern Argentina and Brazil. Phylogenetic analyses suggest that the Middle American/north-western South American clade is sister to the remaining two. Bayesian and maximum likelihood coalescent simulations used to study lineage demographic history, diversification times, migration rates and population expansion together suggested that diversification of the three lineages occurred rapidly during the Pleistocene, with negligible gene flow, leaving genetic signatures of population expansions. The Pleistocene history of the rufous-collared sparrow involved extensive range expansion from a probable Central American origin. Its remarkable morphological and behavioral diversity probably represents recent responses to local conditions overlying deeper patterns of lineage diversity, which are themselves produced by isolation and the history of colonization of South America.


The Interplay Between TGF-β Signaling and Cell Metabolism.
The transforming growth factor-β (TGF-β) signaling plays a critical role in the development and tissue homeostasis in metazoans, and deregulation of TGF-β signaling leads to many pathological conditions. Mounting evidence suggests that TGF-β signaling can actively alter metabolism in diverse cell types. Furthermore, metabolic pathways, beyond simply regarded as biochemical reactions, are closely intertwined with signal transduction. Here, we discuss the role of TGF-β in glucose, lipid, amino acid, redox and polyamine metabolism with an emphasis on how TGF-β can act as a metabolic modulator and how metabolic changes can influence TGF-β signaling. We also describe how interplay between TGF-β signaling and cell metabolism regulates cellular homeostasis as well as the progression of multiple diseases, including cancer.


Rhodium-catalyzed asymmetric allylic substitution with boronic acid nucleophiles.
An enantio-, regio-, and diastereoselective rhodium(I)-catalyzed desymmetrization of a meso-cyclic allylic dicarbonate with organoboronic acid nucleophiles is described. The rhodium(I) catalyst formed in situ from [Rh(cod)OH]2 and Xyl-P-PHOS allowed the S(N)2' allylic substitution product to be obtained with a range of arylboronic acids in enantiomeric excesses of up to 92% with regioselectivities of up to >20:1.


On-line searching: costly or cost effective? A marketing perspective.
The value of acquiring and using information is not well understood. Decisions to purchase information are made on the basis of the perceived need for the information, the anticipated benefit of using it, and the price. The current pricing of on-line information services, which emphasizes the connect hour as the unit of price, does not relate the price of a search to the value of a search, and the education programs of on-line vendors and database suppliers concentrate on the mechanics of information retrieval rather than on the application of information to the customer's problem. The on-line information industry needs to adopt a strong marketing orientation that focuses on the needs of customers rather than the needs of suppliers or vendors.


Order reconstruction in frustrated nematic twist cells.
Within the Landau-de Gennes theory of liquid crystals, we study the equilibrium configurations of a nematic cell with twist boundary conditions. Under the assumption that the order tensor Q be uniaxial on both bounding plates, we find three separate classes of solutions, one of which contains the absolute energy minimizer, a twistlike solution that exists for all values of the distance d between the plates. The solutions in the remaining two classes exist only if d exceeds a critical value d(c). One class consists of metastable, twistlike solutions, while the other consists of unstable, exchangelike solutions, where the eigenvalues of Q are exchanged across the cell. When d=d(c), the metastable solution relaxes back to the absolute energy minimizer, undergoing an order reconstruction somewhere within the cell. The critical distance d(c) equals, in general, a few biaxial coherence lengths. This scenario applies to all the values of the boundary twist but pi/2, which thus appears as a very special case, though it is the one more studied in the literature. In fact, when the directors prescribed on the two plates are at right angles, two symmetric twistlike solutions merge continuously into an exchangelike solution at the critical value of d where the latter becomes unstable. Our analysis shows how the classical bifurcation associated with this phenomenon is unfolded by perturbing the boundary conditions.


Familial DNA searching- an emerging forensic investigative tool.
In recent years, jurisdictions across the United States have expressed a growing interest in aiding criminal investigations through the use of familial DNA searching (FDS)- a forensic technique to identify family members through DNA databases. The National Survey of CODIS Laboratories surveyed U.S. CODIS laboratories about their perceptions, policies, and practices related to FDS. In total, 103 crime labs completed the survey (77% response rate). Labs in 11 states reported using FDS, while labs in 24 states reported using a similar-but distinct- practice of partial matching. Although the majority of labs had positive perceptions about the ability of FDS to assist investigations, labs also reported a number of concerns and challenges with implementing FDS. Respondents reported using either practice a limited amount with modest numbers of convictions resulting from both FDS and partial matching. The article reports on varying practices related to official policies, training, eligibility, the software search, lineage testing, requirements for releasing information, and subsequent investigative work. Finally, the article discusses what can be learned from this survey, accompanying limitations, and implications for decision-makers considering using FDS.


Detrimental Effects of Multiple Mutations in Position 240 of Fusarium graminearum β2-Tubulin.
Fusarium graminearum causes Fusarium head blight (FHB), a destructive disease of cereal crops worldwide. Carbendazim (methylbenzimidazol-2-ylcarbamate [MBC]) is widely used for controlling FHB. A previous study showed that the F240L mutation in the β2-tubulin of F. graminearum (Fgβ2-tubulin) confers hypersensitivity to MBC. Whether the substitution of phenylalanine by other amino acids in position 240 of the Fgβ2-tubulin gene also confers hypersensitivity to MBC is unknown. Moreover, the biological fitness of these mutants is poorly understood. In this study, we substituted position 240 of Fgβ2-tubulin with other amino acids. We found that the F240A, F240E, F240I, and F240Y mutations in Fgβ2-tubulin could also confer F. graminearum hypersensitivity to MBC, although the effective concentration resulting in 50% inhibition (EC50) differed among the mutations. The F240G mutation, in contrast, decreased the sensitivity to MBC. In addition, a molecular docking assay indicated that the binding affinity between Fgβ2-tubulin and MBC were increased by the F240A, F240E, F240I, and F240Y mutations but decreased by the F240G mutation. All mutants had normal conidial morphology, but the growth rates and pathogenicity of the F240A, F240E, F240G, F240I, and F240Y mutants were significantly decreased. Moreover, the F240A and F240G mutants produced twisted hyphae. In addition, microtubules were sparse and rarely observed in β2F240A-EGFP, β2F240E-EGFP, and β2F240G-EGFP. These results indicate that position 240 (phenylalanine) is not only vital to the function of Fgβ2-tubulin but also plays an important role in regulating the sensitivity of F. graminearum to MBC. Any mutation in this site would be detrimental to survival.


Aggressive angiomyxoma of the vaginal wall at the initial stage: a case report.
Aggressive angiomyxoma (AA) is a rare mesenchimal tumor usually located in the pelvic and perineal region. Less than 30 cases of aggressive angiomyxoma with vaginal location have been reported in the literature up to this date. The authors report the case of a 50-year-old female patient diagnosed with vaginal AA whose characteristics at its initial stage were macroscopically indistinguishable from those of a polypoid lesion. Therefore this case suggests that this type of tumor should be considered as part of the differential diagnosis of vaginal polypoid lesions.


Recurrent aneurysmal subarachnoid haemorrhage: bleeding pattern and incidence of posthaemorrhagic ischaemic infarction.
This report is based on a consecutive series of 162 patients with aneurysmal subarachnoid haemorrhage (SAH), including 22 patients (14%) with recurrent SAH, who were treated within 72 h after the most recent bleed. Of the 22 patients with recurrent haemorrhage: 68% were in poor clinical condition (Hunt & Hess grade 4-5); 73% presented with intracerebral haemorrhage (ICH); 41% developed delayed ischaemic infarctions from chronic arterial spasm; 14% made a good recovery, while 41% died. Of the 140 patients with a single bleed: 34% were in poor clinical condition (Hunt & Hess grade 4-5); 33% presented with ICH; 22% developed delayed ischaemic infarctions; 53% made a good recovery, while 19% died. Our results suggest that a high incidence of intracerebral haemorrhage in conjunction with a more severe course of chronic arterial spasm substantially contributes to the high morbidity and mortality associated with recurrent SAH. In poor grade patients not suitable for acute open surgery, endovascular treatment should receive consideration for the prevention of early rebleeding.


Sorptive removal of odorous carbonyl gases by water.
In this study, the removal capacity of deionized water was investigated against five gaseous carbonyl compounds (i.e., acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, and isovaleraldehyde) by means of the gas stripping method. To determine the trapping behavior of these odorants by water, gaseous working standards prepared at three different concentration levels (i.e., for acetaldehyde around 300, 500, and 1,000 ppb) were forced through pure water contained in an impinger at room temperature. The removal efficiency of the target compounds was inspected in terms of two major variables: (1) concentration levels of gaseous standard and (2) impinger water volume (20, 50, 100, and 150 mL). Although the extent of removal was affected fairly sensitively by changes in water volume, this was not the case for standard concentration level changes. Considering the efficiency of sorption media, gas stripping with aqueous solution can be employed as an effective tool for the removal of carbonyl odorants.


Magic and memory: using conjuring to explore the effects of suggestion, social influence, and paranormal belief on eyewitness testimony for an ostensibly paranormal event.
This study uses conjuring to investigate the effects of suggestion, social influence, and paranormal belief upon the accuracy of eyewitness testimony for an ostensibly paranormal event. Participants watched a video of an alleged psychic seemingly bending a metal key by the power of psychokinesis. Half the participants heard the fake psychic suggest that the key continued to bend after it had been put down on a table and half did not. Additionally, participants were exposed to either a negative social influence (a stooge co-witness reporting that the key did not continue to bend), no social influence, or a positive social influence (a stooge co-witness reporting that the key did continue to bend). Participants who were exposed to the verbal suggestion were significantly more likely to report that the key continued to bend. Additionally, more participants reported that the key continued to bend in the positive social influence condition compared to the other two social influence conditions. Finally, believers in the paranormal were more likely to report that the key continued to bend than non-believers.


In-silico ADME Studies for New Drug Discovery: From Chemical Compounds to Chinese Herbal Medicines.
Nowadays, in silico tools are widely used to provide the potential structure of the metabolites formed depending on the site of metabolism. These methods can also highlight the molecular moieties that help to direct the molecule into the cytochrome cavity so that the site of metabolism is in proximity to the catalytic center. In this minireview, we summarized three aspects of the in silico methods in the application of prediction of ADME (absorption, distribution, metabolism and excretion) properties of compounds: structure-based approaches for predicting molecular modeling of drug metabolizing enzymes; in silico metabolite prediction; and pharmacophore models for analysis substrate specificity. Moreover, we also extended the in silico studies in Chinese herbal medicines (CHM) research.


Results of a multicentre dosimetry audit using a respiratory phantom within the EORTC LungTech trial.
The EORTC 22113-08113 LungTech trial assesses the safety and efficacy of SBRT for centrally located NSCLC. To insure protocol compliance an extensive RTQA procedure was implemented. Twelve centres were audited using a CIRS008A phantom. The phantom was scanned using target inserts of 7.5 mm and 12.5 mm radius in static condition. For the 7.5 mm insert a 4DCT was acquired while moving according to a cos6 function. Treatment plans were measured using film and an ionization chamber. Wilcoxon's signed-rank tests were performed to compare the three plans across institutions. A Spearman correlation was calculated to evaluate the influence of factors such as PTV, slice thickness and total number of monitor units on the dosimetric results. The reference output dose median [min, max] variation was 0.5% [-1.1, +1.5]. The median deviations between chamber doses and point-planned doses were 1.8% [-0.1; 6.7] for the 7.5 mm and 1.1% [-2.8; 5.0] for the 12.5 mm sphere in static situation and 3.2% [-3.2; 15.7] for the dynamic situation. Film gamma median pass rates were 92.0% [68.0, 99.0] for 7.5 mm static, 96.2% [73.0, 99.0] for 12.5 mm static and 71.0% [40.0, 99.0] for 7.5 mm dynamic. Wilcoxon's signed-rank tests showed that the dynamic irradiations resulted in significantly lower gamma pass rates compared to the 12.5 mm static plan (p = 0.001). The total number of MUs per plan was correlated to both film and IC results. An end-to-end audit was successfully performed, revealing important variations between institutions especially in dynamic irradiations. This shows the importance of dosimetry audits and the potentials for further technique and methodology improvements.


Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest.
The patent expiration of imatinib mesylate (Gleevec; Novartis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost-effective alternative. The objective of our study was to determine the molecular and cytogenetic responses, survival endpoints (event-free survival, failure-free survival, transformation-free survival, overall survival), and safety of innovator and generic brands of imatinib. In this retrospective analysis, data from 1812 patients with chronic myeloid leukemia treated with frontline imatinib mesylate (innovator/generic) at a single institution between 2008 and 2014 is included. Of these, 445 were excluded owing to inadequate data and follow-up, and a further 156 were excluded as they were in either the accelerated phase or blast crisis at diagnosis. Thus, data from 1067 patients who were treated with Gleevec (Novartis), and 144 patients with Veenat (NATCO) were available for analysis, and included in the study. There was no significant difference in event-free survival (P = .05), failure-free survival (P = .07), transformation-free survival (P = .12), or overall survival (P = .24) between the 2 groups. The frequency of reported nonhematologic adverse events and hematologic adverse events was comparable between the study groups. The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia.


Isolated adult Langerhans' cell histiocytosis in cervical lymph nodes: should it be treated?
We report an extremely rare case of Langerhans' cell histiocytosis involving isolated cervical lymph nodes, and we discuss the diagnosis and treatment of this infrequent disease. We present a case report and literature review concerning this disease entity. A 54-year-old man presented with persistent, multiple, left neck masses. Histopathological study of lymph node specimens showed proliferation of Langerhans' cells coupled with eosinophilic and neutrophilic microabscesses. Positive immunohistochemical staining for Cluster of Differentiation 1a (CD1a) in Langerhans' cells confirmed the diagnosis. No other abnormalities were noted on a series of image studies. The patient was managed with 'watchful waiting' without subsequent therapy. The neck lesions regressed gradually over time, and the patient did well over a two-year follow-up period. The clinical presentation of Langerhans' cell histiocytosis is highly variable, and the choice of treatment depends on the involved organs. Definitive diagnosis depends on identification of characteristic immunohistochemical or ultrastructural features of the biopsy specimen. Watchful waiting may be an effective management strategy in cases of adult isolated lymph node Langerhans' cell histiocytosis, due to its possible spontaneous regression.


Mortality of fire fighters in Western Australia.
All except 17 (1.7%) of 990 fire fighters employed by the Western Australian Fire Brigade between 1 October 1939 and 31 December 1978 were successfully followed up to 31 December 1978. Mortality from all causes was less than expected (SMR 0.80 with 95% confidence interval 0.67 to 0.96). There was evidence of the healthy worker effect but none that mortality increased with increasing duration of employment. A small proportional excess of deaths from road traffic accidents ( SPMR 1.66) appeared to be unrelated to fire service. Deaths from other accidents, poisonings, and violence were significantly less than expected (SMR 0.35 with 95% confidence interval 0.10 to 0.90) and may indicate an effect of training and experience on accident proneness. There was no evidence of increased mortality from cardiovascular or respiratory disease, or from any other cause.


Hematological change parameters in patients with pressure ulcer at long-term care hospital.
To assess factors associated with the development of pressure ulcers, and to compare the effectiveness of pharmacological treatments. The factors associated with the development of pressure ulcers were compared in lesion-carrying patients (n=14) and non-carriers (n=16). Lesion-carrying patients were treated with 1% silver sulfadiazine or 0.6IU/g collagenase and were observed for 8 weeks. The data collected was analyzed with p<0.05 being statistically relevant. The prevalence of pressure ulcers was about 6%. The comparison of carrier and non-carrier groups of pressure ulcers revealed no statistically significant difference in its occurrence with respect to age, sex, skin color, mobility, or the use of diapers. However, levels of hemoglobin, hematocrit, and red blood cells were found to be statistically different between groups, being lower in lesion-carrying patients. There was no significant difference found in lesion area between patients treated with collagenase or silver sulfadiazine, although both groups showed an overall reduction in lesion area through the treatment course. Hematologic parameters showed a statistically significant difference between the two groups. Regarding the treatment of ulcers, there was no difference in the area of the lesion found between the groups treated with collagenase and silver sulfadiazine.


Determination of lomefloxacin, an antibacterial drug, in pharmaceutical preparations based on its polarographic catalytic wave in the presence of 2-iodoacetamide.
In a 0.125 mol/L phosphate (pH 6.6)/2.5 x 10(-4) mol/L 2-iodoacetamide solution, lomefloxacin yields a response of a polarographic catalytic current. The second-order derivative peak current of the catalytic wave of lomefloxacin is proportional to its concentration in the range of 1.0 x 10(-8)-1.0 x 10(-6) mol/L (r = 0.998). The sensitivity of the catalytic wave is 25-times higher than that of the corresponding reduction wave for 5.0 x 10(-7) mol/L lomefloxacin. The proposed method was applied to the determination of lomefloxacin in pharmaceutical preparations. The polarographic reduction wave is ascribed to a one-electron reduction of the C=C bond of lomefloxacin zwitterion accompanied by an acid-base equilibrium. The catalytic wave should be caused by regeneration of the lomefloxacin molecule at electrode surface due to the one-electron reduction product being further oxidized by electroreductive intermediate products of 2-iodoacetamide.


L-type calcium channels mediate transmitter release in isolated, wide-field retinal amacrine cells.
Transmitter release in neurons is triggered by intracellular Ca2+ increase via the opening of voltage-gated Ca2+ channels. Here we investigated the voltage-gated Ca2+ channels in wide-field amacrine cells (WFACs) isolated from the white-bass retina that are functionally coupled to transmitter release. We monitored transmitter release through the measurement of the membrane capacitance (Cm). We found that 500-ms long depolarizations of WFACs from -70 mV to 0 mV elicited about a 6% transient increase in the Cm or membrane surface area. This Cm jump could be eliminated either by intracellular perfusion with 10 mM BAPTA or by extracellular application of 4 mM cobalt. WFACs possess N-type and L-type voltage-gated Ca2+ channels. Depolarization-evoked Cm increases were unaffected by the specific N-type channel blocker omega-conotoxin GVIA, but they were markedly reduced by the L-type blocker diltiazem, suggesting a role for the L-type channel in synaptic transmission. Further supporting this notion, in WFACs the synaptic protein syntaxin always colocalized with the pore-forming subunit of the retinal specific L-type channels (Cav1.4 or alpha1F), but never with that of the N-type channels (Cav2.2 or alpha1B ).


Comparing Adherence to the Experience Sampling Method Among Patients With Schizophrenia Spectrum Disorder and Unaffected Individuals: Observational Study From the Multicentric DiAPAson Project.
The Experience Sampling Method (ESM) is a valid method of remotely recording activities and mood, but the predictors of adherence to ESM in patients with Schizophrenia Spectrum Disorder (SSD) are not known. Studies on adherence are significant as they highlight the strengths and weaknesses of ESM-based study designs and allow the development of recommendations and practical guidelines for implementing future studies or treatment plans. The aim of this study was to compare the adherence to ESM in patients with SSD and unaffected control individuals, investigate their patterns, and report the predictors of adherence. In total, 131 patients with SSD (74 in residential facilities and 57 outpatients) and 115 unaffected control individuals were recruited at 10 different centers in Italy as part of the DiAPAson project. Demographic information, symptom severity, disability level, and level of function were recorded for the clinical sample. Participants were evaluated for daily time use and mood through a smartphone-based ESM 8 times a day for 7 consecutive days. Adherence was measured by the response rate to ESM notifications. Results were analyzed using the chi-square test, ANOVA, Kruskal-Wallis test, and Friedman test, and a logistic regression model. The overall adherence rate in this study was 50% for residents, 59% for outpatients, and 78% for unaffected control individuals. Indeed, patients with SSD had a lower rate of adherence to ESM than the unaffected control group (P≤.001), independent of time slot, day of monitoring, or day of the week. No differences in adherence rates between weekdays and weekends were found among the 3 groups. The adherence rate was the lowest in the late evening time slot (8 PM to 12 AM) and days 6-7 of the study for both patients with SSD and unaffected control individuals. The adherence rate among patients with SSD was not predicted by sociodemographic characteristics, cognitive function, or other clinical features. A higher adherence rate (ie, ≥70%) among patients with SSD was predicted by higher collaboration skills (odds ratio [OR] 2.952; P=.046) and self-esteem (OR 3.394; P=.03), and lower positive symptom severity (OR 0.835; P=.04). Adherence to ESM prompts for both patients with SSD and unaffected control individuals decreased during late evening and after 6 days of monitoring. Higher self-esteem and collaboration skills predicted higher adherence to ESM among patients with SSD, while higher positive symptom scores predicted lower adherence rates. This study provides important information to guide protocols for future studies using ESM. Future clinical or research studies should set ESM monitoring to waking hours, limit the number of days of monitoring, select patients with more collaborative skills and avoid those with marked positive symptoms, provide intensive training sessions, and improve participants' self-confidence with technologies. RR2-10.1186/s12888-020-02588-y.


Synergistic hematopoietic growth factors.
A number of growth factors acting on hematopoietic stem cells have now been purified and characterized. These include erythropoietin, granulocyte-macrophage colony-stimulating activity (GM-CSA), granulocyte colony-stimulating activity and colony-stimulating factor-1 (CSF-1). Factors which act in concert with these defined factors and appear to act relatively early in the hematopoietic stem cell lineage are currently under study. Interleukin 3 appears to have both the characteristics of a differentiating hormone and the ability to generate proliferation of relatively early stem cells. Interleukin 3 acts in concert with at least CSF-1 and erythropoietin to enhance their effect on stem cell proliferation and differentiation. A new class of hematopoietic growth factor activities termed synergizing activities also exist. These activities appear to have no intrinsic capacity to stimulate hematopoietic colony formation by themselves but enhance the effects of other differentiating hormones such as GM-CSA and CSF-1. Activities which appear to represent synergizing activities have now been found to evolve from a human bladder carcinoma line, a cell line derived from murine marrow adherent cells and normal murine marrow and thymic cells. These activities may act on very primitive hematopoietic progenitors to allow them to express receptors to various differentiating hormones or alternatively they may act as commitment factors in a commitment-progression model of stem cell regulation.


Fasciola hepatica Immune Regulates CD11c+ Cells by Interacting with the Macrophage Gal/GalNAc Lectin.
Fasciolosis, caused by Fasciola hepatica and Fasciola gigantica, is a trematode zoonosis of interest in public health and livestock production. Like other helminths, F. hepatica modulates the host immune response by inducing potent polarized Th2 and regulatory T cell immune responses and by downregulating the production of Th1 cytokines. In this work, we show that F. hepatica glycans increase Th2 immune responses by immunomodulating TLR-induced maturation and function of dendritic cells (DCs). This process was mediated by the macrophage Gal/GalNAc lectin (MGL) expressed on DCs, which recognizes the Tn antigen (GalNAc-Ser/Thr) on parasite components. More interestingly, we identified MGL-expressing CD11c+ cells in infected animals and showed that these cells are recruited both to the peritoneum and the liver upon F. hepatica infection. These cells express the regulatory cytokines IL-10, TNFα and TGFβ and a variety of regulatory markers. Furthermore, MGL+ CD11c+ cells expand parasite-specific Th2/regulatory cells and suppress Th1 polarization. The results presented here suggest a potential role of MGL in the immunomodulation of DCs induced by F. hepatica and contribute to a better understanding of the molecular and immunoregulatory mechanisms induced by this parasite.


Factors Promoting Development of Fibrosis in Crohn's Disease.
The concepts on the pathophysiology of intestinal fibrosis in Crohn's disease (CD) have changed in recent years. Some years ago fibrosis was regarded to be a consequence of long-standing inflammation with subsequent destruction of the gut wall matrix followed by scar formation and collagen deposition. Fibrosis in CD patients appeared to be an irreversible process that could hardly be influenced. Therefore, the main target in CD therapy was to control inflammation to avoid fibrosis development. Many of these assumptions seem to be only partially true. Inflammation may be a necessary prerequisite for the initiation of fibrosis. However, when the pathophysiologic processes that lead to fibrosis in CD patients have been initiated fibrosis development may be independent of inflammation and may continue even when inflammation is under good medical control. Fibrosis in CD also may be reversible. After strictureplasty local collagen deposits decrease or even disappear. With new animal models for intestinal fibrosis on the horizon, we need to spend more efforts on understanding the factors influencing fibrosis in CD patients to finally find specific therapies. In this context, it will be as important to find markers and quantitative imaging tools to have reliable endpoints for clinical trials in fibrosing CD.


Thapsigargin attenuates the potentiation of positive inotropic effect of digoxin induced by pretreatment with rimalkalim in the guinea pig heart.
The influence of thapsigargin, a selective inhibitor of sarcoplasmic reticulum (SR) Ca2+ ATPase, on the positive inotropic effects of digoxin before and after pretreatment with rimalkalim [(3S,4R)-3-hydroxy-2,2-dimethyl-4-(oxopyrrolidinyl)-6-phenyl-su lfonylchroman hemihydrate (formerly HOE 234)], a known activator of ATP-sensitive K+ channels, was studied in the guinea pig heart. The isolated papillary muscles from the guinea pig heart were used to study these effects. The following parameters were measured: force of contraction (Fc), rate of rise (+dF/dt) and rate of fall (-dF/dt) of Fc, time to peak contraction (ttp) and time to 10% of the total amplitude of force (tt10). After pretreatment with rimalkalim (1 microM), digoxin caused a significant increase in the amplitude of Fc and significant shortening of ttp and tt10 (p < 0.05 compared with the values obtained with digoxin alone). Thapsigargin (1 microM), a selective inhibitor of sarcoplasmic reticulum Ca2+ ATPase, added to rimalkalim, prevented the enhancement of the amplitude of Fc induced by digoxin after pretreatment with rimalkalim but had no significant influence on the effects of digoxin itself. The results demonstrate significant influence of activation of KATP channels on digoxin-induced positive inotropic effects in the guinea pig heart. Attenuation of this effects of rimalkalim by addition of thapsigargin suggests that activation of SR Ca2+ ATPase can be included in this interaction.


Acute Megakaryoblastic Leukemia With Diffuse Periosteal Reaction of Bilateral Lower Extremities.
We report the case of a 3-year-old girl diagnosed with acute megakaryoblastic leukemia, who presented after >1 year of bilateral leg pain. At times the pain was severe enough to prevent ambulation, prompting visits to her primary care provider. However, it was not until acute respiratory failure occurred with subsequent hospitalization in the pediatric intensive care unit that severe anemia and thrombocytopenia were discovered and the diagnosis of acute myeloid leukemia was made. Bilateral lower extremity swelling was noted on admission and radiographs showed diffusely abnormal appearance of the long bones of her lower extremities with periosteal reaction and echogenic debris in the subperiosteal space, thought to represent leukemic cells. This case highlights the importance of recognizing atypical signs and symptoms of myelodysplastic syndrome progressing to acute leukemia in the context of abnormal bone pain and radiographic changes.


Stepwise analysis of MIR9 loci identifies miR-9-5p to be involved in Oestrogen regulated pathways in breast cancer patients.
miR-9 was initially identified as an epigenetically regulated miRNA in tumours, but inconsistent findings have been reported so far. We analysed the expression of miR-9-5p, miR-9-3p, pri-miRs and MIR9 promoters methylation status in 131 breast cancer cases and 12 normal breast tissues (NBTs). The expression of both mature miRs was increased in tumours as compared to NBTs (P < 0.001) and negatively correlated with ER protein expression (P = 0.005 and P = 0.003, for miR-9-3p and miR-9-5p respectively). In addition, miR-9-5p showed a significant negative correlation with PgR (P = 0.002). Consistently, miR-9-5p and miR-9 3p were differentially expressed in the breast cancer subgroups identified by ER and PgR expression and HER2 amplification. No significant correlation between promoter methylation and pri-miRNAs expressions was found either in tumours or in NBTs. In the Luminal breast cancer subtype the expression of miR-9-5p was associated with a worse prognosis in both univariable and multivariable analyses. Ingenuity Pathway Analysis exploring the putative interactions among miR-9-5p/miR-9-3p, ER and PgR upstream and downstream regulators suggested a regulatory loop by which miR-9-5p but not miR-9-3p is induced by steroid hormone receptor and acts within hormone-receptor regulated pathways.


Knockdown of lncRNA MALAT1 alleviates bupivacaine-induced neurotoxicity via the miR-101-3p/PDCD4 axis.
Bupivacaine, a common local anesthetic, can cause neurotoxicity and abnormal neuro-disorders. However, the precise underlying mechanisms have not been fully elucidated. In this study, we investigated the function of lncRNA MALAT1 in the bupivacaine-induced neurotoxicity process. SH-SY5Y cells and neonatal mouse DRG neurons were cultured in vitro and treated with bupivacaine to establish a neurotoxicity model. Caspase3 activity and cell survival rates were detected to evaluate the function of lncRNA MALAT1. Western blotting was used to detect the expression levels of PDCD4 and cleaved-caspase-3. A dual-luciferase reporter assay was used to explore the potential binding target of lncRNA MALAT1. We found that the expression of lncRNA MALAT1 was upregulated upon exposure to bupivacaine. Knockdown of lncRNA MALAT1 significantly increased the cell death rates, and Caspase3 activity assays revealed that the apoptosis rates were manifestly increased in the MALAT1 downregulation group. In addition, we screened the possible target and found that miR-101-3p is the direct target of MALAT1 using a dual-luciferase reporter assay; these results suggest that lncRNA MALAT1 may function as a decoy to sponge miR-101-3p. Furthermore, we demonstrated that activation of the MALAT1/miR-101-3p/PDCD4 axis protected cells against bupivacaine treatment. We elucidated the function and mechanism of MALAT1 in bupivacaine-induced neurotoxicity. Targeting MALAT1 might provide new methods to prevent neurotoxicity.


Case report. synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome.
A case of the SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome in a 35-year-old woman is presented. Ignorance of this entity on the part of the physicians treating the patient may have contributed to her having repeated diagnostic procedures and treatment, some of which may have been unnecessary. Dentists are encouraged to suspect the SAPHO syndrome when they encounter a patient with mandibular osteomyelitis together with symptoms involving other bones and skin lesions such as pustulosis or psoriasis.


Quantitative mRNA expression analysis in kidney glomeruli using microdissection techniques.
The introduction of new tools for molecular analysis, such as RT-qPCR and microarrays, has provided researchers with powerful applications to study renal disease and development. However, the high cellular heterogeneity of the renal tissue complicates the molecular analysis of specific cells and cell groups such as glomerular or tubular cells. In the past, glomerular sieving and manual dissection were used for the isolation of glomeruli. However, these techniques cannot be used for the isolation of specific glomeruli or for the co-isolation of additional tissue fractions. In recent decades, new microdissection techniques such as laser-assisted microdissection have been developed. These applications allow the isolation of small cell groups from heterogeneous tissue for molecular analysis, including microarray and RT-qPCR. Although very promising, some drawbacks are associated with these techniques. The isolated sample material is generally small and requires sensitive assays. In addition, the long sample processing time may result in a considerable loss of RNA integrity. Careful optimization and rigorous quality analysis should overcome these drawbacks. In the present paper, the recent literature on the application of microdissection techniques in kidney research is reviewed, together with a discussion of the critical issues that are essential for the application of quantitative mRNA expression analysis with RT-qPCR on microdissected samples.


[Phytophotodermatitis. Some photobiological aspects of psoralens].
The frequency of plant dermatitis, in general, depends on the type of plants, the climate, occupation and lifestyle of the local inhabitants. Many plants produce adverse effects on the skin like irritation, allergic reactions and phototoxicity. Generally, allergic contact dermatitis is emphasized but it is necessary to give more attention to phototoxicity produced by plants. The patients may be exposed not only to the phototoxic plant itself but also to its derivatives in perfumes, cosmetics and industry.


3D dynamic culture of rabbit articular chondrocytes encapsulated in alginate gel beads using spinner flasks for cartilage tissue regeneration.
Cell-based therapy using chondrocytes for cartilage repair suffers from chondrocyte dedifferentiation. In the present study, the effects of an integrated three-dimensional and dynamic culture on rabbit articular chondrocytes were investigated. Cells (passages 1 and 4) were encapsulated in alginate gel beads and cultured in spinner flasks in chondrogenic and chondrocyte growth media. Subcutaneous implantation of the cell-laden beads was performed to evaluate the ectopic chondrogenesis. It was found that cells remained viable after 35 days in the three-dimensional dynamic culture. Passage 1 cells demonstrated a proliferative growth in both media. Passage 4 cells showed a gradual reduction in DNA content in growth medium, which was attenuated in chondrogenic medium. Deposition of glycosaminoglycans (GAG) was found in all cultures. While passage 1 cells generally produced higher amounts of GAG than passage 4 cells, GAG/DNA became similar on day 35 for both cells in growth media. Interestingly, GAG/DNA in growth medium was greater than that in chondrogenic medium for both cells. Based on GAG quantification and gene expression analysis, encapsulated passage 1 cells cultured in growth medium displayed the best ectopic chondrogenesis. Taken together, the three-dimensional and dynamic culture for chondrocytes holds great potential in cartilage regeneration.